A third way of evolution?

. Dionisio

. Dionisio

The correct identification and classification of AS and GD is fundamental to improve the understanding of the evolution of both processes. A single evolutionary model of AS after GD may not be solely responsible for AS events, instead a combination of multiple models is more likely. Identifying the mechanisms governing which models are utilized in specific genes will improve our understanding of the evolutionary relationship between GD and AS.

The Evolutionary Relationship between Alternative Splicing and Gene Duplication Luis P. Iñiguez* and Georgina Hernández Front Genet. 2017; 8: 14. doi: 10.3389/fgene.2017.00014

Where's the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

The gene structure in eukaryotes requires the removal of non-coding sequences, introns, to produce mature mRNAs. This process, known as cis-splicing, referred to here as splicing, is regulated by several factors which can lead to numerous splicing arrangements, commonly designated as alternative splicing (AS). These two processes are now considered the main contributors to the increasing protein diversity and therefore their relationship is a relevant, yet understudied, area of evolutionary study.

The Evolutionary Relationship between Alternative Splicing and Gene Duplication Luis P. Iñiguez* and Georgina Hernández Front Genet. 2017; 8: 14. doi: 10.3389/fgene.2017.00014

Dionisio

Temporal collinearity is often considered the main force preserving Hox gene clusters in animal genomes. Hox genes are transcription factors that bind to regulatory regions via a helix-turn-helix domain to enhance or suppress gene transcription [...] [...] other factors, such as unequal rates of genome rearrangements in different lineages and shared enhancers between genes, also might contribute to the genomic evolution of Hox genes.

Clustered brachiopod Hox genes are not expressed collinearly and are associated with lophotrochozoan novelties Sabrina M. Schiemann, José M. Martín-Durán, Aina Børve, Bruno C. Vellutini,a Yale J. Passamaneck,b and Andreas Hejnol Proc Natl Acad Sci U S A. 114(10): E1913–E1922. doi: 10.1073/pnas.1614501114

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Hox genes pattern the anteroposterior axis of all animals that have left and right body sides. In many animals, Hox genes are clustered along the chromosomes and expressed in spatial and temporal order. This coordinated regulation is thought to have preserved the cluster through a developmental constraint. [...] the hard tissues (chaetae and shells) of segmented worms, mollusks, and brachiopods share a common origin that dates back to the Early Cambrian.

Clustered brachiopod Hox genes are not expressed collinearly and are associated with lophotrochozoan novelties Sabrina M. Schiemann, José M. Martín-Durán, Aina Børve, Bruno C. Vellutini,a Yale J. Passamaneck,b and Andreas Hejnol Proc Natl Acad Sci U S A. 114(10): E1913–E1922. doi: 10.1073/pnas.1614501114

expressed in spatial and temporal order? How does it do that? Did somebody say "coordinated regulation"? What does the coordination? Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Future studies will be needed to unravel the biological significance of phyla specific sequences and whether they fine tune telomerase processivity to life history strategy. A future endeavour will be to unravel mechanistic linkages that connect unique sequence evolution and the dynamic regulation of TERT to actual biological roles.

The protein subunit of telomerase displays patterns of dynamic evolution and conservation across different metazoan taxa Alvina G. Lai, Natalia Pouchkina-Stantcheva, Alessia Di Donfrancesco, Gerda Kildisiute, Sounak Sahu, and A. Aziz Aboobaker BMC Evol Biol. 2017; 17: 107. doi: 10.1186/s12862-017-0949-4

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Most animals employ telomerase, which consists of a catalytic subunit known as the telomerase reverse transcriptase (TERT) and an RNA template, to maintain telomere ends. Our work establishes that the evolutionary history and structural evolution of TERT involves previously unappreciated levels of change and the emergence of lineage specific motifs. The sequence conservation we describe within phyla suggests that these new motifs likely serve essential biological functions of TERT, which along with changes in splicing, underpin diverse functions of TERT important for animal life histories.

The protein subunit of telomerase displays patterns of dynamic evolution and conservation across different metazoan taxa Alvina G. Lai, Natalia Pouchkina-Stantcheva, Alessia Di Donfrancesco, Gerda Kildisiute, Sounak Sahu, and A. Aziz Aboobaker BMC Evol Biol. 2017; 17: 107. doi: 10.1186/s12862-017-0949-4

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Our analyses across the broader Malacostraca have allowed us to not only draw analogies with other arthropods but also to identify evolutionary novelties in immune modulation components and form strong hypotheses as to when key pathways have evolved or diverged.

Comparative genomic analysis of innate immunity reveals novel and conserved components in crustacean food crop species Alvina G. Lai and A. Aziz Aboobaker BMC Genomics. 2017; 18: 389. doi: 10.1186/s12864-017-3769-4

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

[...] the precursor of insect E-cadherin originated through stepwise reductive changes after the earliest divergence of extant arthropod groups. Future studies should investigate the structural mechanisms underlying the multistep transition from the arthropod ancestral type III cadherin to the more recent insect E-cadherin.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

[...] the relationships between the hexapods and other pancrustacean subgroups remain a controversial topic [...] One of the major conflicts regarding the pancrustacean phylogeny concerns the relationships between hexapods, branchiopods, and malacostracans. [...] our phylogenetic proposals remain highly hypothetical.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

[...] questions of how the two N-terminal-most ECs of type IVb cadherin contribute to the functioning of the type IVb cadherin and how the large number of EC domains in type III cadherin are utilized to mediate homophilic cell-cell adhesion are key to a better understanding of the stepwise reductive changes involved in the evolution of insect E-cadherin.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

[...] it is likely that reductive changes also preceded the establishment of the type III cadherin [...] Investigating the mechanism by which the classical cadherins were able to evolve via simplification is a typical challenge in experimentation-based evolutionary biology. [...] type IVa cadherin might have inherited part of an as-yet-uncharacterized mechanism of homophilic binding from the type III cadherin.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

The key issue is what form the last common precursor of type IVa and type IVb cadherins had. To fill the possible gaps in reconstruction of the transition processes between type III and type IVa/IVb cadherins, more data from the myriapod group, as well as from the crustacean group, will be required. [...] the transition from the ancestral type III cadherin to the derived insect type IVa cadherin was a multistep process that involved several progressive reductive changes.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Here are some figures for the referenced paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473995/figure/Fig8/

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

An unexpected and important finding of this work was the identification of a novel form of classical cadherin in isopod and amphipod crustaceans that was similar to, but distinct from, the known hexapod and branchiopod type IV cadherins. This finding led us to propose a revision of the type IV cadherin category and to define two subclasses, type IVa and type IVb.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Did somebody say "unexpected"? Why? Were they expecting something else or nothing at all? Did somebody say "revision"? Another one? :) Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Classical cadherins are a metazoan-specific family of homophilic cell-cell adhesion molecules that regulate morphogenesis. Although both type III and type IV cadherins have been identified in hexapods and branchiopods, the process by which the type IV cadherin evolved is still largely unclear. [...] following the divergence of early arthropods, the precursor of the insect type IV cadherin evolved through stepwise reductive changes from the ancestral type III state. [...] the complementary distributions of polarized genomic characters related to type IVa/IVb cadherins may have implications for our interpretations of pancrustacean phylogeny.

Evolutionary origin of type IV classical cadherins in arthropods Mizuki Sasaki,1,4 Yasuko Akiyama-Oda,1,2 and Hiroki Oda BMC Evol Biol. 2017; 17: 142. doi: 10.1186/s12862-017-0991-2

Where’s the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

[...] little is known about the evolutionary processes by which allorecognition novelty is produced. The existence of these commonalities between unrelated metazoan allorecognition systems suggests there are similar selective pressures driving the evolution and function of these divergent systems, regardless of the fact that allorecognition molecules vary markedly between taxa. The AFs appear to have evolved rapidly by mechanisms including exon shuffling and nucleotide mutation, and continue to generate within-species variation required for self–nonself recognition by the means listed above. [...] understanding of the sponge AF gene family sheds light on one of the central features of being an animal, self–nonself recognition.

Origin and Evolution of the Sponge Aggregation Factor Gene Family Laura F. Grice,1 Marie E.A. Gauthier,1 Kathrein E. Roper,1 Xavier Fernàndez-Busquets,2,3,4 Sandie M. Degnan,1 and Bernard M. Degnan Mol Biol Evol. 34(5): 1083–1099. doi: 10.1093/molbev/msx058

Where's the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

Although discriminating self from nonself is a cardinal animal trait, metazoan allorecognition genes do not appear to be homologous. The evolution of AFs suggests that their diversification occurs via high allelism, and the continual and rapid gain, loss and shuffling of domains over evolutionary time. Given the marked differences in metazoan allorecognition genes, we propose the rapid evolution of AFs in sponges provides a model for understanding the extensive diversification of self–nonself recognition systems in the animal kingdom.

Origin and Evolution of the Sponge Aggregation Factor Gene Family Laura F. Grice,1 Marie E.A. Gauthier,1 Kathrein E. Roper,1 Xavier Fernàndez-Busquets,2,3,4 Sandie M. Degnan,1 and Bernard M. Degnan Mol Biol Evol. 34(5): 1083–1099. doi: 10.1093/molbev/msx058

Where's the beef? Are they talking about the built-in variability framework seen in the biological systems? Can they show valid macroevolution cases using the formulation posted @1090? Dionisio

@1263 error: It should read "hope" instead of "home". My fault. Dionisio

We hope that these findings can bring a new viewpoint to understand the mechanisms of brain information transmission and information processing [...]

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

We home so too... :) complex complexity. Where's the beef? Dionisio

[...] the change of quantum state would likely lead to information transfer if such a state is in quantum entanglement [...]

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

huh? :) complex complexity. Where's the beef? Dionisio

[...] it is still not clear how the brain carry out neural information transfer, coding and storage via biophotons.

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

complex complexity. Where's the beef? Dionisio

The work of the brain involves neural information processing that is mainly transmitted along axons and dendrites, which are analogous to optic fibers.

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

Did somebody say “information processing”? :) complex complexity. Where's the beef? Dionisio

The neocortex in the brain is organized into columnar modules, which seem to be units of information processing (24), analogous to chips in a computer.

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

Did somebody say "information processing"? :) complex complexity. Where's the beef? Dionisio

There is no universally accepted definition of animal intelligence and no procedure to measure and compare the differences in different species [...]

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

complex complexity. Where's the beef? Dionisio

Despite remarkable advances in our understanding of brain functions, it is still unclear why human beings hold higher intelligence than other animals on Earth and which brain properties might explain the differences [...]

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

complex complexity. Where's the beef? Dionisio

Human beings hold higher intelligence than other animals on Earth; however, it is still unclear which brain properties might explain the underlying mechanisms.

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

complex complexity. Where's the beef? Dionisio

It is still unclear why human beings hold higher intelligence than other animals on Earth and which brain properties might explain the differences. [...] biophotons may play a key role in neural information processing and encoding [...] [...] biophotons may be involved in quantum brain mechanism [...]

Human high intelligence is involved in spectral redshift of biophotonic activities in the brain Zhuo Wang,a,b Niting Wang,a,b Zehua Li,a,b Fangyan Xiao,a,c and Jiapei Dai Proc Natl Acad Sci U S A. 113(31): 8753–8758. doi: 10.1073/pnas.1604855113

complex complexity. Where's the beef? Dionisio

It turns out that humans have a brain that is roughly eight times larger than expected from average mammalian BBR [...] There is no clear correlation between absolute or relative brain size and intelligence. Thus, other factors have to be considered. However, this alone cannot explain the superiority of primate—including human—intelligence. [...] it is the combination of very many cortical neurons and a relatively high IPC that appears to make our brains very smart. Despite intense search, no anatomical or physiological properties have been identified so far that would distinguish qualitatively the human brain from other mammalian or in general animal brains, except perhaps Broca's speech area. The question remains why corvids and parrots, with absolutely small brains compared with those of most mammals including primates, reveal such a high intelligence. [...] high intelligence can be realized by very different neuronal architectures.

Neuronal factors determining high intelligence Ursula Dicke and Gerhard Roth Philos Trans R Soc Lond B Biol Sci. 371(1685): 20150180. doi: 10.1098/rstb.2015.0180

complex complexity. Where's the beef? So much archaic pseudoscientific hogwash in one paper. Dionisio

Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. It is clear that it is not the brain in total that counts, but only some parts—above all the cortex in mammals or the meso-nidopallium (MNP) in birds—because those are the parts of the brain that are believed to be most closely related to intelligence [...]

Neuronal factors determining high intelligence Ursula Dicke and Gerhard Roth Philos Trans R Soc Lond B Biol Sci. 371(1685): 20150180. doi: 10.1098/rstb.2015.0180

Did somebody say "believed" in a scientific paper? complex complexity. Where's the beef? So much archaic pseudoscientific hogwash in one paper. Dionisio

Complex brains are supposed to have evolved at least several times independently, often in distantly related taxa, although presumably from an ancestral tripartite brain [2], and with them high intelligence. [...] we have to restrict ourselves to relatively informal comparisons regarding brain complexity, especially when comparing distantly related taxa. There is much speculation about differences in the ‘driving forces' with respect to increases in brain size and complexity as well as cognitive abilities [...]

Convergent evolution of complex brains and high intelligence. Roth G Philos Trans R Soc Lond B Biol Sci. 370(1684). pii: 20150049. doi: 10.1098/rstb.2015.0049.

complex complexity. Where's the beef? Tons of archaic pseudoscientific hogwash in one paper. Dionisio

Answering this non-exhaustive catalog of open questions is not only important to provide new insights into cnidarian muscle plasticity, but will also help providing a better understanding of the mechanisms underlying initial cnidarian muscle development.

Diversity of Cnidarian Muscles: Function, Anatomy, Development and Regeneration Lucas Leclère1,* and Eric Röttinger Front Cell Dev Biol. 4: 157. doi: 10.3389/fcell.2016.00157

Where’s the beef? Dionisio

[...] currently little is known about their capacity to reform/regenerate injured muscles. In order to better understand the similarities and differences of muscle plasticity in cnidarians, an emphasis has to be put on carrying out functional studies in existing as well as new models. Recent technological advances will be greatly beneficial for both aspects.

Diversity of Cnidarian Muscles: Function, Anatomy, Development and Regeneration Lucas Leclère1,* and Eric Röttinger Front Cell Dev Biol. 4: 157. doi: 10.3389/fcell.2016.00157

Where’s the beef? Dionisio

Additional analyses are required to understand the process of muscle fiber regeneration and repolarization as well as the role that muscles and muscle contractions play during wound healing and regeneration in Nematostella.

Diversity of Cnidarian Muscles: Function, Anatomy, Development and Regeneration Lucas Leclère1,* and Eric Röttinger Front Cell Dev Biol. 4: 157. doi: 10.3389/fcell.2016.00157

Where’s the beef? Dionisio

The development of novel tools to study those organisms has created new opportunities to investigate in depth the development and regeneration of cnidarian muscle cells and how they contribute to the regenerative process.

Diversity of Cnidarian Muscles: Function, Anatomy, Development and Regeneration Lucas Leclère1,* and Eric Röttinger Front Cell Dev Biol. 4: 157. doi: 10.3389/fcell.2016.00157

Where’s the beef? Dionisio

[...] crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins. Additional functional studies on these genes and the related sequences in Hydractinia (Sox22 and Sox24) will help to clarify their position in the Sox family. Members of the HDAC family fulfill multiple critical roles in animal development and tissue homeostasis through deacetylation of proteins. Our phylogeny shows that all HDAC sub-families were already present in the common eumetazoan ancestor and that they have been jointly inherited by cnidarians and bilaterians. Our study ties together many pieces of evidence, confirming the essential role of SoxB-Hdac1/2 crosstalk in neural development and suggesting it to be an ancient but conserved feature of metazoan neurogenesis.

An evolutionarily conserved SoxB-Hdac2 crosstalk regulates neurogenesis in a cnidarian Hakima Flici,1 Christine E. Schnitzler,2,3,4 R. Cathriona Millane,1 Graham Govinden,1 Amy Houlihan,1 Stephanie D. Boomkamp,5 Sanbing Shen,5 Andreas D. Baxevanis,4 and Uri Frank Cell Rep. 18(6): 1395–1409. doi: 10.1016/j.celrep.2017.01.019

Where’s the beef? Dionisio

Clarification of terms: the question: Where is the beef? is about the lack of a coherent & comprehensive evo-devo case that may satisfy the fundamental evo-devo conditions described @1090. The Galapagos finch variety was grossly extrapolated to macroevolutionary pseudoscientific hogwash. At the end of the day birds remain birds. So instead of writing so much "parole" simply show me the money! :) Dionisio

[...] future work will aim to uncover how PIWI function impacts regeneration. These analyses will provide insight into both novel and conserved features within model hydrozoans. Hydrozoan research will contribute to our understanding of the evolution of immune responses in animals [...] [...] future work is required to understand the molecular underpinnings of these observations. [...] Hydra uses its innate immune system to regulate its interactions with viruses. [...] larger scaffold sizes make it possible to explore synteny among diverse animal genomes with the goal of determining the organization of chromosomes and arrangement of genes in the genome of the last common ancestor of extant metazoans. Among the multiple techniques available for genome editing, CRISPR/Cas9 has become very popular and is now used in an extraordinarily broad range of species [25]. However, in spite of its widespread use, it is still difficult to streamline experiments using CRISPR/Cas9 because of the numerous parameters that have to be optimized. The gene expression profiles associated with each zooid type are thus of interest. Catriona Munro (Brown University) aims to find out how such changes evolved by measuring them in different species. It is clear that promising opportunities lie ahead in hydrozoan research and this meeting enabled scientists to exchange ideas, plan future work, and discuss how to address the next challenges.

Hydroidfest 2016: celebrating a renaissance in hydrozoan research Christophe Dupre,1 Juris A. Grasis,2 Robert E. Steele,3 Christine E. Schnitzler,4,5 and Celina E. Juliano EvoDevo. 2017; 8: 7. doi: 10.1186/s13227-017-0070-1

Where’s the beef? Dionisio

“The central goal of evolutionary developmental biology is to understand how evolutionary modification of developmental processes leads to morphological or physiological differences between populations, species and higher taxa.”

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B Biological Sciences http://rstb.royalsocietypublishing.org/content/372/1713/20150480

Where's the beef? :) Dionisio

Refer to related comments made in another thread: https://uncommondescent.com/informatics/why-evolution-can-never-get-any-smarter/#comment-633829 Dionisio

Based on (i) an analysis of the regularities in the standard genetic code and (ii) comparative genomics of the anticodon modification machinery in the three branches of life, we derive the tRNA set and its anticodon modifications as it was present in LUCA. Previously we proposed that an early ancestor of LUCA contained a set of 23 tRNAs with unmodified anticodons that was capable of translating all 20 amino acids while reading 55 of the 61 sense codons of the standard genetic code (SGC). Here we use biochemical and genomic evidence to derive that LUCA contained a set of 44 or 45 tRNAs containing 2 or 3 modifications while reading 59 or 60 of the 61 sense codons. Subsequent tRNA modifications occurred independently in the Bacteria and Eucarya, while the Archaea have remained quite close to the tRNA set as it was present in LUCA.

Anticodon Modifications in the tRNA Set of LUCA and the Fundamental Regularity in the Standard Genetic Code. van der Gulik PT, Hoff WD PLoS One. 11(7):e0158342. doi: 10.1371/journal.pone.0158342.

Still I prefer the Cinderella story, because it's more interesting than this boring pseudoscientific hogwash. At least in the Cinderella story things make more sense: a pumpkin becomes an elegant carriage, the mice turn into beautiful horses and the grasshopper works as the cochero. Nonsense remains nonsense regardless of who says it. Anyway, where's the beef? Dionisio

Mammalian cerebral cortex comprises the neocortex, the hippocampus, and the olfactory cortex. The olfactory cortex is part of the mammalian cerebral cortex together with the neocortex and the hippocampus. It receives direct input from the olfactory bulbs and participates in odor discrimination, association, and learning [...] The olfactory cortex, so-called “simple” cortex in the literature when compared with the six-layered neocortex, is often presented as a general model for cortical sensory processing. However, the molecular identities and the specific functions of cells composing each olfactory cortex layer remain poorly described. Further investigations will allow understanding whether the different VZ origins and migratory properties of olfactory cortex neurons during development are correlated with their heterogeneous identities and functions in odor processing. Unraveling precise neuronal origins and identities in both the neocortex and the olfactory cortex will further elucidate the evolutionarily conserved properties of sensory cortices.

Development and Organization of the Evolutionarily Conserved Three-Layered Olfactory Cortex Esther Klingler eNeuro. 4(1): ENEURO.0193-16.2016. doi: 10.1523/ENEURO.0193-16.2016

So much pseudoscientific hogwash in one paper. Parole, parole, parole… Where's the beef? Complex complexity. Dionisio

[...] a differentiation gradient that was ancestrally established in the tangential axis, became expressed in the radial domain by virtue of the superposition of the different signaling molecules that acted at different developmental stages, i.e., dorsal-derived Wnts at early stages, and laterally-derived Pax6 signals at late developmental stages. In subsequent lineages, the isocortex expanded enormously both in absolute and relative size. In line with these arguments, Lewitus et al. (2014) have recently proposed that the ancestor of crown mammals might have had a gyrencephalic brain with a well differentiated isocortex, which would imply that the origin of isocortex is to be traced back to earlier mammalian groups, possibly living in the Jurassic period (Luo, 2007; Lee and Beck, 2015).

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

So much pseudoscientific hogwash in one paper. Parole, parole, parole... Where's the beef? Complex complexity. Dionisio

[...] brain evolution cannot be fully understood through developmental, anatomical, functional, or behavioral perspectives alone. This is because we need to combine such approaches to reach a comprehensive understanding of the genetic and epigenetic mechanisms generating developmental variability, in concert with the selective pressures exerted by the ecological and behavioral conditions animals face to successfully reproduce. Given this background, brain evolution is subject to conserved processes to which contingent adaptations are added, that may leave enduring marks in subsequent evolutionary modifications (like isocortical lamination). On the other hand, there are also conserved requirements for proper brain function and for the generation of complex perception and behavior that shape circuit and network architecture in similar ways in different lineages.

Olfaction, navigation, and the origin of isocortex Francisco Aboitiz and Juan F. Montiel Front Neurosci. 9: 402. doi: 10.3389/fnins.2015.00402

So much pseudoscientific hogwash in one paper. Parole, parole, parole… Where's the beef? Complex complexity. Dionisio

[...] pre-existing complex cis-regulatory loci that already interact with potentially relevant transcription factors are more likely to acquire novel functions in wing patterning. [...] the shape of wing regulatory networks may constrain evolutionary change to one or a few loci. Overall, genomic approaches that have identified wing patterning loci in these butterflies offer broad insight into how gene regulatory networks evolve to produce diversity.

Waiting in the wings: what can we learn about gene co-option from the diversification of butterfly wing patterns? Chris D. Jiggins, Richard W. R. Wallbank, Joseph J. Hanly DOI: 10.1098/rstb.2015.0485 Philosophical Transactions of the Royal Society B: Biological Sciences

Where's the beef? Complex complexity. Dionisio

WntA is a patterning morphogen that alters spatial information in the wing. Optix is a transcription factor that acts later in development to paint specific wing regions red. Both of these loci fit the paradigm of conserved protein-coding loci with diverse regulatory elements and developmental roles that have taken on novel derived functions in patterning wings.

Waiting in the wings: what can we learn about gene co-option from the diversification of butterfly wing patterns? Chris D. Jiggins, Richard W. R. Wallbank, Joseph J. Hanly DOI: 10.1098/rstb.2015.0485 Philosophical Transactions of the Royal Society B: Biological Sciences

Where's the beef? Complex complexity. Dionisio

A major challenge is to understand how conserved gene regulatory networks control the wonderful diversity of form that we see among animals and plants. Butterfly wing patterns are an excellent example of this diversity. Butterfly wings form as imaginal discs in the caterpillar and are constructed by a gene regulatory network, much of which is conserved across the holometabolous insects.

Waiting in the wings: what can we learn about gene co-option from the diversification of butterfly wing patterns? Chris D. Jiggins, Richard W. R. Wallbank, Joseph J. Hanly DOI: 10.1098/rstb.2015.0485 Philosophical Transactions of the Royal Society B: Biological Sciences

Where's the beef? Complex complexity. Dionisio

Morphogen gradient in Academia.edu 1. A changing morphogen gradient is interpreted by continuous transduction flow 2. A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning 3. Activin signalling and response to a morphogen gradient 4. Application of Fractional Calculus to Reaction-Subdiffusion Processes and Morphogen Gradient Formation 5. Bicoid by the Numbers: Quantifying a Morphogen Gradient 6. Biophysical studies of morphogen gradient formation in Drosophila melanogaster 7. Biophysics problems in early embryonic development: precision and dynamics in the bicoid morphogen gradient 8. Butterfly eyespot patterns: evidence for specification by a morphogen diffusion gradient 9. Determining the scale of the Bicoid morphogen gradient 10. Development of morphogen gradient: The role of dimension and discreteness 11. Direct and Long-Range Action of a DPP Morphogen Gradient 12. Distance measurements via the morphogen gradient of Bicoid in Drosophila embryos 13. Dynamics of the Dorsal morphogen gradient 14. Fgf8 morphogen gradient forms by a source-sink mechanism with freely diffusing molecules 15. Formation of the Long Range Dpp Morphogen Gradient 16. Fractional calculus and morphogen gradient formation 17. Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc 18. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism 19. Kinetics of Morphogen Gradient Formation 20. Measurement and Perturbation of Morphogen Lifetime: Effects on Gradient Shape 21. Microscopic approach to nonlinear reaction-diffusion: The case of morphogen gradient formation 22. Modeling morphogen gradient formation from arbitrary realistically shaped sources 23. Morpheus unbound: reimagining the morphogen gradient 24. Morphogen Gradient Formation and Vesicular Trafficking 25. Position Along The Anterior/Posterior Axis Of Neocortex Is Specified By A Classic Morphogen Gradient 26. Precision and scaling in morphogen gradient read-out 27. Pre-Steady-State Decoding of the Bicoid Morphogen Gradient 28. Probing Intrinsic Properties of a Robust Morphogen Gradient in Drosophila 29. Reaction-subdiffusion model of morphogen gradient formation 30. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein 31. Re-examining the Stability of the Bicoid Morphogen Gradient 32. Self-induced patched receptor down-regulation modulates cell sensitivity to the hedgehog morphogen gradient 33. Shape and function of the Bicoid morphogen gradient in dipteran species with different sized embryos 34. Single cells can sense their position in a morphogen gradient 35. Stability and Nuclear Dynamics of the Bicoid Morphogen Gradient 36. The Decapentaplegic morphogen gradient: a precise definition 37. The dorsal gradient morphogen regulates stripes of rhomboid expression in the presumptive neuroectoderm of the Drosophila embryo 38. The Wingless morphogen gradient is established by the cooperative action of Frizzled and Heparan Sulfate Proteoglycan receptors Please, note that some papers may appear referenced in more than one list, because their titles include more than one target keyword. Dionisio

Cytokinesis in Academia.edu 1. [Chromatin morphology and cytokinesis in pleurocapsalean cyanobacteria] 2. 14-3-3? controls mitotic translation to facilitate cytokinesis 3. A 3D multiphase hydrodynamic model for cytokinesis of eukaryotic cells 4. A fluid mechanical model of cytokinesis in animal cells 5. Aurora B -TACC1 protein complex in cytokinesis 6. Bacterial cytokinesis: From Z ring to divisome 7. Biochemical Analyses of Human IST1 and Its Function in Cytokinesis 8. Biological and taphonomic implications of Ediacaran fossil embryos undergoing cytokinesis 9. Breaking up is hard to do - membrane traffic in cytokinesis 10. Bub2 regulation of cytokinesis and septation in budding yeast 11. Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis 12. Cell Division in Spirogyra. II. Cytokinesis 13. Cell division: Plant-like properties of animal cell cytokinesis 14. Cell migration regulates the kinetics of cytokinesis 15. Centriole movements in mammalian epithelial cells during cytokinesis 16. Centrosomes in Cytokinesis, Cell Cycle Progression and Ciliogenesis: a Dissertation 17. Chromosome Tips Damaged in Anaphase Inhibit Cytokinesis 18. Clues to CD2-associated Protein Involvement in Cytokinesis 19. Cyk3, a novel SH3-domain protein, affects cytokinesis in yeast 20. Cytokinesis and cancer 21. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells 22. Cytokinesis in Bacteria 23. Cytokinesis in Drosophila male meiosis 24. Cytokinesis in Eukaryotes 25. Cytokinesis in plant male meiosis 26. Cytokinesis Monitoring during Development 27. Cytokinesis remnants define first neuronal asymmetry in vivo 28. Cytokinesis series Midbodies and phragmoplasts: analogous structures involved in cytokinesis 29. Cytokinesis: mind the GAP 30. Cytokinesis: Rho and Formins Are the Ringleaders 31. Cytokinesis: welcome to the Rho zone 32. Cytokinesis-block micronucleus cytome assay 33. Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms 34. Dissociation of Cytokinesis Initiation From Mitotic Control In a Eukaryote 35. Drosophila Polo Kinase Is Required for Cytokinesis 36. Endocytic traffic in animal cell cytokinesis 37. Endosome positioning during cytokinesis 38. Engulfment of the midbody remnant after cytokinesis in mammalian cells 39. Essential role of citron kinase in cytokinesis of spermatogenic precursors 40. Essential role of hIST1 in cytokinesis 41. Ethylene Stimulates Endoreduplication But Inhibits Cytokinesis in Cucumber Hypocotyl Epidermis 42. Exocyst proteins in cytokinesis: Regulation by Rab11 43. Flow cytometry to sort mammalian cells in cytokinesis 44. Forced expression of chimeric human fibroblast tropomyosin mutants affects cytokinesis 45. Furrow Constriction in Animal Cell Cytokinesis 46. Furrowing During Cytokinesis in Mammalian Cells 47. Furrow-Specific Endocytosis during Cytokinesis of Zebrafish Blastomeres 48. Geminin overexpression induces mammary tumors via suppressing cytokinesis 49. GiantDrosophila neurons differentiated from cytokinesis-arrested embryonic neuroblasts 50. Human ASPM participates in spindle organisation, spindle orientation and cytokinesis 51. Inhibition of cytokinesis by Clostridium difficile toxin B and cytotoxic necrotizing factors--reinforcing the critical role of RhoA in cytokinesis 52. Integrin Trafficking Regulated by Rab21 Is Necessary for Cytokinesis 53. Iqg1p links spatial and secretion landmarks to polarity and cytokinesis 54. Isolation and characterization of new fission yeast cytokinesis mutants 55. Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis 56. Membrane Trafficking During Plant Cytokinesis 57. Midbodies and phragmoplasts: analogous structures involved in cytokinesis 58. Mitosis in : Multiple Modes of Cytokinesis 59. Mitosis, Cytokinesis, and Cell Elongation in the Desmid, Closterium Littorale 60. NoCut: Cytokinesis in Check 61. Novel interactors and a role for supervillin in early cytokinesis 62. Parameters that Specify the Timing of Cytokinesis 63. Phosphoinositide Function in Cytokinesis 64. Plant Cytokinesis Requires De Novo Secretory Trafficking but Not Endocytosis 65. Polar opposites: Fine-tuning cytokinesis through SIN asymmetry 66. Polarity sets the stage for cytokinesis 67. Proper timing of cytokinesis is regulated by Schizosaccharomyces pombe Etd1 68. RacGAP50C is sufficient to signal cleavage furrow formation during cytokinesis 69. Rap1-dependent pathways coordinate cytokinesis in Dictyostelium 70. Regulation of cytokinesis by spindle-pole bodies 71. Requirement for Microtubules in New Membrane Formation during Cytokinesis ofXenopusEmbryos 72. REVIEW: DNA damage associated with mitosis and cytokinesis failure 73. Roles of BCCIP in chromosome stability and cytokinesis 74. Saccharomyces cerevisiae Mob1p Is Required for Cytokinesis and Mitotic Exit 75. Small GTPase RhoD suppresses cell migration and cytokinesis 76. Syndecan-4 promotes cytokinesis in a phosphorylation-dependent manner 77. Talin Concentrates to the Midbody Region During Mammalian Cell Cytokinesis 78. The Class I PITP Giotto Is Required for Drosophila Cytokinesis 79. The septins: roles in cytokinesis and other processes 80. Tying the knot: linking cytokinesis to the nuclear cycle 81. Vesicle Trafficking during Somatic Cytokinesis Please, note that some papers may appear referenced in more than one list, because their titles include more than one target keyword. Dionisio

Spindle Assembly Checkpoint in Academia.edu (2017-02-25) 1. 731 Chemical induction of mitotic slippage by proteolytic degradation of spindle assembly checkpoint proteins 2. A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint 3. Abnormal kinetochore structure activates the spindle assembly checkpoint in budding yeast 4. An overview of the spindle assembly checkpoint status in oral cancer 5. Analysis of Bub3 spindle checkpoint function in Xenopus egg extracts 6. Anaphase Inactivation of the Spindle Checkpoint 7. Antitumor agents 283. Further elaboration of Desmosdumotin C analogs as potent antitumor agents: Activation of spindle assembly checkpoint as possible mode of action 8. Atta-ur-Rahman (Ed) All rights reserved-© 2014 Bentham Science Publishers CHAPTER 2 Spindle Assembly Checkpoint (SAC): More New Targets for Anti-Cancer Drug Therapies 9. Aurora Kinase Inhibitor ZM447439 Blocks Chromosome-induced Spindle Assembly, the Completion of Chromosome Condensation, and the Establishment of the Spindle Integrity Checkpoint in Xenopus Egg Extracts 10. Bioinformatic search for plant homologs of the protein kinase Bub1—a key component of the mitotic spindle assembly checkpoint 11. Bub1 Maintains Centromeric Cohesion by Activation of the Spindle Checkpoint 12. Bub1-Mediated Adaptation of the Spindle Checkpoint 13. Characterization of a Putative Spindle Assembly Checkpoint Kinase Mps1, Suggests Its Involvement in Cell Division, Morphogenesis and Oxidative Stress Tolerance in Candida albicans 14. Characterization of MAD2B and Other Mitotic Spindle Checkpoint Genes 15. Components of the Spindle Assembly Checkpoint Regulate the Anaphase-Promoting Complex During Meiosis in Caenorhabditis elegans 16. Deficient Spindle Assembly Checkpoint in Multiple Myeloma 17. Deletion of Mia1/Alp7 activates Mad2-dependent spindle assembly checkpoint in fission yeast 18. Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the spindle assembly checkpoint 19. Distinct chromosome segregation roles for spindle checkpoint proteins 20. Drosophila Mis12 Complex Acts as a Single Functional Unit Essential for Anaphase Chromosome Movement and a Robust Spindle Assembly Checkpoint 21. Elm1 kinase activates the spindle position checkpoint kinase Kin4 22. Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells 23. Error-prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension 24. Evaluating putative mechanisms of the mitotic spindle checkpoint 25. Expression profiles of cohesins, shugoshins and spindle assembly checkpoint genes in rhesus macaque oocytes predict their susceptibility for aneuploidy during embryonic development 26. Germline Mutations in the Spindle Assembly Checkpoint Genes BUB1 and BUB3 Are Risk Factors for Colorectal Cancer 27. High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint 28. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage 29. Kinetochore Localization of Spindle Checkpoint Proteins: Who Controls Whom? 30. La regulación del Spindle Assembly Checkpoint en Schizosaccharomyces pombe 31. Mad1 contribution to spindle assembly checkpoint signalling goes beyond presenting Mad2 at kinetochores 32. Mad2-independent Spindle Assembly Checkpoint Activation and Controlled Metaphase-Anaphase Transition in Drosophila S2 Cells 33. Mimicking Ndc80 phosphorylation triggers spindle assembly checkpoint signalling 34. miR-433 overexpression attenuates the spindle assembly checkpoint response to paclitaxel 35. Mlp1 Acts as a Mitotic Scaffold to Spatially Regulate Spindle Assembly Checkpoint Proteins in Aspergillus nidulans 36. Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase 37. Noise resistance in the spindle assembly checkpoint 38. Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases 39. Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer 40. P034 Intra -s- DNA damage checkpoint mediated by the spindle assembly factor TPX2 41. Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells 42. Preparation of Monoclonal Antibodies Against the Spindle Checkpoint Kinase Bub1 43. PRP4 is a spindle assembly checkpoint protein required for MPS1, MAD1, and MAD2 localization to the kinetochores 44. Regulation of APC/C Activity in Oocytes by a Bub1-Dependent Spindle Assembly Checkpoint 45. Requirement for proteolysis in spindle assembly checkpoint silencing. 46. RINGO C is required to sustain the spindle-assembly checkpoint 47. RSK2 is a kinetochore-associated protein that participates in the spindle assembly checkpoint 48. Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1 49. Spindle assembly checkpoint and centrosome abnormalities in oral cancer 50. Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis 51. Spindle Assembly Checkpoint Protein Dynamics Reveal Conserved and Unsuspected Roles in Plant Cell Division 52. Spindle assembly checkpoint proteins are positioned close to core microtubule attachment sites at kinetochores 53. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20 54. Targeting the Spindle Assembly Checkpoint for Breast Cancer Treatment 55. The A78V mutation in the Mad3-like domain of S. pombe Bub1p perturbs nuclear accumulation and kinetochore targeting of Bub1p, Bub3p, and Mad3p and spindle assembly checkpoint function 56. The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond 57. The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs 58. The Human Spindle Assembly Checkpoint Protein Bub3 Is Required for the Establishment of Efficient Kinetochore-Microtubule Attachments 59. The Mad1/Mad2 Complex as a Template for Mad2 Activation in the Spindle Assembly Checkpoint 60. The Mad2 Conformational Dimer: Structure and Implications for the Spindle Assembly Checkpoint 61. The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation 62. The Spindle Assembly Checkpoint and Aneuploidy 63. The spindle assembly checkpoint is satisfied in the absence of interkinetochore tension during mitosis with unreplicated genomes 64. The spindle assembly checkpoint: perspectives in tumorigenesis and cancer therapy 65. The spindle assembly checkpoint: Preventing chromosome mis-segregation during mitosis and meiosis 66. The spindle checkpoint 67. The spindle checkpoint: structural insights into dynamic signalling 68. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint 69. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint 70. Three BUB1 and BUBR1/MAD3-related spindle assembly checkpoint proteins are required for accurate mitosis in Arabidopsis 71. Uncoupling anaphase-promoting complex/cyclosome activity from spindle assembly checkpoint control by deregulating polo-like kinase 1 72. Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint 73. Using default constraints of the spindle assembly checkpoint to estimate the associated chemical rates 74. When the Genome Plays Dice: Circumvention of the Spindle Assembly Checkpoint and Near-Random Chromosome Segregation in Multipolar Cancer Cell Mitoses Please, note that some papers may appear referenced in more than one list, because their titles include more than one target keyword. For example, in this list there are several (11?) titles that also appear in the 'kinetochore' list. Dionisio

Centrosome in Academia.edu (2017-02-25) 1. [Centrosome as "a brain" of an animal cell] 2. [The centrosome--a riddle of the "cell processor"] 3. 3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication 4. A cell cycle phosphoproteome of the yeast centrosome 5. A centrosome-autonomous signal that involves centriole disengagement permits centrosome duplication in G2 phase after DNA damage 6. A molecular mechanism of mitotic centrosome assembly in Drosophila 7. A Novel Bipartite Centrosome Coordinates the Apicomplexan Cell Cycle 8. A Role for Centrin 3 in Centrosome Reproduction 9. A Theoretical Model of centrosome functioning 10. Abnormal Centrosome Amplification in the Absence of p53 11. Association of aneuploidy category with centrosome amplification in multiple myeloma 12. Association of nucleus and centrosome: magnet or velcro? 13. Association of TCTP with centrosome and microtubules 14. Biogenesis of the centrosome during mammalian gametogenesis and fertilization 15. BRCA1Dependent Ubiquitination of Tubulin Regulates Centrosome Number 16. Cdk2 and Cdk4 Regulate the Centrosome Cycle and Are Critical Mediators of Centrosome Amplification in p53-Null Cells 17. Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors 18. Centrosome – the cell concertmaster 19. Centrosome Amplification and Chromosomal Instability in Feline Lymphoma Cell Lines 20. Centrosome Amplification Can Initiate Tumorigenesis in Flies 21. Centrosome amplification drives chromosomal instability in breast tumor development 22. Centrosome biogenesis and function: centrosomics brings new understanding 23. Centrosome defects and genetic instability in malignant tumors 24. Centrosome Dynamics during the Meiotic Progression in the Mouse Oocyte 25. Centrosome Function: Sometimes Less Is More 26. Centrosome Functions as a Molecular Dynamo in the Living Cell 27. Centrosome Isolation and Analysis by Mass Spectrometry-Based Proteomics 28. Centrosome organization and centriole architecture: Their sensitivity to divalent cations 29. Centrosome overduplication and mitotic instability in PKD2 transgenic lines 30. Centrosome positioning in interphase cells 31. Centrosome positioning in polarized cells: Common themes and variations 32. Centrosome Reduction during Mouse Spermiogenesis 33. Centrosome reorientation in wound-edge cells is cell type specific 34. Centrosome separation: respective role of microtubules and actin filaments 35. Centrosome: is it a geometric, noise resistant, 3D 36. Centrosome-independent mitotic spindle formation in vertebrates 37. Clinical implication of centrosome amplification in plasma cell neoplasm 38. Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle 39. Dinoflagellate centrosome: Associated proteins old and new 40. Disruption of Clathrin-Mediated Trafficking Causes Centrosome Overduplication and Senescence 41. DNA damage induces Chk1-dependent centrosome amplification 42. DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos 43. Dominant-negative mutant dynein allows spontaneous centrosome assembly, uncouples chromosome and centrosome cycles 44. Drosophila neuroblasts retain the daughter centrosome 45. Effects of dynein on microtubule mechanics and centrosome positioning 46. HOPS is an essential constituent of centrosome assembly 47. Identification and function of the centrosome centromatrix 48. Induction of centrosome and chromosome aberrations by imatinib in vitro 49. Involvement of centrosome amplification in radiation-induced mitotic catastrophe 50. Limiting Amounts of Centrosome Material Set Centrosome Size in C. elegans Embryos 51. Localization of Myosin-V in the Centrosome 52. Loss of polycystin-1 causes centrosome amplification and genomic instability 53. Mammalian RanBP1 regulates centrosome cohesion during mitosis 54. Microtubule nucleation by gamma-tubulin-containing rings in the centrosome 55. Molecular heterogeneity and centrosome-associated genes in multiple myeloma 56. Network modeling links breast cancer susceptibility and centrosome dysfunction 57. Novel centrosome protein, TCC52, is a cancer-testis antigen 58. Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome 59. p16INK4a Prevents Centrosome Dysfunction and Genomic Instability in Primary Cells 60. Pericentrin, a highly conserved centrosome protein involved in microtubule organization 61. Pin1 Regulates Centrosome Duplication, and Its Overexpression Induces Centrosome Amplification, Chromosome Instability, and Oncogenesis 62. Polar expeditions — provisioning the centrosome for mitosis 63. Proximity Interactions among Centrosome Components Identify Regulators of Centriole Duplication 64. Quantitative multi-parametric evaluation of centrosome declustering drugs: centrosome amplification, mitotic phenotype, cell cycle and death 65. Reconstitution of centrosome microtubule nucleation in Drosophila 66. Regulated assembly of a supramolecular centrosome scaffold in vitro 67. SADB kinases license centrosome replication 68. Spindle assembly checkpoint and centrosome abnormalities in oral cancer 69. The Centrosome – a cell concertmaster 70. The Centrosome and Its Duplication Cycle 71. The centrosome and its mode of inheritance: the reduction of the centrosome during gametogenesis and its restoration during fertilization 72. The centrosome and mitotic spindle apparatus in cancer and senescence 73. The centrosome is a dynamic structure that ejects PCM flares 74. The Centrosome: A Target for Cancer Therapy 75. The centrosome-Golgi apparatus nexus 76. The Golgi Protein GM130 Regulates Centrosome Morphology and Function 77. The mammalian SPD-2 ortholog Cep192 regulates centrosome biogenesis 78. The TACC proteins: TACC-ling microtubule dynamics and centrosome function 79. The Xenopus laevis centrosome aurora/lpl1-related kinase Dionisio

Kinetochore in Academia.edu (2017-02-25) 1. A cooperative mechanism drives budding yeast kinetochore assembly downstream of CENP-A 2. A Screen for Kinetochore-Microtubule Interaction Inhibitors Identifies Novel Antitubulin Compounds 3. Abnormal kinetochore structure activates the spindle assembly checkpoint in budding yeast 4. Accurate phosphoregulation of kinetochore-microtubule affinity requires unconstrained molecular interactions 5. Anaphase onset does not require the microtubule-dependent depletion of kinetochore and centromere-binding proteins 6. Architecture and Flexibility of the Yeast Ndc80 Kinetochore Complex 7. Autoantibody to Centromere (Kinetochore) in Scleroderma Sera 8. Basic mechanism for bi-orientation of mitotic chromosomes is provided by the kinetochore geometry and indiscriminate turnover of kinetochore microtubules 9. CaMtw1, a member of the evolutionarily conserved Mis12 kinetochore protein family, is required for efficient inner kinetochore assembly in the pathogenic yeast Candida albicans 10. Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments 11. CENP-C Is a Structural Platform for Kinetochore Assembly 12. CENP-E Is a Plus End–Directed Kinetochore Motor Required for Metaphase Chromosome Alignment 13. CENP-E is a putative kinetochore motor that accumulates just before mitosis 14. Chromosome congression in the absence of kinetochore fibres 15. Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochore 16. Conformational mechanism for the stability of microtubule-kinetochore attachments 17. Control of the spindle checkpoint by lateral kinetochore attachment and limited Mad1 recruitment 18. De Novo Kinetochore Assembly Requires the Centromeric Histone H3 Variant 19. Drosophila Dgt6 Interacts with Ndc80, Msps/XMAP215, and ?-Tubulin to Promote Kinetochore-Driven MT Formation 20. Epigenetics regulate centromere formation and kinetochore function 21. Formation of a Dynamic Kinetochore Microtubule Interface through Assembly of the Dam1 Ring Complex 22. Function and Assembly of DNA Looping, Clustering, and Microtubule Attachment Complexes within a Eukaryotic Kinetochore 23. Gcn5p Plays an Important Role in Centromere Kinetochore Function in Budding Yeast 24. Him-10 Is Required for Kinetochore Structure and Function on Caenorhabditis elegans Holocentric Chromosomes 25. Human Survivin Is a Kinetochore-associated Passenger Protein 26. Implications for Kinetochore-Microtubule Attachment from the Structure of an Engineered Ndc80 Complex 27. In vivo functional dissection of human inner kinetochore protein CENP-C 28. Inactivation of a Human Kinetochore by Specific Targeting of Chromatin Modifiers 29. Inner Kinetochore of the Pathogenic Yeast Candida glabrata 30. Kinesin 5-independent poleward flux of kinetochore microtubules in PtK1 cells 31. Kinetochore appearance during meiosis, fertilization and mitosis in mouse oocytes and zygotes 32. Kinetochore assembly and heterochromatin formation occur autonomously in Schizosaccharomyces pombe 33. Kinetochore kinesin CENP-E is a processive bi-directional tracker of dynamic microtubule tips 34. Kinetochore Localization of Spindle Checkpoint Proteins: Who Controls Whom? 35. Kinetochore reproduction theory may explain rapid chromosome evolution [really?] 36. Kinetochore-driven formation of kinetochore fibers contributes to spindle assembly during animal mitosis 37. Mammalian CLASP1 and CLASP2 Cooperate to Ensure Mitotic Fidelity by Regulating Spindle and Kinetochore Function 38. Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints 39. Merotelic Kinetochore Orientation Is a Major Mechanism of Aneuploidy in Mitotic Mammalian Tissue Cells 40. Microtubule binding by KNL-1 contributes to spindle checkpoint silencing at the kinetochore 41. Molecular analysis of core kinetochore composition and assembly in Drosophila melanogaster 42. Molecular architecture of a kinetochore–microtubule attachment site 43. Molecular mechanisms of kinetochore capture by spindle microtubules 44. Molecular Requirements for Kinetochore-Associated Microtubule Formation in Mammalian Cells 45. Molecular-cytogenetic characterization of a higher plant centromere/kinetochore complex 46. Molecular-Mechanical Model of Kinetochore-Microtubule Interactions Identifies Flexibility of the Kinetochore Mesh as a Key Determinant of Errorless Bi-Orientation 47. Ordered Kinetochore Assembly in the Human-Pathogenic Basidiomycetous Yeast Cryptococcus neoformans 48. p31comet acts to ensure timely spindle checkpoint silencing subsequent to kinetochore attachment 49. Phosphorylation Relieves Autoinhibition of the Kinetochore Motor Cenp-E 50. Pivoting of microtubules around the spindle pole accelerates kinetochore capture 51. Plk1 Phosphorylates Sgt1 at the Kinetochores To Promote Timely Kinetochore-Microtubule Attachment 52. Putting the cenH3 in the Centromere: Arabidopsis KINETOCHORE NULL2 Acts Upstream of cenH3 Deposition 53. RAMA1 is a novel kinetochore protein involved in kinetochore-microtubule attachment 54. Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase 55. Ringing the changes: emerging roles for DASH at the kinetochore–microtubule Interface 56. Searching for Drosophila Dsn1 kinetochore protein 57. Sgt1 is required for human kinetochore assembly 58. Sgt1p and Skp1p modulate the assembly and turnover of CBF3 complexes required for proper kinetochore function 59. Shugoshin 1 Plays a Central Role in Kinetochore Assembly and is Required for Kinetochore Targeting of Plk1 60. Spatiotemporal dynamics of Spc105 regulates the assembly of the Drosophila kinetochore 61. SPDL-1 functions as a kinetochore receptor for MDF-1 in Caenorhabditis elegans 62. Springs, clutches and motors: driving forward kinetochore mechanism by modelling 63. Stable Kinetochore-Microtubule Attachment Constrains Centromere Positioning in Metaphase 64. Supplemental Data Implications for Kinetochore-Microtubule Attachment from the Structure of an Engineered Ndc80 Complex 65. Tension Directly Stabilizes Reconstituted Kinetochore-Microtubule Attachments 66. The budding yeast proteins Spc24p and Spc25p interact with Ndc80p and Nuf2p at the kinetochore and are important for kinetochore clustering and checkpoint control 67. The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond 68. The dynamic protein Knl1 - a kinetochore rendezvous 69. The Fission Yeast Kinetochore Component Spc7 Associates with the EB1 Family Member Mal3 and Is Required for Kinetochore-Spindle Association 70. The Kinetochore and the Centromere: A Working Long Distance Relationship 71. The Kinetochore-Bound Ska1 Complex Tracks Depolymerizing Microtubules and Binds to Curved Protofilaments 72. The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability 73. The path of DNA in the kinetochore 74. The process of kinetochore assembly in yeasts 75. The rough deal protein is a new kinetochore component required for accurate chromosome segregation in Drosophila 76. The Saccharomyces cerevisiae kinetochore 77. The SUMO protease SENP6 is essential for inner kinetochore assembly Note that the word 'evolution' appears in two of the 77 titles: 9 and 35, in both cases having irrelevant meaning. Definitely the folks of the "3rd way" have a lot of work to do in the future. Dionisio

Animal development is the product of distinct components and interactions-genes, regulatory networks, and cells-and it exhibits emergent properties that cannot be inferred from the components in isolation. Often the focus is on the genotype-to-phenotype map, overlooking the process of development that turns one into the other. Challenges still remain in developing methods to analyze this data and to increase the throughput. However this line of research has the potential to bridge the gaps between previously more disparate fields, such as population genetics and development, opening up new avenues of research.

Gene networks and developmental context: the importance of understanding complex gene expression patterns in evolution Sarah A. Signor, Michelle N. Arbeitman and Sergey V. Nuzhdin Journal: Evolution & Development, 2016, Volume 18, Number 3, Page 201 DOI: 10.1111/ede.12187

Where’s the beef? Complex complexity. Dionisio

[...] evolutionary systems biology may indeed be able to provide solutions to some of the most enduring and daunting challenges in modern biology over the next few years.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? OK, let's wait and see. Dionisio

[...] a truly unified and comprehensive theory of development is far beyond our current reach, and may not be possible (or even desirable) to achieve (depending on one’s meaning of comprehensive theory).

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

[...] the staggering complexity and diversity of cellular and developmental regulatory processes. The configuration space for realistic models of such systems is vast, high dimensional, and potentially infinitely complex.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

Today, interest in systems-biology approaches for cell and developmental biology is higher than ever [...]

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Duh! Of course! Apparently they finally woke up to reality! :) Where’s the beef? Dionisio

[...] there is no theory of everything. Instead, perspectivist theories correspond to local models that address a specific problem within a given scope at a given time.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

There is an almost inexhaustible number of possible questions and many possible levels of explanation that complement and inform each other, even though they may never be integrated into a grand unified general theory of evolving developmental systems.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

[...] the complex and historically contingent (and hence messy) nature of developmental evolution makes it absolutely essential to take a pluralistic, pragmatic approach.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

[...] diversity within EvoDevo sometimes impedes communication among practitioners in the field, thus posing a practical problem.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

[...] the main challenge is to find suitable model systems that allow us to combine detailed studies of the mechanisms of development with accessible and informative measures of phenotypic trait variation between closely related species or, even better, between individuals within particular populations.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where’s the beef? Dionisio

The third and last deadlock concerns our difficulty in connecting (macro-)evolutionary comparisons of developmental processes to evolutionary dynamics at the population and species level.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Does this mean they have problems explaining macro-evolution? Maybe the comment @1090 provides a hint? Dionisio

Complications such as homoplasy and system drift are most serious if the comparison is made—as it often is—between relatively distant taxa. A more fine-grained, mechanistic, causal understanding of developmental and evolutionary dynamics will be required to overcome these limitations.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where's the beef? Dionisio

[...] developmental system drift allows conserved networks to change considerably in terms of their component genes and regulatory interactions without changing the phenotypic outcomes such systems produce [...] [...] functionally conserved regulatory networks can become unrecognizably divergent at the molecular and genetic level, especially across large evolutionary time spans.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where's the beef? Dionisio

[...] a common toolkit of genes and signaling pathways is reused over and over again to create a large diversity of different body plans, shapes, and organs [...] [...] similarities in gene expression patterns or morphological structure often do not necessarily imply common ancestry, since they may as well reflect the frequent reuse of the same regulatory or morphogenetic modules.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where's the beef? Dionisio

[...] traditional comparative approaches to the evolution of development—whether focused on the morphological or on the molecular/genetic level—are reaching their limits in terms of explanatory power. The more we learn about the evolution of pattern-forming gene networks, or the ontogeny of complex morphological traits, the more it becomes clear that it is less than straightforward to conclude anything about evolutionary origins or dynamics based on such comparisons alone.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where's the beef? Dionisio

The field of evolutionary developmental biology, or EvoDevo, is experiencing a conceptual crisis on many fronts. One issue is that it is not a unified discipline and its limits are hard to define.

The Comet Cometh: Evolving Developmental Systems Jaeger, J., Laubichler, M. & Callebaut, W. Biol Theory doi:10.1007/s13752-015-0203-5 Volume 10, Issue 1, pp 36–49

Where's the beef? Dionisio

[...] the gain of genes by TGD is more of a flood than a slow drip. Many of the genes generated are rapidly lost, leaving a fraction to be captured for novel roles by natural selection, often through asymmetric divergence.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Dionisio

[...] it will be necessary to deduce how widespread this mode of molecular evolution has been. One future task will be to rigorously examine whether this difference is a general rule [...] [...] a second major task will be to deduce the prevalence of tandem duplication.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Dionisio

There are several routes to gaining genes, including whole-genome duplication (WGD), tandem gene duplication (TGD), segmental duplication (essentially giant multi-gene tandem duplication), retroposition and complex combinations of exon copying, de novo incorporation of non-coding DNA and fusion of mobile genetic elements.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Dionisio

[...] the words ‘predominant’ and ‘largely’ cannot yet be justified, as we do not have a quantitative assessment of the relative roles played by different sorts of mutation across animal evolution.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Dionisio

[...] before the advent of high-throughput transcriptomics and genomics, the dominant techniques for finding genes of interest were biased [...]

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

only those old techniques were biased? could it be that the whole research approach has been and still is biased? otherwise, how could one explain the relatively high frequency of expressions like "surprisingly", "unexpectedly", etc. ? :) Complex complexity. Dionisio

[...] these findings have highlighted the importance of mutations affecting expression of genes, rather than the number of genes or their encoded amino acid sequences.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Well, that seems quite different than what they've been saying for years, doesn't it? Complex complexity. Dionisio

The modularity of cis-regulation, whereby one aspect of expression can be tweaked without affecting other aspects, is key.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Did somebody say "modularity"? :) Complex complexity. Dionisio

[...] there have been several attention-grabbing demonstrations that genes from one species can partially mimic the phenotypic effects of those from another species in transgenic experiments [...] These experiments reveal trans-phyletic conservation of biochemical or cellular function, but they have also been used to give further weight to the idea of a universal toolkit, and hint that important evolutionary changes may not lie within the coding sequences of genes.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Complex complexity. Dionisio

[...] many genes used in development are highly conserved in sequence between disparate taxa (Hox genes, Pax genes, hh genes and many others). This led to the idea of a conserved ‘genetic toolkit’ for development, differing little between animal phyla [...]

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Where's the beef? Complex complexity. Dionisio

One would hope that the two approaches might ultimately converge, but the field is far from that state at present. An over-simplification has crept into the field in evolutionary developmental biology.

New genes from old: asymmetric divergence of gene duplicates and the evolution of development Peter W. H. Holland, Ferdinand Marlétaz, Ignacio Maeso, Thomas L. Dunwell, Jordi Paps DOI: 10.1098/rstb.2015.0480 Philosophical Transactions of the Royal Society B: Biological Sciences Volume 372, issue 1713 Theme issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’ compiled and edited by Cheryll Tickle and Araxi O. Urrutia

Did somebody say "over-simplification"? Does that relate to 'reductionism' or 'bottom-up research'? Multidisciplinary research teams should help to correct that situation. Also humility and open-mind thinking out of biased boxes should come handy. Dionisio

The comprehensive exploration of floral SEP genes can do a great deal to expand the understanding of the genetic basis behind flower development and its prolification in P. mume. This work sets the foundation for further research on the functions of SEP genes during flower organ development. In the future, we will transfer these four genes into A. thaliana to verify their function, which will improve the molecular model of floral organ development.

SEP-class genes in Prunus mume and their likely role in floral organ development Yuzhen Zhou, Zongda Xu, Xue Yong, Sagheer Ahmad, Weiru Yang, Tangren Cheng, Jia Wang, and Qixiang Zhang BMC Plant Biol. 17: 10. doi: 10.1186/s12870-016-0954-6

Work in progress... stay tuned. Dionisio

Flower phylogenetics and genetically controlled development have been revolutionised during the last two decades. However, some of these evolutionary aspects are still debatable. [...] flower development in P. mume might be due to an expression of SEP genes. Our findings can provide a foundation for further investigations of the transcriptional factors governing flower development, their molecular mechanisms and genetic basis.

SEP-class genes in Prunus mume and their likely role in floral organ development Yuzhen Zhou, Zongda Xu, Xue Yong, Sagheer Ahmad, Weiru Yang, Tangren Cheng, Jia Wang, and Qixiang Zhang BMC Plant Biol. 17: 10. doi: 10.1186/s12870-016-0954-6

Work in progress... stay tuned. Dionisio

A major challenge is to understand how conserved gene regulatory networks control the wonderful diversity of form that we see among animals and plants. Butterfly wing patterns are an excellent example of this diversity. Butterfly wings form as imaginal discs in the caterpillar and are constructed by a gene regulatory network, much of which is conserved across the holometabolous insects.

Waiting in the wings: what can we learn about gene co-option from the diversification of butterfly wing patterns? Jiggins CD, Wallbank RW, Hanly JJ Philos Trans R Soc Lond B Biol Sci. 372(1713). pii: 20150485. DOI: 10.1098/rstb.2015.0485

complex complexity Dionisio

Over 2.5 years after this thread was started, it has reached 1,200 posts and 5,200 visits, for a net of 4,000 anonymous visits. i.e. over 3 times more lurking visitors than comments. Not bad for such a boring "nerdy" topic like this. Many thanks to Denyse for writing the interesting OP that started this thread and also -why not?- thanks to the "3rd Way of Evolution" folks for coming up with such an original name for their 'movement'. But primarily and ultimately I thank God for using a nobody like me in order to demonstrate the validity of the following text:

For the word of the cross is folly to those who are perishing, but to us who are being saved it is the power of God. For it is written, “I will destroy the wisdom of the wise, and the discernment of the discerning I will thwart.” Where is the one who is wise? Where is the scribe? Where is the debater of this age? Has not God made foolish the wisdom of the world? For since, in the wisdom of God, the world did not know God through wisdom, it pleased God through the folly of what we preach to save those who believe. For Jews demand signs and Greeks seek wisdom, but we preach Christ crucified, a stumbling block to Jews and folly to Gentiles, but to those who are called, both Jews and Greeks, Christ the power of God and the wisdom of God. For the foolishness of God is wiser than men, and the weakness of God is stronger than men. For consider your calling, [adelphoi]: not many of you were wise according to worldly standards, not many were powerful, not many were of noble birth. But God chose what is foolish in the world to shame the wise; God chose what is weak in the world to shame the strong; God chose what is low and despised in the world, even things that are not, to bring to nothing things that are, so that no human being might boast in the presence of God. And because of Him you are in Christ Jesus, who became to us wisdom from God, righteousness and sanctification and redemption, so that, as it is written, “Let the one who boasts, boast in the Lord.” [1 Corinthians 1:18-31 (ESV)]

Dionisio

The past few years have seen the development of powerful informatic tools for the study of biodiversity that were unimaginable only a decade ago. These developments are not trivial in that biodiversity data on the global scale now being collected and analyzed are inherently complex. [...] tool development for biodiversity science is in its infancy and generally does not yet scale as needed. Moreover, extensive trait information [...] remains ‘trapped’ in metadata and images of natural history collections, and our ability to extract these data is limited. New training that integrates domain knowledge in biodiversity and data science skills is needed to accelerate research in these areas.

Mobilizing and integrating big data in studies of spatial and phylogenetic patterns of biodiversity Douglas E. Soltis, Pamela S. Soltis Plant Diversity Volume 38, Issue 6, Pages 264–270 DOI: http://dx.doi.org/10.1016/j.pld.2016.12.001

Oh, well, what else is new? The usual politically-correct pseudoscientific jargon is sprinkled all over the text of this otherwise interesting paper, which obviously doesn't attempt to answer the fundamental question for evo-devo voodoo stuff: where's the beef? :) Conclusion: Complex complexity. :) Dionisio

The Open Tree of Life https://blog.opentreeoflife.org/ [...] much of the tree is poorly resolved, reflecting both conflict among source trees and the use of taxonomy for placing the 80% of the tree that lacks DNA sequence data [...]

Mobilizing and integrating big data in studies of spatial and phylogenetic patterns of biodiversity Douglas E. Soltis, Pamela S. Soltis Plant Diversity Volume 38, Issue 6, Pages 264–270 DOI: http://dx.doi.org/10.1016/j.pld.2016.12.001

Complex complexity. :) Dionisio

Recent developments in phylogenetics coupled with emerging cyberinfrastructure and new data sources provide unparalleled opportunities for mobilizing and integrating massive amounts of biological data, driving the discovery of complex patterns and new hypotheses for further study. These developments are not trivial in that biodiversity data on the global scale now being collected and analyzed are inherently complex. [...] extracting biological knowledge from the large and complex datasets that will be gathered to facilitate this progress will require highly integrated and powerful tools [...]

Mobilizing and integrating big data in studies of spatial and phylogenetic patterns of biodiversity Douglas E. Soltis, Pamela S. Soltis Plant Diversity Volume 38, Issue 6, Pages 264–270 DOI: http://dx.doi.org/10.1016/j.pld.2016.12.001

Complex complexity. :) Dionisio

A more fully elucidated evolutionary history of Pentapetalae will, therefore, require the integration of these taxa into several facets of contemporary biological research, including phylogenetics, genomics and functional genetics, which probe the relationships between WGDs, gene duplication, sub- or neofunctionalization, morphological novelty, ecological opportunity and biological radiations.

Evolution of floral diversity: genomics, genes and gamma Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Douglas E. Soltis and Pamela S. Soltis Philosophical Transactions of The Royal Society B Biological Sciences DOI: 10.1098/rstb.2015.0509

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Why are some scientists having so much trouble looking at beautiful flowers? :) Dionisio

The flowering plants (angiosperms) constitute the largest and most diverse extant group of the plant kingdom. The precipitous origin and rapid diversification of flowering plants was famously referred to as an ‘abominable mystery’ by Charles Darwin because their rapid appearance contradicted his gradualist view of evolutionary change.

Evolution of floral diversity: genomics, genes and gamma Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Douglas E. Soltis and Pamela S. Soltis Philosophical Transactions of The Royal Society B Biological Sciences DOI: 10.1098/rstb.2015.0509

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Why are some scientists having so much trouble looking at beautiful flowers? :) Dionisio

A salient feature of flowering plant diversification is the emergence of a novel suite of floral features coinciding with the origin of the most species-rich lineage, Pentapetalae. [...] the phylogenetic timing, mechanistic details and molecular evolutionary consequences are as yet not fully resolved. Investigations of these changes associated with the origin of Pentapetalae can lead to a more comprehensive understanding of what is arguably one of the most important evolutionary diversification events within terrestrial plants.

Evolution of floral diversity: genomics, genes and gamma Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Douglas E. Soltis and Pamela S. Soltis Philosophical Transactions of The Royal Society B Biological Sciences DOI: 10.1098/rstb.2015.0509

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Why are some scientists having so much trouble looking at beautiful flowers? :) Dionisio

The development of these approaches would rapidly elucidate evolutionary changes in the regulatory networks underlying floral development.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Dionisio

The development of these systems will herald a new generation of multidisciplinary evo-devo research during which many new plant systems can be the focus of study—species that afford the opportunity to address questions of floral evolution and organization that cannot be addressed with the current set of model systems.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Dionisio

To advance from a comparative approach based on candidate genes to a more mechanistic account of floral diversity, the establishment of collections of mutant phenotypes in phylogenetically relevant nonmodel plant species would be especially valuable.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Yes, that’s fine, but don’t forget to answer the most fundamental question for the evo-devo voodoo stuff: https://www.youtube.com/embed/Ug75diEyiA0 BTW, the comment @1090 may provide a useful hint. Dionisio

Elucidation of the genetic programs of flowers that appear to represent intermediate steps in the transition from bisexual cone to flower, as seen in basal angiosperms and basal eudicots [...] is pivotal to understanding the origin and evolution of flowers, and floral diversification generally. To address such questions, new evolutionary model systems among the basal angiosperms and basal eudicots are necessary.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Yes, that's fine, but don't forget to answer the most fundamental question for the evo-devo folks: https://www.youtube.com/embed/Ug75diEyiA0 The comment @1090 may provide a hint. Dionisio

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

BTW, at the end of the day, when all has been said, after Cinderella recovers her lost slipper (was it the right or the left one?), plants remain plants, flowers remain flowers (at least before they turn into fruits). Birds remain birds (yes, including the cool Galapagos finch), fish remain fish, bacteria remain bacteria, mammals remain mammals, and so on. And humans remain humans, although eventually they might transform themselves into cool robots. :) Conclusion: complex complexity on steroids. And for the evo-devo folks, the most fundamental question they must answer is: where's the beef? :) Dionisio

Studies of model clades therefore could rapidly provide clues about the genetic basis of evolutionary change that would not be achievable via the analysis of a single species from that clade. NGS technology can thus be applied to generate the data required to characterize floral GRNs; these GRNs, in turn, can be compared to identify candidate regulatory changes underlying floral evolutionary shifts. Efforts to develop such integrative research programs are needed.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Great! Let’s look forward, with increasing anticipation, to reading future research papers describing new discoveries that shed more light on the elaborate molecular and cellular choreographies orchestrated within the biological systems. Can’t wait for that! As more discoveries are made, the big picture gets clearer and the observed complex complexity turns more complex. While some outstanding questions get answered, new issues appear. Dionisio

[...] technological advances such as translating ribosome affinity purification (TRAP) (Jiao and Meyerowitz 2010) promise even greater resolution in the future (Ó’Maoiléidigh et al. 2014). Improved knowledge of GRNs involved in floral organ identity, symmetry, cell type, floral color, and synorganization has become more attainable with technological advances in recent years, and further clarification of GRNs should be a goal in the study of flower developmental genetics.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Great! Let’s look forward, with increasing anticipation, to reading future research papers describing new discoveries that shed more light on the elaborate molecular and cellular choreographies orchestrated within the biological systems. Can’t wait for that. ???? As more discoveries are made, the big picture gets clearer and the observed complex complexity turns more complex. While some outstanding questions get answered, new issues appear. Dionisio

It is now possible to obtain enormous amounts of genomic and transcriptomic sequence data for virtually any plant system that poses intriguing evolutionary questions and to do so at low cost. [...] technological advances provide unprecedented research opportunities to characterize and compare floral genetic programs to elucidate the genetic basis of novel floral ground plans. Toward this end, investigations of developmental gene regulatory networks (GRNs) that underlie floral diversity will be equally as valuable.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Great! Let's look forward, with increasing anticipation, to reading future research papers describing new discoveries that shed more light on the elaborate molecular and cellular choreographies orchestrated within the biological systems. Can't wait for that. :) As more discoveries are made, the big picture gets clearer and the observed complex complexity turns more complex. While some outstanding questions get answered, new issues appear. Apparently some reductionist bottom-up reverse-engineering approaches produce more "unexpected" and "surprising" discoveries in the peer-reviewed articles. However, perhaps some folks prefer the unknowns to remain unknown, so that their "just so" pseudoscientific nonsense stories continue to sell in the marketplace. :) Poor things. Science seems moving faster these days, bringing more exciting news from the research leading edge front. :) Dionisio

[...] after a functional flower evolved, genetic innovations continued as new genes originated and/or were recruited into floral genetic programs.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Did somebody say "programs"? :) Dionisio

[...] there appears to have been a shift from the fading borders model of floral developmental gene expression of basal angiosperms and basal eudicots to the canalized ABCE model in Pentapetalae (Chanderbali et al. 2009, 2010; Voelckel et al. 2010; Yoo et al. 2010b), but the precise phylogenetic location of this transition is uncertain.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Really?! :) Where’s the beef? Dionisio

Independent studies have identified three evolutionary events that correspond closely with the origin of Pentapetalae, but their precise roles are unclear.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Really?! :) Where’s the beef? Dionisio

The genetic basis for the origin of this canonical floral ground plan represents one of the major unresolved mysteries of flowering plant evolution.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Really?! :) Where’s the beef? Dionisio

I just didn't want Dionisio to feel lonely. Hi Dionisio. Darwins_downfall

The origin of the flower was a key innovation in the history of complex organisms, dramatically altering Earth’s biota. [...] crucial aspects of floral evolution remain, such as the series of genetic and morphological changes that gave rise to the first flowers; the factors enabling the origin of the pentamerous eudicot flower, which characterizes ?70% of all extant angiosperm species; and the role of gene and genome duplications in facilitating floral innovations. We predict that new evolutionary models will soon emerge as genetic/genomic models, providing unprecedented new insights into floral evolution.

Evolving Ideas on the Origin and Evolution of Flowers: New Perspectives in the Genomic Era Andre S. Chanderbali, Brent A. Berger, Dianella G. Howarth, Pamela S. Soltis and Douglas E. Soltis Genetics. 202(4): 1255–1265. doi: 10.1534/genetics.115.182964

Where’s the beef? Dionisio

[...] it is still unclear whether new mutation or selection on standing genetic variation plays a more important role in stickleback evolution [...] A major challenge for the future is to identify the genes and mutations that underlie additional phenotypic traits in sticklebacks. [...] in most cases, the fitness effects and, therefore, adaptive significance of these genotypes and phenotypes are unknown. Ultimately, combining these approaches will allow us to make connections between genotypes, phenotypes and fitness, to provide a more holistic understanding of the genetic basis of adaptation.

The genetic and molecular architecture of phenotypic diversity in sticklebacks. Peichel CL, Marques DA Philos Trans R Soc Lond B Biol Sci. 372(1713). pii: 20150486. DOI: 10.1098/rstb.2015.0486

See comments @1175. Where’s the beef? Dionisio

A major goal of evolutionary biology is to identify the genotypes and phenotypes that underlie adaptation to divergent environments. [...] mutations in regulatory elements play an important role in the evolution of phenotypic diversity in sticklebacks. [...] the same loci are involved about half of the time when the same phenotypes evolve independently.

The genetic and molecular architecture of phenotypic diversity in sticklebacks. Peichel CL, Marques DA Philos Trans R Soc Lond B Biol Sci. 372(1713). pii: 20150486. DOI: 10.1098/rstb.2015.0486

See comments @1175. Where’s the beef? Dionisio

A recurring theme to emerge from more recent studies in basal land plant lineages such as liverworts and mosses is that antagonistic gene functions arise following duplication. The mechanisms by which such antagonistic transcription factor functions emerge are not yet clear but are accessible to experimental interrogation.

Development and genetics in the evolution of land plant body plans C. Jill Harrison Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150490. doi: 10.1098/rstb.2015.0490

Where’s the beef? Dionisio

The colonization of land by plants shaped the terrestrial biosphere, the geosphere and global climates. The nature of morphological and molecular innovation driving land plant evolution has been an enigma for over 200 years. Reverse and forward genetic approaches in newly emerging model systems are starting to identify the genetic basis of such innovations. The data place plant evo-devo research at the cusp of discovering the developmental and genetic changes driving the radiation of land plant body plans.

Development and genetics in the evolution of land plant body plans C. Jill Harrison Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150490. doi: 10.1098/rstb.2015.0490

Where’s the beef? Dionisio

@1169-1174: Where's the beef? They should take a look at the explanation posted @1090. https://uncommondescent.com/evolution/a-third-way-of-evolution/#comment-621816 Dionisio

@1169-1174: Where's the beef? Gross extrapolation of a built-in adaptability framework onto nonsensical macro-evolutionary la-la-land pie-pie-in-the-sky daydreaming hogwash. Pathetic. They're describing the results of adaptation processes benefiting from the built-in framework within the biological systems that allow robustness and plasticity through changes and adjustments to the components, but the design principles remain the same. It happens in technology. Terms like modularity and scalability come to mind, don’t they? Automobile companies produce different models within a range of types like SUV, trucks, sedans, sport two-doors, convertibles, and the whole nine yard. They have to introduce changes in the production line, which is designed for those changes. But at the end of the day cars remain cars. Now, we have seen other means of transportation too: airplanes, submarines, drones like the eHang, etc. All designed. Dionisio

Comparative studies on living organisms can be complemented by the fossil record and the way in which knowledge both from studies on fossils and existing organisms is being synthesized to understand how particular morphologies might have evolved is illustrated in many of the articles in this issue [...]

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

Where's the beef? Dionisio

The articles in this issue illustrate beautifully (in some cases, quite literally!) the magnificent range of morphologically diverse living organisms being studied in the current evo-devo research landscape (figure 1). It is no accident that many are those that fascinated and intrigued Darwin—such the finch species of the Galapagos islands and the different breeds of dog.

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

Duh! Big deal! Finches remain finches and dogs remain dogs. Where's the beef? Dionisio

Such studies, together with comparative genomics, hold out the promise of identifying the genetic basis for human-specific morphology [...] A long-standing question is whether evolution is based on changes in a few genes that have a large effect or on a combination of changes in many genes that each has a small effect.

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

Where's the beef? Dionisio

Development is central to understanding the origins of morphological diversity because it is the means by which the genetic information of an organism is translated into morphology.

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

Duh! What else is new? Where's the beef? Dionisio

How the extraordinary range of different organisms of all shapes and sizes evolved is such a big question because it brings together many different fields of biology, including evolutionary biology, palaeontology, comparative anatomy and embryology, genetics and genomics.

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

Still struggling with that question? Get a life! :) Where's the beef? Dionisio

A fundamental question in biology is how the extraordinary range of living organisms arose. Development is central because it is the means by which genetic information of an organism is translated into morphology.

Perspectives on the history of evo-devo and the contemporary research landscape in the genomics era Cheryll Tickle and Araxi O. Urrutia Philos Trans R Soc Lond B Biol Sci. 372(1713): 20150473. doi: 10.1098/rstb.2015.0473

A fundamental question in biology is how the living organisms develop and function. Where's the beef? Dionisio

This finding is conceivable with a function of LWS2 other than vision [37, 38], another alternative is that observed level of expression represents transcriptional noise. The retrotransposed opsins are expressed as results of transcriptional activity in the new genomic location. However, additional experiments would be necessary to clarify between the competing hypothesis. [...] the intact ORF, [...] the phylogenetic conservation and expression independently suggests that LWS2 opsins are functional.

Functional opsin retrogene in nocturnal moth Pengjun Xu, Roberto Feuda, Bin Lu, Haijun Xiao, Robert I. Graham, and Kongming Wu Mob DNA. 7: 18. doi: 10.1186/s13100-016-0074-8

Where's the beef? Complex complexity. Dionisio

[...] surprisingly, LWS2 in 1st-instar larvae has an higher relative level of expression compared to the other three opsins (Fig. 2b). The reasons for higher level of expression of LWS2 at the 1st-instar larvae are unclear.

Functional opsin retrogene in nocturnal moth Pengjun Xu, Roberto Feuda, Bin Lu, Haijun Xiao, Robert I. Graham, and Kongming Wu Mob DNA. 7: 18. doi: 10.1186/s13100-016-0074-8

Where's the beef? Complex complexity. Dionisio

Regarding the preceding few posts in this thread: Disney’s stories were more entertaining or at least less boring:

While Cinderella was working, the mice and birds fixed her dress. They added ribbons and beads that the two stepsisters had thrown away. Working together, the animals turned a simple dress into a fabulous gown! Cinderella was overjoyed when she saw the dress. Now she could go to the ball!

[oops, that didn’t work] [let’s give it another try]

Cinderella ran away to the garden to cry. Suddenly, her fairy godmother appeared. With a wave of her wand, she turned a pumpkin into an elegant coach. Cinderella could now go to the ball, but her dress was still ruined. “Bibbidi-bobbidi-boo!” said the Fairy Godmother[*], waving her wand again. Cinderella was now wearing a beautiful gown and sparkling glass slippers.

that worked!!! (*) actually in the story narrated in the referenced paper there were two cool fairies known as Ran Mut and Nat Sel (they worked together, along with the mice, the talking cricket, the pumpkins and the whole nine yard). Dionisio

[...] brain evolution cannot be fully understood through developmental, anatomical, functional, or behavioral perspectives alone. This is because we need to combine such approaches to reach a comprehensive understanding of the genetic and epigenetic mechanisms generating developmental variability, in concert with the selective pressures exerted by the ecological and behavioral conditions animals face to successfully reproduce. Given this background, brain evolution is subject to conserved processes to which contingent adaptations are added, that may leave enduring marks in subsequent evolutionary modifications (like isocortical lamination). On the other hand, there are also conserved requirements for proper brain function and for the generation of complex perception and behavior that shape circuit and network architecture in similar ways in different lineages.

Olfaction, navigation, and the origin of isocortex Francisco Aboitiz1,* and Juan F. Montiel Front Neurosci. 9: 402. oi: 10.3389/fnins.2015.00402

Where’s the beef? Complex complexity. PS. One has to admit that these folks have prolific imaginations. They could easily write fiction book bestsellers. :) Dionisio

[...] we can speculate that increasing somatosensory sensitivity in the mouth, the elaboration of direct motor cortical control of the forepaws (which is more pronounced in digging mammals; Heffner and Masterton, 1983), the development of eyelids and even possibly the loss of scales (for example the naked mole rat; Dhouailly, 2009) may be consequences of another early, burrowing “bottleneck” beside the nocturnal adaptations, that yielded profound modifications in these animals.

Olfaction, navigation, and the origin of isocortex Francisco Aboitiz1,* and Juan F. Montiel Front Neurosci. 9: 402. oi: 10.3389/fnins.2015.00402

Of course they can speculate. That's what they've done many times anyway. Where’s the beef? Complex complexity. Dionisio

Mammals are the descendants of one of the two main amniote clades that colonized the ground by developing an egg that could be laid outside of water. This spectacular innovation yielded two lineages that diverged very early and underwent parallel histories since [...]

Olfaction, navigation, and the origin of isocortex Francisco Aboitiz1,* and Juan F. Montiel Front Neurosci. 9: 402. oi: 10.3389/fnins.2015.00402

just that simple? ???? that's pseudoscientific hogwash. Where’s the beef? what about the spatiotemporal mechanisms that determined the production/transportation of the right stuff in the right amount in/to the right location at the right time? Complex complexity. Dionisio

In line with these arguments, Lewitus et al. (2014) have recently proposed that the ancestor of crown mammals might have had a gyrencephalic brain with a well differentiated isocortex, which would imply that the origin of isocortex is to be traced back to earlier mammalian groups, possibly living in the Jurassic period (Luo, 2007; Lee and Beck, 2015).

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

just that simple? :) Where's the beef? what about the spatiotemporal mechanisms that determined the production/transportation of the right stuff in the right amount in/to the right location at the right time? Complex complexity. Dionisio

[...] the origin of the mammalian brain relies on the amplification of several morphogenetic centers that participate in patterning the dorsal cerebral hemisphere or pallium. [...] mammals underwent a diverging trend by, in addition, enhancing the activity of dorsomedial and anterior telencephalic signaling centers (the anterior forebrain and the cortical hem, respectively) that, together with the proliferation of reelin-producing Cajal-Retzius cells, induced a laminar arrangement and a characteristic pyramidal cell shape for excitatory neurons in the medial and dorsal pallium (note that a rudimentary laminar arrangement of pyramidal cells already exists in the cortex of reptiles and in the olfactory cortex of mammals).

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

just that simple? :) Where's the beef? what about the spatiotemporal mechanisms that determined the production/transportation of the right stuff in the right amount in/to the right location at the right time? Complex complexity. Dionisio

[...] the orchestration and partial overlap of dorsal, lateral and anterior patterning centers gave rise to the laminated mammalian isocortex as an expansion of the dorsal pallial field.

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

Where's the beef? Complex complexity. Dionisio

According to a developmental perspective, brain homologies across vertebrates are supported by anatomical topographic correspondence and embryonic expression of homeobox and homeobox-like genes. However, species-specific pallial morphology and global gene expression patterns exhibit important dissimilarities at adult stages that would be explained by changes in the differential modulation of pallial developmental programs.

Pallial patterning and the origin of the isocortex Juan F. Montiel and Francisco Aboitiz Front Neurosci. 9: 377. doi: 10.3389/fnins.2015.00377

Where's the beef? Complex complexity. Dionisio

A key question to answer will be whether the process of neurogenesis by NPCs in the developing human neocortex is just quantitatively different from that of non-human primates, or features qualitative, albeit subtle, changes.

Human-specific genomic signatures of neocortical expansion Marta Florio1, V?´ctor Borrell and Wieland B Huttner Current Opinion in Neurobiology 2017, 42:33–44 DOI: http://dx.doi.org/10.1016/j.conb.2016.11.004

Perhaps a key question to answer about this and other evo-devo papers is: "Where's the beef?" Complex complexity. Dionisio

[...] it should be a rewarding challenge to determine which changes in our genome are actually responsible for the evolutionary expansion of the human neocortex.

Human-specific genomic signatures of neocortical expansion Marta Florio1, V?´ctor Borrell and Wieland B Huttner Current Opinion in Neurobiology 2017, 42:33–44 DOI: http://dx.doi.org/10.1016/j.conb.2016.11.004

Where's the beef? isn't that what they've been trying to do all these years? why is it taking them so long to figure it out? BTW, it's not only determining which changes did the trick, but how you get those changes. Complex complexity. Dionisio

The human-specific signatures pertaining to gene regulatory elements, non-coding gene products, and protein-encoding genes that have been identified over the last few years offer exciting prospects to elucidate, in a mechanistic manner, the genomic basis of the evolutionary expansion of the human neocortex.

Human-specific genomic signatures of neocortical expansion Marta Florio1, V?´ctor Borrell and Wieland B Huttner Current Opinion in Neurobiology 2017, 42:33–44 DOI: http://dx.doi.org/10.1016/j.conb.2016.11.004

huh? say what? Where's the beef? Complex complexity. Dionisio

Neocortex size is primarily determined by the extent of neurogenesis during fetal development. [...] the molecular evolution of their regulatory mechanisms may have been key in human neocortex expansion and folding. [...] an ancestral network of genes regulating aRG proliferation might have been adapted in humans to also support bRG proliferation. Regulators of cell cycle and neurogenesis were enriched among the targets of these miRNAs. FOXP2 evolution may have also contributed to human-specific aspects of neocortical expansion. It can be anticipated that studying other human-specific copy-number variants [82] operating during cortical neurogenesis will be a worthwhile future effort. [...] FOXP2 evolution may have also contributed to human-specific aspects of neocortical expansion.

Human-specific genomic signatures of neocortical expansion Marta Florio1, V?´ctor Borrell and Wieland B Huttner Current Opinion in Neurobiology 2017, 42:33–44 DOI: http://dx.doi.org/10.1016/j.conb.2016.11.004

Where's the beef? Complex complexity. Dionisio

Several technological advances will further our efforts to gain insight into the molecular basis underlying cortical expansion. [...] complementing experimental data sets based on transcriptomics, live imaging, histology and cell cycle analyses with mathematical modeling is likely to contribute further conceptual insight into the principles underlying cortical expansion. [...] a promising platform has been established to gain a comprehensive and integrative understanding of the molecular basis that underlies the evolutionary expansion of the human neocortex and that provides a framework for our cognitive abilities.

Neural progenitor cells and their role in the development and evolutionary expansion of the neocortex Takashi Namba, Wieland B. Huttner DOI: 10.1002/wdev.256 WIREs Dev Biol 2017, 6:e256. Wiley Interdisciplinary Reviews: Developmental Biology

Where’s the beef? Complex complexity. Dionisio

These provide future avenues for uncovering the molecular basis of cortical expansion. The brain is the most complex organ in our body. With regard to the diversity of cell types, the cytoarchitecture and neural circuitry, this complexity is greatest in the neocortex, the seat of higher cognitive functions. [...] many researchers are fascinated by a fundamental question in neuroscience: how does the neocortex expand in development and evolution?

Neural progenitor cells and their role in the development and evolutionary expansion of the neocortex Takashi Namba, Wieland B. Huttner DOI: 10.1002/wdev.256 WIREs Dev Biol 2017, 6:e256. Wiley Interdisciplinary Reviews: Developmental Biology

Where’s the beef? Complex complexity. Dionisio

We conclude that repressive motifs are strongest next to cryptic exons and that gradual weakening of these motifs contributes to the evolutionary emergence of new alternative exons. Further studies of NMD-inhibitory sequences may help to understand why so many PTC+ transcripts evade NMD. [...] it will require further studies to fully unravel these more complex regulatory networks. Unravelling the coupling of negative and positive splicing elements at cryptic exons would thus help to understand how mutations within the vast intronic regions of our genes cause disease.

Splicing repression allows the gradual emergence of new Alu-exons in primate evolution Jan Attig, Igor Ruiz de los Mozos, Nejc Haberman, Zhen Wang, Warren Emmett, Kathi Zarnack, Julian König and Jernej Ule eLife. 5: e19545. doi: 10.7554/eLife.19545

Where's the beef? Dionisio

[...] the functions of the DE [differentially expressed] genes need to be elucidated for further discussion.

Experimental Approach Reveals the Role of alx1 in the Evolution of the Echinoderm Larval Skeleton Hiroyuki Koga, Haruka Fujitani, Yoshiaki Morino, Norio Miyamoto, Jun Tsuchimoto, Tomoko F. Shibata, Masafumi Nozawa, Shuji Shigenobu, Atsushi Ogura, Kazunori Tachibana, Masato Kiyomoto, Shonan Amemiya and Hiroshi Wada PLoS One. 11(2): e0149067. doi: 10.1371/journal.pone.0149067

there yet? :) nope. bottom-up reverse engineering of a top-down designed system? unending revelation of the ultimate reality (c) work in progress... stay tuned. Dionisio

alx is deeply involved in the formation of two novel structures: the larval skeleton and the calcareous skeleton per se. [...] multiple steps (at least three steps) of gene co-option are required for the acquisition of larval skeleton. Although the activation of several upstream regulators, including Alx1 and VEGF signaling, can account for a modular heterochronic activation of adult skeletogenic GRN, it is not certain whether these trans changes are sufficient for the acquisition of the larval skeleton. Further elucidation of the mechanisms of both adult and larval skeletogenesis among echinoderms will provide greater insight into the processes involved in the acquisition of the larval skeleton.

Experimental Approach Reveals the Role of alx1 in the Evolution of the Echinoderm Larval Skeleton Hiroyuki Koga, Haruka Fujitani, Yoshiaki Morino, Norio Miyamoto, Jun Tsuchimoto, Tomoko F. Shibata, Masafumi Nozawa, Shuji Shigenobu, Atsushi Ogura, Kazunori Tachibana, Masato Kiyomoto, Shonan Amemiya and Hiroshi Wada PLoS One. 11(2): e0149067. doi: 10.1371/journal.pone.0149067

gene co-option? huh? say what? :) Where’s the beef? [emphasis added] Dionisio

The current diversity in animal morphology has resulted from the gradual acquisition of novel structures and, occasionally, the loss of existing structures. Despite recent advances in evolutionary developmental biology, the mechanisms by which animals acquire novel structures remain poorly understood.

Experimental Approach Reveals the Role of alx1 in the Evolution of the Echinoderm Larval Skeleton Hiroyuki Koga, Haruka Fujitani, Yoshiaki Morino, Norio Miyamoto, Jun Tsuchimoto, Tomoko F. Shibata, Masafumi Nozawa, Shuji Shigenobu, Atsushi Ogura, Kazunori Tachibana, Masato Kiyomoto, Shonan Amemiya and Hiroshi Wada PLoS One. 11(2): e0149067. doi: 10.1371/journal.pone.0149067

Where’s the beef? Dionisio

Zika https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192383/pdf/viruses-08-00322.pdf Had we remained in Eden none of this would have been an issue. Too late now. Dionisio

Determining the validity of this general model will require characterizing the molecular-functional evolution of RLRs across a broader range of ligands and over a larger slice of evolutionary history. Testing generalizability will also require mechanistic investigations of the evolution of other immune receptors. Characterizing a large number of receptor-ligand systems is expected to provide important clues about the specific aspects of pathogen-receptor interactions of primary importance in evolutionary history, advancing our understanding of host-pathogen interactions in particular as well as molecular-evolutionary theory in general.

Resurrecting ancestral structural dynamics of an antiviral immune receptor: adaptive binding pocket reorganization repeatedly shifts RNA preference Charles Pugh, Oralia Kolaczkowski, Austin Manny, Bryan Korithoski, and Bryan Kolaczkowski BMC Evol Biol. 16: 241. doi: 10.1186/s12862-016-0818-6

Where's the beef? Dionisio

[...] the exact ligands recognized by modern human RLRs are still unclear [...] Although these studies can shed light on the structural and molecular-functional evolution of immune receptors, it is not possible to confidently infer specific properties of ancient viruses based on limited analyses of receptor-RNA interactions. Making sense of the functional evolution of RLRs and other immune receptors will ultimately require considering the full breadth of molecular interactions determining a receptor’s cellular function. While speculative, we feel our results may reflect general differences in the evolutionary dynamics of immune receptors, compared to those of proteins involved in more stable biological processes.

Resurrecting ancestral structural dynamics of an antiviral immune receptor: adaptive binding pocket reorganization repeatedly shifts RNA preference Charles Pugh, Oralia Kolaczkowski, Austin Manny, Bryan Korithoski, and Bryan Kolaczkowski BMC Evol Biol. 16: 241. doi: 10.1186/s12862-016-0818-6

Where's the beef? Dionisio

Changes in regulatory gene interactions during development play a major role in the evolution of phenotypic differences between species. Yet how these regulatory changes are positioned, facilitated, and constrained within the context of broader gene regulatory networks (GRNs) remains a largely unresolved question for both evolutionary and developmental biologists. Comparative network analysis can thus provide a valuable framework to guide future empirical studies that investigate the functional impact of specific regulatory changes on the development of derived traits [...] Integrating tissue-specific samples and additional time-points will help to alleviate this issue in future investigations.

Comparative Developmental Transcriptomics Reveals Rewiring of a Highly Conserved Gene Regulatory Network during a Major Life History Switch in the Sea Urchin Genus Heliocidaris Jennifer W. Israel, Megan L. Martik, Maria Byrne, Elizabeth C. Raff, Rudolf A. Raff, David R. McClay and Gregory A. Wray PLoS Biol. 14(3): e1002391. doi: 10.1371/journal.pbio.1002391

Parole, parole, parole… Where’s the beef? Dionisio

Although the evolution of lecithotrophy involved substantial changes to larval development and morphology, it is not known to what extent changes in gene expression underlie the developmental differences between species, nor do we understand how these changes evolved within the context of the well-defined gene regulatory network (GRN) underlying sea urchin development. [...] distinct evolutionary processes operate on gene expression during periods of life history conservation and periods of life history divergence, and that this contrast is even more pronounced within the GRN than across the transcriptome as a whole.

Comparative Developmental Transcriptomics Reveals Rewiring of a Highly Conserved Gene Regulatory Network during a Major Life History Switch in the Sea Urchin Genus Heliocidaris Jennifer W. Israel, Megan L. Martik, Maria Byrne, Elizabeth C. Raff, Rudolf A. Raff, David R. McClay and Gregory A. Wray PLoS Biol. 14(3): e1002391. doi: 10.1371/journal.pbio.1002391

Parole, parole, parole… Where’s the beef? Dionisio

We have shown here that, apart from a conserved core of mostly transcription factors, the GRNs for DV patterning and early morphogenesis have diverged significantly between the wasp Nasonia and the fly Drosophila. This fits well with the observations that both the upstream patterning networks, and the downstream morphogenetic events of gastrulation are quite divergent. At present we cannot tell which network is more representative of the ancestral state of the Holometabola, or indeed whether they are both highly divergent. With the advent of increasingly cost-effective large-scale sequencing technologies, and broadly applicable functional approaches, many more taxa can be sampled and characterized at a deep level. This should allow hypothesis of the pattern and direction of phylogenetic change to be tested robustly. Our observation that many lineage restricted genes have been incorporated into the Nasonia DV GRN raises the question of whether such novelty is a common feature of developmental patterning systems, and what role, if any, natural selection plays in setting up the early body plan. Again, broad and deep sampling of taxa at varying phylogenetic distances can shed light on this question and should be a high priority research area where insects can make a uniquely powerful contribution.

Global analysis of dorsoventral patterning in the wasp Nasonia reveals extensive incorporation of novelty in a regulatory network Daniel Pers,1 Thomas Buchta,2 Orhan Özüak,2 Selma Wolff,2 Jessica M. Pietsch,2 Mohammad Bilal Memon,1 Siegfried Roth,2 and Jeremy A. Lynch BMC Biol. 14: 63. doi: 10.1186/s12915-016-0285-y

Parole, parole, parole... Where’s the beef? Dionisio

Patterning and morphogenetic processes in developmental systems rely on the underlying activity of gene regulatory networks (GRNs) [1]. Changes in these networks can lead to new developmental outputs (morphologies, cell types) and thus understanding how these networks vary across phylogenies is critical to understanding the evolution of development [2]. To understand evolutionary variation in GRNs, a comparative approach must be taken. In addition, the networks to be compared must be understood at a high level of detail and completeness if the comparisons are to be robust and valuable sources of evolutionary insight [3]. The embryonic dorsoventral (DV) patterning network of Drosophila melanogaster is one of the few GRNs that are understood well enough to serve as a basis for comparative analysis.

Global analysis of dorsoventral patterning in the wasp Nasonia reveals extensive incorporation of novelty in a regulatory network Daniel Pers,1 Thomas Buchta,2 Orhan Özüak,2 Selma Wolff,2 Jessica M. Pietsch,2 Mohammad Bilal Memon,1 Siegfried Roth,2 and Jeremy A. Lynch BMC Biol. 14: 63. doi: 10.1186/s12915-016-0285-y

Where’s the beef? Dionisio

Gene regulatory networks (GRNs) underlie developmental patterning and morphogenetic processes, and changes in the interactions within the underlying GRNs are a major driver of evolutionary processes. In order to make meaningful comparisons that can provide significant insights into the evolution of regulatory networks, homologous networks from multiple taxa must be deeply characterized. One of the most thoroughly characterized GRNs is the dorsoventral (DV) patterning system of the Drosophila melanogaster embryo.

Global analysis of dorsoventral patterning in the wasp Nasonia reveals extensive incorporation of novelty in a regulatory network Daniel Pers,1 Thomas Buchta,2 Orhan Özüak,2 Selma Wolff,2 Jessica M. Pietsch,2 Mohammad Bilal Memon,1 Siegfried Roth,2 and Jeremy A. Lynch BMC Biol. 14: 63. doi: 10.1186/s12915-016-0285-y

Where’s the beef? Dionisio

Bone Morphogenetic Proteins (BMPs) pattern the dorsal-ventral axis of bilaterian embryos; however, their roles in the evolution of body plan are largely unknown. Here we show that the differences in gradient dynamics and tissue specification result from evolutionary changes in the gene regulatory network that controls the activity of a positive feedback circuit on BMP signaling, involving the tumor necrosis factor alpha homolog eiger. These data illustrate an evolutionary mechanism by which spatiotemporal changes in morphogen gradients can guide tissue complexity.

Functional evolution of a morphogenetic gradient Chun Wai Kwan, Jackie Gavin-Smyth, Edwin L Ferguson, Urs Schmidt-Ott DOI: http://dx.doi.org/10.7554/eLife.20894 eLife 2016

Most recent papers on morphogen gradients state no one* knows exactly how morphogen gradients form and this paper says they know how they evolved? Really? Comparing Megaselia and Drosophila? Don't flies remain flies? You're describing the results of adaptation processes benefiting from the built-in framework within the biological systems that allow robustness and plasticity through changes and adjustments to the components, but the design principles remain the same. Where's the beef? (*) except professor L.M. of the U. of T. Dionisio

Although comparative data are limited, acentriolar spindle assembly pathways likely evolved multiple times in animals, and nearly exclusively for use in oocyte meiosis. This in turn suggests that similar selective pressures may have favored the transition to acentriolar oocyte spindles in these lineages. One adaptive advantage might have been to obviate the bookkeeping involved in sorting centrioles from different sources into polar bodies versus eggs.

Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

An otherwise excellent paper* got this completely unnecessary pseudoscientific nonsense included in its text. Where's the beef? (*) Note this paper referenced in the thread "Mystery at the heart of life" Dionisio

Looking back @914:

Evolutionary problems in centrosome and centriole biology L. Ross and B. B. Normark DOI: 10.1111/jeb.12620 Journal of Evolutionary Biology Volume 28, Issue 5, pages 995–1004

that was then, but what's the news on this topic now? Dionisio

The vertebral column has been underrepresented in the functional morphology and morphometric literature, but recent studies have shown that the vertebral form carries rich developmental and ecomorphological signals. While anterior vertebrae may either have evolved under stronger phylogenetic constraints or are more ecologically conservative, posterior vertebrae show clearer differentiation between ecomorphs in Felidae. Future studies, which may benefit from focusing on a more restricted species range or on smaller vertebral regions, would gain from including vertebrae that were not analysed here in order to compare the general patterns found to specific complete regional trends.

Regional differentiation of felid vertebral column evolution: a study of 3D shape trajectories Marcela Randau, Andrew R. Cuff, John R. Hutchinson, tephanie E. Pierce, Anjali Goswami Org Divers Evol (2016). doi:10.1007/s13127-016-0304-4

[emphasis added] underrepresented? Why? the vertebral form carries rich developmental and ecomorphological signals? Duh! of course! Why did it take them so long to figure out that? Where's the beef? Dionisio

Creativity may be largely about tuning one’s mode of thought in a context-specific manner such that each concept’s halo of potential associations is tuned to match to the specifics of the task and how far along one is in it. To tap into this, it may be necessary to use a new breed of creativity tests that investigate how individuals shift between divergent and convergent modes of thought over the course of a creative task.

The Neural Basis and Evolution of Divergent and Convergent Thought Liane Gabora In O. Vartanian & R. Jung (Eds.) The Cambridge Handbook of the Neuroscience of Creativity. Cambridge MA: Cambridge University Press.

interesting... but a little of "where's the beef?" too. :) Dionisio

Behavior is among the most rapidly evolving and derived traits in the animal kingdom, yet we know very little about the genes, genetic architecture, and evolutionary forces that promote their rapid divergence [...] It is intriguing to think that animal behavior, and its crucial importance to survival and reproduction, is largely driven by a genomic legacy of large yet conserved metazoan genes. With a greater comprehensive knowledge of genomes and their annotated genetic elements, this systems genomics framework provides many exciting new hypotheses to test.

Neurogenomics and the role of a large mutational target on rapid behavioral change Craig E. Stanley Jr. and Rob J. Kulathinal Biology Direct 11:60 DOI: 10.1186/s13062-016-0162-1

Where’s the beef? Dionisio

The diversity of behavioral phenotypes in the animal kingdom range from the subtle and cryptic to the extraordinarily bizarre. Behavioral traits, when compared to morphological, physiological, and life history traits, show relatively little phylogenetic signal [3, 4, 5] owing to behavior’s highly derived and labile nature. In addition, our understanding of the genetic basis of behavior is limited due to polygenic inheritance, our modest understanding of the complex interplay between development and physiology on neural circuitries, and plasticity in gene expression and cellular modeling in the face of variable environments [6, 7].

Neurogenomics and the role of a large mutational target on rapid behavioral change Craig E. Stanley Jr. and Rob J. Kulathinal Biology Direct 11:60 DOI: 10.1186/s13062-016-0162-1

Where’s the beef? Dionisio

Despite the long research on chromosome segregation machinery in eukaryotes, we know little about its evolutionary origins or history. [...] there is little trace of prokaryotic traits in kinetochore proteins, making it difficult to reveal what kind of proteins might have been used to bridge between DNA and tubulin-based polymers in this hypothetical eukaryote. Another difficulty stems from the uncertainty of the position of the root of the eukaryotic tree of life, meaning that we still do not have concrete views about which organisms are the earliest-branching eukaryotes [...] [...] it remains unclear whether the unique kinetoplastid kinetochore represents an ancient feature or a derived one. Genome sequences of other Euglenozoa species might provide further insights into this question.

The unconventional kinetoplastid kinetochore: from discovery toward functional understanding. Akiyoshi B Biochem Soc Trans. 44(5):1201-1217. DOI: 10.1042/BST20160112

Where's the beef? [see more here: https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-622432] Dionisio

Taken together, our results reveal some intricate relationships between structure, folding, function and genetic mechanisms affecting protein repeats. [...] binding proteins relevant for immunity and stress response in Metazoa are sometimes similarly located in genomic regions that are prone to recombination. Further studies are certainly required to investigate in more depth this intertwined relationship between genetic processes and selection pressure on protein repeats.

Evolution of Protein Domain Repeats in Metazoa. Schüler A, Bornberg-Bauer E Mol Biol Evol. 33(12):3170-3182 DOI: 10.1093/molbev/msw194

Complex complexity. Dionisio

Diverse modularity-molding factors such as folding, function, and selection, can have a misleading effect when trying to define a given type of module. It is thus important to keep in mind this complexity when defining modularity in protein structures and interpreting the outcome modularity inference approaches. [...] the question of the emergence and retention of modularity remains an open issue. [...] the diversity and nature of all protein structures cannot be explained exclusively by self-organization since it is obvious that the genetics and cellular machinery provide a template and a set of instructions. Although the emergence of modularity can be intuitively explained, a sound methodology to understand its mechanisms and implications for protein structural biology remains to be explored.

The Semantics of the Modular Architecture of Protein Structures. Hleap JS, Blouin C. Curr Protein Pept Sci. 17(1):62-71. https://www.researchgate.net/profile/Jose_Hleap/publication/282346948_The_Semantics_of_the_Modular_Architecture_of_Protein_Structures/links/568aa34108ae1975839d9983.pdf

Complex complexity. Where’s the beef? Dionisio

The formation of protein structural domains requires that biochemical functions, defined by conserved amino acid sequence motifs, be embedded into a structural scaffold. Remarkably, we find that the emergence of molecular functions induces hierarchical modularity and power law behavior in network evolution as the network of motifs and structures expand metabolic pathways and translation. In order to explain the structural and functional complexities of the protein world, protein domain structure must emerge from prior structural states and must fulfill the principle of spatiotemporal continuity (‘lex continui’ of Leibnitz) that implicitly supports evolution. Thus, the generation of biphasic patterns of change may be a general phenomenon in network biology.

The early history and emergence of molecular functions and modular scale-free network behavior M. Fayez Aziz,1 Kelsey Caetano-Anollés,1 and Gustavo Caetano-Anollés Sci Rep. 6: 25058. doi: 10.1038/srep25058

Complex complexity. Where’s the beef? See comment @1119. Dionisio

Glycyl tRNA synthetase (GlyRS) provides a unique case among class II aminoacyl tRNA synthetases, with two clearly widespread types of enzymes: a dimeric (?2) species present in some bacteria, archaea, and eukaryotes; and a heterotetrameric form (?2?2) present in most bacteria. Although the differences between both types of GlyRS at the anticodon binding domain level are evident, the extent and implications of the variations in the catalytic domain have not been described, and it is unclear whether the mechanism of amino acid recognition is also dissimilar. [...] bacterial GlyRS is closely related to alanyl tRNA synthetase, which led us to define a new subclassification of these ancient enzymes and to propose an evolutionary path of ?2?2 GlyRS, convergent with ?2 GlyRS and divergent from AlaRS, thus providing a possible explanation for the puzzling existence of two proteins sharing the same fold and function but not a common ancestor.

Structural Insights into the Polyphyletic Origins of Glycyl tRNA Synthetases Marco Igor Valencia-Sánchez,‡,1 Annia Rodríguez-Hernández,‡§,2 Ruben Ferreira,¶ Hugo Aníbal Santamaría-Suárez,‡ Marcelino Arciniega,‡ Anne-Catherine Dock-Bregeon,? Dino Moras,** Brice Beinsteiner,** Haydyn Mertens,‡‡ Dmitri Svergun,‡‡ Luis G. Brieba,§ Morten Grøtli,¶ and Alfredo Torres-Larios J Biol Chem. 291(28): 14430–14446. doi: 10.1074/jbc.M116.730382

Complex complexity. Where’s the beef? See comment @1119. Dionisio

Maintenance of chromosomal integrity is required for the survival of all organisms, from simple prokaryotes to complex eukaryotes. This maintenance of chromosomal integrity is accomplished by DNA repair enzymes. Recent reports have demonstrated that insertions of retroelements and pseudogenes represent only a fraction of the insertional polymorphisms in the human genome [...] TSIPs encompass several forms of insertion polymorphisms in human genomes, and are mediated via a combination of mechanisms. These TSIPs provide unique polymorphic markers, similar to SNPs and variable tandem repeats, and can be used to track population migration and evolution. Similar to retrotransposon insertions, we suspect that TSIPs, which can disrupt coding regions of the genome, may play a role in both the etiology of genetic diseases as well as mammalian evolution.

Templated Sequence Insertion Polymorphisms in the Human Genome Masahiro Onozawa and Peter D. Aplan Front Chem. 4: 43. doi: 10.3389/fchem.2016.00043

Complex complexity. Where’s the beef? See comment @1119. Dionisio

Templated Sequence Insertion Polymorphism (TSIP) is a recently described form of polymorphism recognized in the human genome, in which a sequence that is templated from a distant genomic region is inserted into the genome, seemingly at random. Similar to other forms of human polymorphism, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases.

Templated Sequence Insertion Polymorphisms in the Human Genome Masahiro Onozawa and Peter D. Aplan Front Chem. 4: 43. doi: 10.3389/fchem.2016.00043

Complex complexity. Dionisio

Dysfunctional family tree? http://phys.org/pdf400405167.pdf :) Dionisio

[...] this new evidence on character evolution, divergence estimates, and rates of diversification indicates that previous conclusions regarding the timing and rate of spider evolution were imprecise.

Spider phylogenomics: untangling the Spider Tree of Life. Garrison NL1, Rodriguez J1, Agnarsson I2, Coddington JA3, Griswold CE4, Hamilton CA1, Hedin M5, Kocot KM6, Ledford JM7, Bond JE PeerJ. 4:e1719. doi: 10.7717/peerj.1719.

Complex complexity Dionisio

There must have been many hurdles to overcome before complex living things arose on the early earth. The first hurdle was the birth of organic compounds. The second hurdle was the assembly of organic compounds to form polymers that can work as information storage molecules, perform enzymatic activities, or carry out other biological functions. The third hurdle was the appearance of a molecule, or a set of molecules, with self-replicating activity, such as a hypothetical self-replicating ribozyme. [...] the fourth hurdle would have had to be overcome—many kinds of molecules needed to work in a concerted manner for the growth and maintenance of the whole. The acquisition of the ability to evolve was the fifth, and perhaps the most difficult, hurdle that had to be overcome during the origins of life. How can a set of molecules achieve self-replication, and how can such molecules then acquire the ability to evolve?

Constructive Approaches for Understanding the Origin of Self-Replication and Evolution Norikazu Ichihashi and Tetsuya Yomo Life (Basel). 6(3): 26. doi: 10.3390/life6030026

Where's the beef? Complex complexity. Dionisio

The mystery of the origin of life can be divided into two parts. The first part is the origin of biomolecules: under what physicochemical conditions did biomolecules such as amino acids, nucleotides, and their polymers arise? The second part of the mystery is the origin of life-specific functions such as the replication of genetic information, the reproduction of cellular structures, metabolism, and evolution. These functions require the coordination of many different kinds of biological molecules.

Constructive Approaches for Understanding the Origin of Self-Replication and Evolution Norikazu Ichihashi and Tetsuya Yomo Life (Basel). 6(3): 26. doi: 10.3390/life6030026

Complex complexity. Dionisio

Now that large-scale ‘omics’ datasets of genomes, transcriptomes, epigenomes, etc. are increasingly becoming available within or across species, trans-disciplinary teams will be more able to understand plant responses to varying environments and long-term adaptation. These studies will contribute to understanding basic biological processes [...] Further work is needed to understand the interplay between TE proliferation, insertion/retention bias in polyploid plants and small RNA biology [...]

Evolution of plant genome architecture Jonathan F. Wendel,corresponding author Scott A. Jackson, Blake C. Meyers, and Rod A. Wing Genome Biol. 17: 37. doi: 10.1186/s13059-016-0908-1

Work in progress. Complex complexity. Dionisio

[...] eukaryotic genomes harbor many families of transposable elements (TEs) that are mobilized by genome shock; these elements may be the primary drivers of genetic reorganization and speciation [...] Given the depauperate genetic foundations of the many documented monophyletic lineages, the evolutionary outcomes are nothing short of astounding. How did genomes of the founding individuals give rise to so much morphological, ecological and behavioral divergence? What genetic mechanism might have driven the explosive evolution and rapid speciation of so many plant and animal lineages in Hawaii, and in other geologically young volcanic islands such as the Galápagos?

Profuse evolutionary diversification and speciation on volcanic islands: transposon instability and amplification bursts explain the genetic paradox. Craddock EM Biol Direct. 11:44. doi: 10.1186/s13062-016-0146-1.

Where’s the beef? Dionisio

[...] spiders are known for their extraordinary biomolecules like venoms and silks [...] The Spider Probe Kit, the first implementation of AHE methodology in Class Arachnida, holds great promise for gathering the types and quantities of molecular data needed to accelerate an understanding of the spider Tree of Life by providing a mechanism whereby different researchers can confidently and effectively use the same loci for independent projects, yet allowing synthesis of data across independent research groups.

Expanding anchored hybrid enrichment to resolve both deep and shallow relationships within the spider tree of life Chris A. Hamilton, Alan R. Lemmon, Emily Moriarty Lemmon and Jason E. Bond BMC Evol Biol. 16: 212. doi: 10.1186/s12862-016-0769-y

Where's the beef? Dionisio

mIcro- mAcro- say what? Ok, let's clarify terminology: What do they mean when they say 'so and so'? No idea. Oops! Just kidding. Now seriously:

It is not necessarily easy to "see" macroevolutionary history; there are no firsthand accounts to be read. Instead, we reconstruct the history of life using all available evidence: geology, fossils, and living organisms. Once we've figured out what evolutionary events have taken place, we try to figure out how they happened.

http://evolution.berkeley.edu/evolibrary/article/evo_48

Common ancestor (ca) .....................descendant #1 (d1) .....................descendant #2 (d2) Dev(d1) = Dev(ca) + Delta(d1) Dev(d2) = Dev(ca) + Delta(d2) Where, Dev(x): developmental process for biological system x Delta(x): required changes in any given Dev(ca) in order to get Dev(x) Where's the beef? :) Dionisio

This finding underscores the general evolvability of microbes […] The mechanism, however, appears fundamentally different. HGT assembles highly nuanced functional pathways from different sources with apparent speed and facility. This includes increase in enzymatic activity, which appears driven by acquisition of gene copies, rather than changes in regulation. This importance of HGT is consistent with recent insights into the evolution of beak shape in the Galapagos Finches, which was accompanied by extensive interspecies gene flow underscoring that in both bacteria and animals, gene import into the population rather than de novo evolution may be important during rapid diversification30. Finally, our results suggest that nuances in the architecture of the same pathway are predictable for ecological association and coexistence among diversifying populations, suggesting that such variation must be explored in detail if we are to understand the rules of microbial community assembly.

Adaptive radiation by waves of gene transfer leads to fine-scale resource partitioning in marine microbes. Hehemann JH1, Arevalo P2, Datta MS3, Yu X4, Corzett CH1, Henschel A1, Preheim SP1, Timberlake S5, Alm EJ1,5,6, Polz MF Nat Commun. 7:12860. doi: 10.1038/ncomms12860.

Mina's song "Parole, parole, parole" comes to mind, doesn't it? Gross extrapolation of a built-in adaptability framework onto nonsensical macro-evolutionary la-la-land pie-pie-in-the-sky daydreaming hogwash. Pathetic. Oh, well. What else is new? Big deal! At the end of the day bacteria remain bacteria. The whole enchilada is just a built-in biological robustness and adaptability framework conducive to adaptation? Without such a framework no mechanism could lead to any adaptation to variable conditions. It happens in technology. Terms like modularity and scalability come to mind, don’t they? The conclusion is: Where's the beef? :) Dionisio

Adaptive radiations are important drivers of niche filling, since they rapidly adapt a single clade of organisms to ecological opportunities. Pathway architecture is predictive of function and ecology, underscoring that horizontal gene transfer without extensive regulatory changes can rapidly assemble fully functional pathways in microbes. A prime example are Darwin's finches, which quickly diverged from a single ancestor into several, locally adapted species on the Galapagos Islands due to evolvability of beak shape, which allowed rapid adaptation to novel resources. Our analysis shows that a very general ecological opportunity creates a surprisingly strong selective regime as evidenced by the rapid, repeated evolution of different ecophysiological types among closely related bacteria. This finding underscores the general evolvability of microbes [...]

Adaptive radiation by waves of gene transfer leads to fine-scale resource partitioning in marine microbes. Hehemann JH1, Arevalo P2, Datta MS3, Yu X4, Corzett CH1, Henschel A1, Preheim SP1, Timberlake S5, Alm EJ1,5,6, Polz MF Nat Commun. 7:12860. doi: 10.1038/ncomms12860.

Our analysis shows that a very general ecological opportunity creates a surprisingly strong selective regime...

surprisingly? Why surprising? What else did they expect? :) [emphasis added]

This finding underscores the general evolvability of microbes [...]

Duh! Why did it take them so long to figure that out? :) Oh, well. What else is new? Big deal! At the end of the day bacteria remain bacteria. The whole enchilada is just a built-in biological robustness and adaptability framework conducive to adaptation? Without such a framework no mechanism could lead to any adaptation to variable conditions. It happens in technology. Terms like modularity and scalability come to mind, don’t they? Where's the beef? :) Dionisio

Darwin's finches, inhabiting the Galápagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives. Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis), a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and, thereby, to an expanded utilization of food resources.

Evolution of Darwin's finches and their beaks revealed by genome sequencing. Lamichhaney S1, Berglund J1, Almén MS1, Maqbool K2, Grabherr M1, Martinez-Barrio A1, Promerová M1, Rubin CJ1, Wang C1, Zamani N3, Grant BR4, Grant PR4, Webster MT1, Andersson L5. Nature. 518(7539):371-5. doi: 10.1038/nature14181.

A built-in biological robustness and adaptability framework conducive to adaptation? Without such a framework no change will lead to any adaptation to variable conditions. It happens in technology. Terms like modularity and scalability come to mind, don't they? Where's the beef? Dionisio

Ecological character displacement is a process of morphological divergence that reduces competition for limited resources. We used genomic analysis to investigate the genetic basis of a documented character displacement event in Darwin's finches on Daphne Major in the Galápagos Islands: The medium ground finch diverged from its competitor, the large ground finch, during a severe drought. We discovered a genomic region containing the HMGA2 gene that varies systematically among Darwin's finch species with different beak sizes. Two haplotypes that diverged early in the radiation were involved in the character displacement event: Genotypes associated with large beak size were at a strong selective disadvantage in medium ground finches (selection coefficient s = 0.59). Thus, a major locus has apparently facilitated a rapid ecological diversification in the adaptive radiation of Darwin's finches.

A beak size locus in Darwin's finches facilitated character displacement during a drought. Lamichhaney S1, Han F1, Berglund J1, Wang C1, Almén MS1, Webster MT1, Grant BR2, Grant PR2, Andersson L3. Science. 352(6284):470-4. doi: 10.1126/science.aad8786.

Where's the beef? Dionisio

The radiation of Darwin's finches on the Galápagos archipelago has long been regarded as an iconic study system for field ecology and evolutionary biology. The continued unification of genomic data with field biology promises to further elucidate the molecular basis of adaptation in Darwin's finches and well beyond. [...] Darwin's finches have been providing critical insight into the evolutionary process for over 150 years and it seems that they still have plenty more to tell us. Future work including expanded sampling and sequencing of G. fortis from Daphne Major, and analyses of DNA sequence divergence and ABBA-BABA patterns of allele sharing among putatively introgressed ALX1 haplotypes will help clarify this history.

Divergence and gene flow among Darwin's finches: a genome-wide view of adaptive radiation driven by interspecies allele sharing Daniela H. Palmer1,* and Marcus R. Kronforst1 Bioessays. 37(9): 968–974. doi: 10.1002/bies.201500047

Bottom line: birds remain birds. Where's the beef? Dionisio

Understanding the mechanisms and selective forces leading to adaptive radiations and origin of biodiversity is a major goal of evolutionary biology. [...] our knowledge of mechanisms and selective forces driving their radiation is limited. [...] genome-wide data across autosomes and the whole Z chromosome would be needed to understand mechanisms responsible for the parallel adaptive evolution at the same loci in multiple species and its possible role in Acrocephalus speciation.

Patterns of gene flow and selection across multiple species of Acrocephalus warblers: footprints of parallel selection on the Z chromosome Radka Reifová,corresponding author Veronika Majerová, Ji?í Reif, Markus Ahola, Antero Lindholm, and Petr Procház BMC Evol Biol. 16: 130. doi: 10.1186/s12862-016-0692-2

Where’s the beef? Dionisio

A central issue in the evolution of development involves how a diversity of phenotypes arose from a presumably universal set of mechanisms. Embryonic development proceeds through a series of differentiation events. [...] at the level of differentiation trees, there are broad similarities between distantly related mosaic embryos that might be essential to understanding evolutionary change and phylogeny reconstruction. Differentiation trees may therefore provide a basis for an Evo-Devo Postmodern Synthesis. That both modes of development, mosaic and regulative, must have a common basis is obvious, because both are found in each phylogenetic group.

Quantifying Mosaic Development: Towards an Evo-Devo Postmodern Synthesis of the Evolution of Development via Differentiation Trees of Embryos. Alicea B, Gordon R Biology (Basel). 5(3). pii: E33. doi: 10.3390/biology5030033.

Where's the beef? Dionisio

The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels [micro-]evolution. [...] genetic mechanisms regulating phenotypic plasticity and their overlap with the environment specific regulators is not well understood. [...] the environments can be divided into two categories based on the phenotypic diversity of the population within them and the two categories have differential regulators of phenotypic plasticity. [...] regulation of phenotypic plasticity is overlapping but different than the regulation of phenotypic variation in each environment. Phenotypic plasticity is a property of the genotype, unveiled by the environments. [...] plasticity QTL* are not same as pleiotropic QTL. [...] all loci showing gene-environment interaction (GEI) exhibit phenotypic plasticity. [...] a plasticity QTL is a locus whose one allele shows a canalised behaviour whereas the other allele shows phenotypic plasticity across diverse environments [...] Differential regulation of phenotypic plasticity provides a potential reason underlying the high interconnectivity observed in the genotype-phenotype map. This interconnectivity could be an outcome of cross talk between different genetic modules that either maintain canalisation or induce plasticity across different environments and phenotypes.

Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth Anupama Yadav, Kaustubh Dhole and Himanshu Sinha PLoS One. 11(9): e0162326. doi: 10.1371/journal.pone.0162326

(*) Quantitative trait locus (QTL) Where’s the beef? Dionisio

[...] most of the genes involved in the rough phenotype act in or are influenced by the Ras pathway [...] [...] further characterizing cryptic variation in the Ras pathway in yeast might provide valuable new insights into the mechanisms that give rise to genetically complex phenotypes [...] [...] perturbation of Ras pathway components in humans can lead to cancer and other diseases [...]

Diverse genetic architectures lead to the same cryptic phenotype in a yeast cross Matthew B. Taylor, Joann Phan, Jonathan T. Lee, Madelyn McCadden, and Ian M. Ehrenreich Nat Commun. 7: 11669. doi: 10.1038/ncomms11669

Where’s the beef?* (*) this question is mainly about the modern synthesis 'microevolution' ideas. See the rules posted @1090. :) Dionisio

While many studies have sought to identify individual loci that contribute to GxE, obtaining a deeper understanding of this phenomenon may require defining how sets of loci collectively alter the relationship between genotype, environment, and phenotype. [...] the involved alleles contribute to temperature sensitivity in different ways. While alleles of the transcription factor MSS11 specify the potential temperatures at which the trait can occur, alleles at the other loci modify temperature sensitivity within the range established by MSS11 in a genetic background- and/or temperature-dependent manner.

Multi-locus Genotypes Underlying Temperature Sensitivity in a Mutationally Induced Trait. Lee JT, Taylor MB, Shen A, Ehrenreich IM PLoS Genet. 12(3):e1005929. doi: 10.1371/journal.pgen.1005929.

Where’s the beef? Dionisio

Phenotypic plasticity allows organisms to change their phenotype in response to shifts in the environment. While a central topic in current discussions of evolutionary potential, a comprehensive understanding of the genetic underpinnings of plasticity is lacking in systems undergoing adaptive diversification. [...] while plasticity is largely determined by loci specific to a given environment, it may also be influenced by loci operating across environments.

Foraging environment determines the genetic architecture and evolutionary potential of trophic morphology in cichlid fishes. Parsons KJ, Concannon M, Navon D, Wang J, Ea I, Groveas K, Campbell C, Albertson RC Mol Ecol. doi: 10.1111/mec.13801.

Where’s the beef? Dionisio

How combinations of gene-environment interactions collectively give rise to genotype-environment interactions is not fully understood. [...] polymorphisms in stress response can show effects that are intensified by environmental stress, thereby resulting in major genotype-environment interactions when multiple of these variants co-occur. [...] our basic knowledge of the genetic and molecular mechanisms that underlie GxE remains incomplete. [...] when many loci show similar gene-environment interactions with environmental stress, decanalization can occur across conditions while trait variation retains an additive genetic architecture within conditions. [...] epistasis does not meaningfully contribute to GxE in growth variation under our assay conditions.

Gene-Environment Interactions in Stress Response Contribute Additively to a Genotype-Environment Interaction Takeshi Matsui and Ian M. Ehrenreich PLoS Genet. 12(7): e1006158. doi: 10.1371/journal.pgen.1006158

Where's the beef? PS. Off topic English grammar question: I'm not familiar with this grammatical format: In the Conclusion section, second paragraph, third sentence:

Although we have could have underestimated the contribution of epistasis to our study [...] http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006158

It does not seem like a frequently used grammar format, does it? Dionisio

Structural variation segregating within species forms a powerful basis for rapid chromosomal diversification among species. Orphan genes were not distributed randomly among chromosomes. The genomic defense mechanisms against TE activity in Z. tritici include silencing through changes in the chromatin state from euchromatin to heterochromatin, which are driven by posttranslational histone modifications. [...] the association of orphan genes with TE* can lead to a combined mutational load of nonhomologous recombination and gene silencing due to genomic defense mechanisms. To trace the evolutionary fate of orphan genes in the species, we will require knowledge about the frequency of individual orphan genes in populations and processes affecting their inheritance. [...] pangenomic analyses are in their infancy for complex eukaryotic genomes. The development of tools to integrate pangenomes into population genomics analyses remains a major challenge. The discovery of extensive orphan regions in populations of sexually reproducing species raises intriguing questions about the functional importance of such regions. A key question to address is how orphan regions arise in genomes and are maintained over evolutionary time. The role played by transposable elements will provide important clues to explain the emergence of genome compartmentalization.

The Evolution of Orphan Regions in Genomes of a Fungal Pathogen of Wheat. Plissonneau C, Stürchler A, Croll D MBio. 7(5). pii: e01231-16. doi: 10.1128/mBio.01231-16.

(*) transposable elements Complex complexity. Where’s the beef? Dionisio

Behavior is among the most rapidly evolving and derived traits in the animal kingdom, yet we know very little about the genes, genetic architecture, and evolutionary forces that promote their rapid divergence [...] It is intriguing to think that animal behavior, and its crucial importance to survival and reproduction, is largely driven by a genomic legacy of large yet conserved metazoan genes. With a greater comprehensive knowledge of genomes and their annotated genetic elements, this systems genomics framework provides many exciting new hypotheses to test.

Neurogenomics and the role of a large mutational target on rapid behavioral change. Stanley CE Jr1, Kulathinal RJ Biol Direct. 11(1):60. DOI: 10.1186/s13062-016-0162-1

Where’s the beef? Dionisio

Most investigations of biogeochemically important microbes have focused on plastic (short-term) phenotypic responses in the absence of genetic change, whereas few have investigated adaptive (long-term) responses. [...] one potential genetic assimilation mechanism may be that an epigenetic mutation produces an optimal (plastic) phenotype that is then later replaced by a genetic mutation to maintain it (now an adaptive phenotype) [...] [...] future efforts examining both genetic and epigenetic effects on adaptation should provide insight into potential mechanisms driving ultimate differences in expression levels between experimental conditions [...]

Molecular and physiological evidence of genetic assimilation to high CO2 in the marine nitrogen fixer Trichodesmium. Walworth NG, Lee MD, Fu FX, Hutchins DA, Webb EA Proc Natl Acad Sci U S A. 113(47):E7367-E7374. DOI: 10.1073/pnas.1605202113

Where's the beef? Dionisio

Most, if not all, organisms possess the ability to alter their phenotype in direct response to changes in their environment, a phenomenon known as phenotypic plasticity. Identifying and characterizing the proximate mechanisms involved in phenotypic plasticity and genetic assimilation promises to help advance our basic understanding of evolutionary innovation and diversification.

Genetic assimilation: a review of its potential proximate causes and evolutionary consequences. Ehrenreich IM, Pfennig DW Ann Bot. 117(5):769-79. doi: 10.1093/aob/mcv130.

Where's the beef? Dionisio

[...] depending on the stability of the environment, the molecular architecture underlying plastic traits can facilitate diversification, followed by fixation and consolidation of an adaptive phenotype and degeneration of nonadaptive ones.

How plasticity, genetic assimilation and cryptic genetic variation may contribute to adaptive radiations Ralf F. Schneider, Axel Meyer DOI: 10.1111/mec.13880 Molecular Ecology The Molecular Mechanisms of Adaptation and Speciation: Integrating Genomic and Molecular Approaches

where's the beef? Dionisio

Evolution has acted to shape the action potential in different regions of the heart in order to produce a maximally stable and efficient pump. This has been achieved by creating regional differences in ion channel expression levels within the heart as well as differences between equivalent cardiac tissues in different species. These region- and species-dependent differences in channel expression are established by regulatory evolution, evolution of the regulatory mechanisms that control channel expression levels. Ion channel auxiliary subunits are obvious targets for regulatory evolution, in order to change channel expression levels and/or modify channel function.

Transmural gradients in ion channel and auxiliary subunit expression Progress in Biophysics and Molecular Biology DOI: 10.1016/j.pbiomolbio.2016.09.012 David McKinnon, Barbara Rosati

in order to produce a maximally stable and efficient pump. ? Does evolution have goals? does it have purpose? does it pursue specific objectives? Where's the beef? Dionisio

Several different mechanisms have been proposed to be involved in the maintenance of diversity within the gut microbiota (Figures 2A–D), but their relative importance for shaping and maintaining intra-species diversity is largely unknown. Is the gut simply an environment, which supports a high degree of micro-niche differentiation? Or do bacterial strains depend on or benefit from each other’s presence? And to what extent is the host involved in controlling and manipulating these highly complex communities? In order to answer these questions, we need to be able to quantify and follow the abundance of bacterial strains over time and in response to experimental manipulation, directly from bacterial communities.

Beyond 16S rRNA Community Profiling: Intra-Species Diversity in the Gut Microbiota Kirsten M. Ellegaard* and Philipp Engel Front Microbiol. 7: 1475. doi: 10.3389/fmicb.2016.01475

Where's the beef? :) Dionisio

Marine mammals play crucial ecological roles in the oceans, but little is known about their microbiotas. Host habitat, diet and phylogeny all contribute to variation in marine mammal distal gut microbiota composition. Marine mammals play essential roles in the marine ecosystem as apex predators, primary and secondary consumers, and indicators of ocean health. Marine mammals, positioned at the top of the marine food web, fulfil important ecological roles in the ocean and serve as sentinel species in many marine census studies. The relatively distant ancestral relationships among extant marine mammals point to the importance of other shared adaptations to life in the sea that may have shaped the structure, and presumably the function of the marine mammal microbiotas. Further studies of bacterial, archaeal, eukaryotic and viral diversity in a broader and larger selection of marine and terrestrial mammal species with differing functional capacity, lifestyle and environment will be useful for elucidating the underlying relationships between indigenous microbial communities and their marine mammal hosts.

Marine mammals harbor unique microbiotas shaped by and yet distinct from the sea Elisabeth M. Bik,1,2 Elizabeth K. Costello,1 Alexandra D. Switzer,1 Benjamin J. Callahan,3 Susan P. Holmes,3 Randall S. Wells,4 Kevin P. Carlin,5 Eric D. Jensen,6 Stephanie Venn-Watson,5 and David A. Relman Nat Commun. 7: 10516. doi: 10.1038/ncomms10516

Interesting. Dionisio

Repetitive short interspersed elements (SINEs) are retrotransposons ubiquitous in mammalian genomes and are highly informative markers to identify species and phylogenetic associations. The availability of whole genome sequences has dramatically increased our understanding of mammalian non-coding DNAs. Identification of a currently active SINE subfamily with Felidae will provide opportunities to test hypotheses about the role of CanSINEs in somatic functional diversity. Patterns of insertion also support species designations, affirming CanSINEs as systematic markers and confirming complex evolutionary processes including incomplete lineage sorting following rapid species divergence, hybridization and SINE mediated genome rearrangement.

The dynamic proliferation of CanSINEs mirrors the complex evolution of Feliforms Kathryn B Walters-Conte,corresponding author1 Diana LE Johnson,2 Warren E Johnson,3 Stephen J O’Brien,4 and Jill Pecon-Slattery BMC Evol Biol. 14: 137. doi: 10.1186/1471-2148-14-137

Where's the beef? Dionisio

Truth Will Set You Free @1094:

Don’t expect any honest responses based on empirical science. The most you will get are atheistic philosophical assumptions based on speculation and wishful thinking. Sad but true.

Agree. They don't know where's the beef (a funny Wendy's TV commercial in 1984). There's a hint for them posted @1090. Thank you for commenting on this. Dionisio

The morphological disparity of species within major clades shows a variety of trajectory patterns through evolutionary time. However, there is a significant tendency for groups to reach their maximum disparity relatively early in their histories, even while their species richness or diversity is comparatively low. Much like the species and individuals that constitute them, all clades have an origin and all must ultimately suffer extinction. Their intervening histories, however, can follow a variety of complex trajectories. The study of these patterns is central to the study of macroevolution, with questions centring on whether there is a typical pattern [1–7], whether the fortunes of clades are positively or negatively correlated [8–13] and whether there are particular responses to marked environmental changes The precise limits on the evolution of disparity are probably unique to each clade, and comprise some combination of factors. Determining the relative importance of these is not straightforward, and direct tests are impossible with the present data. There are some strongly suggestive patterns, however.

What limits the morphological disparity of clades? Jack W. Oyston, Martin Hughes, Peter J. Wagner, Sylvain Gerber and Matthew A. Wills Interface Focus. 5(6): 20150042. doi: 10.1098/rsfs.2015.0042

Where’s the beef? Dionisio

Geographical gradients in species diversity are often explained by environmental factors such as climate and productivity. Biotic interactions play a key role in evolutionary diversification and may therefore also affect diversity patterns, but this has rarely been assessed. [...] biogeographic history combine with biotic interactions to shape the global species richness patterns in the two main extant groups of terrestrial mammal carnivores, the suborders Caniformia and Feliformia. [...] feliform and caniform richness patterns cannot be fully explained by the environment, but instead show signatures of biogeographic history and contingent biotic interaction effects. [...] mammalian carnivores exemplify the idea that biotic interactions may indeed play a key role in shaping global-scale diversity patterns via effects on evolutionary diversification. Future studies should assess how generally important such effects are, their spatial scale dependency, and how such effects relates to geographic patterns in functional diversity and thereby community functioning.

Macroecological Evidence for Competitive Regional-Scale Interactions between the Two Major Clades of Mammal Carnivores (Feliformia and Caniformia) Rasmus Østergaard Pedersen,* Brody Sandel, and Jens-Christian Svenning PLoS One. 9(6): e100553. doi: 10.1371/journal.pone.0100553

Where's the beef? Dionisio

Dionisio @ 1092: Great stuff. Don't expect any honest responses based on empirical science. The most you will get are atheistic philosophical assumptions based on speculation and wishful thinking. Sad but true. Truth Will Set You Free

[...] the immunocompetence of threatened felids such as the cheetah has been underestimated and its assessment ought to consider both innate and adaptive components of the immune system. [...] results are intriguing from at least two perspectives: (1) The strong selection pressure assumed to be exerted by different environments as represented by variation in foraging behaviour, body size or social organisation did not fine-tune the innate immune system, being – in comparison with the adaptive response – the evolutionarily older part of the immune system [...] (2) The ancestors of feliform carnivores developed a superior form of constitutive innate immune response. All feliform species had BKA values an order of magnitude higher than those previously reported from various vertebrates and those of black-backed jackals.

Feliform carnivores have a distinguished constitutive innate immune response Sonja K. Heinrich,1 Bettina Wachter,1 Ortwin H. K. Aschenborn,2 Susanne Thalwitzer,1,* Jörg Melzheimer,1 Heribert Hofer,1 and Gábor Á. Czirják Biol Open. 5(5): 550–555. doi: 10.1242/bio.014902

Where's the beef? Dionisio

wait! not rats, weren't they mice? :) anyway we all know that extended modern synthesis can turn a mouse into a horse and backward, hence the Cinderella story wasn't that 'magic' after all. just a few boring transformations. What's the big deal? :) Dionisio

What's the LUCA for cats and dogs? Apply the rules described @1090. Dev(cats) = Dev(LUCA) + Delta(cats) Dev(dogs) = Dev(LUCA) + Delta(dogs) In the above equations all the Dev(x) (Dev(cats), Dev(dogs), Dev(LUCA)) are known and we have to find Delta(cats) and Delta(dogs). Here's one of the several hints seen online:

The exact MRCA (Most Recent Common Ancestor) may never be known. Not that it really matters to that degree of precision. But what is known is that not long after the emergence of the Order Carnivora appeared it split off into two suborders: Feliformia (“Cat like”) and, Caniformia (“Dog like”) This occurred around 42 million years ago in the Eocene period. From here the Feliformia produced the families: Felidae (Domestic Cats, Tiger, Lion, Ocelot, etc.) Eupleridae (“Malagasy carnivores”) Fossa, Falanouc, Malagasy Civet and Malagasy mongooses etc. All from Madagascar. Hyaenidae (hyenas and Aardwolf) Herpestidae (the Mongooses, kusimanses, Meerkat, etc.) Nandiniidae (African Palm Civet) Viverridae (the Binturong, civets, genets, Asiatic and African linsang) And the Caniformia produced: Canidae (canids; dogs and wolves) Ursidae (bears) Ailuridae (red panda) Mephitidae (skunks) Mustelidae (weasels and otters) Procyonidae (raccoons, coatis, etc.) Pinnipedia (seals, sea lions, walruses.) http://greenanswers.com/question/what-common-ancestor-cats-and-dogs/

So far the most fundamental question remains: Where's the beef? :) Cinderella lost her shoe, the carriage turned back into a pumpkin and the horses into rats. and they lived happily ever after Dionisio

Here's a hint to answer the fundamental question "where's the beef?" Given any case of known evolutionary divergence, it could be described as: Dev(d1) = Dev(ca) + Delta(d1) Dev(d2) = Dev(ca) + Delta(d2) Where Dev(x) is the developmental process of any given biological system x Delta(x) is the whole set of spatiotemporal procedural differences required to produce Dev(x). d1 and d2 are two descendants of their common ancestor (ca). Assuming the Dev(x) are well known, what hypothetical Delta(d1) and Delta(d2) could be suggested for the following cases? Case 1: d1 = placental mammals; d2 = marsupials; Case 2: d1 = placental; d2 = monotreme; Case 3: d1 = cats; d2 = dogs; (use LUCA for ca) Just point to the literature that explains this in details. The explanation must be comprehensive, logically coherent and it must hold water under any kind of thorough examination. Dionisio

Their precise geographical origin remains uncertain, but it is plausible that southern North America served as an important stage for a very early phase of amphicyonid radiation.

Whence the beardogs? Reappraisal of the Middle to Late Eocene 'Miacis' from Texas, USA, and the origin of Amphicyonidae (Mammalia, Carnivora). Tomiya S1, Tseng ZJ R Soc Open Sci. 3(10):160518 DOI: 10.1098/rsos.160518

Where's the beef? Dionisio

Article: e1082480 | Received 24 Sep 2014, Accepted 07 Aug 2015, Published online: 17 Feb 2016

New carnivoraforms from the latest Paleocene of Europe and their bearing on the origin and radiation of Carnivoraformes (Carnivoramorpha, Mammalia) Floréal Solé, Thierry Smith, Eric De Bast, Vlad Codrea & Emmanuel Gheerbrant DOI:?http://dx.doi.org/10.1080/02724634.2016.1082480 Journal of Vertebrate Paleontology ? Volume 36, Issue 2

Why did it take that long to review it? :) Dionisio

This paper analyzes the transformation from the human zygote to the implanted embryo under the prism of substantial change. After a brief introduction, it vindicates the Aristotelian ideas of substance and accident, and those of substantial and accidental change. It then claims that the transformation from the multicelled zygote to the implanted embryo amounts to a substantial change. Pushing further, it contends that this substantial change cannot be explained following patterns of genetic reductionism, emergence, and self-organization, and proposes Gustavo Bueno's idea of anamorphosis as a means to encapsulate criticism against such positions.

The Constitution of the Human Embryo as Substantial Change. Alvargonzález D J Med Philos. 41(2):172-91. doi: 10.1093/jmp/jhv062

Where's the beef? :) Dionisio

Overall, our results show that the production of reorganized phenotypes can occur as a consequence of modularity and developmental plasticity, due to differential plastic responses among modules. This scenario still needs to be refined by comparing the regulatory gene networks underlying development of both intercastes and novel castes [...], and by studying the behavior of developmental anomalies and quantifying their contribution to colony fitness. More generally, our work underlines the need to take into account developmental plasticity in modern evolutionary thought because it determines which phenotypes can or cannot be produced and thus significantly affects the evolutionary potential of populations.

Phenotypic plasticity and modularity allow for the production of novel mosaic phenotypes in ants Sylvain Londe,corresponding author Thibaud Monnin, Raphaël Cornette, Vincent Debat, Brian L. Fisher, and Mathieu Molet EvoDevo. 2015; 6: 36. doi: 10.1186/s13227-015-0031-5

Where's the beef? :) Dionisio

Natural populations and laboratory isolates adjust their elemental quotas widely in response to nutrient supply by a variety of intriguing mechanisms. Genome-scale metabolic (GEM) network reconstructions represent a cornerstone of systems biology Metabolic network reconstruction and constraint-based modeling revealed previously unknown evolutionary strategies for organisms perpetually coping with low phosphate availability. These strategies include a redesign of the metabolic network to alleviate metabolic control by a single substrate, global control of phosphorus partitioning in biomass components, and optimization of photosynthetic electron flow.

Adaptive Evolution of Phosphorus Metabolism in Prochlorococcus John R. Casey, Adil Mardinoglu, Jens Nielsen, David M. Karl DOI: 10.1128/mSystems.00065-16 American Society for Microbiology

redesign of the metabolic network? redesign? Where's the beef? :) Dionisio

#1083 follow up Some research papers contain pseudoscientific statements that spoil otherwise interesting reports of gathered data. In some cases the papers are filled with so much hogwash and nonsense that make them incomprehensible and unreadable because they lose focus in the essential concepts of the main topic of a given paper. Dionisio

#1082 follow up What went wrong in the preceding story? Lack of humble thinking with open mind out of any preconceived box that is based on unproven presuppositions many times associated with ideological bias. That simple.

"test everything; hold fast what is good." [1 Thessalonians 5:21 (ESV)]

Dionisio

Reading how the experimental facts are interpreted in some of the papers referenced in the preceding posts reminds me of the following story:

One day after sleeping badly, an anatomist went to his frog laboratory and removed from a cage one frog with white spots on its back. He placed it on a table and drew a line just in front of the frog. "Jump frog, jump!" he shouted. The little critter jumped two feet forward. In his lab book, the anatomist scribbled, "Frog with four legs jumps two feet." Then, he surgically removed one leg of the frog and repeated the experiment. "Jump, jump!" To which, the frog leaped forward 1.5 feet. He wrote down, "Frog with three legs jumps 1.5 feet." Next, he removed a second leg. "Jump frog, jump!" The frog managed to jump a foot. He scribbled in his lab book, "Frog with two legs jumps one foot." Not stopping there, the anatomist removed yet another leg. "Jump, jump!" The poor frog somehow managed to move 0.5 feet forward. The scientist wrote, "Frog with one leg jumps 0.5 feet." Finally, he eliminated the last leg. "Jump, jump!" he shouted, encouraging forward progress for the frog. But despite all its efforts, the frog could not budge. "Jump frog, jump!" he cried again. It was no use; the frog would not response. The anatomist thought for a while and then wrote in his lab book, "Frog with no legs goes deaf." http://www.jupiterscientific.org/sciinfo/jokes/biologyjokes.html

Dionisio

[...] archaic human DNA likely contributed to this impressive adaptation. [...] adaptive introgression is a widespread phenomenon in humans and was a key evolutionary force in other human adaptations, such as to UV exposure and pathogen defense [...] [...] many questions remain to be answered. We still do not know the biological mechanism that enables Tibetans to deal with the low-oxygen conditions at high altitude. The absence of coding mutations under selection suggests that the adaptation might instead modulate the expression of the gene rather than change its protein sequence or structure. The precise mechanism by which the protective effect is conferred might be related to vasoconstrictive and vascular remodeling factors (such as endothelin-1) that are known to be mediated by EPAS1 response to hypoxia. Other open questions are the extent of Denisovan admixture in Tibetans genome-wide, and whether other loci under adaptive pressures (e.g., EGLN1) harbor Denisovan-like haplotypes. A combination of approaches and the availability of whole-genome sequence data from multiple individuals will provide a clearer picture of Tibetan demographic history and confirm the sequence of events that led to this remarkable example of adaptation. [...] we need to consider adaptive introgression as one of the main evolutionary forces behind human adaptation.

Archaic inheritance: supporting high-altitude life in Tibet. Huerta-Sánchez E1, Casey FP J Appl Physiol 119(10):1129-34. doi: 10.1152/japplphysiol.00322.2015.

Where's the beef? Dionisio

[...] recent reviews have described a bias in the use of relative divergence measures towards incorrectly identifying genomic regions that are seemingly immune to introgression. [...] absolute divergence measures and individual sequence analysis suggest that haplotype structuring occurred as the result of within-species processes. The potential for this type of misinference may occur with any haplotype that recently spread within a species. [...] absolute measures of genetic divergence are necessary for confirming putative regions of introgression.

Mistaken Identity: Another Bias in the Use of Relative Genetic Divergence Measures for Detecting Interspecies Introgression Kathryn R. Ritz* and Mohamed A. F. Noor PLoS One. 2016; 11(10): e0165032. doi: 10.1371/journal.pone.0165032

bias? incorrect identification? misinference? introgression? What else? Where's the beef? Dionisio

Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. The immune response to stress is a highly complex phenotype. The contribution of host genetic factors in explaining such heterogeneity is increasingly documented by genome-wide association studies (GWASs), which have identified variants, often located in non-coding regions [...] [...] it remains unknown how these variants functionally impact immune responses across populations. [...] marked differences in immune responses exist between populations due to the contribution of cis- and trans-acting regulatory variants. [...] admixture with Neandertals introduced regulatory variants affecting responsiveness to immune stimuli into European genomes. [...] tradeoff between activating efficient responses to sense microorganisms, both pathogenic and commensal, while avoiding aberrant, deleterious inflammation. Genetic variation transmitted through admixture with Neandertals can also represent a source of functional, potentially advantageous variants [...] [...] genetic segments introgressed from Neandertals have preferentially introduced regulatory variants into European genomes [...] The functional roles of the introgressed regulatory variants require further investigation, but our results clearly establish that archaic admixture, whether adaptive or not, has increased the diversity of the immune repertoire of contemporary Europeans.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations. Quach H1, Rotival M1, Pothlichet J1, Loh YE1, Dannemann M2, Zidane N1, Laval G1, Patin E1, Harmant C1, Lopez M3, Deschamps M3, Naffakh N4, Duffy D5, Coen A6, Leroux-Roels G6, Clément F6, Boland A7, Deleuze JF7, Kelso J2, Albert ML8, Quintana-Murci L9 Cell. 167(3):643-656.e17. doi: 10.1016/j.cell.2016.09.024.

admixture, introgression, what else? Where's the beef? Dionisio

[...] the source of adaptation was likely due to the introduction of genetic variants from archaic Denisovan-like individuals (individuals closely related to the Denisovan individual from the Altai Mountains) into the ancestral Tibetan gene pool. [...] adaptation to local environments may have been facilitated by gene-flow from other hominins that may already have been adapted to those environments.

Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Huerta-Sánchez E1, Jin X2, Asan3, Bianba Z4, Peter BM5, Vinckenbosch N5, Liang Y6, Yi X6, He M7, Somel M8, Ni P9, Wang B9, Ou X9, Huasang9, Luosang J9, Cuo ZX10, Li K11, Gao G12, Yin Y9, Wang W9, Zhang X13, Xu X9, Yang H14, Li Y9, Wang J15, Wang J16, Nielsen R17. Nature. 512(7513):194-7. doi: 10.1038/nature13408.

Where's the beef? Dionisio

[...] while it is largely accepted that the genetic code underwent expansion during its evolution, there is no consensus regarding the specific route that led its development, which may indeed be unknowable. While the exact details may never be known, we contend that universal and generalizable features and principles may still be elucidated.

Genetic Code Evolution Reveals the Neutral Emergence of Mutational Robustness, and Information as an Evolutionary Constraint Steve Massey DOI: 10.3390/life5021301 http://www.mdpi.com/2075-1729/5/2/1301/pdf Life 5, 1301-1332;

[Emphasis mine] Here it goes again: it is largely accepted The standard expression seen in some "evo" literature, as pointed to by gpuccio recently. Anyway, the conclusion is: Where's the beef? Dionisio

New levels of semiosis emerge via functional integration of interacting agents (meta-system transition). Multilevel semiotic networks are needed to support the plasticity, robustness, and evolvability of organisms. They coordinate the appearance of features developed via learning and evolution of cooperating and/or conflicting subagents.

Evolutionary Biosemiotics and Multilevel Construction Networks Alexei A. Sharov DOI: 10.1007/s12304-016-9269-0 http://alexei.nfshost.com/biosem/Sharov_multi-level_2016_NIHversion.pdf

Where's the beef? Dionisio

The origin of life is a very long multi-step process, which cannot be replicated in laboratory conditions. It would never be possible to mix inorganic chemicals and generate functional cells with a membrane, self-supporting metabolism, and nucleic acids as hereditary molecules. [...] life originated from simple (not polymeric) but already functional molecules, and its gradual evolution towards higher complexity was driven by cooperation and natural selection.

Coenzyme world model of the origin of life Alexei Sharov Bio Systems 144 · DOI: 10.1016/j.biosystems.2016.03.003

Where's the beef? Dionisio

Embryonic development proceeds through a series of differentiation events. A central issue in the evolution of development involves how a diversity of phenotypes arose from a presumably universal set of mechanisms. For future work we will investigate the relationships between the differentiation trees of very closely related organisms [...] With the vast increase in our ability to track all of the cells in developing embryos, both mosaic and regulating, we hope that our work will provide incentives to ascertain not only cell trajectories, but differentiation events, quantification of asymmetric cleavages, and recording of differentiation waves, across many species.

Quantifying Mosaic Development: Towards an Evo-Devo Postmodern Synthesis of the Evolution of Development via Differentiation Trees of Embryos Bradly Alicea and Richard Gordon John S. Torday, Academic Editor Biology (Basel). 5(3): 33. doi: 10.3390/biology5030033

Where's the beef? Complex complexity. Dionisio

Gene content varies greatly between bacteria. If indeed, gene loss is most frequently driven by genetic drift, rather than by shifts in natural selection, we would expect it to occur in a largely clocklike manner, both within and between species. [...] it is still not clear whether gene loss also occurs in a time-dependent manner within bacterial species. [...] within bacterial species, gene loss tends to occur in a fairly clocklike manner, and mostly within a pool of genes that were less conserved and constrained even prior to the loss event. [...] strong caution should be exercised when ascribing specific gene loss events to changes in the environment. [...] even within such pathogens that experience relatively high proportions of gene loss, gene loss appears to be time-dependent and that those genes that are lost tend to be less constrained and conserved to begin with. [...] genes that are lost within species tend to be lost in a clocklike manner, mostly from a less constrained and conserved gene pool. [...] caution needs to be taken when using convergent gene loss as a signal of positive selection. [...] bacterial intra-species gene loss occurs in a largely clocklike manner within a pool of genes that are less conserved and constrained, even prior to their loss and across species.

Bacterial intra-species gene loss occurs in a largely clocklike manner mostly within a pool of less conserved and constrained genes. Bolotin E, Hershberg R Sci Rep. 6: 35168. doi: 10.1038/srep35168

Where's the beef? Dionisio

Since the synthetic processes of secondary metabolites are usually more time-consuming and complex, there is more possibility that they will be affected by the external environment, hence the higher GC3 content downstream in the synthetic pathway. The formation of codon usage bias is affected by many factors [...] [...] both codon usage bias and amino acid composition was associated with gene expression. In microorganisms, studies have shown that optimal codons can effectively regulate the folding and elongation rate of proteins, thus significantly promoting synthesis of proteins. [...] GC3 might be affected by independent factors in different species.

Analysis of codon usage patterns in Ginkgo biloba reveals codon usage tendency from A/U-ending to G/C-ending Bing He,1 Hui Dong,1 Cong Jiang,2,3 Fuliang Cao,1 Shentong Tao,1 and Li-an Xu Sci Rep. 6: 35927. doi: 10.1038/srep35927

Where's the beef? All the alleged mutations and/or selections take place on top of a robust built-in complex functional specified information framework that is conducive to that kind of activity. That framework is not hidden. It’s an undeniable fact. It’s extensively documented in the scientific literature, specially in the most recent papers, although many outstanding questions remain unanswered and many new questions keep popping up with every new discovery. That complex functional specified information framework includes the genetic code, the codons, synonymous codons, their meaningful sequences, the sense/antisense strands, the gene regulatory networks, the signaling pathways, the fantastic transcriptional and translational mechanisms, the post-transcriptional splicing, the post-translational modifications, the chaperon proteins, the protein folding, the epigenetic switches, the circadian clocks, the feedback and feedforward loops, the biological oscillators, the cell cycle with all its fascinating paraphernalia, and the whole nine yards. Taken together, all that marvelous stuff is very conducive to adaptation mechanisms that are observed in biology, which in the given case may include some changes of the codon bias and/or genome composition in response to environmental cues like for example the abundance or scarcity of certain nutrients. All within that built-in framework that we got for free. Dionisio

Although most aspects of world and self-consciousness are inherently subjective, neuroscience studies in humans and non-human animals provide correlational and causative indices of specific links between brain activity and representation of the self and the world. [...] understanding the link between consciousness and representation of the self existentially in both social and non-social worlds, is a challenging enterprise for both psychology and neuroscience. Consciousness can be considered as the appearance of a world during both waking or dreaming states [...] It is often divided into primary (anoetic) consciousness mainly related to perception-, affect-, and action- related representations; and in higher- order consciousness linked to interpretation of the primary consciousness contents (noetic) including self-related notions (autonoetic) of past and future [...] [...] in addition to language, theory of mind and mental time traveling, the varieties of higher-order states of consciousness (Lewis-Williams and Clottes, 1998; Lewis-Williams, 2002) may have driven culture and ultimately made humans unique.

Evolutionary aspects of self- and world consciousness in vertebrates Franco Fabbro,1,2,* Salvatore M. Aglioti,3,4 Massimo Bergamasco,2 Andrea Clarici,5 and Jaak Panksepp Front Hum Neurosci. 9: 157. doi: 10.3389/fnhum.2015.00157

And the conclusion is... Where’s the beef? :) Dionisio

Biosemiotics is devoted to establish a paradigmatic background for research on the evolution of cognition and communication in all living systems going beyond mechanical molecular biology. The central research question is in what way it is possible to add a semiotic view to the modeling of biological science(Cobley,2010) in order to get out of the rigid mechanistic understanding of living systems and make it possible to integrate a ?rst person view to living systems. The dynamics of semiotic freedom (Brier, 2012a) is adding the interactions of forms to the mechanical as well as the informational view of the world as differences.

Can biosemiotics be a "science" if its purpose is to be a bridge between the natural, social and human sciences? Brier S Prog Biophys Mol Biol. 119(3):576-87. doi: 10.1016/j.pbiomolbio.2015.08.001.

There goes another case of Mina’s “parole, parole, parole” ...and the conclusion is...? not there yet... work in progress... stay tuned. complex complexity. :) PS. this post referenced here: https://uncommondescent.com/intelligent-design/ud-guest-post-dr-eugen-s-on-biological-memory-vs-memory-of-materials/#comment-620646 Dionisio

If viruses are signals, what selection forces could have acted to keep interpretation mechanisms within the cell that result, in many cases, in the death of that same cell? [...] the cell somehow would have blocked its toxic properties. [...] the cell would have remained rooted in a state of tension, of latent internal conflict between its components, while it became more and more complex. [...] we can conceive that in some cases, the cells having fortuitously incorporated stricter control mechanisms over their own internal elements would resist a new virus. [...] found an RNA structural element capable of operating in both bacterial and eukaryotic translation systems, albeit with a different mechanism. The focus should be on identifying potentially hidden ontological entities within the cell at the molecular level by taking advantage of a viral infection. [...] the origins of these alliances should be traced back, if possible, to try to theoretically identify the ancient “beings” still living in our cells.

Virus is a Signal for the Host Cell Jordi Gómez, Ascensión Ariza-Mateos, and Isabel Cacho Biosemiotics. 8(3): 483–491. doi: 10.1007/s12304-015-9245-0

Where's the beef? How much pseudo-scientific hogwash can be written in a single paper? Dionisio

Detailed comparison of the two subgenomes will facilitate identification of specific sequences that control cis-regulatory differences between homoeologues. [...] the remodelling of the S genome could have been a response to the L–S merger itself, a ‘genomic shock’ resulting from the activation of transposable elements [...]

Genome evolution in the allotetraploid frog Xenopus laevis. Session AM1,2, Uno Y3, Kwon T4,5, Chapman JA2, Toyoda A6, Takahashi S7, Fukui A8, Hikosaka A9, Suzuki A7, Kondo M10, van Heeringen SJ11, Quigley I12, Heinz S13, Ogino H14, Ochi H15, Hellsten U2, Lyons JB1, Simakov O16, Putnam N17, Stites J17, Kuroki Y18, Tanaka T19, Michiue T20, Watanabe M21, Bogdanovic O22, Lister R22, Georgiou G11, Paranjpe SS11, van Kruijsbergen I11, Shu S2, Carlson J2, Kinoshita T23, Ohta Y24, Mawaribuchi S25, Jenkins J2,26, Grimwood J2,26, Schmutz J2,26, Mitros T1, Mozaffari SV27, Suzuki Y28, Haramoto Y29, Yamamoto TS30, Takagi C30, Heald R31, Miller K31, Haudenschild C32, Kitzman J33, Nakayama T34, Izutsu Y35, Robert J36, Fortriede J37, Burns K37, Lotay V38, Karimi K38, Yasuoka Y39, Dichmann DS1, Flajnik MF24, Houston DW40, Shendure J33, DuPasquier L41, Vize PD38, Zorn AM37, Ito M42, Marcotte EM4, Wallingford JB4, Ito Y29, Asashima M29, Ueno N30,43, Matsuda Y3, Veenstra GJ11, Fujiyama A6,44,45, Harland RM1, Taira M46, Rokhsar DS1,2,16. Nature. 538(7625):336-343. doi: 10.1038/nature19840.

Where's the beef? There goes another case of Mina's "parole, parole, parole" :) resulting from the activation of transposable elements? Does this relate to the transposons gpuccio refers to? [Emphasis added] Dionisio

The bloom of genomics is revealing gene loss as a pervasive evolutionary force generating genetic diversity that shapes the evolution of species. Outside bacteria and yeast, however, the understanding of the process of gene loss remains elusive, especially in the evolution of animal species. [...] the survival and extensive duplication of Cco and RdhE2 in O. dioica correlated with the acquisition of complex compartmentalization of expression domains in the digestive system and a process of enzymatic neofunctionalization of the Cco, while the surviving Aldh8 could be related to its ancestral housekeeping role against toxic aldehydes.

Coelimination and Survival in Gene Network Evolution: Dismantling the RA-Signaling in a Chordate. Martí-Solans J1, Belyaeva OV2, Torres-Aguila NP1, Kedishvili NY2, Albalat R3, Cañestro C3. Mol Biol Evol. 33(9):2401-16. doi: 10.1093/molbev/msw118.

Speculative pseudoscience or pseudoscientific speculation? Where's the beef? :) Dionisio

[...] the evolutionary development of brain cavity systems, CSF, and CSF composition and regulation are milestones in vertebrate (and human) brain evolutionary development. They need to be further analysed to fully understand brain function, and may have implications for the increase in behavioural repertoire. It will be interesting to investigate, in the light of evolution, whether the blood-eCSF embryonic barrier transfer system initially developed when brain cavities become sealed in early brain developmental stages, and thus is specific to the vertebrate lineage. [...] further and deeper examination of the mechanisms regulating CSF composition and homeostasis as well as the functions it exerts on neuroepithelial progenitor cells in model organisms from different deuterostome taxa may provide new and important data for the evolutionary and developmental comprehension of the vertebrate brain.

Evolutionary development of embryonic cerebrospinal fluid composition and regulation: an open research field with implications for brain development and function David Bueno and Jordi Garcia-Fernàndez Fluids and Barriers of the CNS201613:5 DOI: 10.1186/s12987-016-0029-y

Work in progress... stay tuned. This sounds like pseudoscientific speculation. Dionisio

teleological character of living systems?

I also agree that the concept of a nonlinear attractor is a useful tool for thinking about the teleological character of living systems. What do we mean by “teleology” if not the tendency of a system to move towards the function that serves its interests in the organism as a whole, i.e., to have a goal? As I will argue later in this Dialogue, that does not require us to believe that there was a creator that designed the cardiac pacemaker. The term “final cause” has unfortunately created the impression that there is some ultimate goal in the universe from which all other forms of teleology derive. By contrast it is sufficient in my view to see teleological behavior as emergent during evolution.

Denis Noble Interview @ TBS blog http://www.thebestschools.org/dialogues/evolution-denis-noble-interview/ [emphasis mine] "emergent during evolution" - whatever that means. :) Dionisio

There was thought to be little in common between fish fin bones and the finger bones of land-dwellers. But zebrafish studies reveal that hox genes have a surprisingly similar role in patterning the two structures.

Evolutionary biology: Fin to limb within our grasp Aditya Saxena & Kimberly L. Cooper Nature 537, 176–177 doi:10.1038/nature19425

Dionisio

@1062 addendum:

These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates.

Digits and fin rays share common developmental histories Tetsuya Nakamura, Andrew R. Gehrke, Justin Lemberg, Julie Szymaszek & Neil H. Shubin Nature 537, 225–228 doi:10.1038/nature19322

Next let's find out how? Dionisio

There never were any transitional forms making both dermal bone and endochondral bone. Organisms made one or the other. There never were any transitional forms with fin rays and digits. And I predict that no matter how extensively the fossil record is searched, the phenotypic gap between fins and limbs will remain even as the genetic gap continues to diminish.

Genetic Similarities Between Fins and Limbs -- Evidence for Evolution, Maybe, but Not for Darwinism Michael Denton http://www.evolutionnews.org/2016/09/genetic_similar103120.html

Dionisio

A few things these guys say seem to make sense, though somewhere else they show quite a prolific imagination that transcends falsifiable science and get into incoherent philosophy mixed with fantasy:

Rethinking Time, Space, Consciousness, and the Illusion of Death? [...] re-examine everything we thought we knew about life, death, the universe and the nature of reality itself. [...] our existing model of reality is looking increasingly creaky in the face of recent scientific discoveries. Science tells us with some precision that over 95% of the universe is mostly composed of dark matter and dark energy, but must confess that it doesn’t really know what dark matter is, and knows even less about dark energy. All of science is based on information passing through our consciousness, but science doesn’t have a clue what consciousness is. Biologists describe the origin of life as a random occurrence in a dead universe, but we have no real understanding of how life began, or why the universe appears to be exquisitely designed for the emergence of life. This forces a fundamental rethinking of everything we thought we knew about life, death, and our place in the universe. https://beyondbiocentrism.com/

Pseudoscience is in big trouble. Old dogmas are obsolete and new 'attractive' (but not falsifiable, hence unscientific) ideas are popping up like mushrooms in a humid forest. Third way of evolution, biocentrism, beyond biocentrism, etc. Dionisio

Strikingly, we also found selection in eight genes related to blood clotting or platelet formation. [...] cetaceans show accelerated wound healing, reducing infection and accelerating tissue repair [...] [...] our results seem to suggest that cetaceans and hippos evolved most aquatic adaptations separately. On the other hand, we found similar selection pressures acting on genes implicated in lipids in both groups, and more work is needed to determine whether these signatures are related to specialized lipid-rich integuments that characterize semi-aquatic and aquatic animals

A phylogenomic analysis of the role and timing of molecular adaptation in the aquatic transition of cetartiodactyl mammals Georgia Tsagkogeorga,1 Michael R. McGowen,1 Kalina T. J. Davies,1 Simon Jarman,2 Andrea Polanowski,2 Mads F. Bertelsen,3 and Stephen J. Rossiter R Soc Open Sci. 2(9): 150156. doi: 10.1098/rsos.150156

Pseudoscientific hogwash. Where's the beef? Dionisio

The PCP pathway antedates the radiation of Porifera and may have arisen in the last common ancestor of animals. Oscarella species now appear as key organisms to understand the ancestral function of PCP signaling and its potential links with Wnt pathways. This discovery spotlights the retrieval of a unique, complete PCP pathway - in Homoscleromorph sponges - and thus calls for functional studies in this particular sponge lineage to investigate the mechanisms involved in the coordination of cell orientation in a non planulozoan lineage (Bilateria?+?Cnidaria). Nevertheless, whether or not the absence of key proteins means that no PCP mechanisms occurs in other sponge lineages also requires investigation. The present study provides yet another strong affirmation that each sponge lineage is of high interest to gain a better understanding of the evolution of key molecular toolkits in metazoans. Finally, this study highlights how the accumulation of data concerning the evolution of multigene families may help us to trace early metazoan evolution when no phylogenetic consensus is currently accepted.

Retracing the path of planar cell polarity. Schenkelaars Q1,2, Fierro-Constain L3, Renard E3, Borchiellini C BMC Evol Biol. ;16:69. doi: 10.1186/s12862-016-0641-0.

Pseudoscientific nonsense. Where's the beef? Dionisio

The tree of life is currently an active object of research, though next to vertical gene transmission non vertical gene transfers proved to play a significant role in the evolutionary process. [...] a decision is always made concerning a hypothesis, necessarily concealing – in parts of a tree in construction – uncertainties or lack of knowledge. [...] inciting the authors to question the monophyly of these taxa. [...] our proposition introduces an uncertainty principle in the search of the phylogenetic relationships between all of the cellular organisms. [...] further studies on other molecules or parts of the genome are needed to check consistency and thus validate the method.

Partitional Classification: A Complement to Phylogeny Marc Salomon and Bruno Dassy Evol Bioinform Online. 12: 149–156. doi: 10.4137/EBO.S38288

Dionisio

The origin of eukaryotic cells is one of the most fascinating challenges in biology, and has inspired decades of controversy and debate. The relative contributions of genetic drift [54], mutation [55] and selection [56,57]—perhaps at multiple levels [58]—to the origin and evolution of eukaryotes and their genomes remains a fascinating area of debate, and broad comparative data of the type presented by Elliott & Gregory [53] will continue to play an important role in contrasting the predictions of the leading hypotheses. Inferring ancient events from small amounts of data using methods that are not completely up to the job is unlikely to be error-free, and some views will no doubt change again. [...] it is very clear, and has been for some time [8,9,88], that widespread HGT means that no single tree can depict the history of all genes on prokaryotic or eukaryotic genomes.

Changing ideas about eukaryotic origins Tom A. Williams and T. Martin Emblem Philos Trans R Soc Lond B Biol Sci.370(1678): 20140318. doi: 10.1098/rstb.2014.0318

Dionisio

One of the more intriguing enterprises in comparative genomics is to infer the nature of the last universal common ancestor, also called Luca, on the basis of gene content [...] [...] Luca means different things to different people anyway. [...[ many studies score genes as present in Luca if the genes are present in several archaea and one (or more) bacterium, or present in several bacteria and one (or more) archaeon [...] Transdomain LGT generates gene distribution patterns that complicate the inference of Luca's gene content. If a gene family was invented relatively late in evolution [...]

One step beyond a ribosome: The ancient anaerobic core Filipa L. Sousa,? Shijulal Nelson-Sathi, and William F. Martin Biochim Biophys Acta. 1857(8): 1027–1038. doi: 10.1016/j.bbabio.2016.04.284

Huh? invented ? Let's assume we have all the building blocks for LUCA. How do we use them to assemble LUCA -at least theoretically? Where's the beef? Emphasis mine. Dionisio

A growing theme in the field is now the roles and connections between metabolism and cell homeostasis mediated by tRNA post-transcriptional modifications.

From Prebiotics to Probiotics: The Evolution and Functions of tRNA Modifications Katherine M. McKenney and Juan D. Alfonzo Life (Basel). 6(1): 13. doi: 10.3390/life6010013

Dionisio

All nucleic acids in cells are subject to post-transcriptional chemical modifications. These are catalyzed by a myriad of enzymes with exquisite specificity and that utilize an often-exotic array of chemical substrates. In no molecule are modifications more prevalent than in transfer RNAs. [...] the choice of tRNA is not a whimsical one but rather highlights its critical function as an essential invention for the evolution of protein enzymes.

From Prebiotics to Probiotics: The Evolution and Functions of tRNA Modifications Katherine M. McKenney and Juan D. Alfonzo Life (Basel). 6(1): 13. doi: 10.3390/life6010013

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

The division of species of organisms into the three domains of Bacteria, Archaea and Eukarya represents an outstanding discovery [...] and its causes need to be deciphered. [...] the possible roles played by inter-domain variations in rRNA sequences, or the divergence between formylated and non-formylated Met-tRNAi, in bringing about domain separations are unclear.

Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life J. Tze-Fei Wong,* Siu-Kin Ng, Wai-Kin Mat, Taobo Hu, and Hong Xue Life (Basel). 6(1): 12. doi: 10.3390/life6010012

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

The anticodon loop of tRNA, like the genetic code it underwrites, is a product of intense evolutionary engineering. [...] both the base sequence and the nature of modified nucleosides in the anticodon loop need to be highly optimized [...] [...] the stringent challenge faced by the evolving anticodon loops furnished an important incentive [...] The surprising ultra-conservation displayed by some archaeons [...]

Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life J. Tze-Fei Wong,* Siu-Kin Ng, Wai-Kin Mat, Taobo Hu, and Hong Xue Life (Basel). 6(1): 12. doi: 10.3390/life6010012

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

[...] any question relating to the first-appearance domain is unanswerable as long as the relative primitivities of Bacteria, Archaea and Eukarya remain undetermined. [...] the major contribution made by the tRNA introns to pre-Lucans was likely to be anticodon loop diversification resulting from imprecise splicing of the primitive tRNA intron in the anticodon loop. The imprecision gave rise to mutations that facilitated [...]

Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life J. Tze-Fei Wong,* Siu-Kin Ng, Wai-Kin Mat, Taobo Hu, and Hong Xue Life (Basel). 6(1): 12. doi: 10.3390/life6010012

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

The chain of information transfers from DNA to messenger RNA, and through genetic coding to proteins requires the assembly of multiple essential components. Although a range of physicochemical systems have been investigated with respect to their potential to generate informational macromolecule evolution, including chaos theory, complexity theory, fractals, rugged fitness landscapes, Markov chains, hypercycles, dissipative structures, Shannon information theory, autopoiesis, evolutionary algorithms and directed evolution, none of them can selectively give rise to enrichment of RNAs endowed with prescriptive functional information [...]

Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life J. Tze-Fei Wong,* Siu-Kin Ng, Wai-Kin Mat, Taobo Hu, and Hong Xue Life (Basel). 6(1): 12. doi: 10.3390/life6010012

Dionisio

“Why CCA?” is the fundamental unanswered question [...] [...] the question remains as to whether the minihelix is the real progenitor of modern tRNA. What is the real origin of the genetic code? What happened during the evolution of the full-length tRNA from a primitive tRNA? These are still critical issues that should be further investigated.

Origins and Early Evolution of the tRNA Molecule Koji Tamura Life (Basel). 5(4): 1687–1699. doi: 10.3390/life5041687 PMCID: PMC4695843

Dionisio

[...] the correct identification of H3K4me3 peaks in duplicated regions might require separate efforts due to the misannotation of recent and highly similar segmental duplications in genomes. Is this human-specific enrichment in cortex truly singular or a mere reflection of the lower quality achieved by the chimpanzee compared with the human genome, especially within pericentromeric regions? Further studies are warranted to confirm/refute these differences. [...] novelties and neighboring sequences should be investigated not only for gene expression differences and as fertile ground for the emergence of novel genes and transcripts, but also in the quest for lineage-specific epigenetic and regulatory changes.

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures Giuliana Giannuzzi, Eugenia Migliavacca and Alexandre Reymond Genome Res. 24(9): 1455–1468. doi: 10.1101/gr.167742.113

Where's the beef? :) Dionisio

Human and chimpanzee genomes are 98.8% identical within comparable sequences. However, they differ structurally in nine pericentric inversions, one fusion that originated human chromosome 2, and content and localization of heterochromatin and lineage-specific segmental duplications. The possible functional consequences of these cytogenetic and structural differences are not fully understood and their possible involvement in speciation remains unclear. Our results reveal an association between plastic regions and potential novel regulatory elements.

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures Giuliana Giannuzzi, Eugenia Migliavacca and Alexandre Reymond Genome Res. 24(9): 1455–1468. doi: 10.1101/gr.167742.113

Dionisio

Both the concepts of homology and convergence can be united for a common aim: that of identifying the ‘geometry of life’ [41] whose algorithms, if uncovered, would enable an explanation [...] [...] what might be the laws of nature that can lead to nervous system centralization and the formation of brains, or their evolved reduction and loss several times during the course of evolution? It is becoming clear that more than genes, genomes and morphologies are needed to elucidate the origin and evolution of the nervous system, although a start has been made.

Introduction to 'Homology and convergence in nervous system evolution'. Strausfeld NJ1, Hirth F2. Philos Trans R Soc Lond B Biol Sci. ;371(1685):20150034. doi: 10.1098/rstb.2015.0034.

Emphasis mine. Dionisio

Comparisons of rhythmic movements and the central pattern generators (CPGs) that control them uncover principles about the evolution of behaviour and neural circuits. Over the course of evolutionary history, gradual evolution of behaviours and their neural circuitry within any lineage of animals has been a predominant occurrence. Small changes in gene regulation can lead to divergence of circuit organization and corresponding changes in behaviour. However, some behavioural divergence has resulted from large-scale rewiring of the neural network. Divergence of CPG circuits has also occurred without a corresponding change in behaviour. When analogous rhythmic behaviours have evolved independently, it has generally been with different neural mechanisms. Repeated evolution of particular rhythmic behaviours has occurred within some lineages due to parallel evolution or latent CPGs. Particular motor pattern generating mechanisms have also evolved independently in separate lineages. The evolution of CPGs and rhythmic behaviours shows that although most behaviours and neural circuits are highly conserved, the nature of the behaviour does not dictate the neural mechanism and that the presence of homologous neural components does not determine the behaviour. This suggests that although behaviour is generated by neural circuits, natural selection can act separately on these two levels of biological organization.

Evolution of central pattern generators and rhythmic behaviours. Katz PS Philos Trans R Soc Lond B Biol Sci. 371(1685):20150057. doi: 10.1098/rstb.2015.0057.

Dionisio

Bird beaks are textbook examples of ecological adaptation to diet, but their shapes are also controlled by genetic and developmental histories. To test the effects of these factors on the avian craniofacial skeleton, we conducted morphometric analyses on raptors, a polyphyletic group at the base of the landbird radiation. Despite common perception, we find that the beak is not an independently targeted module for selection. Instead, the beak and skull are highly integrated structures strongly regulated by size, with axes of shape change linked to the actions of recently identified regulatory genes. Together, size and integration account for almost 80% of the shape variation seen between different species to the exclusion of morphological dietary adaptation. Instead, birds of prey use size as a mechanism to modify their feeding ecology. The extent to which shape variation is confined to a few major axes may provide an advantage in that it facilitates rapid morphological evolution via changes in body size, but may also make raptors especially vulnerable when selection pressures act against these axes. The phylogenetic position of raptors suggests that this constraint is prevalent in all landbirds and that breaking the developmental correspondence between beak and braincase may be the key novelty in classic passerine adaptive radiations.

The shapes of bird beaks are highly controlled by nondietary factors. Bright JA1, Marugán-Lobón J2, Cobb SN3, Rayfield EJ4. Proc Natl Acad Sci U S A.;113(19):5352-7. doi: 10.1073/pnas.1602683113.

Dionisio

Epistasis in protein evolution. Starr TN1, Thornton JW2. Protein Sci. ;25(7):1204-18. doi: 10.1002/pro.2897. How mutational epistasis impairs predictability in protein evolution and design. Miton CM1, Tokuriki N1. Protein Sci. 25(7):1260-72. doi: 10.1002/pro.2876. Evolving Methanococcoides burtonii archaeal Rubisco for improved photosynthesis and plant growth. Wilson RH1, Alonso H1, Whitney SM1. Sci Rep. ;6:22284. doi: 10.1038/srep22284. Selection on different genes with equivalent functions: the convergence story told by Hox genes along the evolution of aquatic mammalian lineages. Nery MF1, Borges B2, Dragalzew AC2, Kohlsdorf T3. BMC Evol Biol. ;16(1):113. doi: 10.1186/s12862-016-0682-4. Hundreds of Genes Experienced Convergent Shifts in Selective Pressure in Marine Mammals. Chikina M1, Robinson JD2, Clark NL1. Mol Biol Evol. pii: msw112. doi: 10.1093/molbev/msw112

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

[...] this idea has gone from speculation to a prevailing idea. The immediate future of RNA World research should be a very dynamic one.

The RNA World: molecular cooperation at the origins of life. Higgs PG1, Lehman N2. Nat Rev Genet. 16(1):7-17. doi: 10.1038/nrg3841.

Where’s the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

In sum, all of these papers serve to richen the discussion of the RNA World, in all of its various forms. Although definitive confirmation of any of these ideas may require a time machine, I sense that we are at the precipice of a unified theory that accommodates a wide spectrum of RNA-related observations.

The RNA World: 4,000,000,050 years old Niles Lehman Life (Basel). 5(4): 1583–1586. doi: 10.3390/life5041583

Where’s the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

In conclusion, the easiest way to deal with multiple mutations is to assume mutational independence (multiplicative effects), although it slightly overestimates the decrease in fitness due to multiple mutations. We still hasten to add that more data on triple and higher order mutants as well as systematic investigation of multiple mutations of known ribozymes would greatly help us to assess the combined effects of multiple mutations.

Fitness Landscapes of Functional RNAs Ádám Kun1,2,3,* and Eörs Szathmáry1,3 Life (Basel). 5(3): 1497–1517. doi: 10.3390/life5031497

Where’s the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

The prebiotic synthesis of biomolecules, the catalytic aid offered by mineral surfaces, and the vast enzymatic repertoire of ribozymes are only pieces of the origin of life puzzle; the full picture can only emerge if the pieces fit together by either following from one another or coexisting with each other. The dynamical view of the origin of life allows us to pinpoint the missing and the not fitting pieces: (1) How can the first self-replicating ribozyme emerge in the absence of template-directed information replication? (2) How can nucleotide replicators avoid competitive exclusion despite utilizing the very same resources (nucleobases)? (3) How can the information catastrophe be avoided? (4) How can enough genes integrate into a cohesive system in order to transition to a cellular stage? (5) How can the way information is stored and metabolic complexity coevolve to pave to road leading out of the RNA world to the present protein-DNA world?

The dynamics of the RNA world: insights and challenges. Kun Á1, Szilágyi A, Könny? B, Boza G, Zachar I, Szathmáry E. Ann N Y Acad Sci. 1341:75-95. doi: 10.1111/nyas.12700.

Dionisio

In the RNA world, such a takeover may have been triggered by the emergence of some ribozyme favoring the formation of deoxynucleotides. The transition may initially have been “weak”, but could have been reinforced by environmental changes unfavorable to RNA (such as temperature or pH rise), and would have ultimately become irreversible accompanying the genome’s enlargement. Several virtues of DNA (versus RNA) – higher stability against hydrolysis, greater suitability as template and higher fidelity in replication, should have, each in its own way, all been significant for the genetic takeover in evolution.

The emergence of DNA in the RNA world: an in silico simulation study of genetic takeover Wentao Ma, Chunwu Yu, Wentao Zhang, Sanmao Wu, and Yu Fong BMC Evol Biol. 2015; 15: 272. doi: 10.1186/s12862-015-0548-1

Where's the beef? https://www.youtube.com/embed/1hejSyjn760 Dionisio

? Dionisio

[...] phyllosphere colonization by bacteria, fungi, and oomycetes is determined by various mechanisms of species sorting. These include seasonal effects, partitioning between epiphytic and endophytic leaf compartments, and host genetic differences. Because of complementary or antagonistic functions of these hubs, their resolution in plant, human, and other host contexts will improve understanding of what a holobiont is and how it functions. [...] identifying hub interactions will reveal central targets to quickly revolutionize how we understand host–microbe–microbe relationships and to enable better future management of plant microbiomes—a crucial tool for biocontrol and resource saving food security.

Microbial Hub Taxa Link Host and Abiotic Factors to Plant Microbiome Variation Matthew T. Agler,1 Jonas Ruhe,1 Samuel Kroll,1 Constanze Morhenn,1 Sang-Tae Kim,2 Detlef Weigel,3 and Eric M. Kemen PLoS Biol. 2016 Jan; 14(1): e1002352. doi: 10.1371/journal.pbio.1002352

Dionisio

Some now question whether existing conceptual frameworks are adequate to explain microbe-host systems. These scientific discoveries, made possible by sequencing technologies, have led some to question whether the conceptual framework and methodologies of ecology, genetics, and evolution are adequate as a research approach for understanding microbe-host interactions.

Holes in the Hologenome: Why Host-Microbe Symbioses Are Not Holobionts Angela E. Douglas and John H. Werren mBio. 7(2): e02099-15. doi: 10.1128/mBio.02099-15

Dionisio

[...] Koonin contended that these studies indicate that natural selection is not the only force that shapes evolution and may not even be dominant. Others have distanced themselves from the Modern Synthesis to an even greater extent. Woese and Goldenfeld in 2009 urged casting away the Modern Evolutionary Synthesis to permit a fuller reconsideration of the last century of dogma in favor of a full integration of evolutionary theory with microbiology and molecular biology [44]. Shapiro has provided a link towards that goal, calling for a critical rethinking of evolution with natural genetic engineering rather than natural selection as the major mechanism [19]. Perhaps the most comprehensive attempt at a full and comprehensive alternative to the Modern Synthesis has been the promulgation of an Extended Evolutionary Synthesis (EES) [1,2]. Shapiro wrote, “Forty years’ experience as a bacterial geneticist has taught me that bacteria possess many cognitive, computational and evolutionary capabilities unimaginable in the first six decades of the twentieth century.” Evolution can then be properly defined as an information transfer system and can no longer be represented as primarily related to either material biological form as phenotype or natural selection acting upon it. [...] what is hologenomic evolution if not a further appendage of Darwinism and competitive natural selection theory? The primary differences are clear. Hologenomic evolution, in which cognitive entanglement has primacy, is the settling of ambiguities that arise from self-awareness.

Cognition, Information Fields and Hologenomic Entanglement: Evolution in Light and Shadow William B. Miller, Jr. Biology (Basel). 5(2): 21. doi: 10.3390/biology5020021

Where's the beef? Dionisio

[...] the entire cell including its cytoskeletal apparatus and membranes that participate in the resolution of biological uncertainties must be considered as having equivalent primacy with genomes in evolutionary terms.

Biologic relativity: Who is the observer and what is observed? Torday JS, Miller WB Jr. Prog Biophys Mol Biol.121(1):29-34. doi: 10.1016/j.pbiomolbio.2016.03.001

The closest anyone can get to hogwash these days. :) Dionisio

The zygotic unicell is both nexus and point source, both observer and participant, collapsing the superimposition of some but not all Epigenomic states towards robust biologic outcomes in continuous adjustment against a background of a less acutely flexible central genome, and it is through this unique cellular agency that Bohm’s entwined realms of the explicate and implicate intimately connect, the present as past and future, welding physics and biology together in its own form of singular quantum entanglement.

The Unicellular State as a Point Source in a Quantum Biological System John S. Torday, and William B. Miller, Jr. Biology (Basel). 5(2): 25. doi: 10.3390/biology5020025

Where's the beef? Dionisio

It will be interesting to investigate [...] whether the blood-eCSF embryonic barrier transfer system initially developed when brain cavities become sealed in early brain developmental stages, and thus is specific to the vertebrate lineage. [...] further and deeper examination of the mechanisms regulating CSF composition and homeostasis as well as the functions it exerts on neuroepithelial progenitor cells in model organisms from different deuterostome taxa may provide new and important data for the evolutionary and developmental comprehension of the vertebrate brain.

Evolutionary development of embryonic cerebrospinal fluid composition and regulation: an open research field with implications for brain development and function David Bueno and Jordi Garcia-Fernandez Fluids Barriers CNS. 13: 5. doi: 10.1186/s12987-016-0029-y

Dionisio

#1029 follow-up addendum Testing for functionality could be misleading in some cases. For example, let's assume we don't know what the small dark screens attached to back of many airline seats in economy class (mainly long routes) are for. Now let's say we want to thoroughly test their functionality regarding several important criteria: 1. The airplanes capability to take off and land. 2. The fuel efficiency of the airplanes. 3. The maximum number of passengers that can be transported on every flight. 4. The maximum altitude the airplane can reach. 5. The maximum speed the airplanes can fly at. 6. The easiness of boarding and deplaning at the terminals. 7. The ruggedness and reliability of the cockpit instruments. 8. The experience of the pilots. 9. The flight schedules. 10. The airport fees. At the end of the thorough examination -performed redundantly by several teams of experts- we conclude -without any doubt- that the small dark screens attached to the back of the economy seats are definitely non-functional. Would such a conclusion be accurate? Dionisio

It is useful to keep in mind that if our ability to spot lineage-specific coding genes is problematic and fraught with error, the identification of functional human-specific ncRNAs would be even more difficult. [...] it might be beyond our current experimental abilities to obtain causal evidence for certain functional ncRNAs. It is clear that the human genome contains a large number of functional ncRNAs. Indeed it is likely that the list of biologically validated ncRNAs, as listed in the LncRNA Database (Quek et al., 2014), will continue to grow.

Non-coding RNA: what is functional and what is junk? Alexander F. Palazzo* and Eliza S. Lee Front Genet. 6: 2. doi: 10.3389/fgene.2015.00002

I would refrain from classifying anything as either functional or non-functional prematurely. One thing is clear, though: had we stayed in Eden, there wouldn't have been any non-functional parts. However, that's not the case, hence it is expected that some messy/noisy stuff resides in the biological systems. Actually, it's possible that more garbage is being added these days. Still, the presence of that undesired stuff testifies to the robustness of the biological systems, which can operate under adverse thermodynamic noise in stochastic environments. Dionisio

Whether the distinct methods generate similar or distinct epigenetic states of human pluripotent SCs, and more importantly, which of these potentially naïve human pluripotent SCs are more similar to the cells of the human epiblast remain to be determined.

Searching for naïve human pluripotent stem cells Simone Aparecida Siqueira Fonseca, Roberta Montero Costas, and Lygia Veiga Pereira World J Stem Cells. 7(3): 649–656. doi: 10.4252/wjsc.v7.i3.649

Work in progress... stay tuned. Dionisio

The difficulties in classifying HERVs and their complex distribution patterns reflects a long history of cross-species transmission and clade-specific amplification that have been shaped by host, viral, and ecological factors and by species-specific barriers to infection. Unraveling these challenging dynamics will help clarify the origins and evolution of not only retroviral taxa, but of a significant portion of genomic sequences that have originated from retroviral-like elements in vertebrates. Concurrently, the more we learn about ERVs, the clearer it is that HERVs can represent ancient infections among different mammals, some of which are the results of cross-species transmissions.

On the classification and evolution of endogenous retrovirus: human endogenous retroviruses may not be ‘human’ after all Marina Escalera-Zamudio and Alex D. Greenwood DOI: 10.1111/apm.12489 APMIS Special Issue: Human Endogenous Retroviruses Volume 124, Issue 1-2, pages 44–51

Dionisio

#1024 followup Given any case of known evolutionary divergence, it could be described as: Dev(d1) = Dev(ca) + Delta(d1) Dev(d2) = Dev(ca) + Delta(d2) Where Dev(x) is the developmental process of any given biological system x Delta(x) is the whole set of spatiotemporal procedural differences required to produce Dev(x). d1 and d2 are two descendants of their common ancestor (ca). Assuming the Dev(x) are well known, what hypothetical Delta(d1) and Delta(d2) could be suggested for the following cases? Case 1: d1 = placental mammals; d2 = marsupials; Case 2: d1 = placental; d2 = monotreme; Just point to the literature that explains this in details. The explanation must be comprehensive, logically coherent and it must hold water under any kind of thorough examination. Dionisio

A conversation with Denis Noble and Michael J. Joyner at Experimental Biology 2015. Moderated by David J. Paterson, Editor-in-Chief, The Journal of Physiology. At around the 4:30 minutes mark the moderator has setup the framework of the conversation and asks the first question to Dennis Noble: “what is a gene?” and professor Noble’s answer couldn’t be funnier, though very serious at the same time: “let’s be clear – nobody knows.” Then he explains his answer. Here’s the link to the video: https://www.youtube.com/embed/A_q_bOWc8i0

As outstanding questions get answered, new questions are raised. The more we know, more is ahead for us to learn. Complex complexity. Work in progress… stay tuned. The big picture looks more interesting with every new discovery. That's why we look forward, with increasing anticipation, to reading newer research papers that shed more light on the elaborate cellular and molecular choreographies operating within the biological systems. Dionisio

Endogenous retroviruses (ERVs) are proviral DNA elements that insert into the germline cells of the host organism, being vertically transmitted from one generation to the next. [...] we may be approaching the maximum achievable lookback time—at least as far as the mammals are concerned. It may be possible, although very difficult, to identify orthologous insertions between placental mammals and marsupials (both owing to the divergence date of 147 Ma, and also to relatively fast rates of neutral evolution in the extant marsupials) but the placental and monotreme divergence date (167 Ma) may remain beyond reach.

Identification of an ancient endogenous retrovirus, predating the divergence of the placental mammals Adam Lee, Alison Nolan, Jason Watson, Michael Tristem Phil. Trans. R. Soc. B 2013 368 20120503; DOI: 10.1098/rstb.2012.0503.

Dionisio

The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, “young” proviruses competent for retrotransposition—found in many mammals, but not humans—represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.

Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire Peter J. Thompson, Todd S. Macfarlan, Matthew C. Lorincz DOI: http://dx.doi.org/10.1016/j.molcel.2016.03.029 Molecular Cell, Volume 62, Issue 5, p766–776,

Dionisio

Transposable elements (TEs) are notable drivers of genetic innovation. [...] TE insertions can supply new promoter, enhancer, and insulator elements to protein-coding genes and establish novel, species-specific gene regulatory networks. [how?] Conversely, ongoing TE-driven insertional mutagenesis, nonhomologous recombination, and other potentially deleterious processes can cause sporadic disease by disrupting genome integrity or inducing abrupt gene expression changes. Mammalian embryonic development is governed by a complex set of genetic and epigenetic instructions. While L1-mediated somatic mosaicism in neurons may eventually be shown to have functional or behavioral consequences, numerous additional experiments are required to assess this hypothesis. Whether perturbation of L1 regulation and retrotransposition in the brain is connected to neurological disease is not yet clear. The mammalian genome clearly strives to limit TE activity in pluripotent cells. The silencing mechanisms involved are collectively complex and broadly potent and yet are also capable of great specificity and dynamism in targeting individual TE copies. Why are TEs active, and apparently essential, in the embryo? [...] indispensability of ERV-mediated regulatory effects in natural pluripotency and embryogenesis in vivo is still an open question.

Transposable elements in the mammalian embryo: pioneers surviving through stealth and service Patricia Gerdes, Sandra R. Richardson, Dixie L. MagerEmail author and Geoffrey J. Faulkner Genome Biology 201617:100 DOI: 10.1186/s13059-016-0965-5

Complex complexity Work in progress… stay tuned Dionisio

One tissue that has attracted continued interest is the placenta. Placenta formation involves extensive cell fusion to form the syncytial trophoblast layer and it is easy to see how the fusogenic properties of the Env protein might be put to use in this regard. [ok, but how?] [...] small interfering RNA-mediated suppression of syncytin expression in spontaneously differentiating trophoblasts interferes with cell–cell fusion, suggesting role(s) in placenta formation [...] [ok, which specific roles?] Apparently, a mechanism involving gap junction formation compensates for fusion loss. [ok, but how?] Further examples of ERV capture and utilization in placenta formation have been reported in a variety of mammalian orders [...] [ok, and...?] It is tempting to suggest that the variety of structures of placenta seen in different orders of mammals can be explained by the expression, receptor, and fusion properties of the specific ERVs put to use in each case. [ok, but how?] This would imply that ERV capture has played a major role in the evolutionary history of placental mammals. [ok, but how?]

Mager D, Stoye J. 2015. Mammalian Endogenous Retroviruses. Microbiol Spectrum 3(1):MDNA3-0009-2014. doi:10.1128/microbiolspec.MDNA3-0009-2014.

tempting to suggest can be explained put to use would imply played a major role is that all they can explain? oh, no! I expected much more than that! :( oh, well... too bad... next time. :) Let's keep looking for other papers that shed more light on the subject. There are bunch of those papers out there and more coming out of the wet and dry labs all the time. Eventually they should figure it all out. :) Dionisio

ERVs have an enigmatic relationship with their host species. [...] the negative effects of active ERVs as genomic mutagens and cancer-causing agents are well established. As the field of noncoding RNA continues to grow, it is likely that many cellular roles for ERV-derived RNAs will be uncovered. ERV-mediated involvement in gene regulation via the production of lncRNAs is an intriguing emerging topic. How Fv1 selects it target and restricts replication are still open questions. [...] the detailed mechanisms of target recognition and restriction remain to be elucidated.

Mager D, Stoye J. 2015. Mammalian Endogenous Retroviruses. Microbiol Spectrum 3(1):MDNA3-0009-2014. doi:10.1128/microbiolspec.MDNA3-0009-2014.

Dionisio

The mammalian placenta exhibits elevated expression of endogenous retroviruses (ERVs), but the evolutionary significance of this feature remains unclear. Retroviruses facilitate the rapid evolution of the mammalian placenta Edward B. Chuong DOI: 10.1002/bies.201300059 BioEssays Volume 35, Issue 10, pages 853–861, Dionisio

Protein folding has been viewed as a difficult problem of molecular self-organization. The search problem involved in folding however has been simplified through the evolution of folding energy landscapes that are funneled. The funnel hypothesis can be quantified using energy landscape theory based on the minimal frustration principle. Strong quantitative predictions that follow from energy landscape theory have been widely confirmed both through laboratory folding experiments and from detailed simulations. Energy landscape ideas also have allowed successful protein structure prediction algorithms to be developed. The selection constraint of having funneled folding landscapes has left its imprint on the sequences of existing protein structural families. Quantitative analysis of co-evolution patterns allows us to infer the statistical characteristics of the folding landscape. These turn out to be consistent with what has been obtained from laboratory physicochemical folding experiments signaling a beautiful confluence of genomics and chemical physics.

Evolution, energy landscapes and the paradoxes of protein folding http://www.ncbi.nlm.nih.gov/pubmed/25530262

Dionisio

The advent of whole-genome sequencing and inexpensive genotyping has reinvigorated strategies for identifying genes undergoing adaptive change. [...] fly populations have a large reservoir of common variation that can fuel their rapid response to a selective challenge. [...] few hundred naturally existing common variants in at least 100 genes are likely to regulate egg-size differences in D. melanogaster.

Whole-Genome Resequencing of Experimental Populations Reveals Polygenic Basis of Egg-Size Variation in Drosophila melanogaster Aashish R. Jha,*,1,2,3 Cecelia M. Miles,4 Nodia R. Lippert,4 Christopher D. Brown,1,5 Kevin P. White,1,2,3,6 and Martin Kreitman*,1,3,6 Mol Biol Evol (2015) 32 (10): 2616-2632. doi: 10.1093/molbev/msv136 http0://mbe.oxfordjournals.org/content/32/10/2616.full

Where is the beef? Microevolution = built in adaptive mechanisms? At the end flies remain flies, don't they? Dionisio

Metabolic rewiring is considered one of the hallmarks of hypoxia response and it is essential for cellular survival in hypoxia [...] [...] hairy, is a known hypoxia response gene in flies. [...] Egfr activates Ras-raf-MAPK signaling pathway—which is also vital in hypoxia. Both hairy and Egfr are also involved in respiratory system development and influence Notch signaling, which in turn plays an important role in hypoxia tolerance in flies. [...] the individual contributions of these genes in hypoxia remain to be determined. [...] future work with additional RNAi lines may reveal the functional relevance of many of the candidate genes that we have identified in hypoxia response in flies. [...] additional work is required [...] to elucidate the mechanisms by which they affect hypoxia tolerance. There is no doubt that locale-specific signals of adaptation have occurred due to founder effects, de novo beneficial mutations that arose in each population, and introgression of DNA carrying beneficial mutations from nearby populations [...] [...] very little overlap of candidate genes across high-altitude populations has been puzzling. [...] hypoxia tolerance is a highly polygenic trait that involves over 100 genes in diverse biological and molecular processes.

Shared Genetic Signals of Hypoxia Adaptation in Drosophila and in High-Altitude Human Populations Aashish R. Jha*, Dan Zhou, Christopher D. Brown†, Martin Kreitman, Gabriel G. Haddad, and Kevin P. White Mol Biol Evol (2016) 33 (2): 501-517. doi: 10.1093/molbev/msv248 http://mbe.oxfordjournals.org/content/33/2/501.full

single nucleotide polymorphism (SNP) control fly (CF) adapted fly (AF) Where is the beef? Microevolution = built in adaptive mechanisms? At the end flies remain flies and humans remain humans, don't they? Dionisio

Many key steps remain to be reconstructed, including how and when the interaction between GKPID and KHC-73 evolved, the mechanisms by which Pins’ acquired its linker and GoLoco sequences, and the relationship of these components to other molecular complexes and pathways involved in animal spindle orientation.

Evolution of an ancient protein function involved in organized multicellularity in animals Douglas P Anderson, Dustin S Whitney, Victor Hanson-Smith, Arielle Woznica, William Campodonico-Burnett, Brian F Volkman, Nicole King, Kenneth E Prehoda, Joseph W Thornton DOI: http://dx.doi.org/10.7554/eLife.10147 eLife 2016;5:e10147 http://elifesciences.org/content/5/e10147#F1

Complex complexity Work in progress... stay tuned Dionisio

Here's a recent evodevo article containing pseudoscientific nonsense that fails to answer the fundamental question "where's the beef?", because queen and worker ants remain just that, ants, even after shuffled and mixed all they want: http://evodevojournal.biomedcentral.com/articles/10.1186/s13227-015-0031-5 Dionisio

Polyphenisms are adaptations in which a genome produces discrete alternative phenotypes in different environments. The present study begins to address the question, what is the genetic basis of genetic accommodation of a polyphenism? [...] we cannot rule out the presence of other sex-linked modifier genes. It is therefore plausible that polyphenisms in many instances involve a few genes of major effect with many modifiers that allow for fine-tuning of the threshold, reaction norm and endocrine regulation. Although the genetic underpinnings of polyphenisms are not well understood, it is clear that most if not all polyphenisms are regulated by hormonal switches during development. It is possible, although not yet proven, that the larval colour polyphenism reported here may also have evolved by changes in the mechanism that regulates JHE activity. The genetic basis for the genetic assimilation of Drosophila bithorax phenotype has been shown to be attributable to a major effect mutation in the regulation of the Ultrabithorax gene.

Genetic basis of adaptive evolution of a polyphenism by genetic accommodation Y. SUZUKI and H. F. NIJHOUT DOI: 10.1111/j.1420-9101.2007.01464.x Journal of Evolutionary Biology Volume 21, Issue 1, pages 57 http://onlinelibrary.wiley.com/doi/10.1111/j.1420-9101.2007.01464.x/full

Where is the beef? Emphasis mine. Dionisio

It remains to be determined whether such proposed positive and negative inputs are mediated by a single or multiple independent CRM. In future analyses it will also be important to examine BMP-mediated regulation of additional neural identity genes expressed along the dorsal-ventral axis including the Gsh ? ind and Nxk2.2 ? vnd genes as CRMs controlling expression of each of these genes will have undergone independent evolutionary trajectories. It will also be interesting to understand how flexible the ancestral metazoan state was by investigating the relationship between BMPs and msx genes in basal metazoans such as jellyfish.

BMPs Regulate msx Gene Expression in the Dorsal Neuroectoderm of Drosophila and Vertebrates by Distinct Mechanisms Francisco F. Esteves, Alexander Springhorn, Erika Kague, Erika Taylor, George Pyrowolakis, Shannon Fisher, Ethan Bier PLOS •DOI: 10.1371/journal.pgen.1004625 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004625

Where's the beef? So much pseudoscientific hogwash (not quoted here) written in a single paper. What a waste. Complex complexity Work in progress... stay tuned Dionisio

Whether the BMP-responsive site in the 671 bp msxB CRM together with other potential BMP-responsive elements mediate such a biphasic response will be interesting to address in future experiments. In the future, it will also be important to determine whether expression of other msx paralogs in the dorsal CNS of zebrafish [...] or msx genes in other vertebrates [...] are similarly regulated by BMPs. Analysis of these additional vertebrate msx CRMs should reveal whether distinct evolutionary trajectories have shaped the BMP responsiveness of these elements. Such comparative studies may also shed light on whether there is a single or multiple independent origin(s) of BMP regulation of vertebrate msx genes. Furthermore, analysis of the CRM driving BMP-dependent expression of an echinoderm Msx homolog in regions of peak BMP activity [...] will be informative since this gene is expressed in the non-neural ectoderm.

BMPs Regulate msx Gene Expression in the Dorsal Neuroectoderm of Drosophila and Vertebrates by Distinct Mechanisms Francisco F. Esteves, Alexander Springhorn, Erika Kague, Erika Taylor, George Pyrowolakis, Shannon Fisher, Ethan Bier PLOS •DOI: 10.1371/journal.pgen.1004625 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004625

[emphasis mine] job security? in the future provide more funding to continue looking for a black cat in a dark room, believing that the cat is in he room...? where's the beef? Complex complexity Work in progress... stay tuned Dionisio

Whether this unique architecture of the msxB BMP activation site is relevant to activity within the neuroectoderm remains to be explored. Given the opposing mechanisms by which the msh and msxB CRMs respond to BMPs, it is intriguing that a site within the msh CRM closely resembling an activation site (AE2) is required for activation of this CRM. Also, another AE-like site (AE1) lies within a region which when deleted greatly reduces ME driven reporter gene expression, although the role of that AE1 site remains to be examined. [...] it is tempting to speculate that these sites could once have been BMP responsive activation sites and were subsequently co-opted by different transcription factors [...] Identifying such transcriptional activators is an interesting goal for future experiments.

BMPs Regulate msx Gene Expression in the Dorsal Neuroectoderm of Drosophila and Vertebrates by Distinct Mechanisms Francisco F. Esteves, Alexander Springhorn, Erika Kague, Erika Taylor, George Pyrowolakis, Shannon Fisher, Ethan Bier PLOS •DOI: 10.1371/journal.pgen.1004625 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004625

[emphasis mine] intriguing? tempting to speculate? co-opted? where's the beef? Complex complexity Work in progress... stay tuned Dionisio

[...] it is currently unclear if Leishmania chromosomes possess discrete centromeres or where in each chromosome these features might be located [...] [...] it remains only partly understood what features dictate that some potential origins are activated frequently, while others are not. Comparing factors bound to origin-active and non-active SSRs in the two related parasites may reveal how the co-ordination mechanisms needed for origin multiplicity arose in eukaryotes. [oh yeah good luck!]

Genome-wide mapping reveals single-origin chromosome replication in Leishmania, a eukaryotic microbe Catarina A. Marques†, Nicholas J. Dickens†, Daniel Paape, Samantha J. Campbell and Richard McCulloch* Genome Biology 16:230 doi:10.1186/s13059-015-0788-9 http://www.genomebiology.com/2015/16/1/230

Comparing factors... may reveal how... yadayadayada blah blah blah Oh yeah, good luck. Mina's parole, parole, parole... Where's the beef? Sad to see an otherwise good paper being trashed by nonsense hogwash like that. Dionisio

Understanding how Nodal and BMP together with Lefty and Chordin so precisely chisel the position and width of the ciliary band will be a challenge in the future. Taken together, these findings suggest that the evolutionary origin of the Spemann organizer may be more ancient than previously thought and suggest that this origin may be traced back to the common ancestor of deuterostomes. How far can we trace back the evolutionary origin of the D/V organizer? The idea of an even more ancient evolutionary origin of a D/V organizer is strongly suggested by molecular and embryological studies on secondary axis formation in different clades [...] [...] raising the intriguing possibility that the evolutionary origin of the D/V organizer may be traced further back to the basis of the phylogenetic tree.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 doi:10.1038/ncomms9434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Since the "S" organizer seems so conserved, how exactly did it come to be to begin with? How would you have done it, for example? Dionisio

[...] several well-known developmental processes are capable of modifying wing size and shape. [...] it remains to be established whether these processes have been modified during wing evolution, or if natural variation comes from other developmental processes. [...] the genetic basis of variation in wing size and shape is highly polygenic (i.e., influenced by a large number of genes), [...] There are many events that must occur during wing development. [...] the same genes and pathways are often involved in the regulation of several developmental processes. Variation in discrete traits such as presence/absence of an organ or feature can sometimes (but not always [...]) be explained by precise changes in the regulation of expression of one or a small number of genes. Future work will need to address whether the diffuse, multivariate differences in Drosophila wing shape rely on such a simple explanation.

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24255/abstract

Where's the beef? All this trouble just to explain the built-in adaptation mechanisms underlying the wing shape variations? Like the famous Galapagos finch beak shapes story that got grossly extrapolated into a huge theory in the middle of the 19th century? That's microevolution! No one argues against that! But all I see in this and other "evo-devo" papers is Mina's "parole, parole, parole". The beef is in macroevolution. What was the last common ancestor of the flying insects that did not fly (i.e. had no wings)? How did it go from nonflying to flying insects? What exact changes in the developmental processes led to that? How did we get the poorly described built-in adaptation mechanisms for wing shape to begin with? Where are the papers showing the detailed explanation to answer all those and other related questions? Show me the money! Complex complexity. Work in progress... stay tuned. Dionisio

[...] what is known about how the wing achieves its final shape, and what variation in development is capable of generating the variation in wing shape observed in nature? Three major developmental stages need to be considered: larval development, pupariation, and pupal development. The major cellular processes involved in the determination of tissue size and shape are cell proliferation, cell death, oriented cell division and oriented cell intercalation. [...] how variation in temporal and spatial distribution of growth and transcription factors affects these cellular mechanisms, which in turn affects wing shape? [...] which aspects of the wing morphological variation are predictable on the basis of these mechanisms?

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24255/abstract

Isn't this just about the built-in adaptation mechanisms observed in the biological systems -i.e. microevolution? Where's the beef? Dionisio

#1004 addendum

Repertoire diversity in the first exposure to antigen is regulated by opposing forces of poorly known strength. Studies of repeated exposures to similar antigens reveal contrasting observations: repertoires show signatures of both contingent and convergent evolution. In contingent evolution, chance events, like mutations or infections with other pathogens, affect the induced repertoire. By contrast, seemingly diverse responses may eventually converge via evolution.

The evolution within us Sarah Cobey, Patrick Wilson, Frederick A. Matsen DOI: 10.1098/rstb.2014.0235 http://rstb.royalsocietypublishing.org/content/370/1676/20140235 The Royal Society Publishing

Complex complexity. Work in progress... stay tuned. Dionisio

#1003 addendum

While high-throughput sequencing and other technologies are broadening our view of B-cell populations, the resulting data have simultaneously underscored our ignorance. Why are some lineages more frequently seen than others? How can we recognize the members of a clonal family? What selective pressures operate on different B-cell types? Increasingly sophisticated methods of sequence analysis have begun to answer these kinds of questions.

The evolution within us Sarah Cobey, Patrick Wilson, Frederick A. Matsen DOI: 10.1098/rstb.2014.0235 http://rstb.royalsocietypublishing.org/content/370/1676/20140235 The Royal Society Publishing

Complex complexity. Work in progress... stay tuned. Dionisio

#1002 addendum

B cells evolve in each individual through their receptors, which are secreted in soluble form as antibodies by some classes of B cells. B cells further evolve upon exposure to antigen. This process, known as affinity maturation, involves strong competition and selection for B-cell receptor binding to antigen.

The evolution within us Sarah Cobey, Patrick Wilson, Frederick A. Matsen DOI: 10.1098/rstb.2014.0235 http://rstb.royalsocietypublishing.org/content/370/1676/20140235 The Royal Society Publishing

Complex complexity. Work in progress... stay tuned. Dionisio

Here's a kind of evolution we can all agree on, because the word is correctly used in the right context (except in a few parts of the text). This is a type of evolution that must be the focus of attention of many biology researchers:

The B-cell immune response is a remarkable evolutionary system [...] B-cell receptors, the membrane-bound form of antibodies, are capable of evolving high affinity to almost any foreign protein. High germline diversity and rapid evolution upon encounter with antigen explain the general adaptability of B-cell populations, but the dynamics of repertoires are less well understood. B cells evolve on the time scale of pathogen populations and secrete pathogen-specific antibodies that protect us from infection. But despite their importance to our survival and the unique circumstances of their evolution, the dynamics of B-cell populations remain largely unexplored.

The evolution within us Sarah Cobey, Patrick Wilson, Frederick A. Matsen DOI: 10.1098/rstb.2014.0235 http://rstb.royalsocietypublishing.org/content/370/1676/20140235 The Royal Society Publishing

Complex complexity. Work in progress... stay tuned. Dionisio

1000+ posts but so little discussion? Is this that boring? really? :) What about the guys who were supposed to pay Dr. Tour's lunch? Are they still out there? Can they come here and explain all the stuff referenced here? Can they answer all the posted questions? Actually, can they answer any question posted in this thread? Dionisio

Here Mina would have to sing her hit "parole, parole" many times: http://rstb.royalsocietypublishing.org/content/370/1678 There's a lot of "beef" deficit in the listed papers. Dionisio

Could we apply Mina's "parole, parole" to this case, at least partially?

We have explored several heterodox views that imagine [...] [...] we hold that it is not irrational or illogical to question [...] It seems certain that [...] There is no reason to believe that complexity is always and of itself adaptive and destined to increase, and in fact, there are many well-documented examples of genomic reduction and streamlining. [Duh!] More problematic but also more testable would be claims [...] Such claims must be examined on a case-by-case basis, and it is almost certain that such examination will be confounded by (i) disagreements over evolutionary models in phylogenetics, (ii) differing histories of the many components of any complex CSS, (iii) arguments over the role of LGT in those histories, (iv) diversity among eukaryotes and (especially prokaryotes), making nonsense of any generalizations about what is typical for either and (v) problematic attributions of function to proteins known only from genomic or metagenomic DNA sequence data. we may some day achieve consensus [...] Detailed argumentation [...] will be required to reach a consensus [...] A consensus on the meaning of words will be required [...]

Eukaryotes first: how could that be? Carlos Mariscal, W. Ford Doolittle DOI: 10.1098/rstb.2014.0322 The Royal Society

Do they say where's the beef anywhere in this paper? Why don't all those scientists concentrate their efforts on trying to understand how things work, rather than wasting time attempting unsuccessfully to guess how things came to exist? It's fine to describe what is where, but why using that description to guess what could have happened? Dionisio

gpuccio I heard that Italian song many years ago, but didn't know it was associated with a TV show. Now I know it. :) Some "evo-devo" papers remind me of the lyrics of that song, where the guy is saying the most 'romantic' things anybody could think of, but Mina keeps repeating how fake those words are in reality. At least that's the idea I get when I read it, though I don't understand some words or phrases. Please, correct me if I'm wrong. Thanks. Now that I see how the memories associated with that song brought you back here, I'm glad I chose to write the song lyrics in my comment. :) As Mung wrote, we've witnessed a gpuccio sighting in this otherwise 'boring' thread! :) And yes, I also agree with you that there's so much interesting information resulting from biology research, that we could have very serious discussions about what they mean and their implications. We all could learn much from such discussions. Most probably I could learn the most. Dionisio

Mung: :) gpuccio

a gpuccio sighting! Mung

Dionisio: I just couldn't resist! Parole parole reminds me of when I was very, very young, and the song was the ending credits theme music in a very successful italian TV show of those times. OK, I hope I will find some time (and motivation) to stick around. I always appreciate your contributions, which are rather isolated attempts at bringing back the discussion where it should belong: biology and information in biology. Thank you for that. It is frustrating to witness daily how our knowledge of details of what happens constantly increases, while our understandind of why and how it happens remains really lacking. As you say, until we understand why something happens, we cannot really answer the important question: how did what makes it happen come into existence? gpuccio

Mio caro Dottore!!! What a pleasant surprise to see you back here! I (and most probably many folks here) missed your insightful articles and commentaries, along with your highly respectful treatment of opponents and your always refreshing sense of humor. Thank you for writing back! Dionisio

Apparently the pseudoscientific nonsense referenced @991 was -at least in part- a critique of previous papers by other authors, including this:

Lane N. Power, Sex, Suicide: Mitochondria and the Meaning of Life. Oxford Univ Press; Oxford: 2005 http://www.amazon.com/Power-Sex-Suicide-Mitochondria-Meaning/dp/0199205647

Then, the attacked author(s) fired back:

Booth and Doolittle (1) criticize three supposed flaws in our argument (2) that the energetic advantage of mitochondria enabled the prokaryote to eukaryote transition. Their critique, not our paper, is flawed. A reply is in order. First, Booth and Doolittle (1) claim that our paper (2) argued that the energetic benefit of mitochondria is larger genomes. We clearly stated: The energetic cost of possessing many genes is trivial, the cost of expressing them as protein is not (2). This is because DNA synthesis consumes about 3% of a microbial cell’s energy budget, whereas protein synthesis consumes about 75% (3). The energetic hurdle at eukaryote origin is [...]

Eukaryotes really are special, and mitochondria are why Nick Lane and William F. Martin PNAS vol. 112 no. 35 E4823, doi: 10.1073/pnas.1509237112 http://www.pnas.org/content/112/35/E4823.short

Well, a reply came right away:

In their letter, Lane and Martin (1) take us to task for our treatment (2) of their earlier paper (3). In that paper (3), there is much about genes, albeit mostly about the cost of their expression, not their replication. The focus is on how many additional genes mitochondria allow cells to have, and the number of different proteins they might thus make. For example, Lane and Martin write (3), “The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed,” and again that, “Mitochondria increased the number of [...]

Reply to Lane and Martin: Being and becoming eukaryotes Austin Booth and W. Ford Doolittle PNAS vol. 112 no. 35 E4824, doi: 10.1073/pnas.1513285112 http://www.pnas.org/content/112/35/E4824.extract

What's next ? Complex complexity. Dionisio

Dionisio: Ah, Mina! :) gpuccio

The pseudoscientific "evo-devo" daydreaming "hogwash on steroids" papers like this sometimes remind me of this Italian song lyrics:

Una parola ancora Parole, parole, parole Ascoltami Parole, parole, parole Ti prego Parole, parole, parole lo ti giuro Parole, parole, parole parole, soltanto parole parole tra noi.

Eukaryogenesis, how special really? Austin Booth and W. Ford Doolittle PNAS vol. 112 no. 33 10278–10285, doi: 10.1073/pnas.1421376112 http://www.pnas.org/content/112/33/10278.full

They all fall into the dreadful "where's the beef?" category. Simply pathetic. They could have dedicate their time and energy to focus in on trying to understand the complex mechanisms underlying the morphogen gradient formation and interpretation, among other issues associated with morphogenesis, organogenesis and ultimately the whole biological systems. That's the price of this bottom-up reverse-engineering approach they take to analyze complex functional information-processing systems. Dionisio

[...] the mechanisms that lead or have led to the formation of stable patterns of cell differentiation in emerging multicellular organisms are not yet clear [...]

Development of cell differentiation in the transition to multicellularity: a dynamical modeling approach Emilio Mora Van Cauwelaert, Juan A. Arias Del Angel, Mariana Benítez, and Eugenio M. Azpeitia Front. Microbiol., 23 June 2015 | http://dx.doi.org/10.3389/fmicb.2015.00603 http://journal.frontiersin.org/article/10.3389/fmicb.2015.00603/abstract

Where's the beef ? Not yet clear? This is ridiculous. Of course they are not clear, because no one understands even how they work! They're squandering precious time on trying to figure out how we got this complex process known as "morphogen gradient formation", before understanding how exactly it works. Nonsense. Wrong priorities. Oh, well. What else is new? Pathetic. What we need to understand well are both the morphogen gradient formation and interpretation mechanisms. Then, once we get that exactly clear, if you still have any time left, you may waste your time on all that "evo-devo" daydreaming "hogwash on steroids" stuff, if that's what satisfy you. First things first. Dionisio

What is the minimum signaling needed to produce a pattern? We believe that it would be interesting to evaluate these ideas with oriented experiments in order to validate the possible predictions. In fact, we consider that joint theoretical and experimental approaches (e.g., experimental evolution) will be key to uncovering some fundamental principles behind the development and evolution of multicellularity.

Development of cell differentiation in the transition to multicellularity: a dynamical modeling approach Emilio Mora Van Cauwelaert, Juan A. Arias Del Angel, Mariana Benítez, and Eugenio M. Azpeitia Front. Microbiol., 23 June 2015 | http://dx.doi.org/10.3389/fmicb.2015.00603 http://journal.frontiersin.org/article/10.3389/fmicb.2015.00603/abstract

Finding the procedures underlying the morphogen gradient formation is a very challenging task ahead. Don't hold your breadth waiting for that discovery. Dionisio

#986 addendum

A growing body of evidence indicates that genes encoding protein modules are often co-regulated by limited number of transcription factors (‘selector genes’), such as LIM and POU homeodomain family proteins; these factors act via similar cis-regulatory elements, thus forming so-called ‘programming modules’.

"programming modules"? That's interesting. What's next?

Once sets of genes encoding cellular modules and their specifying transcription factors will be attributed, at larger scale, to specific cell types in different species, this will set the stage for the identification of homologous cell types.

That's fine. And...

Also, it will be possible to elucidate sister cell type relationships within a given species.

Ok. However, here they go again with more of the same "hogwash on steroids" stuff:

We predict that the combination of comparative genomics and comparative single cell-transcriptomics will boost our understanding of cell type evolution in animals.

Poor things, they don't realize they're doomed to more shocking, unexpected, surprising, disappointing (to them) discoveries. We told them so. But they don't want to listen. Oh, well. Too bad. :) Dionisio

#986 follow-up IKEA sells many products that the buyer has to assemble him/herself. What the person has to do is simple: 1. Remove the parts from the package. 2. Look at the parts. 3. Put them together. That's it. No step-by-step instructions are required. The parts themselves are self-explanatory. The sequence of assembly is not important at all. Is this right? Well, according to some papers referenced here, that's all we need. Any objection? Dionisio

Where's the beef? This is another boring passive description of what is seen, not how to get it. Using a similar approach to theirs, one could draw a map of the evolution from a Toyota Camry to a Lexus. But wouldn't that only show the parts in one and the other and draw unfounded conclusions based on their comparison? To know how to go from a Camry to a Lexus, shouldn't we ask the Toyota engineers to explain how they designed the two cars, and the assembling procedures to produce them? Are the steps to produce a Lexus exactly the same as the steps to produce a Camry, or a Highlander, or a Tundra truck? http://auto.howstuffworks.com/electric-car-pictures.htm http://auto.howstuffworks.com/under-the-hood/auto-manufacturing/automotive-production-line.htm Refer to comments @937 @942 @984 @985

Structural evolution of cell types by step-wise assembly of cellular modules Kaia Achim, Detlev Arendt doi:10.1016/j.gde.2014.05.001 Current Opinion in Genetics & Development Volume 27, Pages 102–108 Developmental mechanisms, patterning and evolution http://www.sciencedirect.com/science/article/pii/S0959437X14000483

Having certain genes does not necessarily guarantee that they will be expressed or when they will be expressed or whether their transcripts will undergo post-transcriptional regulation or even post-translational regulation. There’s a long way to go from having a certain gene to what effect it could make. There’s much more to cellular and molecular biology than the genome. Nice try, but no, thanks. They should explain the molecular processes to get from any ancestors to their associated descendants (specially changing their specific developmental choreographies). Anywhere in their ever-changing trees, we should point to any item Y and have an accurate molecular explanation about how to get from X (Y’s closest ancestor) to Y and from Y to Z (Y’s closest descendant). X->Y->Z anywhere in their evolving tree, except the root and the tips. For the root item, we could only expect the molecular explanation for Y->Z whereas for the tip items we can only expect the molecular explanation for X->Y. Dionisio

[...] whose genomes encode an expanded repertoire of eukaryotic signature proteins that are suggestive of sophisticated membrane remodelling capabilities. [...] many components that underpin eukaryote-specific features were already present in that ancestor.

Complex archaea that bridge the gap between prokaryotes and eukaryotes Anja Spang, Jimmy H. Saw, Steffen L. Jørgensen, Katarzyna Zaremba-Niedzwiedzka, Joran Martijn, Anders E. Lind, Roel van Eijk, Christa Schleper, Lionel Guy & Thijs J. G. Ettema Nature 521, 173–179 (14 May 2015) doi:10.1038/nature14447 http://www.nature.com/nature/journal/v521/n7551/full/nature14447.html

Having certain genes does not necessarily guarantee that they will be expressed or when they will be expressed or whether their transcripts will undergo post-transcriptional regulation or even post-translational regulation. There's a long way to go from having a certain gene to what effect it could make. There's much more to cellular and molecular biology than the genome. Nice try. Dionisio

What next? Does Loki bridge archaea and eukaryotes as stated in the title of the article by Ettema and colleagues? I think this is still only a halfway bridge. A lot of difficult work remains to be done to join the two banks. Although we can never know what precisely happened [...]. This is an extremely tall order [...]

Archaeal ancestors of eukaryotes: not so elusive any more Eugene V. Koonin BMC Biology 2015, 13:84 doi:10.1186/s12915-015-0194-5 http://www.biomedcentral.com/1741-7007/13/84

Umnitsa! Prosta maladiets! Where's the beef? As a bonus, I would gracefully give them all the gap fillers they want. The whole cellular repertoire. Thus they don't have to keep looking. Then will ask them to explain the molecular processes to get from any ancestors to their associated descendants (specially changing their specific developmental choreographies). Anywhere in their ever-changing trees, we should point to any item Y and have an accurate molecular explanation about how to get from X (Y's closest ancestor) to Y and from Y to Z (Y's closest descendant). X->Y->Z anywhere in their evolving tree, except the root and the tips. For the root item, we could only expect the molecular explanation for Y->Z whereas for the tip items we can only expect the molecular explanation for X->Y. Wouldn't that be fair and easy? :) Dionisio

So much "evo-devo" hogwash spilled in otherwise interesting research papers. So much precious time squandered on writing all that nonsense, while seriously dedicated scientists are working hard, trying to understand the fascinating interwoven mechanisms underlying the elaborate cellular and molecular choreographies orchestrated within the biological systems. Dionisio

[...] raising the intriguing possibility that the evolutionary origin of the D/V organizer may be traced further back to the basis of the phylogenetic tree.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

Interestingly, the ability to regulate and to give rise to well-proportioned embryos after bisection is not restricted to deuterostomes but is also observed in insects [...] It will therefore be very interesting to investigate the function of Nodal and to determine if admp and genes encoding Dpp-like ligands are under opposite transcriptional control in these organisms.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

[...] the evolutionary origin of the Spemann organizer may be more ancient than previously thought [...] How far can we trace back the evolutionary origin of the D/V organizer?

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

The lateral-vegetal ectoderm that overlies the PMC clusters plays a central role in positioning the clusters of PMCs and in promoting growth and patterning of the spicules. However, how this lateral ectoderm is specified is not completely understood.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

Formation of these well-proportioned ectopic structures raises an intriguing question: what is the mechanism that allows the adjustment of pattern with size in these Siamese larvae?

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

Understanding how Nodal and BMP together with Lefty and Chordin so precisely chisel the position and width of the ciliary band will be a challenge in the future.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

[...] the evolutionary origin of the Spemann organizer is more ancient than previously thought and that it may possibly be traced back to the common ancestor of deuterostomes.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

Intriguingly, the evolutionary origin of this crucial signalling centre remains unclear and whether analogous organizers regulate D/V patterning in other deuterostome or protostome phyla is not known.

A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms François Lapraz, Emmanuel Haillot & Thierry Lepage Nature Communications 6, Article number: 8434 http://www.nature.com/ncomms/2015/151001/ncomms9434/full/ncomms9434.html

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

There is a clear difference in the early axon scaffold formation between [...] This difference has not been investigated, but could potentially be due to [...] forming a far more complex cerebral cortex and undergoing different brain morphology changes compared with [...]. Much like we need a road map for directions, later axons also require a “map” of tracts to guide them along the correct path. This is particularly important as some axons have to travel over long distances to reach their target. The correct formation of the early axon scaffold requires that neurons differentiate at specific positions in the developing brain, and at specific stages. [...] the molecules involved in specifying many of the early axon scaffold neurons is not well known.

Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain Michelle Ware, Valérie Dupé and Frank R. Schubert DOI: 10.1002/dvdy.24312 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24312/full

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

While all vertebrates form commissures during early development in the brain, the timing of their appearance is varied. Timing differences may be due to differences in the requirement for sharing information between the two hemispheres or that other longitudinal and transversal tracts are essential for processing information and, therefore, form first. Although some authors have suggested [...] the data are not hugely convincing

Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain Michelle Ware, Valérie Dupé and Frank R. Schubert DOI: 10.1002/dvdy.24312 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24312/full

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

In a relatively short developmental time during early axon scaffold formation, the brain increases in complexity and this will continue throughout the development of the embryo. It is not clear why this population is present in the medaka compared with other anamniotes, further analysis would be required to confirm the MTT homolog. [...] the timing of tract appearance varies. [...] a previous study suggests the POC forms early, however, the POC is not clear in a more recent study [...] the location of these neurons needs more investigation

Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain Michelle Ware, Valérie Dupé and Frank R. Schubert DOI: 10.1002/dvdy.24312 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24312/full

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

The early axon scaffold is the first axonal structure to appear in the rostral brain of vertebrates, paving the way for later, more complex connections. [...] differences both in the organization and the development of the early tracts are apparent. There is still confusion over the nomenclature and homology of these tracts [...] future studies into the molecular regulation of its formation. [...] deeper understanding of many developmental processes during embryogenesis [...] [...] nerve connections need to be precisely made to form a fully functional organism. [...] provide a future reference for studies on patterning and axon guidance [...]

Evolutionary Conservation of the Early Axon Scaffold in the Vertebrate Brain Michelle Ware, Valérie Dupé and Frank R. Schubert DOI: 10.1002/dvdy.24312 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24312/full

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

[...] deep genetic understanding of the relationship between genotype and phenotype and the types of developmental changes that diversify life. We are well on this path to incorporate developmental biology into a new “postmodern” evolutionary synthesis, as evidenced by this selection of papers representing the current state of the field, and we look forward to its continued evolution [of this field?]

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Yes, we look forward too. :) Work in progress... stay tuned. Dionisio

[...] model and experimentally test the relationship between genotype and phenotypes [...] [...] understand morphological diversity across lineages of plants [...] [...] ultrastructural analysis of petal and petal-like structures together with an investigation of expression of genes [...] Their findings suggest floral evolution may be more complex than previously modeled [duh! what else is new?] and will undoubtedly lead to a deeper exploration of putative mechanisms.

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] signaling center in the forebrain that promotes outgrowth of the facial primordial [...] [how did we get such a 'signaling center' to begin with?] [how (spatiotemporally) does it 'promote' anything?] [...] correlated differences in facial shape and shh expression domains [...] [...] signals from the forebrain shape the face in these divergent species [...] [duh! built-in adaptation mechanisms (microevolution?) like the Galapagos finch beak variety story]

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] Other research, primarily in D. melanogaster, promises to shed light on the mysterious mechanisms of phenotypic plasticity in traits that vary in response to environmental conditions, including the weaponry of horned beetles and caste traits in social insects. [...] connects local tissue signaling pathways to the endocrine system and proposes a promising mechanism by which specific structures may be more sensitive to nutrient availability than the body as a whole [...] Future studies will likely focus on the mechanisms of developmental constraint and flexibility in shaping the orbital bones.

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Duh! Just references to the widely known built-in adaptation mechanisms underlying the variations observed in the biological systems. That's all. Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] essential conserved mechanisms of patterning and morphogenesis have been identified via the well-studied wing. [...] mechanisms of wing size and shape variation [...] [duh! built-in adaptation mechanisms or microevolution like the famous Galapagos finch beak variety story]

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] aspects of the earliest stages of gastrulation in distantly related clades [...] Fish and amphibians gastrulate via the blastopore, while amniotes such as birds and mammals ingress cells of the mesoderm and endoderm via the primitive streak [...] [...] hybrid bimodal mechanism of gastrulation that occurs by spatially distinct blastopore-like involution together with streak-like ingression [...] [so far just description of observed differences, but not a thorough (detailed) analysis of the actual cellular and molecular processes that lead to the mechanistic changes underlying the observed differences]

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] the first steps require understanding genetic and developmental variation at both the macro (between species) and microevolutionary (among populations) levels [...] A thorough understanding of the extent and developmental timing of morphological divergence will ultimately provide an opportunity to connect genotype and phenotype within variable populations [...] [...] quantify the developmental timing of morphological divergence at the macroevolutionary level among avian species. [...] further analyses of the mechanisms that generate this phenotypic diversity [...] [...] understand mechanisms underlying the elaboration of neuronal pattern [...] [...] subfunctionalization of paralogues to encompass nearly all of the conserved neurogenic domains [...]

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef ? Complex complexity. Work in progress... stay tuned. Dionisio

[...] if disparate species share such similar genes that control key developmental processes, how do gene regulatory networks shape an organism and generate species diversity? [...] there are currently over 3,000 sequenced eukaryotic genomes with an anticipated acceleration as more species are added to cover phylogenetic diversity [...] [...] we can now select appropriate animal models to understand specific traits and processes based upon their biology [...] [...] does evolution of development follow myriad and unpredictable paths? These are big questions that will likely require bold approaches and many years of dedicated research efforts.

Preface to the special issue on evolution and morphological diversity Kimberly L. Cooper and Michael D. Shapiro DOI: 10.1002/dvdy.24346 Developmental Dynamics Volume 244, Issue 10, pages 1181–1183 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24346/full

Where's the beef? Complex complexity. Work in progress... stay tuned. Dionisio

[...] ribosomal proteins genes (RPGs) are the most highly and coordinately expressed genes in the cell [...] There are several intertwined challenges in understanding how genes are controlled [...] [...] the precise positional organization of RPG-specific factors, chromatin, and the transcription machinery define a binary switch for RPG transcriptional regulation.

Molecular mechanisms of ribosomal protein gene coregulation Rohit Reja, Vinesh Vinayachandran, Sujana Ghosh and B. Franklin Pugh DOI: 10.1101/gad.268896.115 Genes & Dev. 29: 1942-1954 http://genesdev.cshlp.org/content/29/18/1942.full

Unfortunately this otherwise interesting paper contains some pseudoscientific nonsense that doesn't seem to add any valuable information to the text. However, ignoring that kind of hogwash, there are interesting discoveries described within the paper. For this reason, let's be nice and not ask them "where's the beef?". At least not this time, to give them another opportunity to reconsider what they did here. :) Perhaps it would have been more productive trying harder to describe in accurate details the observed complexity, rather than squandering their precious time on fantasizing about how the complexity became so complex. Dionisio

Like most products of evolution, the assembly pathway and final architecture are unlikely to resemble what an engineer would have designed.

Review Article The Evolution and Development of Neural Superposition Journal of Neurogenetics Volume 28, Issue 3-4, 2014 Special Issue: “The Nervous System of Drosophila melanogaster: from Development to Function” Meeting in Freiburg, Germany. DOI:10.3109/01677063.2014.922557 Egemen Agiab, Marion Langena, Steven J. Altschulera, Lani F. Wua, Timo Zimmermannc & Peter Robin Hiesinger*ab pages 216-232

Which engineer? Do all engineers design things the same way? Really? What a nonsense. BTW, how exactly would they design it? So much pseudoscientific hogwash in one paper. Dionisio

#959 follow-up Sorry to see so much obfuscating pseudoscientific nonsense piled up in so called "evo-devo" literature out there. Then, making things worse, some scientists insert pieces of "hogwash" text into their otherwise interesting research papers. Really depressing. Dionisio

As discussed, the expression of eEF1B?L might be taxonomically restricted to avians and mammals, suggesting that the regulation of EEF1D gene expression by alternative splicing is an avian- and mammalian-specific phenomenon. [so?] The orthologs of eEF1B?L are not found in reptiles or lower species. [so?] Furthermore, higher expression is detected in the cerebrum and cerebellum. [so?] We propose that evolution [?] from reptiles to avians and mammals may have required additional proteins that could regulate protein homeostasis in the brain because of the substantial change in brain structure and function in the avian and mammalian lineage. Further study involving knockout mice and human clinical specimens is needed to clarify the role of eEF1B?L in normal mammalian physiology and pathophysiology.

Regulation of Translation Factor EEF1D Gene Function by Alternative Splicing Taku Kaitsuka and Masayuki Matsushita Int. J. Mol. Sci. 2015, 16(2), 3970-3979; doi:10.3390/ijms16023970 http://www.mdpi.com/1422-0067/16/2/3970/htm

Where is the beef? may have required ? Were the required additional regulatory proteins available before the brain had the new structure that required those regulatory proteins? How did it get those required regulatory proteins right in time for their required use in the brain? Or did the brain change happen before having the required proteins to function? But then, how would it function without the required regulatory proteins? Are we having a kind of "chicken-egg" dilemma here? Are they referring to unguided processes? Sorry to see pseudoscientific nonsense included in an otherwise interesting paper. :( Too bad. Dionisio

Role of transcriptional regulation in the evolution of plant phenotype: A dynamic systems approach Emiliano Rodríguez-Mega, Alma Piñeyro-Nelson, Crisanto Gutierrez, Berenice García-Ponce, María De La Paz Sánchez, Estephania Zluhan-Martínez, Elena R. Álvarez-Buylla and Adriana Garay-Arroyo DOI: 10.1002/dvdy.24268 Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1074–1095, September 2015

Where's the beef? Another attempt to describe robust built-in adaptation mechanisms that can produce a wide variety of plants for different environmental conditions (microevolution?). Can they show how they would develop&implement (step by step) the actual adaptation mechanisms they try to describe? Dionisio

#954 follow-up: where's the beef?

[...] would further reinforce the heterogeneous character [...] [...] provide a good example of the remarkable complexity [...] Future studies should focus on [...] These studies and comparisons should concentrate not only on anatomical and developmental traits, but also on genetic traits, and should take into account the possibility that, as is the case with anatomical and developmental traits, at least some genetic traits might have been acquired independently and/or have different functions in different chordate taxa. In addition, future studies should investigate if there is, or not, a parallel between the developmental-genetic specification of [...]

Complex complexity. Dionisio

#954 follow-up: where's the beef?

However, although more defined, the separation between [...] in general, remains uncertain. An illustrative example is [...] one of the best-studied yet most puzzling [...] These studies further complicate [...] Despite its profound implications [...] heterogeneity [...] is poorly documented in textbooks, academic and medical curricula, and even many specialized research publications. Even within the same [...] can follow different genetic programs [...]

Complex complexity. Dionisio

#954 follow-up: where's the beef?

For a long time, it was accepted that [...] However, studies performed in the last three decades [...] strongly contradict this scenario. For many decades, it has been commonly accepted that [...] However, recent works [...] However, there is at least one alternative scenario [...] Further studies are needed to investigate whether [...] [...] is very different developmentally, anatomically and histologically from [...]

Complex complexity. Dionisio

Recent findings [...] have dramatically changed our understanding [...] [...] the dichotomy between [...] appears less clear than previously thought. Structures often considered in textbooks to be [...] are actually [...] [...] emphasizing the striking heterogeneity and [...] complexity [...] Recent data also undermine the clear distinction previously made [...] [...] contrary to previous assumptions and scenarios still often seen in textbooks and even in specialized papers [...] In fact, metamorphosis was probably acquired independently [...]

Special Issue Review Development, metamorphosis, morphology, and diversity: The evolution of chordate muscles and the origin of vertebrates Rui Diogo* and Janine M. Ziermann* Article first published online: 14 JUL 2015 DOI: 10.1002/dvdy.24245 © 2014 Wiley Periodicals, Inc. Issue Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1046–1057, September 2015 ARTICLE TOOLS Get PDF (680K)

Where's the beef? See comment @942. Complex complexity. Dionisio

#952 follow-up Just was told that the DOI number is not exactly related to chronological sequence. Also, the newer PDF for this paper just contains the retraction explanation. The older PDF contains the entire text. That's why they are so different in size. My dumb questions have been answered. Dionisio

Original:

Special Issue Review Development, metamorphosis, morphology, and diversity: The evolution of chordate muscles and the origin of vertebrates Rui Diogo* and Janine M. Ziermann* Article first published online: 14 JUL 2015 DOI: 10.1002/dvdy.24245 © 2014 Wiley Periodicals, Inc. Issue Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1046–1057, September 2015 ARTICLE TOOLS Get PDF (680K)

Retraction (correction):

Retraction: ‘Development, Metamorphosis, Morphology and Diversity: Evolution of Chordates muscles and the Origin of Vertebrates’ Rui Diogo* and Janine M. Ziermann Article first published online: 15 JUL 2015 DOI: 10.1002/dvdy.24236 © 2015 Wiley Periodicals, Inc. Issue Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, page 1179, September 2015 ARTICLE TOOLS Get PDF (89K)

I'm not familiar with the research paper publishing rules, hence I don't understand a few things. Here are a couple of easy questions: How come the older publication has a higher DOI than the newer (corrected) publication? Why was the older PDF so much larger than the newer (corrected) PDF? Dionisio

#945 follow up

Future work will need to address whether the diffuse, multivariate differences in Drosophila wing shape rely on such a simple explanation.

So much research effort has produced so little progress (little bang for the buck) in their OOL daydreaming. Time to dump all that distracting pseudoscientific OOL nonsense and concentrate all the research efforts in trying to understand more accurately all the elaborate molecular and cellular choreographies orchestrated within the biological systems. Complex complexity. Dionisio

#945 follow up

[...] it remains to be established whether these processes have been modified during wing evolution, or if natural variation comes from other developmental processes. There is [...] no study reporting the developmental events responsible for natural variation in the wing shape or size in Drosophila. There are many events that must occur during wing development. [...] the same genes and pathways are often involved in the regulation of several developmental processes.

Complex complexity. Dionisio

#945 follow up

Regarding the anterior and posterior cross-veins, the causes of their differentiation are coming to the light but further research is needed to understand what defines their relative positions in the wing. How the amount and the orientation of cell intercalation is modulated during wing evagination has not been studied. Neither of these studies imaged the spindle orientation in the dividing cells in the wing so the orientation of these divisions is not known. [developmental and evolutionary biology] have not yet succeeded in integrating advances on wing development to explain natural variation of wing size and shape.

Complex complexity. Dionisio

#945 follow-up

How does variation in the mechanisms orienting growth in the larval wing generate variation in the adult shape? Growth control in the wing disc is not fully understood despite being the target of much research. [...] identifying the contributions of growth and of oriented cell division to shape variation through manipulation of gene expression will not be straightforward. The mechanisms determining the final size of the wing are subject of much research

Complex complexity. Dionisio

#945 follow-up

Dachs is thought to orient cell divisions, but whether it does so by regulating cell shape or not is unclear This suggests the existence of other signals polarizing growth even in the absence of the ft-ds PCP system that remain to be discovered. According to this hypothesis, the regulation of ds and fj by vg is crucial for the control of growth direction, raising the question of how the gradient of Vg is established. The regulation of vg gene expression is complex.

Complex complexity. Dionisio

@942-945 Although this paper would just describe important built-in adaptation (i.e. microevolution) mechanisms, now it looks like it doesn't even do that well enough, because it still leaves many knowledge gaps to be filled up in the future? Perhaps they should focus in on trying to understand the elaborate molecular and cellular choreographies orchestrated within the biological systems without getting distracted by controversial speculative OOL thinking? Research time is precious, hence they should not squander it in senseless pseudoscientific wondering. Can they ever write a paper that leaves no unanswered question? Complex complexity. Dionisio

#944 follow-up

The final steps of wing morphogenesis (35 hr AP to eclosion) are less understood than the earlier ones because during this period the wing epithelium is embedded in the adult cuticle, which is synthesized from ?36 hr to ?70 hr AP by the apical surface of the wing epithelial cells.

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1058–1073

@943 & @944 we read that very little is known about the early steps, but now @945 we read that less is known about the later steps? How much is less than very little? Maybe that's not what they meant? Complex complexity. Dionisio

#942 addendum

From ?6 hr AP* to ?18 hr AP, proliferation is arrested, but the blade is considerably elongated, possibly [?] as a result of differential increase of cell area along the P/D axis. Very little is known, however, about the developmental processes taking place during this period because the rate of change is large, and the tissue is fragile and difficult to isolate.

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1058–1073

Complex complexity. (*) after pupariation Dionisio

#942 follow-up

The wing is derived from a precursor group of ?30 cells that invaginates from the embryonic ectoderm. This occurs in the anterior/mid-part of the embryo, at the boundary between the second and third parasegments (the parasegments are sections of the ectoderm established along the whole anterior–posterior axis of the embryo)

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1058–1073

Ok, first things first. What are the spatiotemporal causes for those initial events? IOW, what exactly makes such a precursor group of ?30 cells to invaginate from the embryonic ectoderm at that particular larvae stage (i.e. at that time after fertilization)? Why that? Why there? Why then? Why that many cells? Why in that place? Why at that time? Perhaps these questions are answered in this or another paper. We'll look and see. Complex complexity. Dionisio

Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing Alexis Matamoro-Vidal, Isaac Salazar-Ciudad and David Houle1 DOI: 10.1002/dvdy.24255 Developmental Dynamics Special Issue: Evolution & Morphological Diversity Volume 244, Issue 9, pages 1058–1073 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24255/full

[...] how the wing achieves its final shape, and what variation in development is capable of generating the variation in wing shape observed in nature.

Where's the beef? It's interesting to see how to go from one wing shape to another. Like going from a Galapagos finch beak shape to another. That's microevolution, isn't it? Everybody and their cousins agree with that. But what does that have to do with macroevolution? The biological systems seem to have built-in adaptation mechanisms that can produce all kinds of wing (or beak) configurations. What the ego-devo folks have to describe is how to make (step-by-step) those built-in adaptation mechanisms to begin with. IOW, how to go from a system that does not have a given built-in adaptation mechanism to one that has it? How to go from a system that does not have wings to one that has them? However, perhaps most systems have those built-in adaptation mechanisms already, but they get activated selectively in some cases? In that case, show why and how a given built-in adaptation mechanism get activated. That's all. Why is it taking them so long to do it? Dionisio

Where's the beef?

Exploring the genesis and functions of Human Accelerated Regions sheds light on their role in human evolution Melissa J Hubisz, Katherine S Pollard doi:10.1016/j.gde.2014.07.005 Current Opinion in Genetics & Development Volume 29, Pages 15–21 Genetics of human evolution http://www.sciencedirect.com/science/article/pii/S0959437X14000781

The functional implications of these expression differences remain to be discovered, but it is tempting to speculate that [...] there are still many hurdles to linking genetic changes to divergent traits. [...] the critical downstream functional studies needed to link molecular changes to traits remain low-throughput and challenging for the foreseeable future. Alternatively, positive selection, biased gene conversion, or relaxation of constraint in HAR regions may have driven the enrichment for older, higher frequency alleles in HARs. Future work is needed to disentangle these possibilities.

Dionisio

#939 addendum

Regulation and evolution of cardio-pharyngeal cell identity and behavior: insights from simple chordates Nicole Kaplan, Florian Razy-Krajka, Lionel Christiaen doi:10.1016/j.gde.2015.02.008 Current Opinion in Genetics & Development Volume 32, Pages 119–128 Developmental mechanisms, patterning and organogenesis http://www.sciencedirect.com/science/article/pii/S0959437X15000209

Outstanding questions remain about: [1] the polarized cell–cell signaling in asymmetrical fate choices; [2] the chromatin dynamics underlying multi-lineage priming, early fates’ segregation and commitment to either a cardiac or pharyngeal muscle identity; [3] the molecular underpinnings of collective polarity and directed migration and the genetic changes underlying developmental system drift. Computational approaches using whole genome data from an increasing number of ascidian species will empower gene regulatory network comparisons across ascidians and uncover fundamental rules governing cardio-pharyngeal mesoderm evolution. Future studies will dissect the intricate relationships between TVCs intrinsic transcriptional inputs and signaling pathways that interpret behavioral cues from the environment

Apparently they have a very simplistic "wishful thinking" plan ahead. Just a few easy questions remain unanswered, right? :) Well, future studies will reveal a more complex complexity that will make it even harder to explain how they could go from a biological system A to B through unguided processes. Dionisio

There they go again:

Regulation and evolution of cardiopharyngeal cell identity and behavior: insights from simple chordates Nicole Kaplan, Florian Razy-Krajka, Lionel Christiaen doi:10.1016/j.gde.2015.02.008 Current Opinion in Genetics & Development Volume 32, Pages 119–128 Developmental mechanisms, patterning and organogenesis http://www.sciencedirect.com/science/article/pii/S0959437X15000209

[...] the complexity of vertebrate embryos has hindered the identification of multipotent cardiopharyngeal progenitors. [...] extreme genome sequence divergence, gene network rewiring and specific morphogenetic differences. *

Where's the beef? (*) how could those major changes occur, at least theoretically? Dionisio

Where’s the beef?

Evolution of the fruit endocarp: molecular mechanisms underlying adaptations in seed protection and dispersal strategies Chris Dardick* and Ann M. Callahan Front. Plant Sci., http://dx.doi.org/10.3389/fpls.2014.00284 http://journal.frontiersin.org/article/10.3389/fpls.2014.00284/full

What are the evolutionary mechanisms that enable such dramatic shifts to occur in a relatively short period of time? This remains a fundamental question of plant biology today. the degree to which AG-like genes and their known partners have played a role in natural selection of plant species remains to be seen. Ongoing experiments to unveil the specific changes that have allowed different fruit forms to emerge within the same plant lineage will help shed light on the identity of key developmental pathways, the degree of plasticity of these regulatory systems, and how specific plants have adapted to occupy new niches.

Same-ole, same-ole... what else is new? Can the built-in adaptation mechanisms (like the ones associated with the observed Galapagos finch beak variety) explain major physiological and morphological differences? Dionisio

#936 follow up Can the built-in adaptation mechanisms (like the ones associated with the observed Galapagos finch beak variety) explain major physiological and morphological differences? Dionisio

Where’s the beef?

Evolution of fruit development genes in flowering plants Natalia Pabón-Mora1, Gane Ka-Shu Wong and Barbara A. Ambrose Front. Plant Sci., http://dx.doi.org/10.3389/fpls.2014.00300 http://journal.frontiersin.org/article/10.3389/fpls.2014.00300/full

Analyses of [...] are necessary to understand the role of RPL in fruit development and how the Arabidopsis network evolved to include RPL. [...] given the pleiotropy of the core fruit module genes, comparative molecular genetic analyses of these core genes will be necessary in basal angiosperms and gymnosperms to better understand their potential roles in carpel and fruit evolution in angiosperms. One key element to better understand the evolution of the network will be the assessment of the interactions, a poorly studied aspect, yet critical, as changes in partners between pre-duplication and post-duplication proteins may have provided core eudicots with a more robust fruit developmental network. [...] it is likely that differences in protein interactions and their downstream targets are important for evolution of fruit network. We have analyzed the evolution of protein families known to be the core network controlling fruit development in Arabidopsis and by doing so we have been able to identify three main lines of urgent research in fruit development:

(1) The functional characterization of fruit development genes other than the MADS box members, as there are nearly no mutant phenotypes for bHLH or RPL genes outside of Arabidopsis. (2) Assessing the regulatory network by testing interactions among putative protein partners in all major groups of flowering plants to understand how the core of the ancestral fruit developmental network evolved to build fruits with diverse morphologies and (3) The morpho-anatomical detailed characterization of closely related taxa with divergent fruit types across angiosperms, to better understand what mechanisms are responsible for changes in fruit development and result in homoplasious seed dispersal syndromes, and to postulate proteins from the network likely controlling such changes.

The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

okie dokie bornagain77

bornagain77 That was about a link to my Zotero catalog of paper references, not a link to a post in this blog. I'm just apologizing for not providing the link that I mentioned here months ago. I did not let my yes be yes and my no be no. My bad. I'll keep trying to figure out how to do it, though. Dionisio

Dionisio, just click on the date and time of the post you want to reference, it will update the address, and then copy the your desired address for the specific post you want. bornagain77

BA77 [OT] Sorry, I have not figured out how to provide a link to a specific set of paper references in Zotero without exposing other (unrelated) project information that is also referenced within the same catalog. Dionisio

Here's a paper that seems to point in the right direction, but still falls short of reaching the goal.

Only some general propositions can be offered at this juncture. It is clear from this work that multiple genomic regulatory changes had to be installed in the euechinoid lineage, whatever the exact pathway, and it is obvious that these cannot have entered the system all at once, nor would piecemeal alterations have had functional utility http://authors.library.caltech.edu/58901/

Nice try, but no, thanks. Dionisio

Here’s another recent paper that also fails these two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” *

The Cell’s View of Animal Body-Plan Evolution Deirdre C. Lyons, Mark Q. Martindale and Mansi Srivastava Integr. Comp. Biol. 54 (4): 658-666. doi: 10.1093/icb/icu108 http://icb.oxfordjournals.org/content/54/4/658.full

[..] we are currently lacking in the understanding of how specification of cell types generates specific cells’ biological properties, such as polarity, migration, and adhesion from a highly conserved set of effector proteins (such as actin, integrin, and PARs)

(*) (1) 1984 Wendy’s TV ad with actress Clara Peller (2) 1996 Hollywood movie “Jerry Maguire” with Tom Cruise and Cuba Gooding Perhaps if it were a political speech, it could win a few votes from the submissive herds. But it contains a number of pseudoscientific statements that don’t add any valuable information. The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Alright, this is getting boring. Let's move on... Next please? :) Dionisio

Here’s another recent paper that also fails these two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” *

Tradeoff between robustness and elaboration in carotenoid networks produces cycles of avian color diversification Alexander V. Badyaev*, Erin S. Morrison, Virginia Belloni and Michael J. Sanderson Biology Direct 2015, 10:45 doi:10.1186/s13062-015-0073-6 http://www.biologydirect.com/content/10/1/45

(*) (1) 1984 Wendy’s TV ad with actress Clara Peller (2) 1996 Hollywood movie “Jerry Maguire” with Tom Cruise and Cuba Gooding If it were a political speech it might attract a few votes from the ignoramus. But it contains a number of pseudoscientific statements that don’t add any valuable information. The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

Epigenetic inheritance and evolution: A paternal perspective on dietary influences Adelheid Soubry doi:10.1016/j.pbiomolbio.2015.02.008 http://www.sciencedirect.com/science/article/pii/S0079610715000334 Progress in Biophysics and Molecular Biology Volume 118, Issues 1–2, Pages 79–85 Epigenetic Inheritance and Programming

Although the following is speculative, it is possible that [...] Although the mechanisms have not yet been elucidated, we do not exclude a potential role for [...] Future research is necessary to confirm this hypothesis. [duh!]

This kind of paper seems to fail two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” * (*) (1) 1984 Wendy’s TV ad with actress Clara Peller (2) 1996 Hollywood movie “Jerry Maguire” with Tom Cruise and Cuba Gooding If it were a political speech it might attract a few votes from the ignoramus. But it contains a number of pseudoscientific statements that don't add any valuable information. The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

Here’s another recent paper that also fails these two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” *

Chapter One – Neural Crest Cell Evolution: How and When Did a Neural Crest Cell Become a Neural Crest Cell William A. Muñoz, Paul A. Trainor Current Topics in Developmental Biology Volume 111, 2015, Pages 3–26 Neural Crest and Placodes

The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

Here’s another recent paper that also fails these two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” *

Deciphering principles of morphogenesis from temporal and spatial patterns on the integument Ang Li1, Yung-Chih Lai1,2, Seth Figueroa3, Tian Yang4, Randall B. Widelitz1, Krzysztof Kobielak1, Qing Nie5 and Cheng Ming Chuong1,2,6,* DOI: 10.1002/dvdy.24281 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24281/full

Evo-Devo of Integument Organs Driven by Novel Molecular Modules That Enable New Patterning Processes The morphological diversification of the Metazoa (multicellular animals) is attributable to two major mechanisms. One is the emergence of new paths of cell differentiation (e.g., the cells produce new protein products, or alter their shapes); the other is the adjustment or novel use of molecular modules for pattern formation. It is believed that the genes and gene regulatory networks involved in cell differentiation keep on expanding during evolution while those molecular modules setting up basic biological patterns have minimal changes (Newman et al., 2009). One example of the first type of mechanism would be the expansion of keratin multigene families and the diversification of integument organs. The expansion of ?-keratin genes may have contributed to the independent origin of hair and nails in mammals and baleen in whales (Vandebergh and Bossuyt, 2012). Large-scale expansions of ?-keratin genes in birds and turtles may be involved in the innovation of the feathers and turtle shells (Greenwold and Sawyer, 2010; Li et al., 2013b). In a recent study, we carried out an exhaustive search of ?- and ?-keratin genes in the Galgal4 genome assembly and characterized the expression pattern of some keratin genes. ?-keratin genes have diverse expression patterns in the five types of feathers we examined, and within the same individual feather ?- and ?-keratins are expressed in different regions (Ng et al., 2014). For the second type of mechanism, components of Wnt, BMP, and Hedgehog pathways have been discovered to interact in a specific manner to generate the periodic patterns in the integument (Maini et al., 2006). Many of these components constantly work together as a molecular module. For example the Wnt/Notch module is known to define different morphogenetic fields in different biological processes (Newman et al., 2009; Muñoz Descalzo and Martinez Arias, 2012; Li et al., 2013a). Although these genes have relatively conserved coding sequences, their regulatory regions may still accumulate changes through evolution as these modules are recruited to a new biological process.

The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren’t of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

The evo-devo folks seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that aren't of the same kind but seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? Dionisio

Here’s another recent paper that also fails two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” * More @922

Dorsoventral patterning by the Chordin-BMP pathway: a unified model from a pattern-formation perspective for drosophila, vertebrates, sea urchins and nematostella Hans Meinhardt doi:10.1016/j.ydbio.2015.05.025

Dionisio

Here's something for the "third way" folks to think about: @747 in this thread: https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-572704 Dionisio

Here’s another recent paper that also fails two fundamental requirements: (1) “Where’s the beef?” and (2) “Show me the money!” *

Although much remains to be learned about aRGCs and bRGCs, emerging evidence suggests that both their common and distinctive features are likely relevant for their having distinct roles in cortical development. This raises the possibility that this precious material and highly valuable methodology may have some important biases or limitations, [...] Additional analyses from independent laboratories and in larger cell populations will be necessary to decide whether [...] Intriguingly, this idea is contradicted by analyses [...] [...] has not been yet identified, but such a scenario would explain [...] This is very intriguing because, on the one hand it strongly suggests that the molecular mechanisms regulating Pax6 and Tbr2 expression may be different between the lissencephalic mouse and gyrencephalic species, including absence of mutual repression potentially due to sequence differences in their promoter-enhancer regions. In contrast, the transcriptomic heterogeneity of bRGCs strongly suggests that there may be yet other previously unrecognized progenitor cell subtypes within bRGCs, or that the expression of some of these hallmark genes may be subject to quite dynamic regulation, similar to their morphotype transitions. However, neither ECM nor growth factors seem sufficient to cause [...] Although much promise is held for the future, this blind and completely unbiased method has not yet been able to distinguish cell types as evidently different as aRGCs from bRGCs, much less any of the particular subtypes and morphotypes of bRGCs. Hopefully, combining this novel technology with the already ample knowledge on the cell biological features that distinguish each class and subtype of cortical progenitor cell, will lead us to identify their specific genetic fingerprint. Yet a fundamental question remaining is which might have been the evolutionary mechanisms that led, in the first place, to the expansion of the primitive reptilian cortex into the extraordinarily large mammalian neocortex. In contrast, mechanisms responsible for direct neurogenesis have not been studied as such, [...] But how did this relatively small neocortex evolve into the gigantic cortices of elephants, whales and humans, with many-fold more neurons and additional laminar subdivisions? So if neuron number is not causally related to cortical folding, what are the driving forces for neocortical gyrification? Taken together, it is tempting to speculate that [...] http://onlinelibrary.wiley.com/doi/10.1002/glia.22827/full Coevolution of radial glial cells and the cerebral cortex Camino De Juan Romero and Víctor Borrell DOI: 10.1002/glia.22827 Glia Special Issue: Glial Stem and Progenitor Cells Volume 63, Issue 8, pages 1303–1319, August 2015

Their "Conclusions" only lack this:

Once upon a time... ...and they lived happily ever after.

:) They seem to be trying to figure out how to go from a biological system ‘A’ to a different biological system ‘B’. However, why are they having so much problem with that? All they have to do is take two biological systems ‘A’ and ‘B’ that seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system (‘A’) in order to get the developmental mechanisms in the other system (‘B’), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? (*) (1) 1984 Wendy’s TV ad with actress Clara Peller (2) 1996 Hollywood movie “Jerry Maguire” with Tom Cruise and Cuba Gooding Dionisio

Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development Nucl. Acids Res. (2015) doi: 10.1093/nar/gkv514 Shira Rockowitz1 and Deyou Zheng http://nar.oxfordjournals.org/content/early/2015/05/18/nar.gkv514.full Recent studies have employed cross-species comparisons of transcription factor binding, reporting significant regulatory network ‘rewiring’ between species. Overall, our results point to significant differences between the REST regulatory networks in humans and mice, underscoring the divergence of transcriptional networks between the species. At the level of REST-chromatin interactions, we observed that most REST binding events are markedly different between hESCs and mESCs. [...] future experiments specifically designed to address these important issues will be required. [...] numerous studies have documented the difficulties in using model organisms such as rodents to model human brain development and NDs There are several limitations in the current study. In the analysis of sequence conservation, we identified a region of lower sequence conservation (i.e. conservation valley) proximal to the REST motif. It will be interesting to study in the future if the valley is related to co-factor spacing. Future studies will be required to address the actual order of occurrence of HMs and REST occupancy, as well as how HMs change at REST-bound regions when REST expression is reduced. [...] more studies will be needed to understand if hypomethylation at REST sites are from exclusion of DNA methyltransferases, active recruitment of demethylases by REST or other mechanisms.

Several 'duh!' instances in this paper. A few questions remain unanswered. Work in progress... stay tuned. Dionisio

Science 21 November 2014: Vol. 346 no. 6212 pp. 1007-1012 DOI: 10.1126/science.1246426 http://www.sciencemag.org/content/346/6212/1007.full Unexpectedly, however, ~40% of mouse-human shared DHSs lacked conserved sequence elements. Computing the Jaccard similarity index over all possible combinations of mouse and human cell types revealed surprisingly limited similarity in the tissue-selective usage of shared DHSs, [...] Weak correspondence between orthologous tissues suggested that a substantial fraction of shared DHSs had undergone functional “repurposing” via alteration of tissue activity patterns from one tissue type in mouse to a different one in human [...] Indeed, analysis of well-matched mouse and human tissue pairs confirmed substantial repurposing ranging from 22.9 to 69% of shared DHSs, depending on the tissue [...]. Overall, we found that at least 35.7% of shared DHSs (12.7% of mouse DHSs overall) have undergone repurposing [...], chiefly affecting distal elements [...]. Facile repurposing of regulatory DNA from one tissue context to another thus emerges as an important evolutionary mechanism shaping the mammalian cis-regulatory landscape. Surprisingly, 41.3% of shared DHSs (chiefly repurposed DHSs) lacked any positionally or operationally conserved TF recognition elements Taken together, our results have important implications for understanding the major mechanisms and forces governing the evolution of mammalian regulatory DNA. We speculate that high cis-regulatory plasticity may be a key facilitator of mammalian evolution by increasing the potential for innovation of novel functions in the context of an evolutionarily inflexible trans-regulatory environment.

Nice try, but no, thanks. Unexpectedly? what did they expect? revealed surprisingly limited similarity ? Why surprisingly? functional “repurposing” ? substantial repurposing? have undergone repurposing? Facile repurposing? Any detailed theoretical explanation of those processes? speculate? Can they do better than that? This paper seems to fail two fundamental tests: 1. Where's the beef? 2. Show me the money! Dionisio

Mutations: How They Work and Which Worldview They Favor http://www.reasons.org/articles/mutations-how-they-work-and-which-worldview-they-favor Dionisio

Chemical Complexity and Life Chemical complexity is a defining feature of life. In fact, the cellular operations fundamental to biology require chemical complexity. According to Dunn, this complexity can be achieved only through a large ensemble of macromolecules, each one carrying out a specific task in the cell. However, the macromolecules must be assembled from molecular alphabets because only molecular alphabets allow for the plethora of combinatorial possibilities needed to give macromolecules the range of structural variability that makes possible the functional diversity required for life. Proteins help illustrate Dunn’s point regarding combinatorial potential. Built from an alphabet that consists of 20 different amino acids, proteins are the workhorses of life. Each protein carries out a specific role in the cell. A typical protein might consist of 300 amino acids. So, for a protein of that size, the number of possible amino acid sequences is (20)300. Each sequence has the potential to form a distinct structure and, consequently, perform a distinct function. It is impossible to achieve this kind of complexity using small molecules or uniquely specified macromolecules. http://www.reasons.org/articles/how-the-central-dogma-of-molecular-biology-points-to-design

Dionisio

BIR Pipeline for Preparation of Phylogenomic Data Surendra Kumar, Anders K. Krabberød, Ralf S. Neumann, Katerina Michalickova, Sen Zhao, Xiaoli Zhang and Kamran Shalchian-Tabrizi Evolutionary Bioinformatics 2015:11 79-83 DOI: 10.4137/EBO.S10189 http://www.la-press.com/bir-pipeline-for-preparation-of-phylogenomic-data-article-a4796

Nice tools, but are they sufficient for any "evo-devo" paper to pass the fundamental tests indicated @915? Don't think so. This tools won't suffice to meet the requirements described @911. Anyone can see why. #911: https://uncommondescent.com/evolution/a-third-way-of-evolution/#comment-567227 #915: https://uncommondescent.com/evolution/a-third-way-of-evolution/#comment-568870 Dionisio

Positional specification in the segmental growth pattern of an early arthropod Giuseppe Fusco, Paul S. Hong, Nigel C. Hughes DOI: 10.1098/rspb.2013.3037 [...] although the relative size of body parts is a major trait in animal body organization, the underlying developmental mechanisms producing characteristic proportions are largely unknown. In many arthropods, there is a change in relative segment size during post-embryonic development, but how segment differential growth is produced is little known. In its most frequent usage, the term morphogen refers to a long-range signalling molecule that patterns a developing tissue in a concentration-dependent manner, instructing target cells to respond in specific ways, e.g7. through cell differentiation or cell proliferation, depending on their location within a tissue [...] our morphometric data cannot provide clues about the particular mechanism producing the putative graded signal that likely operated in the trunk of A. koninckii, as different mechanisms can produce the same pattern, especially in a system undergoing growth. Nor can it yield insights into the specific response of the growing tissue, for instance involving the regulation of cell proliferation, in the form of a ‘mitogenic gradient’ The study of mechanisms controlling growth and pattern formation is a topic of high interest in current research [...] http://rspb.royalsocietypublishing.org/content/281/1781/20133037

Dionisio

Here's another recent paper that also fails two fundamental requirements: (1) "Where's the beef?" and (2) "Show me the money!"

Emergence of life: Physical chemistry changes the paradigm Jan Spitzer, Gary J. Pielak and Bert Poolman Biology Direct 2015, 10:33 doi:10.1186/s13062-015-0060-y http://www.biologydirect.com/content/10/1/33

(1) 1984 Wendy's TV ad with actress Clara Peller (2) 1996 Hollywood movie "Jerry Maguire" with Tom Cruise and Cuba Gooding Dionisio

Evolutionary problems in centrosome and centriole biology DOI: 10.1111/jeb.12620 Journal of Evolutionary Biology Volume 28, Issue 5, pages 995–1004, May 2015 Centrosomes have been an enigma to evolutionary biologists. Either they have been the subject of ill-founded speculation or they have been ignored. [...] they lack nucleic acids and thus pose a challenge to conventional views about the mechanisms of heredity. Why the centrosome appears particularly indispensable for male meiosis remains a question open to debate. The reproductive biology of both groups has been poorly studied, and it would be of great interest to see whether PGE might be found in these groups upon further investigation. It is currently unclear why centrioles are lost from oocytes. [...] this remains speculative until we have a better understanding of the role of the paternal centriole in early development. Research into centrosome development and function across a wide diversity of organisms, in particular in those lineages that have independen-tly evolved unusual centrosomes, is needed to resolve the remaining evolutionary problems in centrosome biology. http://onlinelibrary.wiley.com/doi/10.1111/jeb.12620/full

A few issues remain. [highly optimistic] Dionisio

Grand challenges* in evolutionary developmental biology Alessandro Minelli* Front. Ecol. Evol., http://dx.doi.org/10.3389/fevo.2014.00085 http://journal.frontiersin.org/article/10.3389/fevo.2014.00085/full

(*) "Grand challenges" seems like a gross understatement. :) Dionisio

The genetic architecture of gene expression levels in wild baboons DOI: http://dx.doi.org/10.7554/eLife.04729 2015 eLife 2015;4:e04729 we still know little about gene regulation in natural primate populations. genes vary in their tolerance of functional regulatory genetic variation, and, intriguingly, gene-specific robustness to genetic perturbation may be a conserved property across species. http://elifesciences.org/content/4/e04729

intriguingly? why? Dionisio

Constraints on the evolution of a doublesex target gene arising from doublesex’s pleiotropic deployment PNAS vol. 112 no. 8 Shengzhan D. Luo, E852–E861, doi: 10.1073/pnas.1501192112 However, [...] appears to be more complex. [...] however, it requires a functional [...] The activation may require other factors binding in [...] In some of these tissues the regulation might be more resistant to change, consequently placing an evolutionary constraint on the changes in other tissues. This theory leads to the question of how such evolutionary constraints on the pleiotropic transcriptional regulation are overcome. However, very few real examples have been shown to demonstrate that this is the case. One reason might be the difficulty of clearly identifying the in vivo binding sites of that transcription factor within the tissue-specific regulatory modules of the target gene. http://www.pnas.org/content/112/8/E852.full

Let's assume they're not talking about the cellular and molecular built-in adaptation mechanisms operating within the biological systems. They seem to be trying to figure out how to go from a biological system 'A' to a different biological system 'B'. However, why are they having so much problem with that? All they have to do is take two biological systems 'A' and 'B' that seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, asymmetric cell division, and the whole nine yards) in one system ('A') in order to get the developmental mechanisms in the other system ('B'), indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? So far they have failed the two most fundamental scientific requirements: Where's the beef? Show me the money! :) Dionisio

Evolution of Gene Regulatory Networks Controlling Body Plan Development doi:10.1016/j.cell.2011.02.017 To make sense of the physical mechanisms that underlie the origin of animal body plans, we must consider how change in DNA sequence can affect development of the body plan at the system level. For development of the body plan is a heritable regulatory system process, which we can represent and manipulate and comprehend only in terms of genomically encoded GRN architecture. The evidence [...] can only be integrated in a mechanistic way by resolving the meaning of this evidence in terms of its import for developmental GRN architecture. This is the path to demystification of body-plan evolution. This project cannot be approached, except in an indirect exemplary sense, by looking at change in single cis-regulatory modules or single proteins, nor in ignorance of the regulatory gene interactions that constitute the architecture of developmental GRNs. The genomic control of the developmental process itself can only be understood in terms of the genomic regulatory system, and so must time-based change in that regulatory system, the basis of body-plan evolution. http://www.sciencedirect.com/science/article/pii/S0092867411001310

All they have to do is take two biological systems that seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms (GRN, signaling pathways, epigenetic factors, organogenesis, cell fate specification, determination, cell migration, morphogenesis, the whole nine yards) in one system to get the developmental mechanisms in the other system, indicating all the events that caused (triggered) those precise spatiotemporal changes. That’s all. Why is it taking them so long to present such a simple example? :) Dionisio

Developmental gene regulatory network evolution: Insights from comparative studies in echinoderms DOI: 10.1002/dvg.22757 Detailed comparisons of GRNs are only in their infancy. [...] several themes are beginning to emerge [...] [...] it appears likely that [...] [...] data is showing that circuitry involving recursive wiring is maintained in common. These types of analyses are therefore very important for understanding the cis regulatory basis of constraint in GRNS, particularly in recursively wired circuits, and whether the distributions of binding sites is the source of this constraint. Continued exploration of the mechanisms that preserve particular subcircuits and also study of the processes that allow GRNs to evolve are both needed to understand patterns of animal diversity. Although co-option is thought to be central for evolving morphological novelties, the mechanisms that allow cis regulatory modules to operate in different domains are essentially unknown. http://onlinelibrary.wiley.com/doi/10.1002/dvg.22757/full#dvg22757-sec-0009

All they have to do is take two biological systems that seem somehow related, describe their detailed developmental mechanisms and then show how they could change the developmental mechanisms in one system to get the developmental mechanisms in the other system. That's all. Why is it taking them so long to present such a simple example? :) Dionisio

#907 follow-up Organogenesis mechanisms might include many factors which could be associated with ncRNA and/or pseudogenes that until now have no known function. Let's wait and see how things go in the days ahead. Check posts #408 through 413 here: https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-564762 Dionisio

Here's a recent paper supporting the 'junk DNA' concept:

Non-coding RNA: what is functional and what is junk? Front. Genet., 26 January 2015 | http://dx.doi.org/10.3389/fgene.2015.00002 Alexander F. Palazzo* and Eliza S. Lee Department of Biochemistry, University of Toronto, Toronto, ON, Canada It is clear that the human genome contains a large number of functional ncRNAs. Indeed it is likely that the list of biologically validated ncRNAs, as listed in the LncRNA Database (Quek et al., 2014), will continue to grow. As others have pointed out, even if 10% of current lncRNAs prove to be functional, this would represent a wealth of new biology. However, given our current understanding of biochemistry and evolution, it is likely that most of the RNAs generated from the low levels of pervasive transcription, and likely a substantial number of currently annotated “lncRNAs,” are non-functional. http://journal.frontiersin.org/article/10.3389/fgene.2015.00002/full

Let's see how things go as more research is done. Regardless of that, we need to accurately explain all the mechanisms found within the biological systems. Dionisio

Evolution of transcription factor function as a mechanism for changing metazoan developmental gene regulatory networks Alys M Cheatle Jarvela and Veronica F Hinman EvoDevo 2015, 6:3 doi:10.1186/2041-9139-6-3 Transcription factor coding changes are becoming a theoretically more accepted source of GRN evolution, but there are still only a few studies documenting specific changes and tying those to developmental novelties. Many of the studies we have discussed in this review suggest interesting ways GRN evolution can occur via transcription factor change, but further study is still required in order to understand the full mechanism. http://www.evodevojournal.com/content/6/1/3

there are still only a few studies documenting specific changes and tying those to developmental novelties. Do they show valid* results that match what we see in nature? Where are they? Changes to many parts of any system may occur all the time. The problem is to get the right combination of changes to lead to a valid* solution. Most documented changes seem to lead to undesired consequences. Here's a very interesting Italian Pediatrics paper documenting one of many examples of small changes causing a mess: https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-564011 That paper is a serious illustration of how to document a specific case. Evo-devo papers should do the same in order to answer the most basic question: where's the beef? (*) [desirable phenotypic physiological functional] Dionisio

#904 follow-up Here's more: Note the 5 citing papers. None of them seem to answer the main question posed @904.

Article: Evolutionary and Developmental Origins of the Cardiac Neural Crest: Building a Divided Outflow Tract Anna L. Keyte, Martha Alonzo?Johnsen, Mary R. Hutson The cardiac neural crest cells (CNCCs) have played an important role in the evolution and development of the vertebrate cardiovascular system: from reinforcement of the developing aortic arch arteries early in vertebrate evolution, to later orchestration of aortic arch artery remodeling into the great arteries of the heart, and finally outflow tract septation in amniotes. A critical element necessary for the evolutionary advent of outflow tract septation was the co-evolution of the cardiac neural crest cells with the second heart field. This review highlights the major transitions in vertebrate circulatory evolution, explores the evolutionary developmental origins of the CNCCs from the third stream cranial neural crest, and explores candidate signaling pathways in CNCC and outflow tract evolution drawn from our knowledge of DiGeorge Syndrome. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc. Birth Defects Research Part C Embryo Today Reviews 09/2014; 102(3). DOI:10.1002/bdrc.21076 · 3.87 Impact Factor Article: Thymus cDNA library survey uncovers novel features of immune molecules in Chinese giant salamander Andrias davidianus. Rong Zhu, Zhong-Yuan Chen, Jun Wang, Jiang-Di Yuan, Xiang-Yong Liao, Jian-Fang Gui, Qi-Ya Zhang A ranavirus-induced thymus cDNA library was constructed from Chinese giant salamander, the largest extant amphibian species. Among the 137 putative immune-related genes derived from this library, these molecules received particular focus: immunoglobulin heavy chains (IgM, IgD, and IgY), IFN-inducible protein 6 (IFI6), and T cell receptor beta chain (TCR?). Several unusual features were uncovered: IgD displays a structure pattern distinct from those described for other amphibians by having only four constant domains plus a hinge region. A unique IgY form (IgY(?Fc)), previously undescribed in amphibians, is present in serum. Alternative splicing is observed to generate IgH diversification. IFI6 is newly-identified in amphibians, which occurs in two forms divergent in subcelluar distribution and antiviral activity. TCR? immunoscope profile follows the typical vertebrate pattern, implying a polyclonal T cell repertoire. Collectively, the pioneering survey of ranavirus-induced thymus cDNA library from Chinese giant salamander reveals immune components and characteristics in this primitive amphibian. Developmental & Comparative Immunology 06/2014; DOI:10.1016/j.dci.2014.05.019 · 3.71 Impact Factor Article: A novel function for Egr4 in posterior hindbrain development. Chang-Joon Bae, Juhee Jeong, Jean-Pierre Saint-Jeannet Segmentation of the vertebrate hindbrain is an evolutionarily conserved process. Here, we identify the transcription factor early growth response 4 (egr4) as a novel regulator of posterior hindbrain development in Xenopus. egr4 is specifically and transiently expressed in rhombomeres 5 and 6 (r5/r6), and Egr4 knockdown causes a loss of mafb/kreisler and krox20/egr2 expression in r5/r6 and r5, respectively. This phenotype can be fully rescued by injection of frog or mouse Egr4 mRNA. Moreover Egr4-depleted embryos exhibit a specific loss of the neural crest stream adjacent to r5, and have inner ear defects. While the homeodomain protein vHnf1/Hnf1b directly activates Mafb and Krox20 expression in the mouse hindbrain to specify r5, we show that in Xenopus this process is indirect through the activation of Egr4. We provide evidence that rearrangements in the regulatory sequences around egr4 and mafb genes may account for this difference. Scientific Reports 01/2015; 5:7750. DOI:10.1038/srep07750 · 5.08 Impact Factor Article: Developmental expression of chicken FOXN1 and putative target genes during feather development Diana K Darnell, Li S Zhang, Sridhar Hannenhalli, Sergey Y Yaklichkin ABSTRACT: FOXN1 is a member of the forkhead box family of transcription factors. FOXN1 is crucial for hair outgrowth and thymus differentiation in mammals. Unlike the thymus, which is found in all amniotes, hair is an epidermal appendage that arose after the last shared common ancestor between mammals and birds, and hair and feathers differ markedly in their differentiation and gene expression. Here, we show that FOXN1 is expressed in embryonic chicken feathers, nails and thymus, demonstrating an evolutionary conservation that goes beyond obvious homology. At embryonic day (ED) 12, FOXN1 is expressed in some feather buds and at ED13 expression extends along the length of the feather filament. At ED14 FOXN1 mRNA is restricted to the proximal feather filament and is not detectable in distal feather shafts. At the base of the feather, FOXN1 is expressed in the epithelium of the feather sheath and distal barb and marginal plate, whereas in the midsection FOXN1 transcripts are mainly detected in the barb plates of the feather filament. FOXN1 is also expressed in claws; however, no expression was detected in skin or scales. Despite expression of FOXN1 in developing feathers, examination of chick homologs of five putative mammalian FOXN1 target genes shows that, while these genes are expressed in feathers, there is little similarity to the FOXN1 expression pattern, suggesting that some gene regulatory networks may have diverged during evolution of epidermal appendages. The International Journal of Developmental Biology 01/2014; 58(1):57-64. DOI:10.1387/ijdb.130023sy · 2.57 Impact Factor Article: The lamprey: A jawless vertebrate model system for examining origin of the neural crest and other vertebrate traits Stephen A. Green, Marianne E. Bronner Lampreys are a group of jawless fishes that serve as an important point of comparison for studies of vertebrate evolution. Lampreys and hagfishes are agnathan fishes, the cyclostomes, which sit at a crucial phylogenetic position as the only living sister group of the jawed vertebrates. Comparisons between cyclostomes and jawed vertebrates can help identify shared derived (i.e. synapomorphic) traits that might have been inherited from ancestral early vertebrates, if unlikely to have arisen convergently by chance. One example of a uniquely vertebrate trait is the neural crest, an embryonic tissue that produces many cell types crucial to vertebrate features, such as the craniofacial skeleton, pigmentation of the skin, and much of the peripheral nervous system (Gans and Northcutt, 1983). Invertebrate chordates arguably lack unambiguous neural crest homologs, yet have cells with some similarities, making comparisons with lampreys and jawed vertebrates essential for inferring characteristics of development in early vertebrates, and how they may have evolved from nonvertebrate chordates. Here we review recent research on cyclostome neural crest development, including research on lamprey gene regulatory networks and differentiated neural crest fates. Differentiation 01/2014; 87(1-2). DOI:10.1016/j.diff.2014.02.001 · 2.84 Impact Factor http://www.researchgate.net/publication/233746004_Early_development_of_the_thymus_in_Xenopus_laevis

Where's the beef? Dionisio

Evolution of thymus organogénesis doi:10.1016/j.dci.2012.01.002 http://www.sciencedirect.com/science/article/pii/S0145305X12000031 http://dx.doi.org/10.1016/j.dci.2012.01.002 The thymus is the primary organ for functional T lymphocyte development in jawed vertebrates. A new study in the jawless fish, lampreys, indicates the existence of a primitive thymus in these surviving representatives of the most ancient vertebrates, providing strong evidence of co-evolution of T cells and thymus. This review summarizes the wealth of data that have been generated towards understanding the evolution of the thymus in the vertebrates. Progress in identifying genetic networks and cellular mechanisms that control thymus organogenesis in mammals and their evolution in lower species may inspire the development of new strategies for medical interventions targeting faulty thymus functions.

Can phenotypically thymus homology and/or analogy prove anything before someone can seriously describe how genetic networks and cellular mechanisms that control thymus organogenesis could have evolved? Are there any papers that pass the above requirement? The following papers don't seem to do it:

Article: A Tour of the Thymus: A Review of Thymic Lesions With Radiologic and Pathologic Correlation Alan J Goldstein, Isabel Oliva, Hedieh Honarpisheh, Ami Rubinowitz The thymus is routinely encountered on cross-sectional imaging studies of the chest. It has a variable appearance, undergoes dynamic changes during periods of stress, and demonstrates numerous different pathologic lesions. Understanding the imaging characteristics of these different lesions facilitates accurate radiographic diagnosis and can prevent unnecessary follow-up imaging and intervention. This article will review normal thymic anatomy and development, thymic hyperplasia and associated medical conditions, and the imaging and pathologic features of various benign and malignant thymic lesions. Canadian Association of Radiologists Journal 04/2014; 66(1). DOI:10.1016/j.carj.2013.09.003 · 0.58 Impact Factor Article: Early development of the thymus in Xenopus laevis Young-Hoon Lee, Allison Williams, Chang-Soo Hong, Youngjae You, Makoto Senoo, Jean-Pierre Saint-Jeannet Although Xenopus laevis has been a model of choice for comparative and developmental studies of the immune system, little is known about organogenesis of the thymus, a primary lymphoid organ in vertebrates. Here we examined the expression of three transcription factors that have been functionally associated with pharyngeal gland development, gcm2, hoxa3 and foxn1, and evaluated the neural crest contribution to thymus development. In most species Hoxa3 is expressed in the third pharyngeal pouch endoderm where it directs thymus formation. In Xenopus, the thymus primordium is derived from the second pharyngeal pouch endoderm, which is hoxa3-negative, suggesting that a different mechanism regulates thymus formation in frogs. Unlike other species foxn1 is not detected in the epithelium of the pharyngeal pouch in Xenopus, rather, its expression is initiated as thymic epithelial cell starts to differentiate and express MHC class II molecules. Using transplantation experiments we show that while neural crest cells populate the thymus primordia, they are not required for the specification and initial development of this organ or for T cell differentiation in frogs. These studies provide novel information on early thymus development in Xenopus, and highlight a number of features that distinguish Xenopus from other organisms. © 2012 Wiley Periodicals, Inc., a Wiley company. Developmental Dynamics 02/2013; 242(2). DOI:10.1002/dvdy.23905 · 2.67 Impact Factor Article: Teleost T and NK cell immunity. Uwe Fischer, Erling Olaf Koppang, Teruyuki Nakanishi The main function of the immune system is to maintain the organism's homeostasis when invaded by foreign material or organisms. Prior to successful elimination of the invader it is crucial to distinguish self from non-self. Most pathogens and altered cells can be recognized by immune cells through expressed pathogen- or danger-associated molecular patterns (PAMPS or DAMPS, respectively), through non-self (e.g. allogenic or xenogenic cells) or missing major histocompatibility (MHC) class I molecules (some virus-infected target cells), and by presenting foreign non-self peptides of intracellular (through MHC class I - e.g. virus infected target cells) or extracellular (through MHC class II - e.g. from bacteria) origin. In order to eliminate invaders directly or by destroying their ability to replicate (e.g. virus-infected cells) specialized immune cells of the innate and adaptive responses appeared during evolution. The first line of defence is represented by the evolutionarily ancient macrophages and natural killer (NK) cells. These innate mechanisms are well developed in bony fish. Two types of NK cell homologues have been described in fish: non-specific cytotoxic cells and NK-like cells. Adaptive cell-mediated cytotoxicity (CMC) requires key molecules expressed on cytotoxic T lymphocytes (CTLs) and target cells. CTLs kill host cells harbouring intracellular pathogens by binding of their T cell receptor (TCR) and its co-receptor CD8 to a complex of MHC class I and bound peptide on the infected host cell. Alternatively, extracellular antigens are taken up by professional antigen-presenting cells such as macrophages, dendritic cells and B cells to process those antigens and present the resulting peptides in association with MHC class II to CD4(+) T helper cells. During recent years, genes encoding MHC class I and II, TCR and its co-receptors CD8 and CD4 have been cloned in several fish species and antibodies have been developed to study protein expression in morphological and functional contexts. Functional assays for innate and adaptive lymphocyte responses have been developed in only a few fish species. This review summarizes and discusses recent results and developments in the field of T and NK cell responses with focus on economically important and experimental model fish species in the context of vaccination. Fish &amp Shellfish Immunology 05/2013; DOI:10.1016/j.fsi.2013.04.018 · 3.03 Impact Factor http://www.researchgate.net/publication/221767723_Evolution_of_thymus_organogenesis

Next? Dionisio

Does this Russian biology professor say that Darwin wasn't always right? https://www.youtube.com/embed/FR7ZffPK59M Dionisio

Mechanical basis of morphogenesis and convergent evolution of spiny seashells doi: 10.1073/pnas.1220443110 http://www.pnas.org/content/110/15/6015.full From this point of view, it should be noted that spines are prevalent in a number of mollusk species and may be associated with other kinds of 3D ornamentations on shells whose morphogenesis remains unknown, and it is natural to ask whether in fact each of these forms can be produced with different parameter regimes within a single mechanical model. Such a unifying theory would provide a new, far-reaching perspective of the phenotypic evolution of the shells of the second largest phylum in the animal kingdom.

Where's the beef? Dionisio

Shared developmental programme strongly constrains beak shape diversity in songbirds doi:10.1038/ncomms4700 The striking diversity of bird beak shapes is an outcome of natural selection, yet the relative importance of the limitations imposed by the process of beak development on generating such variation is unclear. Untangling these factors requires mapping developmental mechanisms over a phylogeny far exceeding model systems studied thus far. We address this issue with a comparative morphometric analysis of beak shape in a diverse group of songbirds. Here we show that the dynamics of the proliferative growth zone must follow restrictive rules to explain the observed variation, with beak diversity constrained to a three parameter family of shapes, parameterized by length, depth and the degree of shear. We experimentally verify these predictions by analysing cell proliferation in the developing embryonic beaks of the zebra finch. Our findings indicate that beak shape variability in many songbirds is strongly constrained by shared properties of the developmental programme controlling the growth zone. http://www.nature.com/ncomms/2014/140416/ncomms4700/full/ncomms4700.html

Dionisio

Darwin’s iconic finches join genome club Scientists pinpoint genes behind famous beak variations. The study, published online in Nature this week, also redraws the family tree of these iconic birds, whose facial variations helped Charles Darwin to formulate his theory of natural selection. The birds are a textbook example of adaptive radiation, in which a single ancestor responds to a selective pressure — in this case, food availability — by diversifying into several species [of birds]. But nobody had compared whole-genome data from all 15 species until a team led by Leif Andersson, a geneticist at Uppsala University in Sweden, analysed samples from 120 individual birds. “When we did the whole DNA sequence of all the species, we could redraw that tree,” he says. [where are the spatiotemporal developmental mechanisms for the beaks and the whole birds described in details?] Andersson suspects that ALX1 drove that adaptation, but others say the picture is more complicated. [duh! of course it's much more complicated!] Beaks “differ in many parameters, not just being blunt or pointed”, says Ricardo Mallarino, an evolutionary biologist at Harvard University in Cambridge, Massachusetts. Functional studies of ALX1 should help to reveal exactly what the gene controls, he says. What would Darwin make of the findings? “We would have to give him a crash course in genetics,” Grant says. “But then he would be delighted. The results are entirely consistent with his ideas.” [well, not quite so... he made a scandalous extrapolation error by letting his prolific imagination take his ideas too far beyond what he had observed] http://www.nature.com/news/darwin-s-iconic-finches-join-genome-club-1.16896

Dionisio

Evolution of Darwin’s finches and their beaks revealed by genome sequencing doi:10.1038/nature14181 Darwin’s finches, inhabiting the Galápagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin’s finch species and two close relatives. Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis), a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin’s finches and, thereby, to an expanded utilization of food resources. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14181.html

How did they get the mechanisms for adaptive evolution setup to begin with? Where are the exact spatiotemporal mechanisms for the beak development described? What paper? What about the entire finch? IOW, where's the beef? Dionisio

Micro-evolution within humans. We'll remain humans, no matter what. Just using the built in adaptation mechanisms embedded within the biological systems. That's all. http://www.laboratoryequipment.com/news/2015/02/evolution-continues-despite-low-mortality-fertility?et_cid=4402451&et_rid=653535995&type=cta Someone posted this comment:

So where does Darwin's theory of evolution fit into this story? I get that families in the 1800's were larger than families today and that a much greater percentage of children today survive into adulthood because of advances in medicine standards of living, but that's not exactly a groundbreaking revelation.

Same as the Galapagos finch beaks story. Amazingly complex built in adaptation mechanisms. They remained birds after all their seasonal beak changes in subsequent generations. Dionisio

Amazingly complex built in adaptability mechanisms embedded within the biological systems. No available tech spec for assembling those wonderful mechanisms. Not yet. Still searching. Work in progress. Meanwhile, trying to figure out exactly how they operate. Here's another example:

Explaining the sawtooth: latitudinal periodicity in a circadian gene correlates with shifts in generation number. Many temperate insects take advantage of longer growing seasons at lower latitudes by increasing their generation number or voltinism. In some insects, development time abruptly decreases when additional generations are fit into the season. Consequently, latitudinal 'sawtooth' clines associated with shifts in voltinism are seen for phenotypes correlated with development time, like body size. However, latitudinal variation in voltinism has not been linked to genetic variation at specific loci. [...] http://www.ncbi.nlm.nih.gov/pubmed/25430782

Dionisio

Evolution of time-keeping mechanisms: early emergence and adaptation to photoperiod DOI: 10.1098/rstb.2010.0409 . Virtually all species have developed [how?] cellular oscillations and mechanisms that synchronize these cellular oscillations to environmental cycles. Such environmental cycles in biotic (e.g. food availability and predation risk) or abiotic (e.g. temperature and light) factors may occur on a daily, annual or tidal time scale. Internal timing mechanisms may facilitate behavioural or physiological adaptation to such changes in environmental conditions. These timing mechanisms commonly involve an internal molecular oscillator (a ‘clock’) that is synchronized (‘entrained’) to the environmental cycle by receptor mechanisms responding to relevant environmental signals (‘Zeitgeber’, i.e. German for time-giver). To understand the evolution of such timing mechanisms, we have to understand the mechanisms leading to selective advantage. Although major advances have been made in our understanding of the physiological and molecular mechanisms driving internal cycles (proximate questions), studies identifying mechanisms of natural selection on clock systems (ultimate questions) are rather limited. http://rstb.royalsocietypublishing.org/content/366/1574/2141

Basically, work in progress... not there yet, many unanswered questions remain. Dionisio

No genome-wide protein sequence convergence for echolocation. doi: 10.1093/molbev/msv014 Toothed whales and two groups of bats independently acquired echolocation, the ability to locate and identify objects by reflected sound. Echolocation requires physiologically complex and coordinated vocal, auditory, and neural functions, but the molecular basis of the capacity for echolocation is not well understood. [even after this paper?] A recent study suggested that convergent amino acid substitutions widespread in the proteins of echolocators underlay the convergent origins of mammalian echolocation. Here we show that genomic signatures of molecular convergence between echolocating lineages are generally no stronger than those between echolocating and comparable non-echolocating lineages. The same is true for the group of 29 hearing-related proteins claimed to be enriched with molecular convergence. Reexamining the previous selection test reveals several flaws and invalidates the asserted evidence for adaptive convergence. Together, these findings indicate that the reported genomic signatures of convergence largely reflect the background level of sequence convergence unrelated to the origins of echolocation. http://mbe.oxfordjournals.org/content/early/2015/01/27/molbev.msv014.abstract?sid=a20f8e3f-fb89-4585-a4a4-59

Work in progress... (what else is new?) :) Dionisio

In Search of Beneficial Coding RNA Editing RNA editing is a posttranscriptional modification that can lead to a change in the encoded protein sequence of a gene. Although a few cases of mammalian coding RNA editing are known to be functionally important, the vast majority of over 2,000 A-to-I editing sites that have been identified from the coding regions of the human genome are likely nonadaptive, representing tolerable promiscuous targeting of editing enzymes. Finding the potentially tiny fraction of beneficial editing sites from the sea of mostly nearly neutral editing is a difficult but important task. Here, we propose and provide evidence that evolutionarily conserved or “hardwired” residues that experience high-level nonsynonymous RNA editing in a species are enriched with beneficial editing. This simple approach allows the prediction of sites where RNA editing is functionally important. We suggest that priority be given to these candidates in future characterizations of the functional and fitness consequences of RNA editing. http://mbe.oxfordjournals.org/content/32/2/536.abstract

The search continues... :) Dionisio

Conserved syntenic clusters of protein coding genes are missing in birds doi:10.1186/s13059-014-0565-1 Birds are one of the most highly successful and diverse groups of vertebrates, having evolved [how?] a number of distinct characteristics, including feathers and wings, a sturdy lightweight skeleton and unique respiratory and urinary/excretion systems. However, the genetic basis of these traits is poorly understood. [even after this research?] Using comparative genomics based on extensive searches of 60 avian genomes, we have found that birds lack approximately 274 protein coding genes that are present in the genomes of most vertebrate lineages and are for the most part organized [why?] in conserved syntenic clusters in non-avian sauropsids and in humans. Functional enrichment analysis combined with orthogroup analysis and paralog searches revealed enrichments that were shared by non-avian species, present only in birds, or shared between all species. Together these results provide a clearer definition of the genetic background of extant birds, extend the findings of previous studies on missing avian genes, and provide clues about molecular events that shaped avian evolution. [but many more clues still needed?] http://genomebiology.com/2014/15/12/565

Interesting work in progress. Still many unanswered questions. Dionisio

The evolution we are witnessing and enjoying these days

Since the invention of the first microscope, a procession of new technologies has enabled scientists to study individual cells at increasingly fine levels of detail. The last two years have witnessed an important next stage in this evolution, with the arrival of the first devices for genetically profiling single cells on a genome-wide scale.

http://systemsbiology.columbia.edu/genome-center/news/improving-single-cell-rna-seq-at-the-columbia-genome-center Dionisio

'Brain Drain' Threatens Academic Research, JHU President Warns http://www.genengnews.com/gen-news-highlights/brain-drain-threatens-academic-research-jhu-president-warns/81250771/ Dionisio

Assessing Research Productivity A new way of evaluating academics’ research output using easily obtained data By Ushma S. Neill, Craig B. Thompson, and Donna S. Gibson | January 1, 2015 It can often be difficult to gauge researcher productivity and impact, but these measures of effectiveness are important for academic institutions and funding sources to consider in allocating limited scientific resources and funding. Much as in the lab, where it is important for the results to be repeatable, developing an algorithm or an impartial process to appraise individual faculty research performance over multiple disciplines can deliver valuable insights for long-term strategic planning. Unfortunately, the development of such evaluation practices remains at an embryonic stage. http://www.the-scientist.com//?articles.view/articleNo/41682/title/Assessing-Research-Productivity/

Well, at least they're reporting fascinating results that the rest of us are enjoying. :) Dionisio

Perhaps this is good news for the third way folks? https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-540581 Dionisio

Gathering and organizing research information using Zotero and Mind Meister along with a combination of interconnected web logs has turned very time consuming. Some of the reviewed articles have been shared here in this thread the last several months. As soon as a shareable link to the zotero-based collection is available, it will be posted here so others can review it too. However this might take quite some time. May you all have a Merry Christmas and a blessed new year! ciao amici! Dionisio

Spindle assembly checkpoint: the third decade. The spindle assembly checkpoint controls cell cycle progression during mitosis, synchronizing it with the attachment of chromosomes to spindle microtubules. After the discovery of the mitotic arrest deficient (MAD) and budding uninhibited by benzymidazole (BUB) genes as crucial checkpoint components in 1991, the second decade of checkpoint studies (2001-2010) witnessed crucial advances in the elucidation of the mechanism through which the checkpoint effector, the mitotic checkpoint complex, targets the anaphase-promoting complex (APC/C) to prevent progression into anaphase. Concomitantly, the discovery that the Ndc80 complex and other components of the microtubule-binding interface of kinetochores are essential for the checkpoint response finally asserted that kinetochores are crucial for the checkpoint response. Nevertheless, the relationship between kinetochores and checkpoint control remains poorly understood. Crucial advances in this area in the third decade of checkpoint studies (2011-2020) are likely to be brought about by the characterization of the mechanism of kinetochore recruitment, activation and inactivation of checkpoint proteins, which remains elusive for the majority of checkpoint components. Here, we take a molecular view on the main challenges hampering this task. http://www.bioportfolio.com/resources/pmarticle/270912/Spindle-Assembly-Checkpoint-The-Third-Decade.html Dionisio

This was posted here in UD over 3 years ago: https://uncommondescent.com/biology/cell-biology-a-%e2%80%9cspindle-checkpoint%e2%80%9d-mechanism-prevents-cancer-cells-in-a-variety-of-life-forms-humans-to-yeast/#comments Dionisio

Over 3 years ago here in UD: https://uncommondescent.com/biology/cell-biology-a-%e2%80%9cspindle-checkpoint%e2%80%9d-mechanism-prevents-cancer-cells-in-a-variety-of-life-forms-humans-to-yeast/#comments Dionisio

RGM Regulates BMP-Mediated Secondary Axis Formation DOI: http://dx.doi.org/10.1016/j.celrep.2014.11.009 Patterning of the metazoan dorsoventral axis is mediated by a complex interplay of BMP signaling regulators. Repulsive guidance molecule (RGM) is a conserved BMP coreceptor that has not been implicated in axis specification. We show that NvRGM is a key positive regulator of BMP signaling during secondary axis establishment in the cnidarian Nematostella vectensis. NvRGM regulates first the generation and later the shape of a BMP-dependent Smad1/5/8 gradient with peak activity on the side opposite the NvBMP/NvRGM/NvChordin expression domain. Full knockdown of Smad1/5/8 signaling blocks the formation of endodermal structures, the mesenteries, and the establishment of bilateral symmetry, while altering the gradient through partial NvRGM or NvBMP knockdown shifts the boundaries of asymmetric gene expression and the positioning of the mesenteries along the secondary axis. These findings provide insight into the diversification of axis specification mechanisms and identify a previously unrecognized role for RGM in BMP-mediated axial patterning. http://www.cell.com/cell-reports/abstract/S2211-1247(14)00963-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124714009632%3Fshowall%3Dtrue Dionisio

When Mad met Bob DOI 10.1002/embr.201438574 The faithful segregation of chromosomes into daughter cells is essential for cellular and organismal viability. Errors in this process cause aneuploidy, a hallmark of cancer and several congenital diseases. For proper separation, chromosomes attach to microtubules of the mitotic spindle via their kinetochores, large protein structures assembled on centromeric chromatin. Kinetochores are also crucial for a cell cycle feedback mechanism known as the spindle assembly checkpoint (SAC) [1]. The SAC forces cells to remain in mitosis until all chromosomes are properly attached to microtubules. At the beginning of mitosis, the SAC proteins—Mad1, Mad2, Bub1, Bub3, BubR1, Mps1, and Cdc20—are recruited to kinetochores in a hierarchical and interdependent fashion (Fig 1A). There they monitor, in ways that are not fully clarified, the formation of kinetochore–microtubule attachments [1]. Two studies recently published in EMBO reports by the groups of Silke Hauf [2] and Jakob Nilsson [3], and a recent study by London and Biggins in Genes & Development [4], shed new light on the conserved SAC protein Mad1. http://embor.embopress.org/content/15/4/326 Dionisio

Mad1 contribution to spindle assembly checkpoint signalling goes beyond presenting Mad2 at kinetochores DOI 10.1002/embr.201338114 The spindle assembly checkpoint inhibits anaphase until all chromosomes have become attached to the mitotic spindle. A complex between the checkpoint proteins Mad1 and Mad2 provides a platform for Mad2:Mad2 dimerization at unattached kinetochores, which enables Mad2 to delay anaphase. Here, we show that mutations in Bub1 and within the Mad1 C?terminal domain impair the kinetochore localization of Mad1:Mad2 and abrogate checkpoint activity. Artificial kinetochore recruitment of Mad1 in these mutants co?recruits Mad2; however, the checkpoint remains non?functional. We identify specific mutations within the C?terminal head of Mad1 that impair checkpoint activity without affecting the kinetochore localization of Bub1, Mad1 or Mad2. Hence, Mad1 potentially in conjunction with Bub1 has a crucial role in checkpoint signalling in addition to presenting Mad2. http://embor.embopress.org/content/15/3/291 Dionisio

A direct role of Mad1 in the spindle assembly checkpoint beyond Mad2 kinetochore recruitment DOI 10.1002/embr.201338101 The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation by delaying entry into anaphase until all sister chromatids have become bi?oriented. A key component of the SAC is the Mad2 protein, which can adopt either an inactive open (O?Mad2) or active closed (C?Mad2) conformation. The conversion of O?Mad2 into C?Mad2 at unattached kinetochores is thought to be a key step in activating the SAC. The “template model” proposes that this is achieved by the recruitment of soluble O?Mad2 to C?Mad2 bound at kinetochores through its interaction with Mad1. Whether Mad1 has additional roles in the SAC beyond recruitment of C?Mad2 to kinetochores has not yet been addressed. Here, we show that Mad1 is required for mitotic arrest even when C?Mad2 is artificially recruited to kinetochores, indicating that it has indeed an additional function in promoting the checkpoint. The C?terminal globular domain of Mad1 and conserved residues in this region are required for this unexpected function of Mad1. http://embor.embopress.org/content/early/2014/01/28/embr.201338101 Dionisio

Phosphodependent Recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 Kinase Maintains the Spindle Checkpoint DOI: http://dx.doi.org/10.1016/j.cub.2012.03.051 The spindle assembly checkpoint (SAC) is the major surveillance system that ensures that sister chromatids do not separate until all chromosomes are correctly bioriented during mitosis. Components of the checkpoint include Mad1, Mad2, Mad3 (BubR1), Bub3, and the kinases Bub1, Mph1 (Mps1), and Aurora B [ 1 ]. Checkpoint proteins are recruited to kinetochores when individual kinetochores are not bound to spindle microtubules or not under tension [ 2–5 ]. Kinetochore association of Mad2 causes it to undergo a conformational change, which promotes its association to Mad3 and Cdc20 to form the mitotic checkpoint complex (MCC). The MCC inhibits the anaphase-promoting complex/cyclosome (APC/C) until the checkpoint is satisfied. SAC silencing derepresses Cdc20-APC/C activity. This triggers the polyubiquitination of securin and cyclin, which promotes the dissolution of sister chromatid cohesion and mitotic progression [ 6–8 ]. We, and others, recently showed that association of PP1 to the Spc7/Spc105/KNL1 family of kinetochore proteins is necessary to stabilize microtubule-kinetochore attachments and silence the SAC [ 9–12 ]. We now report that phosphorylation of the conserved MELT motifs in Spc7 by Mph1 (Mps1) recruits Bub1 and Bub3 to the kinetochore and that this is required to maintain the SAC signal. http://www.cell.com/current-biology/abstract/S0960-9822(12)00338-7 Dionisio

The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint doi: 10.1242/dev.117044. Asymmetric cell division is utilized by a broad range of cell types to generate two daughter cells with distinct cell fates. In stem cell populations asymmetric cell division is believed to be crucial for maintaining tissue homeostasis, failure of which can lead to tissue degeneration or hyperplasia/tumorigenesis. Asymmetric cell divisions also underlie cell fate diversification during development. Accordingly, the mechanisms by which asymmetric cell division is achieved have been extensively studied, although the check points that are in place to protect against potential perturbation of the process are poorly understood. Drosophila melanogaster male germline stem cells (GSCs) possess a checkpoint, termed the centrosome orientation checkpoint (COC), that monitors correct centrosome orientation with respect to the component cells of the niche to ensure asymmetric stem cell division. To our knowledge, the COC is the only checkpoint mechanism identified to date that specializes in monitoring the orientation of cell division in multicellular organisms. Here, by establishing colcemid-induced microtubule depolymerization as a sensitive assay, we examined the characteristics of COC activity and find that it functions uniquely in GSCs but not in their differentiating progeny. We show that the COC operates in the G2 phase of the cell cycle, independently of the spindle assembly checkpoint. This study may provide a framework for identifying and understanding similar mechanisms that might be in place in other asymmetrically dividing cell types. http://www.ncbi.nlm.nih.gov/pubmed/25480919 Dionisio

Negative feedback at kinetochores underlies a responsive spindle checkpoint signal doi:10.1038/ncb3065 Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability1. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached2. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF2, 3, 4. We show that this responsiveness arises because the SAC primes kinetochore phosphatases to induce negative feedback and silence its own signal. Active SAC signalling recruits PP2A-B56 to kinetochores where it antagonizes ?Aurora B to promote PP1 recruitment. PP1 in turn silences the SAC and delocalizes PP2A-B56. Preventing or bypassing key regulatory steps demonstrates that this spatiotemporal control of phosphatase feedback underlies rapid signal switching at the kinetochore by: allowing the SAC to quickly transition to the ON state in the absence of antagonizing phosphatase activity; and ensuring phosphatases are then primed to rapidly switch the SAC signal OFF when kinetochore kinase activities are diminished by force-producing microtubule attachments. http://www.nature.com/ncb/journal/v16/n12/full/ncb3065.html Dionisio

Non-canonical function of spindle assembly checkpoint proteins after APC activation doi:10.1038/ncomms4444 The spindle assembly checkpoint (SAC) prevents aneuploidy by coupling anaphase onset, through anaphase-promoting complex (APC) activation, with chromosome attachment to spindle microtubules. Here, we examine APC activity in oocytes, noted for their susceptibility to chromosome mis-segregation during the first meiotic division (MI). We find that MI oocytes only contain sub-maximal APC activity, measured through cyclin B1–GFP degradation, because inhibition of SAC proteins when the APC is normally fully active increases cyclin B1 degradation twofold and reduces the length of this division by 2?h. In addition, inhibiting the SAC component Mps1 only when the APC is already active increases aneuploidy rates in the resulting egg by up to 30%. We therefore establish that the activities of SAC proteins and the APC co-exist in oocytes, and such concurrence has a vital role in reducing aneuploidy rates by extending MI, probably by allowing time for numerous erroneous microtubule attachments to be corrected. http://www.nature.com/ncomms/2014/140318/ncomms4444/full/ncomms4444.html Dionisio

TRAIP is a regulator of the spindle assembly checkpoint doi: 10.1242/?jcs.152579 Accurate chromosome segregation during mitosis is temporally and spatially coordinated by fidelity-monitoring checkpoint systems. Deficiencies in these checkpoint systems can lead to chromosome segregation errors and aneuploidy, and promote tumorigenesis. Here, we report that the TRAF-interacting protein (TRAIP), a ubiquitously expressed nucleolar E3 ubiquitin ligase important for cellular proliferation, is localized close to mitotic chromosomes. Its knockdown in HeLa cells by RNA interference (RNAi) decreased the time of early mitosis progression from nuclear envelope breakdown (NEB) to anaphase onset and increased the percentages of chromosome alignment defects in metaphase and lagging chromosomes in anaphase compared with those of control cells. The decrease in progression time was corrected by the expression of wild-type but not a ubiquitin-ligase-deficient form of TRAIP. TRAIP-depleted cells bypassed taxol-induced mitotic arrest and displayed significantly reduced kinetochore levels of MAD2 (also known as MAD2L1) but not of other spindle checkpoint proteins in the presence of nocodazole. These results imply that TRAIP regulates the spindle assembly checkpoint, MAD2 abundance at kinetochores and the accurate cellular distribution of chromosomes. The TRAIP ubiquitin ligase activity is functionally required for the spindle assembly checkpoint control. http://jcs.biologists.org/content/127/24/5149.short Dionisio

The Cdc20-binding Phe Box of the Spindle Checkpoint Protein BubR1 Maintains the Mitotic Checkpoint Complex during Mitosis. The spindle checkpoint ensures accurate chromosome segregation by monitoring kinetochore-microtubule attachment. Unattached or tensionless kinetochores activate the checkpoint and enhance the production of the mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, Mad2, and Cdc20. MCC is a critical checkpoint inhibitor of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase required for anaphase onset. The N-terminal region of BubR1 binds to both Cdc20 and Mad2, thus nucleating MCC formation. The middle region of human BubR1 (BubR1M) also interacts with Cdc20, but the nature and function of this interaction are not understood. Here we identify two critical motifs within BubR1M that contribute to Cdc20 binding and APC/C inhibition: a destruction box (D box) and a phenylalanine-containing motif termed the Phe box. A BubR1 mutant lacking these motifs is defective in MCC maintenance in mitotic human cells, but is capable of supporting spindle-checkpoint function. Thus, the BubR1M-Cdc20 interaction indirectly contributes to MCC homeostasis. Its apparent dispensability in the spindle checkpoint might be due to functional duality or redundant, competing mechanisms. http://www.ncbi.nlm.nih.gov/pubmed/25505175 Dionisio

Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number DOI: http://dx.doi.org/10.1016/j.neuron.2014.12.017 Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development. http://www.cell.com/neuron/abstract/S0896-6273(14)01098-8 Dionisio

Cohesin cleavage is insufficient for centriole disengagement DOI: http://dx.doi.org/10.1016/j.cub.2013.04.003 Centriole disengagement is thought to act as a licensing mechanism restricting centrosome duplication to once per cell cycle [1] and to depend on cleavage of the cohesin complex by separase [1–3] . Whether this is a conserved mechanism in eukaryotic cells remains to be determined. We show that artificial cohesin cleavage in Drosophila embryos fails to cause detectable centriole disengagement. In contrast, inhibition of Cyclin-dependent kinase (Cdk1) triggers rapid disengagement in metaphase-arrested embryos. Our results raise the possibility that in these early embryonic divisions centriole engagement depends on Cdk1 activity, not cohesin. http://www.cell.com/current-biology/abstract/S0960-9822(13)00411-9 Dionisio

Have the "third way" folks published any coherent comprehensive description of how the mechanisms referenced in 800+ posts in this thread came to be? Meanwhile many scientists work hard trying to figure out how those mechanisms work and what they do. Dionisio

Multiple Mechanisms Contribute to Centriole Separation DOI: http://dx.doi.org/10.1016/j.cub.2013.06.043 Centrosome function in cell division requires their duplication, once, and only once, per cell cycle. Underlying centrosome duplication are alternating cycles of centriole assembly and separation [ 1 ]. Work in vertebrates has implicated the cysteine protease separase in anaphase-coupled centriole separation (or disengagement) and identified this as a key step in licensing another round of assembly [ 2 ]. Current models have separase cleaving a physical link between centrioles, potentially cohesin [ 3, 4 ], that prevents reinitiation of centriole assembly unless disengaged. Here, we examine separase function in the C. elegans early embryo. We find that depletion impairs separation and consequently duplication of sperm-derived centrioles at the meiosis-mitosis transition. However, subsequent cycles proceed normally. Whereas mitotic centrioles separate in the context of cortical forces acting on a disassembling pericentriolar material, sperm centrioles are not associated with significant pericentriolar material or subject to strong forces. Increasing centrosomal microtubule nucleation restores sperm centriole separation and duplication in separase-depleted embryos, while forced pericentriolar material disassembly drives premature separation in mitosis. These results emphasize the critical role of cytoskeletal forces and the pericentriolar material in centriole separation. Separase contributes to separation where forces are limited, offering a potential explanation for results obtained in different experimental models [ 5–7 ]. http://www.cell.com/current-biology/abstract/S0960-9822(13)00768-9 Dionisio

The potentially negative side effects of some medical treatments. Link Between DNA Damage and Centriole Disengagement/Reduplication in Untransformed Human Cells DOI: 10.1002/jcp.24579 The radiation and radiomimetic drugs used to treat human tumors damage DNA in both cancer cells and normal proliferating cells. Centrosome amplification after DNA damage is well established for transformed cell types but is sparsely reported and not fully understood in untransformed cells. We characterize centriole behavior after DNA damage in synchronized untransformed human cells. One hour treatment of S phase cells with the radiomimetic drug, Doxorubicin, prolongs G2 by at least 72?h, though 14% of the cells eventually go through mitosis in that time. By 72?h after DNA damage we observe a 52% incidence of centriole disengagement plus a 10% incidence of extra centrioles. We find that either APC/C or Plk activities can disengage centrioles after DNA damage, though they normally work in concert. All disengaged centrioles are associated with ?-tubulin and maturation markers and thus, should in principle be capable of reduplicating and organizing spindle poles. The low incidence of reduplication of disengaged centrioles during G2 is due to the p53-dependent expression of p21 and the consequent loss of Cdk2 activity. We find that 26% of the cells going through mitosis after DNA damage contain disengaged or extra centrioles. This could produce genomic instability through transient or persistent spindle multipolarity. Thus, for cancer patients the use of DNA damaging therapies raises the chances of genomic instability and evolution of transformed http://onlinelibrary.wiley.com/doi/10.1002/jcp.24579/abstract Dionisio

lack of centrioles and primary cilia impairs Hedgehog signaling and further embryonic development. doi: 10.4161/15384101.2014.946830. Although most animal cells contain centrosomes, consisting of a pair of centrioles, their precise contribution to cell division and embryonic development is unclear. Genetic ablation of STIL, an essential component of the centriole replication machinery in mammalian cells, causes embryonic lethality in mice around mid gestation associated with defective Hedgehog signaling. Here, we describe, by focused ion beam scanning electron microscopy, that STIL(-/-) mouse embryos do not contain centrioles or primary cilia, suggesting that these organelles are not essential for mammalian development until mid gestation. We further show that the lack of primary cilia explains the absence of Hedgehog signaling in STIL(-/-) cells. Exogenous re-expression of STIL or STIL microcephaly mutants compatible with human survival, induced non-templated, de novo generation of centrioles in STIL(-/-) cells. Thus, while the abscence of centrioles is compatible with mammalian gastrulation, lack of centrioles and primary cilia impairs Hedgehog signaling and further embryonic development. http://www.ncbi.nlm.nih.gov/pubmed/25486474 Dionisio

SAS-6 Assembly Templated by the Lumen of Cartwheel-less Centrioles Precedes Centriole Duplication DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.008 Centrioles are 9-fold symmetric structures duplicating once per cell cycle. Duplication involves self-oligomerization of the centriolar protein SAS-6, but how the 9-fold symmetry is invariantly established remains unclear. Here, we found that SAS-6 assembly can be shaped by preexisting (or mother) centrioles. During S phase, SAS-6 molecules are first recruited to the proximal lumen of the mother centriole, adopting a cartwheel-like organization through interactions with the luminal wall, rather than via their self-oligomerization activity. The removal or release of luminal SAS-6 requires Plk4 and the cartwheel protein STIL. Abolishing either the recruitment or the removal of luminal SAS-6 hinders SAS-6 (or centriole) assembly at the outside wall of mother centrioles. After duplication, the lumen of engaged mother centrioles becomes inaccessible to SAS-6, correlating with a block for reduplication. These results lead to a proposed model that centrioles may duplicate via a template-based process to preserve their geometry and copy number. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00310-4 Dionisio

Mother Centrioles Do a Cartwheel to Produce Just One Daughter DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.013 In this issue of Developmental Cell, Fong et al. (2014) present evidence for a model of centriole duplication whereby the cartwheel—the starting building block in centriole biogenesis—assembles within the lumen of the mother centriole before templating the daughter centriole to ensure a single duplication event per cell cycle. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00455-9?cc=y Dionisio

RBM14 prevents assembly of centriolar protein complexes and maintains mitotic spindle integrity. Formation of a new centriole adjacent to a pre-existing centriole occurs only once per cell cycle. Despite being crucial for genome integrity, the mechanisms controlling centriole biogenesis remain elusive. Here, we identify RBM14 as a novel suppressor of assembly of centriolar protein complexes. Depletion of RBM14 in human cells induces ectopic formation of centriolar protein complexes through function of the STIL/CPAP complex. Intriguingly, the formation of such structures seems not to require the cartwheel structure that normally acts as a scaffold for centriole formation, whereas they can retain pericentriolar material and microtubule nucleation activity. Moreover, we find that, upon RBM14 depletion, a part of the ectopic centriolar protein complexes in turn assemble into structures more akin to centrioles, presumably by incorporating HsSAS-6, a cartwheel component, and cause multipolar spindle formation. We further demonstrate that such structures assemble in the cytoplasm even in the presence of pre-existing centrioles. This study sheds light on the possibility that ectopic formation of aberrant structures related to centrioles may contribute to genome instability and tumorigenesis. http://www.ncbi.nlm.nih.gov/pubmed/25385835 Dionisio

Direct interaction of Plk4 with STIL ensures formation of a single procentriole per parental centriole. doi: 10.1038/ncomms6267. Formation of one procentriole next to each pre-existing centriole is essential for centrosome duplication, robust bipolar spindle assembly and maintenance of genome integrity. However, the mechanisms maintaining strict control over centriole copy number are incompletely understood. Here we show that Plk4 and STIL, the key regulators of centriole formation, form a protein complex that provides a scaffold for recruiting HsSAS-6, a major component of the centriolar cartwheel, at the onset of procentriole formation. Furthermore, we demonstrate that phosphorylation of STIL by Plk4 facilitates the STIL/HsSAS-6 interaction and centriolar loading of HsSAS-6. We also provide evidence that negative feedback by centriolar STIL regulates bimodal centriolar distribution of Plk4 and seemingly restricts occurrence of procentriole formation to one site on each parental centriole. Overall, these findings suggest a mechanism whereby coordinated action of three critical factors ensures formation of a single procentriole per parental centriole. http://www.ncbi.nlm.nih.gov/pubmed/25342035 Dionisio

Centriole cartwheel assembly. doi: 10.1098/rstb.2013.0458. The cartwheel is a subcentriolar structure consisting of a central hub and nine radially arranged spokes, located at the proximal end of the centriole. It appears at the initial stage of the centriole assembly process as the first ninefold symmetrical structure. The cartwheel was first described more than 50 years ago, but it is only recently that its pivotal role in establishing the ninefold symmetry of the centriole was demonstrated. Significant progress has since been made in understanding its fine structure and assembly mechanism. . [this is encouraging news] Most importantly, the central part of the cartwheel, from which the ninefold symmetry originates, is shown to form by self-association of nine dimers of the protein SAS-6. This finding, together with emerging data on other components of the cartwheel, has opened new avenues in centrosome biology. http://www.ncbi.nlm.nih.gov/pubmed/25047612 Dionisio

Spastin-Interacting Protein NA14/SSNA1 Functions in Cytokinesis and Axon Development. doi: 10.1371/journal.pone.0112428 Hereditary spastic paraplegias (HSPs) are a genetically diverse group of inherited neurological disorders (SPG1-72) with the cardinal feature of prominent lower-extremity spasticity due to a length-dependent axonopathy of corticospinal motor neurons. The most frequent form of autosomal dominant HSP results from mutations of the SPG4 gene product spastin. This is an ATPase associated with diverse cellular activities (AAA) protein that binds to and severs microtubules. While spastin participates in crucial cellular processes such as cytokinesis, endosomal tubulation, and axon development, its role in HSP pathogenesis remains unclear. Spastin interacts in cells with the NA14 protein, a major target for auto-antibodies in Sjögren's syndrome (nuclear autoantigen 1; SSNA1). Our analysis of endogenous spastin and NA14 proteins in HeLa cells and rat cortical neurons in primary culture revealed a clear distribution of both proteins to centrosomes, with NA14 localizing specifically to centrioles. Stable NA14 knockdown in cell lines dramatically affected cell division, in particular cytokinesis. Furthermore, overexpression of NA14 in neurons significantly increased axon outgrowth and branching, while also enhancing neuronal differentiation. We postulate that NA14 may act as an adaptor protein regulating spastin localization to centrosomes, temporally and spatially regulating the microtubule-severing activity of spastin that is particularly critical during the cell cycle and neuronal development. http://www.ncbi.nlm.nih.gov/pubmed/25390646 Dionisio

Building a centriole. doi: 10.1016/j.ceb.2012.10.016. Centrioles are the key foundation of centrosomes and cilia, yet a molecular understanding of how they form has only recently begun to emerge. Building a fully functional centriole that can form a centrosome and cilium requires two cell cycles. Centriole building starts with procentriole nucleation, a process that is coordinated by the conserved proteins Plk4/Zyg-1, and Asterless/Cep152. Subsequently, Sas-6, a conserved procentriole protein, self-assembles to provide nine-fold symmetry to the centriole scaffold. The procentriole then continues to elongate into a centriole, a process controlled by Sas-4/CPAP and CP110. Then, centrioles recruit Sas-4-mediated pre-assembled centrosomal complexes from the cytoplasm to form the pericentriolar material (PCM). Finally, CP110 and its interacting proteins are involved in controlling the timing of centriole templating of the cilium. http://www.ncbi.nlm.nih.gov/pubmed/23199753 Dionisio

Centrobin-centrosomal protein 4.1-associated protein (CPAP) interaction promotes CPAP localization to the centrioles during centriole duplication. doi: 10.1074/jbc.M113.531152. Centriole duplication is the process by which two new daughter centrioles are generated from the proximal end of preexisting mother centrioles. Accurate centriole duplication is important for many cellular and physiological events, including cell division and ciliogenesis. Centrosomal protein 4.1-associated protein (CPAP), centrosomal protein of 152 kDa (CEP152), and centrobin are known to be essential for centriole duplication. However, the precise mechanism by which they contribute to centriole duplication is not known. In this study, we show that centrobin interacts with CEP152 and CPAP, and the centrobin-CPAP interaction is critical for centriole duplication. Although depletion of centrobin from cells did not have an effect on the centriolar levels of CEP152, it caused the disappearance of CPAP from both the preexisting and newly formed centrioles. Moreover, exogenous expression of the CPAP-binding fragment of centrobin also caused the disappearance of CPAP from both the preexisting and newly synthesized centrioles, possibly in a dominant negative manner, thereby inhibiting centriole duplication and the PLK4 overexpression-mediated centrosome amplification. Interestingly, exogenous overexpression of CPAP in the centrobin-depleted cells did not restore CPAP localization to the centrioles. However, restoration of centrobin expression in the centrobin-depleted cells led to the reappearance of centriolar CPAP. Hence, we conclude that centrobin-CPAP interaction is critical for the recruitment of CPAP to procentrioles to promote the elongation of daughter centrioles and for the persistence of CPAP on preexisting mother centrioles. Our study indicates that regulation of CPAP levels on the centrioles by centrobin is critical for preserving the normal size, shape, and number of centrioles in the cell. http://www.ncbi.nlm.nih.gov/pubmed/24700465 Dionisio

#858 follow-up Unexpected? Again? What did they expect ? What were their expectations based on? Oh, well... whatever. :) Dionisio

unexpected centriolar asymmetry ? Centriole amplification by mother and daughter centrioles differs in multiciliated cells. doi: 10.1038/nature13770. The semi-conservative centrosome duplication in cycling cells gives rise to a centrosome composed of a mother and a newly formed daughter centriole. Both centrioles are regarded as equivalent in their ability to form new centrioles and their symmetric duplication is crucial for cell division homeostasis. Multiciliated cells do not use the archetypal duplication program and instead form more than a hundred centrioles that are required for the growth of motile cilia and the efficient propelling of physiological fluids. The majority of these new centrioles are thought to appear de novo, that is, independently from the centrosome, around electron-dense structures called deuterosomes. Their origin remains unknown. Using live imaging combined with correlative super-resolution light and electron microscopy, we show that all new centrioles derive from the pre-existing progenitor cell centrosome through multiple rounds of procentriole seeding. Moreover, we establish that only the daughter centrosomal centriole contributes to deuterosome formation, and thus to over ninety per cent of the final centriole population. This unexpected centriolar asymmetry grants new perspectives when studying cilia-related diseases and pathological centriole amplification observed in cycling cells and associated with microcephaly and cancer. http://www.ncbi.nlm.nih.gov/pubmed/25307055 Dionisio

Centrioles light video Dionisio

Centrioles light video https://www.youtube.com/embed/5lN-Yf6Pv2c Dionisio

Cellular Commitment in the Developing Cerebellum doi: 10.3389/fncel.2014.00450 The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we then discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum. http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00450/abstract Dionisio

Prospero-related homeobox 1 (Prox1) at the crossroads of diverse pathways during adult neural fate specification Over the last decades, adult neurogenesis in the central nervous system (CNS) has emerged as a fundamental process underlying physiology and disease. Recent evidence indicates that the homeobox transcription factor Prox1 is a critical intrinsic regulator of neurogenesis in the embryonic CNS and adult dentate gyrus (DG) of the hippocampus, acting in multiple ways and instructed by extrinsic cues and intrinsic factors. CIn the embryonic CNS, Prox1 is mechanistically involved in the regulation of proliferation versus differentiation decisions of NSCs, promoting cell cycle exit and neuronal differentiation, while inhibits astrogliogenesis. During the complex differentiation events in adult hippocampal neurogenesis, Prox1 is required for maintenance of intermediate progenitors (IPs), differentiation and maturation of glutamatergic interneurons, as well as specification of DG cell identity over CA3 pyramidal fate. The mechanism by which Prox1 exerts multiple functions involves distinct signaling pathways currently not fully highlighted. In this mini-review, we thoroughly discuss the Prox1-dependent phenotypes and molecular pathways in adult neurogenesis in relation to different upstream signaling cues and cell fate determinants. In addition, we discuss the possibility that Prox1 may act as a cross-talk point between diverse signaling cascades to achieve specific outcomes during adult neurogenesis. http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00454/abstract Dionisio

Lymphocyte fate specification as a deterministic but highly plastic process doi:10.1038/nri3734 The cellular progeny of a clonally selected lymphocyte must execute function. However, their function must often occur in more than one way, in more than one place and at more than one time. Experimental evidence supports the view that a single activated lymphocyte can produce a variety of cellular descendants. The mechanisms that are responsible for generating diversity among the progeny of a single lymphocyte remain a subject of lively controversy. Some groups have suggested stochastic mechanisms that are analogous to the diversification of the antigen receptor repertoire. We suggest that the complexity of lymphocyte fates in space and time can be derived from a single naive lymphocyte using the principles of cell diversification that are common in developmental and regenerative biology, including (but not limited to) asymmetric cell division. http://www.nature.com/nri/journal/v14/n10/full/nri3734.html Dionisio

Stochastic transport through carbon nanotubes in lipid bilayers and live cell membranas doi:10.1038/nature13817 There is much interest in developing synthetic analogues of biological membrane channels1 with high efficiency and exquisite selectivity for transporting ions and molecules. Bottom-up2 and top-down3 methods can produce nanopores of a size comparable to that of endogenous protein channels, but replicating their affinity and transport properties remains challenging. http://www.nature.com/nature/journal/v514/n7524/full/nature13817.html Dionisio

#851 follow-up Oh no, gimme a break, are they kidding? now when I thought I was almost holding the bull by its horns, they tell me there might be another wild bull running in the arena and coming my way? :) Dionisio

at least two distinct parallel mechanisms drive chromosome segregation in mammalian cells? Direct kinetochore-spindle pole connections are not required for chromosome segregation. doi: 10.1083/jcb.201401090 Segregation of genetic material occurs when chromosomes move to opposite spindle poles during mitosis. This movement depends on K-fibers, specialized microtubule (MT) bundles attached to the chromosomes' kinetochores. A long-standing assumption is that continuous K-fibers connect every kinetochore to a spindle pole and the force for chromosome movement is produced at the kinetochore and coupled with MT depolymerization. However, we found that chromosomes still maintained their position at the spindle equator during metaphase and segregated properly during anaphase when one of their K-fibers was severed near the kinetochore with a laser microbeam. We also found that, in normal fully assembled spindles, K-fibers of some chromosomes did not extend to the spindle pole. These K-fibers connected to adjacent K-fibers and/or nonkinetochore MTs. Poleward movement of chromosomes with short K-fibers was uncoupled from MT depolymerization at the kinetochore. Instead, these chromosomes moved by dynein-mediated transport of the entire K-fiber/kinetochore assembly. Thus, at least two distinct parallel mechanisms drive chromosome segregation in mammalian cells. http://www.ncbi.nlm.nih.gov/pubmed/25023516 Dionisio

Any comments on https://www.zotero.org/ ? Has anyone here used it? Thanks. Dionisio

Signalling dynamics in the spindle checkpoint response doi:10.1038/nrm3888 The spindle checkpoint ensures proper chromosome segregation during cell division. Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation. New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin. In contrast to the traditional view of a binary checkpoint response — either completely on or off — new findings indicate that the checkpoint response strength is variable. This revised perspective provides insight into how checkpoint bypass can lead to aneuploidy and informs strategies to exploit these errors for cancer treatments. http://www.nature.com/nrm/journal/v15/n11/pdf/nrm3888.pdf Dionisio

The TRAF-interacting protein (TRAIP) is a regulator of the spindle assembly checkpoint doi: 10.1242/?jcs.152579 Accurate chromosome segregation during mitosis is temporally and spatially coordinated by fidelity-monitoring checkpoint systems. Deficiencies in these checkpoint systems can lead to chromosome segregation errors and aneuploidy and promote tumorigenesis. We report that the TRAF-interacting protein (TRAIP), a ubiquitously expressed nucleolar E3 ubiquitin ligase important for cellular proliferation, was localized close to mitotic chromosomes. Its functional inactivation in HeLa cells by siRNAs decreased the time of early mitosis progression from nuclear envelope breakdown to anaphase onset and increased the percentages of chromosome alignment defects in metaphase and lagging chromosomes in anaphase compared to control cells. The decrease in progression time was corrected by the expression of wild-type but not by an ubiquitin ligase deficient form of TRAIP. TRAIP-depleted cells by-passed taxol-induced mitotic arrest, and significantly reduced kinetochore levels of MAD2 but not of other spindle checkpoint proteins in the presence of nocodazole. These results imply that TRAIP regulates the spindle assembly checkpoint, MAD2 abundance at kinetochores and the accurate cellular distribution of chromosomes. The TRAIP ubiquitin ligase activity is functionally required for the spindle assembly checkpoint control. http://jcs.biologists.org/content/early/2014/10/14/jcs.152579 Dionisio

How receptor diffusion influences gradient sensing DOI: 10.1098/rsif.2014.1097. Chemotaxis, or directed motion in chemical gradients, is critical for various biological processes. Many eukaryotic cells perform spatial sensing, i.e. they detect gradients by comparing spatial differences in binding occupancy of chemosensory receptors across their membrane. In many theoretical models of spatial sensing, it is assumed, for the sake of simplicity, that the receptors concerned do not move. However, in reality, receptors undergo diverse modes of diffusion, and can traverse considerable distances in the time it takes such cells to turn in an external gradient. This sets a physical limit on the accuracy of spatial sensing, which we explore using a model in which receptors diffuse freely over the membrane. We find that the Fisher information carried in binding and unbinding events decreases monotonically with the diffusion constant of the receptors. http://rsif.royalsocietypublishing.org/content/12/102/20141097.abstract Dionisio

A cellular solution to an information-processing problem doi: 10.1073/pnas.1406608111 Cell-surface signaling receptors are organized into different architectures that have been arrived at multiple times in diverse contexts. To understand the trade-offs that lead to these architectures, we pose the generic information-processing problem of identifying the optimal strategy for distributed mobile noisy sensors to faithfully “read” an incoming signal that varies in space–time. This involves balancing two opposing requirements: clustering noisy sensors to reduce statistical error and spreading sensors to enhance spatial coverage, resulting in a phase transition that explains the frequent reemergence of a set of architectures. Our results extend to a variety of engineering and communication applications that involve mobile and distributed sensing, and suggest that biology might offer solutions to hard optimization problems that arise in these applications. Signaling receptors on the cell surface are mobile and have evolved to efficiently sense and process mechanical or chemical information. We pose the problem of identifying the optimal strategy for placing a collection of distributed and mobile sensors to faithfully estimate a signal that varies in space and time. The optimal strategy has to balance two opposing objectives: the need to locally assemble sensors to reduce estimation noise and the need to spread them to reduce spatial error. This results in a phase transition in the space of strategies as a function of sensor density and efficiency. We show that these optimal strategies have been arrived at multiple times in diverse cell biology contexts, including the stationary lattice architecture of receptors on the bacterial cell surface and the active clustering of cell-surface signaling receptors in metazoan cells. http://www.pnas.org/content/111/34/12402.abstract Dionisio

Cell division: SACing the anaphase problem. Curr Biol 2014 Mar;24(6):R224-6 Errors in chromosome segregation are safeguarded by the spindle assembly checkpoint. Yet the very defects that trigger this checkpoint are inescapable consequences of sister chromatid segregation in anaphase. Three new studies provide clues to how cells cope with this problem. http://www.pubfacts.com/detail/24650905/Cell-division:-SACing-the-anaphase-problem. Dionisio

ATM-mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint. DOI: 10.1093/carcin/bgu087 The spindle assembly checkpoint (SAC), which blocks anaphase onset until all chromosomes have bi-oriented, is one of the key self-monitoring systems of the eukaryotic cell cycle for genome stability. The mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is hyper-phosphorylated in mitosis. However, the kinases responsible for Mad1 phosphorylation and its functional significance are not fully understood. Here we report that Mad1 is phosphorylated on Serine 214 by the ATM kinase, a critical DNA damage response protein also activated in mitosis and required for the SAC. We demonstrate that Mad1 Serine 214 phosphorylation promotes the formation of homo-dimerization of Mad1 and its hetero-dimerization with Mad2. Further we show that Mad1 Serine 214 phosphorylation contribute to activation of the SAC. Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis. http://www.researchgate.net/publication/261609309_ATM-mediated_Mad1_Serine_214_phosphorylation_regulates_Mad1_dimerization_and_the_spindle_assembly_checkpoint Dionisio

potent G2/M cell cycle arrest targeting microtubules DOI: 10.1007/s10637-014-0126-1 Natural products play a pivotal role in the treatment of cancer; identification of compounds such as taxanes and the vinca alkaloids were seminal landmarks in natural product drug discovery. Jerantinine A, a novel Aspidosperma alkaloid isolated from plant species Tabernaemontana corymbosa, was previously reported to possess cytotoxic activity against vincristine-resistant nasopharyngeal carcinoma cells and is therefore an ideal candidate for biological investigation. Furthermore, Tabernaemontana corymbosa, has been placed in the endangered list of threatened species by the International Union for Conservation of Nature thus making it a priority to elucidate the biological activity of this alkaloid. Herein, we report detailed biological evaluation of jerantinine A on various human-derived carcinoma cell lines. Our preliminary screens showed that significant inhibition of cell growth and colony formation accompanied time- and dose-dependent induction of apoptosis in human cancer cell lines after treatment with jerantinine A. Dose-dependent accumulations of cleaved PARP and caspase 3 further confirmed apoptosis. Profound G2/M cell cycle arrest was observed 24 h after treatment in all cell lines. Characteristics of mitotic arrest including inhibition of tubulin polymerisation, microtubule disruption, aneuploidy, and cyclin B1 down-regulation were clearly observed. The potent anti-proliferative, pro-apoptotic, and tubulin-destabilising activities of jerantinine A warrant further development of this molecule as a potential chemotherapeutic agent. http://www.researchgate.net/publication/263095524_Novel_antitumour_indole_alkaloid_Jerantinine_A_evokes_potent_G2M_cell_cycle_arrest_targeting_microtubules Dionisio

Dependency of the spindle assembly checkpoint on Cdk1 renders the anaphase transition irreversible. Curr Biol 2014 Mar 27;24(6):630-7. Epub 2014 Feb 27. Activation of anaphase-promoting complex/cyclosome (APC/C(Cdc20)) by Cdc20 is delayed by the spindle assembly checkpoint (SAC). When all kinetochores come under tension, the SAC is turned off and APC/C(Cdc20) degrades cyclin B and securin, which activates separase [1]. The latter then cleaves cohesin holding sister chromatids together [2]. Because cohesin cleavage also destroys the tension responsible for turning off the SAC, cells must possess a mechanism to prevent SAC reactivation during anaphase, which could be conferred by a dependence of the SAC on Cdk1 [3-5]. To test this, we analyzed mouse oocytes and embryos expressing nondegradable cyclin B together with a Cdk1-resistant form of separase. After biorientation and SAC inactivation, APC/C(Cdc20) activates separase but the resulting loss of (some) cohesion is accompanied by SAC reactivation and APC/C(Cdc20) inhibition, which aborts the process of further securin degradation. Cyclin B is therefore the only APC/C(Cdc20) substrate whose degradation at the onset of anaphase is necessary to prevent SAC reactivation. The mutual activation of tension sensitive SAC and Cdk1 creates a bistable system that ensures complete activation of separase and total downregulation of Cdk1 when all chromosomes have bioriented. http://www.pubfacts.com/detail/24583015/Dependency-of-the-spindle-assembly-checkpoint-on-Cdk1-renders-the-anaphase-transition-irreversible. Dionisio

Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase. Curr Biol 2014 Mar 27;24(6):638-45. Epub 2014 Feb 27. Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/C(Cdc20)) [2]. Upon satisfaction of both pathways, the APC/C(Cdc20) elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood[4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/C(Cdc20) is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/C(Cdc20) couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit. http://www.pubfacts.com/detail/24583019/Cdk1-inactivation-terminates-mitotic-checkpoint-surveillance-and-stabilizes-kinetochore-attachments- Dionisio

Slow checkpoint activation kinetics as a safety device in anaphase Curr Biol 2014 Mar 27;24(6):646-51. Epub 2014 Feb 27. Chromosome attachment to the mitotic spindle in early mitosis is guarded by an Aurora B kinase-dependent error correction mechanism [1, 2] and by the spindle assembly checkpoint (SAC), which delays cell-cycle progression in response to errors in chromosome attachment [3, 4]. The abrupt loss of sister chromatid cohesion at anaphase creates a type of chromosome attachment that in early mitosis would be recognized as erroneous, would elicit Aurora B-dependent destabilization of kinetochore-microtubule attachment, and would activate the checkpoint [5, 6]. However, in anaphase, none of these responses occurs, which is vital to ensure progression through anaphase and faithful chromosome segregation. The difference has been attributed to the drop in CDK1/cyclin B activity that accompanies anaphase and causes Aurora B translocation away from centromeres [7-12] and to the inactivation of the checkpoint by the time of anaphase [10, 11, 13, 14]. Here, we show that checkpoint inactivation may not be crucial because checkpoint activation by anaphase chromosomes is too slow to take effect on the timescale during which anaphase is executed. In addition, we observe that checkpoint activation can still occur for a considerable time after the anaphase-promoting complex/cyclosome (APC/C) becomes active, raising the question whether the checkpoint is indeed completely inactivated by the time of anaphase under physiologic conditions. http://www.pubfacts.com/detail/24583014/Slow-checkpoint-activation-kinetics-as-a-safety-device-in-anaphase. Dionisio

Cenp-meta is required for sustained spindle checkpoint doi: 10.1242/?bio.20148490 Cenp-E is a kinesin-like motor protein required for efficient end-on attachment of kinetochores to the spindle microtubules. Cenp-E immunodepletion in Xenopus mitotic extracts results in the loss of mitotic arrest and massive chromosome missegregation, whereas its depletion in mammalian cells leads to chromosome segregation defects despite the presence of a functional spindle assembly checkpoint (SAC). Cenp-meta has previously been reported to be the Drosophila homolog of vertebrate Cenp-E. In this study, we show that cenp-meta? mutant neuroblasts arrest in mitosis when treated with colchicine. cenp-meta? mutant cells display a mitotic delay. Yet, despite the persistence of the two checkpoint proteins Mad2 and BubR1 on unattached kinetochores, these cells eventually enter anaphase and give rise to highly aneuploid daughter cells. Indeed, we find that cenp-meta? mutant cells display a slow but continuous degradation of cyclin B, which eventually triggers the mitotic exit observed. Thus, our data provide evidence for a role of Cenp-meta in sustaining the SAC response. http://bio.biologists.org/content/early/2014/05/23/bio.20148490.abstract Dionisio

Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint doi:10.1038/ncomms5795 The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle. Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment. Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules towards spindle poles. Here we incorporate this streaming behavior into a theoretical model that accounts for the robustness of checkpoint silencing. Poleward streams are integrated at spindle poles, but are diverted by any unattached kinetochore; consequently, accumulation of checkpoint components at spindle poles increases markedly only when every kinetochore is properly attached. This step change robustly triggers checkpoint silencing after, and only after, the final kinetochore-spindle attachment. Our model offers a conceptual framework that highlights the role of spatiotemporal regulation in mitotic spindle checkpoint signaling and fidelity of chromosome segregation. http://www.nature.com/ncomms/2014/140912/ncomms5795/full/ncomms5795.html Dionisio

Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells doi: 10.1085/jgp.201311123 The sinoatrial node, whose cells (sinoatrial node cells [SANCs]) generate rhythmic action potentials, is the primary pacemaker of the heart. During diastole, calcium released from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) interacts with membrane currents to control the rate of the heartbeat. This “calcium clock” takes the form of stochastic, partially periodic, localized calcium release (LCR) events that propagate, wave-like, for limited distances. The detailed mechanisms controlling the calcium clock are not understood. http://jgp.rupress.org/content/143/5/577.abstract?sid=0ba1aacc-bf2e-4776-b89a-364c054cdbe1 Dionisio

Surveillance of Nuclear Pore Complex Assembly DOI: http://dx.doi.org/10.1016/j.cell.2014.09.012 Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and -independent stable pluripotent states. LEarly transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org. Dionisio

Divergent reprogramming routes lead to alternative stem-cell status doi:10.1038/nature14047 Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states. http://www.nature.com/nature/journal/v516/n7530/full/nature14047.html Dionisio

The Cdc20-binding Phe Box of the Spindle Checkpoint Protein BubR1 Maintains the Mitotic Checkpoint Complex during Mitosis doi: 10.1074/jbc.M114.616490 The spindle checkpoint ensures accurate chromosome segregation by monitoring kinetochore-microtubule attachment. Unattached or tensionless kinetochores activate the checkpoint and enhance the production of the mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, Mad2, and Cdc20. MCC is a critical checkpoint inhibitor of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase required for anaphase onset. The N-terminal region of BubR1 binds to both Cdc20 and Mad2, thus nucleating MCC formation. The middle region of human BubR1 (BubR1M) also interacts with Cdc20, but the nature and function of this interaction are not understood. Here we identify two critical motifs within BubR1M that contribute to Cdc20 binding and APC/C inhibition: a destruction box (D box) and a phenylalanine-containing motif termed the Phe box. A BubR1 mutant lacking these motifs is defective in MCC maintenance in mitotic human cells, but is capable of supporting spindle-checkpoint function. Thus, the BubR1M-Cdc20 interaction indirectly contributes to MCC homeostasis. Its apparent dispensability in the spindle checkpoint might be due to functional duality or redundant, competing mechanisms. http://www.jbc.org/content/early/2014/12/10/jbc.M114.616490.abstract Dionisio

Speeding Past a Mitotic Checkpoint Mitotic checkpoints orchestrate the cell cycle, keeping cells from proliferating uncontrollably, but how does this work? Sarah Williams checks in with three research groups tackling this question. Find out what they discovered... When a cell replicates its genetic material, divvies up its chromosomes, and then separates into two new, daughter cells, a lot can go wrong. Mistakes in this process can be biologically costly—leading to genetic mutations, cell death, or cancer—so living cells have evolved ways to ensure that the steps of mitosis proceed in the right order and at the right speed. Molecular checkpoints detect the state of a cell by measuring levels of signaling molecules, tension, or DNA damage, and only send signals for mitosis to proceed when certain conditions are met. Now, in three separate papers simultaneously published in Current Biology, scientists have examined the details behind one checkpoint, and discovered that the inactivation of a checkpoint may be as important—and complex—as activation. http://www.biotechniques.com/news/biotechniquesNews/biotechniques-351182.html Dionisio

The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C doi:10.1038/nature13911 The spindle assembly checkpoint (SAC) maintains genomic stability by delaying chromosome segregation until the last chromosome has attached to the mitotic spindle. The SAC prevents the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase from recognizing cyclin B and securin by catalysing the incorporation of the APC/C co-activator, CDC20, into a complex called the mitotic checkpoint complex (MCC). The SAC works through unattached kinetochores generating a diffusible ‘wait anaphase’ signal1, 2 that inhibits the APC/C in the cytoplasm, but the nature of this signal remains a key unsolved problem. Moreover, the SAC and the APC/C are highly responsive to each other: the APC/C quickly targets cyclin B and securin once all the chromosomes attach in metaphase, but is rapidly inhibited should kinetochore attachment be perturbed3, 4. How this is achieved is also unknown. Here, we show that the MCC can inhibit a second CDC20 that has already bound and activated the APC/C. We show how the MCC inhibits active APC/C and that this is essential for the SAC. Moreover, this mechanism can prevent anaphase in the absence of kinetochore signalling. Thus, we propose that the diffusible ‘wait anaphase’ signal could be the MCC itself, and explain how reactivating the SAC can rapidly inhibit active APC/C. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13911.html Dionisio

Dependency of the spindle assembly checkpoint on Cdk1 renders the anaphase transition irreversible. doi: 10.1016/j.cub.2014.01.033 Activation of anaphase-promoting complex/cyclosome (APC/C(Cdc20)) by Cdc20 is delayed by the spindle assembly checkpoint (SAC). When all kinetochores come under tension, the SAC is turned off and APC/C(Cdc20) degrades cyclin B and securin, which activates separase [1]. The latter then cleaves cohesin holding sister chromatids together [2]. Because cohesin cleavage also destroys the tension responsible for turning off the SAC, cells must possess a mechanism to prevent SAC reactivation during anaphase, which could be conferred by a dependence of the SAC on Cdk1 [3-5]. To test this, we analyzed mouse oocytes and embryos expressing nondegradable cyclin B together with a Cdk1-resistant form of separase. After biorientation and SAC inactivation, APC/C(Cdc20) activates separase but the resulting loss of (some) cohesion is accompanied by SAC reactivation and APC/C(Cdc20) inhibition, which aborts the process of further securin degradation. Cyclin B is therefore the only APC/C(Cdc20) substrate whose degradation at the onset of anaphase is necessary to prevent SAC reactivation. The mutual activation of tension sensitive SAC and Cdk1 creates a bistable system that ensures complete activation of separase and total downregulation of Cdk1 when all chromosomes have bioriented. http://www.ncbi.nlm.nih.gov/pubmed/24583015 Dionisio

Slow checkpoint activation kinetics as a safety device in anaphase. doi: 10.1016/j.cub.2014.02.005 Chromosome attachment to the mitotic spindle in early mitosis is guarded by an Aurora B kinase-dependent error correction mechanism [1, 2] and by the spindle assembly checkpoint (SAC), which delays cell-cycle progression in response to errors in chromosome attachment [3, 4]. The abrupt loss of sister chromatid cohesion at anaphase creates a type of chromosome attachment that in early mitosis would be recognized as erroneous, would elicit Aurora B-dependent destabilization of kinetochore-microtubule attachment, and would activate the checkpoint [5, 6]. However, in anaphase, none of these responses occurs, which is vital to ensure progression through anaphase and faithful chromosome segregation. The difference has been attributed to the drop in CDK1/cyclin B activity that accompanies anaphase and causes Aurora B translocation away from centromeres [7-12] and to the inactivation of the checkpoint by the time of anaphase [10, 11, 13, 14]. Here, we show that checkpoint inactivation may not be crucial because checkpoint activation by anaphase chromosomes is too slow to take effect on the timescale during which anaphase is executed. In addition, we observe that checkpoint activation can still occur for a considerable time after the anaphase-promoting complex/cyclosome (APC/C) becomes active, raising the question whether the checkpoint is indeed completely inactivated by the time of anaphase under physiologic conditions. http://www.ncbi.nlm.nih.gov/pubmed/24583014 Dionisio

Cdk1 Inactivation Terminates Mitotic Checkpoint Surveillance and Stabilizes Kinetochore Attachments in Anaphase doi: 10.1016/j.cub.2014.01.034 Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/CCdc20) [2]. Upon satisfaction of both pathways, the APC/CCdc20 elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood [4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/CCdc20 is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/CCdc20 couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969148/ Dionisio

The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint doi: 10.1242/dev.117044 Asymmetric cell division is utilized by a broad range of cell types to generate two daughter cells with distinct cell fates. In stem cell populations asymmetric cell division is believed to be crucial for maintaining tissue homeostasis, failure of which can lead to tissue degeneration or hyperplasia/tumorigenesis. Asymmetric cell divisions also underlie cell fate diversification during development. Accordingly, the mechanisms by which asymmetric cell division is achieved have been extensively studied, although the check points that are in place to protect against potential perturbation of the process are poorly understood. Drosophila melanogaster male germline stem cells (GSCs) possess a checkpoint, termed the centrosome orientation checkpoint (COC), that monitors correct centrosome orientation with respect to the component cells of the niche to ensure asymmetric stem cell division. To our knowledge, the COC is the only checkpoint mechanism identified to date that specializes in monitoring the orientation of cell division in multicellular organisms. Here, by establishing colcemid-induced microtubule depolymerization as a sensitive assay, we examined the characteristics of COC activity and find that it functions uniquely in GSCs but not in their differentiating progeny. We show that the COC operates in the G2 phase of the cell cycle, independently of the spindle assembly checkpoint. This study may provide a framework for identifying and understanding similar mechanisms that might be in place in other asymmetrically dividing cell types. http://dev.biologists.org/content/early/2014/12/05/dev.117044.abstract Dionisio

The internal ?Cdc20 binding site in ?BubR1 facilitates both spindle assembly checkpoint signalling and silencing doi:10.1038/ncomms6563 Improperly attached kinetochores activate the spindle assembly checkpoint (SAC) and by an unknown mechanism catalyse the binding of two checkpoint proteins, ?Mad2 and ?BubR1, to ?Cdc20 forming the mitotic checkpoint complex (MCC). Here, to address the functional role of ?Cdc20 kinetochore localization in the SAC, we delineate the molecular details of its interaction with kinetochores. We find that ?BubR1 recruits the bulk of ?Cdc20 to kinetochores through its internal Cdc20 binding domain (IC20BD). We show that preventing ?Cdc20 kinetochore localization by removal of the IC20BD has a limited effect on the SAC because the IC20BD is also required for efficient SAC silencing. Indeed, the IC20BD can disrupt the MCC providing a mechanism for its role in SAC silencing. We thus uncover an unexpected dual function of the second ?Cdc20 binding site in ?BubR1 in promoting both efficient SAC signalling and SAC silencing. http://www.nature.com/ncomms/2014/141208/ncomms6563/full/ncomms6563.html Dionisio

Negative feedback at kinetochores underlies a responsive spindle checkpoint signar doi:10.1038/ncb3065 Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability 1. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached 2. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF 412, 3, 4. We show that this responsiveness arises because the SAC primes kinetochore phosphatases to induce negative feedback and silence its own signal. Active SAC signalling recruits PP2A-B56 to kinetochores where it antagonizes ?Aurora B to promote PP1 recruitment. PP1 in turn silences the SAC and delocalizes PP2A-B56. Preventing or bypassing key regulatory steps demonstrates that this spatiotemporal control of phosphatase feedback underlies rapid signal switching at the kinetochore by: allowing the SAC to quickly transition to the ON state in the absence of antagonizing phosphatase activity; and ensuring phosphatases are then primed to rapidly switch the SAC signal OFF when kinetochore kinase activities are diminished by force-producing microtubule attachments. http://www.nature.com/ncb/journal/v16/n12/full/ncb3065.html Dionisio

The complexity of miRNA-mediated repression doi:10.1038/cdd.2014.112 Since their discovery 20 years ago, miRNAs have attracted much attention from all areas of biology. These short (~22?nt) non-coding RNA molecules are highly conserved in evolution and are present in nearly all eukaryotes. They have critical roles in virtually every cellular process, particularly determination of cell fate in development and regulation of the cell cycle. Although it has long been known that miRNAs bind to mRNAs to trigger translational repression and degradation, there had been much debate regarding their precise mode of action. It is now believed that translational control is the primary event, only later followed by mRNA destabilisation. This review will discuss the most recent advances in our understanding of the molecular underpinnings of miRNA-mediated repression. Moreover, we highlight the multitude of regulatory mechanisms that modulate miRNA function. http://www.nature.com/cdd/journal/v22/n1/abs/cdd2014112a.html?WT.ec_id=CDD-201501 Dionisio

timely mitotic progression and chromosome movement doi: 10.1242/?jcs.160036 Upon establishment of proper kinetochore-microtubule attachment, the spindle assembly checkpoint (SAC) must be silenced to allow anaphase onset in which sister chromatids segregate equally to two daughter cells. However, how proper kinetochore-microtubule attachment leads to timely anaphase onset remains elusive. Furthermore, the molecular mechanisms of chromosome movement during anaphase A remain unclear. In this study, we show that the fission yeast Alp7/TACC protein recruits a protein complex consisting of the kinesin-8 (Klp5-Klp6) and protein phosphatase 1 (PP1) to the kinetochore upon kinetochore-microtubule attachment. Accumulation of this complex at the kinetochore on one hand facilitates SAC inactivation through PP1, and on the other hand accelerates poleward chromosome movement by the Klp5-Klp6 motor. We identified an alp7 mutant with specific defects in binding to the Klp5-Klp6-PP1 complex, whilst retaining normal microtubule and kinetochore localising activity. Consistent with our proposition, this mutant shows delayed anaphase onset and decelerated chromosome movement during anaphase A. We propose that the recruitment of kinesin-8-PP1 to the kinetochore via Alp7/TACC interaction plays a crucial role in regulation of timely mitotic progression and chromosome movement during anaphase A. http://jcs.biologists.org/content/early/2014/12/01/jcs.160036.short?rss=1 Dionisio

microtubule–kinetochore attachment doi:10.1038/ncomms5588 The early event of microtubule–kinetochore attachment is a critical stage for precise chromosome segregation. Here we report that ?NCAPG2, which is a component of the condensin II complex, mediates chromosome segregation through microtubule–kinetochore attachment by recruiting ?PLK1 to prometaphase kinetochores. ? NCAPG2 colocalizes with ?PLK1 at prometaphase kinetochores and directly interacts with the polo-box domain (PBD) of ?PLK1 via its highly conserved C-terminal region. In both humans and Caenorhabditis elegans, when ?NCAPG2 is depleted, the attachment of the spindle to the kinetochore is loosened and misoriented. This is caused by the disruption of ?PLK1 localization to the kinetochore and by the decreased phosphorylation of its kinetochore substrate, ?BubR1. In addition, the crystal structure of the PBD of ?PLK1, in complex with the C-terminal region of ?NCAPG2, 1007VLS-pT-L1011, exhibits structural conservation of PBD-phosphopeptides, suggesting that the regulation of ?NCAPG2 function is phosphorylation-dependent. These findings suggest that ?NCAPG2 plays an important role in regulating proper chromosome segregation through a functional interaction with ?PLK1 during mitosis. http://www.nature.com/ncomms/2014/140811/ncomms5588/full/ncomms5588.html Dionisio

bipolar mitotic spindle attachment DOI 10.15252/embj.201489054 Faithful chromosome segregation during mitosis is tightly regulated by opposing activities of Aurora B kinase and protein phosphatase?1 (PP1). PP1 function at kinetochores has been linked to SDS22, but the exact localization of SDS22 and how it affects PP1 are controversial. Here, we confirm that SDS22 is required for PP1 activity, but show that SDS22 does not normally localize to kinetochores. Instead, SDS22 is kept in solution by formation of a ternary complex with PP1 and inhibitor?3 (I3). Depletion of I3 does not affect the amount of PP1 at kinetochores but causes quantitative association of SDS22 with PP1 on KNL1 at the kinetochore. Such accumulation of SDS22 at kinetochores interferes with PP1 activity and inhibits Aurora B threonine?232 dephosphorylation, which leads to increased Aurora B activity in metaphase and persistence in anaphase accompanied with segregation defects. We propose a model in which I3 regulates an SDS22?mediated PP1 activation step in solution that precedes SDS22 dissociation and transfer of PP1 to kinetochores, and which is required for PP1 to efficiently antagonize Aurora B. http://emboj.embopress.org/content/33/22/2704 Dionisio

On the move: organelle dynamics during mitotic DOI: http://dx.doi.org/10.1016/j.tcb.2014.10.005 A cell constitutes the minimal self-replicating unit of all organisms, programmed to propagate its genome as it proceeds through mitotic cell division. The molecular processes entrusted with ensuring high fidelity of DNA replication and subsequent segregation of chromosomes between daughter cells have therefore been studied extensively. However, to process the information encoded in its genome a cell must also pass on its non-genomic identity to future generations. To achieve productive sharing of intracellular organelles, cells have evolved complex mechanisms of organelle inheritance. Many membranous compartments undergo vast spatiotemporal rearrangements throughout mitosis. These controlled organizational changes are crucial to enabling completion of the division cycle and ensuring successful progeny. Herein we review current understanding of intracellular organelle segregation during mitotic division in mammalian cells, with a focus on compartment organization and integrity throughout the inheritance process. Dionisio

Cytokinetic Abscission: Molecular Mechanisms and Temporal Control DOI: http://dx.doi.org/10.1016/j.devcel.2014.11.006 Cytokinesis mediates the physical separation of dividing cells after chromosome segregation. In animal cell cytokinesis, a contractile ring, mainly composed of actin and myosin filaments, ingresses a cleavage furrow midway between the two spindle poles. A distinct machinery, involving the endosomal sorting complex required for transport III (ESCRT-III), subsequently splits the plasma membrane of nascent daughter cells in a process termed abscission. Here, we provide a brief overview of early cytokinesis events in animal cells and then cover in depth recently emerging models for the assembly and function of the abscission machinery and its temporal coordination with chromosome segregation. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00723-0?elsca1=etoc&elsca2=email&elsca3=1534-5807_20141208_31_5_&elsca4=Cell%20Press Dionisio

Interferon Gamma Signaling Positively Regulates Hematopoietic Stem Cell Emergence DOI: http://dx.doi.org/10.1016/j.devcel.2014.11.007 Vertebrate hematopoietic stem cells (HSCs) emerge in the aorta-gonad-mesonephros (AGM) region from “hemogenic” endothelium. Here we show that the proinflammatory cytokine interferon-? (IFN-?) and its receptor Crfb17 positively regulate HSC development in zebrafish. This regulation does not appear to modulate the proliferation or survival of HSCs or endothelial cells, but rather the endothelial-to-HSC transition. Notch signaling and blood flow positively regulate the expression of ifng and crfb17 in the AGM. Notably, IFN-? overexpression partially rescues the HSC loss observed in the absence of blood flow or Notch signaling. Importantly, IFN-? signaling acts cell autonomously to control the endothelial-to-HSC transition. IFN-? activates Stat3, an atypical transducer of IFN-? signaling, in the AGM, and Stat3 inhibition decreases HSC formation. Together, our findings uncover a developmental role for an inflammatory cytokine and place its action downstream of Notch signaling and blood flow to control Stat3 activation and HSC emergence. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00724-2 Dionisio

The centrosome duplication cycle in health and disease. doi: 10.1016/j.febslet.2014.06.030. Centrioles function in the assembly of centrosomes and cilia. Structural and numerical centrosome aberrations have long been implicated in cancer, and more recent genetic evidence directly links centrosomal proteins to the etiology of ciliopathies, dwarfism and microcephaly. To better understand these disease connections, it will be important to elucidate the biogenesis of centrioles as well as the controls that govern centriole duplication during the cell cycle. Moreover, it remains to be fully understood how these organelles organize a variety of dynamic microtubule-based structures in response to different physiological conditions. In proliferating cells, centrosomes are crucial for the assembly of microtubule arrays, including mitotic spindles, whereas in quiescent cells centrioles function as basal bodies in the formation of ciliary axonemes. In this short review, we briefly introduce the key gene products required for centriole duplication. Then we discuss recent findings on the centriole duplication factor STIL that point to centrosome amplification as a potential root cause for primary microcephaly in humans. We also present recent data on the role of a disease-related centriole-associated protein complex, Cep164-TTBK2, in ciliogenesis. http://www.ncbi.nlm.nih.gov/pubmed/24951839 Dionisio

ENCODE September 8, 2014 meeting https://www.youtube.com/embed/F1aCvlkEwTI https://www.youtube.com/embed/-2VSrU6lknA Dionisio

More cool stuff: CRISPR/Cas9 https://www.youtube.com/embed/0dRT7slyGhs Genome Editing with CRISPR-Cas9 https://www.youtube.com/embed/2pp17E4E-O8 ENCODE update meeting Sept 2014 https://www.youtube.com/embed/-2VSrU6lknA Dionisio

PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator doi: 10.1101/gad.242644.114 dsRNA-dependent protein kinase R (PKR) is a ubiquitously expressed enzyme well known for its roles in immune response. Upon binding to viral dsRNA, PKR undergoes autophosphorylation, and the phosphorylated PKR (pPKR) regulates translation and multiple signaling pathways in infected cells. Here, we found that PKR is activated in uninfected cells, specifically during mitosis, by binding to dsRNAs formed by inverted Alu repeats (IRAlus). While PKR and IRAlu-containing RNAs are segregated in the cytosol and nucleus of interphase cells, respectively, they interact during mitosis when nuclear structure is disrupted. Once phosphorylated, PKR suppresses global translation by phosphorylating the ? subunit of eukaryotic initiation factor 2 (eIF2?). In addition, pPKR acts as an upstream kinase for c-Jun N-terminal kinase and regulates the levels of multiple mitotic factors such as CYCLINS A and B and POLO-LIKE KINASE 1 and phosphorylation of HISTONE H3. Disruption of PKR activation via RNAi or expression of a transdominant-negative mutant leads to misregulation of the mitotic factors, delay in mitotic progression, and defects in cytokinesis. Our study unveils a novel function of PKR and endogenous dsRNAs as signaling molecules during the mitosis of uninfected cells. http://genesdev.cshlp.org/content/28/12/1310 Dionisio

So many pieces, one puzzle: cell type specification and visual circuitry doi: 10.1101/gad.248245.114 The visual system is a powerful model for probing the development, connectivity, and function of neural circuits. Two genetically tractable species, mice and flies, are together providing a great deal of understanding of these processes. Current efforts focus on integrating knowledge gained from three cross-fostering fields of research: (1) understanding how the fates of different cell types are specified during development, (2) revealing the synaptic connections between identified cell types (“connectomics”) by high-resolution three-dimensional circuit anatomy, and (3) causal testing of how identified circuit elements contribute to visual perception and behavior. Here we discuss representative examples from fly and mouse models to illustrate the ongoing success of this tripartite strategy, focusing on the ways it is enhancing our understanding of visual processing and other sensory systems. http://genesdev.cshlp.org/content/28/23/2565.abstract?sid=d39dadee-d1bd-4d92-bd0d-d2df5507fab6 Dionisio

Handedness helps homing in swimming and flying animals doi:10.1038/srep01128 Swimming and flying animals rely on their ability to home on mobile targets. In some fish, physiological handedness and homing correlate, and dolphins exhibit handedness in their listening response. Here, we explore theoretically whether the actuators, sensors, and controllers in these animals follow similar laws of self-regulation, and how handedness affects homing. We find that the acoustic sensor (combined hydrophone-accelerometer) response maps are similar to fin force maps—modeled by Stuart-Landau oscillators—allowing localization by transitional vortex-propelled animals. The planar trajectories of bats in a room filled with obstacles are approximately reproduced by the states of a pair of strong and weak olivo-cerebellar oscillators. The stereoscopy of handedness reduces ambiguity near a mobile target, resulting in accelerated homing compared to even-handedness. Our results demonstrate how vortex-propelled animals may be localizing each other and circumventing obstacles in changing environments. Handedness could be useful in time-critical robot-assisted rescues in hazardous environments. http://www.nature.com/srep/2013/130124/srep01128/full/srep01128.html Dionisio

Modeling how shark and dolphin skin patterns control transitional wall-turbulence vorticity patterns using spatiotemporal phase reset mechanisms doi:10.1038/srep06650 Many slow-moving biological systems like seashells and zebrafish that do not contend with wall turbulence have somewhat organized pigmentation patterns flush with their outer surfaces that are formed by underlying autonomous reaction-diffusion (RD) mechanisms. In contrast, sharks and dolphins contend with wall turbulence, are fast swimmers, and have more organized skin patterns that are proud and sometimes vibrate. A nonlinear spatiotemporal analytical model is not available that explains the mechanism underlying control of flow with such proud patterns, despite the fact that shark and dolphin skins are major targets of reverse engineering mechanisms of drag and noise reduction. Comparable to RD, a minimal self-regulation model is given for wall turbulence regeneration in the transitional regime—laterally coupled, diffusively—which, although restricted to pre-breakdown durations and to a plane close and parallel to the wall, correctly reproduces many experimentally observed spatiotemporal organizations of vorticity in both laminar-to-turbulence transitioning and very low Reynolds number but turbulent regions. We further show that the onset of vorticity disorganization is delayed if the skin organization is treated as a spatiotemporal template of olivo-cerebellar phase reset mechanism. The model shows that the adaptation mechanisms of sharks and dolphins to their fluid environment have much in common. http://www.nature.com/srep/2014/141023/srep06650/full/srep06650.html Dionisio

Ok, let's take a break from challenging bio issues and look at some cool stuff instead. :) Dionisio

The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. SNP: single-nucleotide polymorphisms. http://www.ncbi.nlm.nih.gov/pubmed/24316577 pleotropic gene: producing more than one effect; especially : having multiple phenotypic expressions Dionisio

VaDE: a manually curated database of reproducible associations between various traits and human genomic polymorphisms. http://www.ncbi.nlm.nih.gov/pubmed/25361969 Dionisio

GRASP v2.0: an update on the Genome-Wide Repository of Associations between SNPs and phenotypes. http://www.ncbi.nlm.nih.gov/pubmed/25428361 Dionisio

@804 gpuccio

we really don’t know how many segments of intragenic or intergenic DNA has enhancer function, but is still not annotated as such. In Drosophila, and probably much more in humans. The role of non coding genome and of its 3D spatial organization in ensuring functionality is being discovered at a practically daily rate.

Very insightful observation. Thank you.

But still our neo-darwinist “friends” go on with their indignant defense of the “non functional DNA” concept.

Too bad. That's their problem. They ain't seen nothing yet. We're busy reviewing the overwhelming "big data" avalanche caused by the increasing rate of "unexpected, surprising" discoveries made in research labs by serious dedicated scientists (perhaps underpaid when compared to other less significant and less demanding jobs out there). :) Dionisio

GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies (GWAS) and corresponding open access database. doi: 10.1093/bioinformatics/btu273. Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights. The GRASP database is available at http://apps.nhlbi.nih.gov/grasp. http://www.ncbi.nlm.nih.gov/pubmed/24931982 pleiotropic: producing more than one effect; especially : having multiple phenotypic expressions Dionisio

Dionisio: from the paper you referenced in #791:

The extent of 3D connectivity is surprising given the relative simplicity of the Drosophila genome. On average, each promoter-proximal element interacted with four distal promoters and two annotated enhancers,whereas each distal enhancer interacted with two promoters and three other enhancers. These numbers are probably underestimates, as 60% of interactions involved intragenic or intergenic fragments containing no annotated cis-regulatory elements. Despite this, the level of connectivity is similar to that recently observed in humans, where active promoters contacted on average 4.75 enhancers and 25% of enhancers interacted with two or more promoters. The multi-component contacts that we observe for Drosophila enhancers indicate topologicallycomplex structures and suggest that, despite its non-coding genome being an order of magnitude smaller than humans,Drosophila may require a similar 3D spatial organization to ensure functionality.

IOWs, we really don't know how many segments of intragenic or intergenic DNA has enhancer function, but is still not annotated as such. In Drosophila, and probably much more in humans. The role of non coding genome and of its 3D spatial organization in ensuring functionality is being discovered at a practically daily rate. But still our neo-darwinist "friends" go on with their indignant defense of the "non functional DNA" concept. gpuccio

And speaking of "topologically associating domains" I found this:

The Hierarchy of the 3D Genome Johan H. Gibcus, Job Dekkeremail DOI: http://dx.doi.org/10.1016/j.molcel.2013.02.011 Enduring Connections: Linked Loci Stay Together The large size of chromosomes prevents them from freely mingling throughout the nucleus (Rosa and Everaers, 2008; Walter et al., 2003). Within the nucleus, DNA is organized into individual chromosome territories (CTs). The chromosomal arrangement into CTs was comprehensively visualized by chromosome painting (Lichter et al., 1988; Pinkel et al., 1988) (Figure 1A). CT formation was subsequently confirmed by genome-wide Hi-C analysis (Lieberman-Aiden et al., 2009; Zhang et al., 2012) that showed that loci located on the same chromosome interact far more frequently, even when separated by more than 200 Mb, than any two loci located on different chromosomes (Figure 1D). Yet, neighboring chromosomes can overlap considerably and chromatin loops from one CT can intermingle with neighboring CTs (Branco and Pombo, 2006; Misteli, 2010) (see below in the section Birds of a Feather Flock Together). Genomic linkage is clearly a very dominant factor in determining the three-dimensional connections of any gene or regulatory element. CTs themselves are not randomly positioned in the nucleus. In both mouse and human cells, chromosomes of similar size and gene density were shown to be more likely to interact in nuclear space: short gene dense chromosomes group together near the center of the nucleus, whereas the longer and less-gene-dense chromosomes are more often located near the nuclear periphery. This property is reflected in different propensities for interchromosomal connections (Croft et al., 1999; Lieberman-Aiden et al., 2009; Tanabe et al., 2002; Zhang et al., 2012). Topologically Associating Domains Microscopy has revealed that CTs contain much smaller but structurally defined chromosomal domains (CDs) that are ?100 kb to several Mb in size (Cremer and Cremer, 2010). CDs have been observed at the borders of the CTs, where they project into the chromatin poor areas that separate chromosomes (Figure 1B) (Markaki et al., 2010). CDs appear as clumps of chromatin with an outer shell that contains gene-dense arrangements known as the perichromatin region (PR), which is a 100–200 nm wide area that is rich in ribonucleoprotein-containing perichromatin fibrils (Cmarko et al., 1999; Fakan and van Driel, 2007) (Figure 1C). Their small size suggests that CDs are not directly related to A and B compartments, which are typically much larger. Recently, high-resolution Hi-C and 5C data led to the identification of small domains within larger A and B compartments in human, mouse, and Drosophila genomes (Dixon et al., 2012; Nora et al., 2012; Sexton et al., 2012) (Figure 1H). These domains, referred to as topologically associating domains (TADs), are characterized by pronounced long-range associations between loci located in the same domain, but less frequent interactions between loci located in adjacent domains. Thus, chromosomes are composed of a string of domains that are topologically separated from each other. TADs have a median size of 880 kb in mice, with a range of tens of kb to several Mb (Dixon et al., 2012). Interestingly, this is the same length scale as the microscopic CDs, suggesting that TADs might represent the same structures (Figures 1C, 1H, and 1I). Other structural features that were based on long-range interactions identified by 3C-based techniques and correlation analyses, such as chromatin globules (Baù et al., 2011), chroperons (Li et al., 2012), and enhancer-promoter units (Shen et al., 2012), have been described at this length scale. Although few reports have been published on the subject, we anticipate that these observed structures are descriptions of the same topological organization. This argues for a distinct, fundamental domainal organization of chromatin at the length scale of 100 kb–1 Mb. Interestingly, genes located within the same TAD tend to have coordinated dynamics of expression during differentiation, pointing to a role of TADs in coordinating the activity of groups of neighboring genes. Further evidence for a critical functional role of these domains in genome regulation is that CDs (and perhaps TADs) appear to correlate with units of DNA replication (Markaki et al., 2010). Through the use of a modified genome-wide 3C approach in Drosophila, specific building blocks of 10–500 kb epigenetic domains have been described that are flanked by insulators and that seem to represent TADs (Sexton et al., 2012). Thus far, TADs or TAD-like structures have not been described in bacteria (Umbarger et al., 2011), yeast (Duan et al., 2010), or plants (Moissiard et al., 2012). It is unclear whether the larger plant chromosomes do allow for a TAD-like organization. It is also currently unknown whether TADs exist without the presence of compartments. TADs do, however, represent a feature of chromosome organization that is largely conserved across mammalian cell types (Dixon et al., 2012; Nora et al., 2012), in contrast to A and B compartments that are related to cell-type-specific gene expression. Consistently, TADs are separated by boundaries that appear to be genetically defined: deletion of a boundary region in the X chromosome inactivation center led to partial fusion and the two flanking TADs (Nora et al., 2012). Formal proof for a genetically defined boundary would require insertion of a boundary in the middle of a TAD and observation of the splitting of the TAD in two. It is currently not clear what defines TAD boundary regions. These boundary regions are enriched in a number of features, including transcription start sites and binding sites for the CTCF protein. Finding CTCF at these boundaries is particularly intriguing given its role as an architectural protein implicated in both mediating and blocking long-range interactions (Phillips and Corces, 2009). However, the large majority of CTCF-bound sites are located within TADs, suggesting that they are not sufficient for boundary function (Dixon et al., 2012; Nora et al., 2012). It has been proposed that CTCF-bound sites must recruit additional proteins, such as the cohesin complex (Parelho et al., 2008; Rubio et al., 2008; Wendt et al., 2008), to acquire boundary activity. Connecting Genes and Regulatory Elements The best-studied long-range interactions are those between genes and their distal regulatory elements, such as enhancers. Classical genetic studies of translocations and deletions have shown that distal regions, located at tens to hundreds of kilobases from a gene, affect the correct regulation of transcription, indicating that regulatory elements can exert their effect over large genomic distances (Kleinjan and van Heyningen, 2005). Several mechanisms have been proposed to explain this phenomenon of long-range gene regulation, including looping of chromatin, linking by large protein complexes, and tracking of regulatory complexes along the DNA toward the target genes, to name a few (Bulger and Groudine, 1999; Ptashne, 1986). The most widely supported looping model states that gene regulatory elements interact with promoters through direct protein interactions, while looping out intervening DNA (reviewed in Bulger and Groudine, 2011). http://www.cell.com/molecular-cell/fulltext/S1097-2765(13)00139-1

The rest of the paper goes into further detail on how the contents of complex DNA memory systems are being addressed:

http://en.wikipedia.org/wiki/Memory_address In computing, memory address is a data concept used at various levels by software and hardware to access the computer's primary storage memory.

Gary S. Gaulin

Insulator function and topological domain border strength scale with architectural protein occupancy doi:10.1186/gb-2014-15-5-r82 Background Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions. Results By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals. Conclusions We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains. http://genomebiology.com/2014/15/6/R82/abstract Dionisio

Centriole Function Centriole is a structure found in eukaryotic animal cells. Plant cells and fungi do no contain centrioles. Centriole is the part of the cell, which acts as the center for producing microtubules, which are the component of cytoskeleton. Cytoskeleton is the skeleton of the cell that provides both shape and structure to a cell. Animal cells contain 2 centrioles, which together form the structure, centrosome. In other words, the centrioles are found within the centrosomes, which is a small region in the cytoplasm near the nucleus. Within the centrosomes, the two centrioles are positioned in such a way that both are perpendicular to each other. Like other structures of a cell, centrioles too perform several important functions. Below here is a brief discussion about the centriole function and structure in the study of biology. Structure of the Centriole Centriole is a cylindrical or barrel shaped structure that can be found lying adjacent to the nucleus. It basically consists of microtubules. Each centriole consists of nine microtubules. Both the centrioles are found in pairs, and they are positioned at a right angle to one another. At the time of cell division, both the centrioles move in the opposite direction towards the poles or ends of the nucleus. Centrioles become evident only at the time of cell division. At other times, one can see only the centrosome as a darker area of the cytoplasm. What is the Function of the Centriole? Centriole plays a crucial role at the time of cell division. At the time of cell division, centrioles replicate to form two centrosomes, each with two centrioles. The two centrosomes then move in the opposite direction towards the opposite ends of the nucleus. From each centrosome, some thread like microtubules appear, which are known as spindle or mitotic spindle. During cell division, the single parent cell divides itself into two daughter cells, and the spindle is responsible for separating or pulling the replicated chromosomes to the two daughter cells. So, centrioles helps in the organization of the mitotic spindle, as well as the completion of cytokinesis. Centrioles as a part of centrosome also play a significant role in cellular organization, especially in organizing the microtubules in the cytoplasm and the spatial arrangement of the cell. Even the position of the nucleus is determined by the position of the centrioles. The mother centriole (the original or older centriole, from which a new centriole develops during cell division) determines the position of cilia and flagella in the organisms with these organelles. In fact, the mother centriole become the basal body in these organisms. A failure of the cell to make functional cilia and flagella with the help of centrioles has been found to be associated with several developmental and genetic diseases. Another important fact about centriole functions is that during mammalian development, proper orientation of cilia via centriole positioning toward the posterior of embryonic node cells is considered as quite crucial for the establishment of left-right asymmetry. Know more about the ? Cell Division Stages ? Cell Nucleus: Structure and Functions ? Structure and Functions of the Cytoplasm So, these are the main centriole functions in animal cells. Centrioles take part in several important functions like, organization of the microtubules and formation of cilia and flagella. It is also involved in determining the position of the nucleus. Earlier, it was thought that centrioles were essential for the formation of mitotic spindle. But recent experiments in this regard have revealed that cells whose centrioles have been removed can too progress through the G1 stage of inter-phase (stage in which the cell grows and increases in mass to prepare for cell division, prior to DNA synthesis) before both the centrioles can be synthesized. Even mutant flies without centriole can be found to develop normally. However, such adult flies could not develop cilia and flagella, which once again emphasizes the importance of centrioles in the formation of these organelles. http://www.sciencecontrol.com/centriole-function.html Dionisio

Dynein light intermediate chains maintain spindle bipolarity by functioning in centriole cohesion doi: 10.1083/jcb.201408025 Dynein has numerous functions in mitosis, but the function of the motor complex's light intermediate chains is poorly understood. Jones et al. reveal that dynein's light intermediate chains are required to maintain centrosome integrity during mitosis, preventing the premature separation of mother-daughter centrioles and the formation of multipolar spindles. http://jcb.rupress.org/content/207/4/499/suppl/DC2 Dionisio

Centriole amplification by mother and daughter centrioles differs in multiciliated cells doi:10.1038/nature13770 The semi-conservative centrosome duplication in cycling cells gives rise to a centrosome composed of a mother and a newly formed daughter centrioles 1. Both centrioles are regarded as equivalent in their ability to form new centrioles and their symmetric duplication is crucial for cell division homeostasis 2, 3, 4. Multi-ciliated cells do not use the archetypal duplication program and instead form more than a hundred centrioles that are required for the growth of motile cilia and the efficient propelling of physiological fluids 5. The majority of these new centrioles are thought to appear de novo, that is, independently from the centrosome, around electron-dense structures called deuterosomes 6, 7, 8. Their origin remains unknown. Using live imaging combined with correlative super-resolution light and electron microscopy, we show that all new centrioles derive from the pre-existing progenitor cell centrosome through multiple rounds of procentriole seeding. Moreover, we establish that only the daughter centrosomal centriole contributes to deuterosome formation, and thus to over ninety per cent of the final centriole population. This unexpected centriolar asymmetry grants new perspectives when studying cilia-related diseases 5, 9 and pathological centriole amplification observed in cycling cells and associated with microcephaly and cancer 2, 3, 4, 10. http://www.nature.com/nature/journal/v516/n7529/full/nature13770.html Dionisio

Speaking of cell-level regulation of tissue-level development: I need to add this to my earlier information on mechanotransduction channels to show what cells have for antenna to provide chemosensation, mechanosensation, and thermosensation needed for migration and other things: http://en.wikipedia.org/wiki/Antenna_(biology)#Cellular_antennae Although simple swarming does not (per ID theory I develop) qualify as intelligent (as it does in AI where Artificial is OK) the related Wikipedia information on this page should be helpful for indicating where science is going in regards to cellular intelligence. http://en.wikipedia.org/wiki/Microbial_intelligence And in case you did not find it yet this has long been an ID favorite in regards cell/cellular intelligence even though Guenter wants nothing to do with "evolution" denial: http://www.basic.northwestern.edu/g-buehler/FRAME.HTM Gary S. Gaulin

Interplay of Cell Shape and Division Orientation Promotes Robust Morphogenesis of Developing Epithelial DOI: http://dx.doi.org/10.1016/j.cell.2014.09.007 Epithelial cells acquire functionally important shapes (e.g., squamous, cuboidal, columnar) during development. Here, we combine theory, quantitative imaging, and perturbations to analyze how tissue geometry, cell divisions, and mechanics interact to shape the presumptive enveloping layer (pre-EVL) on the zebrafish embryonic surface. We find that, under geometrical constraints, pre-EVL flattening is regulated by surface cell number changes following differentially oriented cell divisions. The division pattern is, in turn, determined by the cell shape distribution, which forms under geometrical constraints by cell-cell mechanical coupling. An integrated mathematical model of this shape-division feedback loop recapitulates empirical observations. Surprisingly, the model predicts that cell shape is robust to changes of tissue surface area, cell volume, and cell number, which we confirm in vivo. Further simulations and perturbations suggest the parameter linking cell shape and division orientation contributes to epithelial diversity. Together, our work identifies an evolvable design logic that enables robust cell-level regulation of tissue-level development. http://www.cell.com/cell/abstract/S0092-8674(14)01155-6 Dionisio

The following educational video that goes with an earlier work from this research group (of sorts that explores how intelligent human behavior works) very much belongs in a list of scientific resources to help ID theory along: Music video by Powerman 5000 performing How To Be A Human. (C) 2014 Universal Music Enterprises, a Division of UMG Recordings, Inc. https://www.youtube.com/watch?v=_Ug9XflUB0A The systematics of intelligence demonstrated by the ID Lab computer models is useful for explaining why we are this way, its origin. But other than generalizations that only conclude "it evolved" what does Darwinian (evolutionary) theory have to say about the origin of this seemingly puzzling behavior? Anyone? Gary S. Gaulin

Identification of Causal Genetic Drivers of Human Disease through Systems-Level Analysis of Regulatory Networks DOI: http://dx.doi.org/10.1016/j.cell.2014.09.021 Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBP? and C/EBP?. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in > 50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer’s disease. http://www.cell.com/cell/abstract/S0092-8674(14)01170-2 Dionisio

Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes DOI: http://dx.doi.org/10.1016/j.cell.2014.09.030 The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here, we use ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure. http://www.cell.com/cell/abstract/S0092-8674(14)01179-9 Dionisio

Special chromosomal structures control key genes Within almost every human cell is a nucleus six microns in diameter—about one 300th of a human hair’s width—that is filled with roughly three meters of DNA. As the instructions for all cell processes, the DNA must be accessible to the cell’s transcription machinery yet be compressed tightly enough to fit inside the nucleus. Scientists have long theorized that the way DNA is packaged affects gene expression. Whitehead Institute researchers present the first evidence that DNA scaffolding is responsible for enhancing and repressing gene expression. DNA scaffolding has a hierarchy that ranges from beads-on-a-string, where a strand of DNA is wrapped around histone proteins to form a nucleosome, to topological associating domains akin to DNA balls containing multiple DNA loops interacting with various regulatory elements, to highly condensed chromosomes. http://wi.mit.edu/news/archive/2014/special-chromosomal-structures-control-key-genes Dionisio

Dionisio:

What made you think that I was an “impartial observer“?

It was your mentioning that you were a "student" and suggesting that you are the type who follows evidence wherever it leads without caring about which world view most benefits from what is discovered along the way. Dionisio:

What did you mean by “evolution“?

From my experience the word "evolution" is a generalization from Darwinian theory for change over time with (depending on who you ask) many definitions used in place of the word "development" (or more specifically "genomic development") that later led to the phrase "evo-devo" to try elimianting the ambiguity caused by generalizing that way but the new phrase only caused more confusion then more or less went out of fashion. The word "evolution" is also used as a sales pitch, even though some say that is wrong. By being specific I was able to eliminate all "evo" words and "natural selection" from my scientific vocabulary. Never once are they used for ID theory, and to make sure they stay out of the ID vocabulary I include a preface to explain why they do not work in the logical construct of this theory. Dionisio:

What made you think that I had enough knowledge of “the issues“?

At this point in time the ID action is now at UD. You are in the right place at the right time to see what is around, including what what I now have for theory that goes with what others in the movement are working on. Dionisio:

What did you mean by “the issues“?

The issues are primarily over the usefulness of Theory of Intelligent Design in science and science education. Only thing needed for the primary issue to surprisingly go the other way is for something to come out of the ashes of ID that is found to be scientifically useful by others for understanding how intelligence and intelligent cause/causation works. That goal was years ago already accomplished. Science remains the same. Just like before the Darwinian camp is free to all it wants generalize, while ID does fine by having to be more scientifically precise to be able to unify so many areas of science with what Alfred Russel Wallace also described missing from Darwinian theory. Even the normally ignored co-discoverer (who tried to go past that into explaining the phenomenon of intelligence) gets their fair share of glory, after all... Gary S. Gaulin

Unexpected stability and complexity in transcriptional enhancers' interactions Contrary to what was thought, sequences of DNA called enhancers – which control a gene's output – find their targets long before they are activated during embryonic development, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found. Their study, published in Nature, also reveals that, surprisingly, the degree of complexity of enhancers' interactions in the 'simple' fruit fly Drosophila is comparable to what is seen in vertebrates. http://phys.org/news/2014-07-unexpected-stability-complexity-transcriptional-interactions.html#inlRlv Dionisio

Special chromosomal structures control key genes Within almost every human cell is a nucleus six microns in diameter—about one 300th of a human hair's width—that is filled with roughly three meters of DNA. As the instructions for all cell processes, the DNA must be accessible to the cell's transcription machinery yet be compressed tightly enough to fit inside the nucleus. Scientists have long theorized that the way DNA is packaged affects gene expression. Whitehead Institute researchers present the first evidence that DNA scaffolding is responsible for enhancing and repressing gene expression. DNA scaffolding has a hierarchy that ranges from beads-on-a-string, where a strand of DNA is wrapped around histone proteins to form a nucleosome, to topological associating domains akin to DNA balls containing multiple DNA loops interacting with various regulatory elements, to highly condensed chromosomes. http://phys.org/news/2014-10-special-chromosomal-key-genes.html Dionisio

Principles of regulatory information conservation... doi:10.1038/nature13985 http://www.nature.com/nature/journal/v515/n7527/full/nature13985.html Conservation of trans-acting circuitry... doi:10.1038/nature13972 http://www.nature.com/nature/journal/v515/n7527/full/nature13972.html Dionisio

Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains doi: 10.1093/nar/gku698 Genomes of eukaryotes are partitioned into domains of functionally distinct chromatin states. These domains are stably inherited across many cell generations and can be remodeled in response to developmental and external cues, hence contributing to the robustness and plasticity of expression patterns and cell phenotypes. Remarkably, recent studies indicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments. However, the general mechanisms behind such compartmentalization including the contribution of epigenetic regulation remain unclear. Here, we address the question of the coupling between chromatin folding and epigenome. Using polymer physics, we analyze the properties of a block copolymer model that accounts for local epigenomic information. Considering copolymers build from the epigenomic landscape of Drosophila, we observe a very good agreement with the folding patterns observed in chromosome conformation capture experiments. Moreover, this model provides a physical basis for the existence of multistability in epigenome folding at sub-chromosomal scale. We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other. Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics. http://nar.oxfordjournals.org/content/early/2014/08/25/nar.gku698.full Dionisio

Early timing transition region borders align with topologically associating domains and lamina associated domains. doi:10.1038/nature13986 http://www.nature.com/nature/journal/v515/n7527/fig_tab/nature13986_F1.html Dionisio

@786 Zachriel Thanks for the answers. Have a good weekend. :) Dionisio

Dionisio: Including the first cell(s)? Cell Theory, just like the Theory of Evolution, (or Newton's Theory of Gravity for that matter) breaks down in the limit. Dionisio: What does the term “life” mean to you? There's no single definition of life, and the definition used will vary somewhat depending on the field of study; but in evolutionary biology, the primary characteristic is the ability to reproduce. Zachriel

@781 Zachriel

The cell is the most basic unit of life.

What does the term "life" mean to you? Thank you. Dionisio

@781 Zachriel

All cells arise from pre-existing, living cells.

Including the first cell(s)? Dionisio

@779 Gary S. Gaulin Before I can respond to your post, I want to understand the exact meaning of what you wrote. Here's part of your commentary:

Even though it’s sometimes hard to know what your objective is it seemed like you qualify as an impartial observer who is not in denial of “evolution” and has enough knowledge of the issues to have a useful opinion (although not visibly a representative from the Darwinian camp).

What made you think that I was an "impartial observer"? What did you mean by "evolution"? What made you think that I had enough knowledge of "the issues"? What did you mean by "the issues"? Thank you. Dionisio

Darwin’s theory posits that disparate organisms share a common ancestor, something not entailed in either Mendelian Gene Theory or Cell Theory.

And that is an untestable claim and therefor not science. Joe

Gary S. Gaulin: Along with Cell Theory (that Charles Darwin did not write either) Darwin’s Theory of Evolution appears to be for the most part redundant. That is incorrect. Darwin's theory posits that disparate organisms share a common ancestor, something not entailed in either Mendelian Gene Theory or Cell Theory. It also posits that natural selection is a mechanism of adaptation. Gary S. Gaulin: The only thing Darwinian Theory seems to add to science are common sense things like the easier to see bugs are the first to be selected for lunch and more likely to all be eaten. That's a mechanism, but the posited result is adaptation. Gary S. Gaulin: According to Cell Theory all cells come from preexisting cells therefore “all life is related and has descended from a common ancestor” No. These are the tenets of cell theory: * All living organisms are composed of one or more cells. * The cell is the most basic unit of life. * All cells arise from pre-existing, living cells. Zachriel

Topologically associating domains are stable units of replication-timing regulation doi:10.1038/nature13986 Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program 1. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400–800 kilobases (‘replication domains’), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements 2, 3, 4, 5, 6, 7. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs) 4, 5, 8, 9. Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains 8, 10. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale 11, 12. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure 8, 9, 13. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function. http://www.nature.com/nature/journal/v515/n7527/full/nature13986.html Dionisio

Dionisio:

Are you sure you are addressing the right person? You may want to double check and see if you had someone else in mind. Or maybe you saw another Dionisio in another blog? I’m not an expert in anything, as far as I’m aware of. Not even in the field I dedicated a number of years to: engineering design software development, which is a grandiose name for my work as a simple computer programmer. As my colleagues used to say, we were plankton in the corporate ladder. :) Sorry for not being able to help you. I wish I could. These days I’m just a student. Perhaps gpuccio can help you with your questions. He has been very helpful explaining difficult concepts to many folks here, including myself. He seems very intelligent and has shown to possess the gift of patience, which I lack.

Thanks for your opinion. Even though it's sometimes hard to know what your objective is it seemed like you qualify as an impartial observer who is not in denial of "evolution" and has enough knowledge of the issues to have a useful opinion (although not visibly a representative from the Darwinian camp). It would not help to ask someone who is obviously part of the ID movement since no matter how good it is critics can easily brush off any answer they provide by throwing insults. This morning I asked Zachriel who simply answerd "No", which at least indicates that it's a very tough question to get an answer for. It looks like I'm on my own again. But thankfully it's easy enough to find the premise for Darwin's Theory of Evolution online. This is a wordy version (as opposed to a single sentence version) but it's perhaps best to start with plenty of detail:

Darwin's Theory of Evolution - The Premise Darwin's Theory of Evolution is the widely held notion that all life is related and has descended from a common ancestor: the birds and the bananas, the fishes and the flowers -- all related. Darwin's general theory presumes the development of life from non-life and stresses a purely naturalistic (undirected) "descent with modification". That is, complex creatures evolve from more simplistic ancestors naturally over time. In a nutshell, as random genetic mutations occur within an organism's genetic code, the beneficial mutations are preserved because they aid survival -- a process known as "natural selection." These beneficial mutations are passed on to the next generation. Over time, beneficial mutations accumulate and the result is an entirely different organism (not just a variation of the original, but an entirely different creature). See more at: http://www.darwins-theory-of-evolution.com/#sthash.UcbJsrDq.dpuf

The premise of (Gregor Mendel's) Gene Theory is:

Gene Theory Gene theory is the idea that genes are the unit of inheritance. This theory has been modified many times over the years, as new evidence has become available. In the nineteenth century, Gregor Mendel, an Austrian monk, studied peas and how certain characteristics were transmitted from one generation to another. Mendel realized that the transmission was occurring through their gametes. He found that the adult plants contained two copies of a factor controlling the observed characteristic, but that the gametes only had the one copy. More at: http://www.bookrags.com/research/gene-theory-wob/#gsc.tab=0

Along with Cell Theory (that Charles Darwin did not write either) Darwin's Theory of Evolution appears to be for the most part redundant. The only thing Darwinian Theory seems to add to science are common sense things like the easier to see bugs are the first to be selected for lunch and more likely to all be eaten. According to Cell Theory all cells come from preexisting cells therefore "all life is related and has descended from a common ancestor" and how many common ancestors there are is not yet known for sure but either way Darwinian Theory will still be said to be right even though major predictions (such as only "random" mutations will be found) were wrong. I'm willing to stand corrected on anything I just said, but after separating out from "evolutionary theory" other theories that Charles Darwin did not develop I'm left with what the theory Al-Jahiz wrote over 1000 years ago. Does that sound about right to you too? Gary S. Gaulin

Single-Cell Analysis Hints at Stem Cell Code Linking Transcription and Development Looking at the findings, the researchers now believe there is a “code” that relates patterns of dynamic behavior in stem cell regulatory circuits to the developmental path a cell ends up taking. "...different classes of genes manifest high or low expression variability in PSCs, with housekeeping and metabolic gene sets showing consistent expression across individual cells, while genes involved in signaling pathways and development were considerably more variable. Moreover, expression states of variable regulatory factors were coupled together, implying the presence of a regulated biological network.” http://www.genengnews.com/gen-news-highlights/single-cell-analysis-hints-at-stem-cell-code-linking-transcription-and-development/81250670/ Dionisio

Deconstructing transcriptional heterogeneity in pluripotent stem cells doi:10.1038/nature13920 Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates; however, the regulatory circuits specifying these states and enabling transitions between them are not well understood. Signalling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signaling pathways and chromatin regulators. Notably, either removal of mature microRNAs or pharmacological blockage of signaling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal and a distinct chromatin state, an effect mediated by opposing microRNA families acting on the Myc/Lin28/let-7 axis. These data provide insight into the nature of transcriptional heterogeneity in PSCs. http://www.nature.com/nature/journal/v516/n7529/full/nature13920.html Dionisio

"the constant mix of functional conservation and functional divergence in different species is really the fascinating leitmotiv of all recent epigenomics. However we look at it, function is always the central concept." -gpuccio.

:) Dionisio

Dionisio: "Are they qualified scientists?" Sure they are! ENCODE and FANTOM are probably the best large scale projects today. The criticism is essentially about the concept of functionality: strict neo darwinists love to adhere to their concept that most of the genome is non functional, which in their opinion reinforces the idea that it is the result of random neutral variation. The ENCODE people, instead, have always defended a position where a large part of the genome should be functional. And they stick to it, even if with more caution than in the beginning, given the harsh attacks received. Of course, you know where I stay: with the ENCODE people, absolutely. It is perfectly reasonable to consider many aspects as still open to discussion. I don't know if 20% of the genome is functional (which is really the minimum), or 40%, or 60%, or 80%. We will see. But I am absolutely confident that function is not to be found only in the protein coding 2%, or in the conserved 5-7%. As shown by the last ENCODE papers, a lot of function is in the diverging sequences, for example in enhancers. I am sure that non coding DNA still has a lot of precious things to reveal. By the way, the constant mix of functional conservation and functional divergence in different species is really the fascinating leitmotiv of all recent epigenomics. However we look at it, function is always the central concept. Let our darwinist "friends" stick to their junk concepts of junk. In the meanwhile, we are having all the fun! :) gpuccio

@773 addendum gpuccio perhaps reading the interesting papers you have provided have caused my mind to get too distracted, hence I haven't noticed the errors introduced by the 'autocorrect' feature that is constantly changing what I'm writing. It seems to use a syntactic/semantic type-ahead guessing approach that sometimes goes just wrong. Dionisio

@772 error correction gpuccio Sorry, I misspelled your name. I know exactly how to spell it. No idea what went wrong. Mea culpa. Dionisio

gluccio

The role of transposons as tools to shape functional evolution can no more be denied

Interesting suggestion. Isn't that an important promotion after being considered just randomly repetitive 'selfish'/'junk' jumping segments of DNA? BTW, the ENCODE papers you provided are very interesting and shed much light on important issues. However, I've noticed they have met some harsh criticism in certain circles. Why? Anything wrong with their reports? Are they qualified scientists? Dionisio

Dionisio: From one of the ENCODE new papers:

How can species-specific gains or loss ofcis-regulatory elements during evolution be compatible with their putative regulatory function? The finding of different rates of divergence associated with regulatory programs of distinct biological pathways suggests complex forces driving the evolution of the cis-regulatory landscape in mammals. We discovered that specific classes of endogenous retroviral elements are enriched at the species-specific putative cis-regulatory elements, implicating transposition of DNA as a potential mechanism leading to divergence of gene regulatory programs during evolution. Previous studies have shown that endogenous retroviral elements can be transcribed in a tissue-specific manner, with a fraction of them derived from enhancers and necessary for transcription of genes involved in pluripotency. Future studies will be necessary to determine whether retroviral elements at or near enhancers are generally involved in driving tissue-specific gene expression programs in different mammalian species.

Emphasis mine. The role of transposons as tools to shape functional evolution can no more be denied, IMO. gpuccio

gpuccio Here's another minor observation on the 'editorial' paper:

Many questions remain though: how do the genomes remain their identities after entering in the same nucleus? How do the regulatory networks reorganize after the merger of two separate genomes? http://scitechnol.com/2324-8548/2324-8548-1-e105.pdf

They wrote that many questions remain, but only listed two? However, the two questions seem to address pretty complex issues, don't they? Maybe that's why they wrote that many questions remain? In the first question, shouldn't it read 'retain' instead of 'remain'? Does anybody proofread scientific papers before they get published? Dionisio

gpuccio Again, back to the 2-page (6-paragraph) agitprop 'editorial':

In eukaryotic cells, gene sets that require tight co-regulation are no longer functionally constrained to be in the same ‘neighborhood’, possibly due to the asynchronous nature of transcription through the existence regulatory motifs on individual genes rather than on linked gene sets. http://scitechnol.com/2324-8548/2324-8548-1-e105.pdf

What are the "existence regulatory motifs? Why are they called "existence"? Are there other types? Dionisio

gpuccio

I suppose that in a biological context, the sum total of genome and epigenome could be considered as “hardware + software”. In the end, we have some configuration of matter which can perform complex tasks. I would distinguish between the total information in the genome/epigenome, which can maybe considered as global information in some form of mass memory, and the information which is active (genomically and epigenomically) in a specific cell, which is probably more similar to the information loaded in the RAM and CPU memory.

This makes much more sense to me than the original analogy quoted in post #764. Thank you. Dionisio

gpuccio

You are lucky. There are many more things that I don’t understand in that “editorial”.

Lucky? That's really funny. I quoted the very first sentence of the very first paragraph of that 2-page "editorial". Just started reading and the first question popped up. There are many more things that I don't understand in that agitprop document, which you so rightly called "editorial". BTW, your definition makes much more sense than the simplistic reductionist analogy they wrote. :) Dionisio

Dionisio: "I don’t understand this:" You are lucky. There are many more things that I don't understand in that "editorial". I suppose that in a biological context, the sum total of genome and epigenome could be considered as "hardware + software". In the end, we have some configuration of matter which can perform complex tasks. I would distinguish between the total information in the genome/epigenome, which can maybe considered as global information in some form of mass memory, and the information which is active (genomically and epigenomically) in a specific cell, which is probably more similar to the information loaded in the RAM and CPU memory. gpuccio

Zachriel: That was supposed to be ironic! :) gpuccio

gpuccio RE: http://scitechnol.com/2324-8548/2324-8548-1-e105.pdf I don't understand this:

Genomes are often referred to as the “operating system” of living cells and organisms [1]. Analogous to the operating system of a computer or a smart phone, the architecture and the layout of the components within the genome are crucial to the coordination of gene expression and regulation.

The operating system in a computer or mobile device is the software that operates on the microprocessor circuitry, code ansignals. If the genome is compared to the operating system (including multiple drivers), what would be the equivalent of the microprocessor, devices, other components, which have their own circuitry, code, signals? Did I understand this wrong? Thank you. Dionisio

gpuccio

I am fascinated by the TAD concept. A couple of things that make it really interesting: a) TADs seem to be grossly constant (as a topological unit) in all cells of one organism, in different stages and pathways of differentiation. That makes them a very useful “functional unit” in the genome. b) ON the other hand, they change their state (more or less active) in different conditions. c) Finally, they remain however somewhat flexible (see the possible shift of boundaries). Another interesting thing is that they are topological units which reflect, in some way, the 3D aggregation of genes, promoters, enhancers and TFs, including loops, and they are constantly modified by the other epigenetic layers (methylome, histone modifications, and so on). SO, I think they are a good starting point to make some clarity in the dark wood of the procedures…

Definitely you have written a very practical summary on the interesting TAD concept. I will continue to study this subject too. Thank you. I'm glad to see you're working so seriously on that extremely difficult paper about the biological built-in procedures. I could be wrong, but I believe such a paper would become a game changer in any serious discussion anywhere, because it takes us closer to what you call dFSCI, but in a more complex way than what you have covered on your most recent OPs and commentaries in other threads. Dionisio

gpuccio

Don’t despair, they always have more answers than questions!

LOL - they've got a clever strategy. "We've answered almost all the questions we asked ourselves." And let's not ask if the the answers are correct. The answers are like evolution itself: "experimental". So, they might be right and that's pretty good. :-) Silver Asiatic

gpuccio

Maybe you need some “Turing oracle”, to make the concept computable! :)

Will consider it. :) But at this point I just want to make it (logically, coherently, comprehensively) understandable. However, it's much more difficult than I originally thought. Specially when one doesn't have the required biology knowledge. The free classes I took online have helped me to understand the basic concepts, but still have a long way to reach the level of understanding I want to get to. As outstanding questions get answered, new ones pop up. Definitely this seems one of the most fascinating areas of science these days. Let's enjoy it! :) Dionisio

Silver Asiatic: The researchers only gave us a taste with two of the “many questions”. gpuccio: Don’t despair, they always have more answers than questions! Quite the contrary. Every discovered "missing link" means two new gaps! Zachriel

Silver Asiatic: Don't despair, they always have more answers than questions! :) Luckily, when I was young, I learnt from a very wise Carl Bark's Disney classic that answers are not so important, and that the real difficulty is in having the right questions. gpuccio

Dionisio: Again from ENCODE, in Nature: http://www.nature.com/nature/journal/v515/n7527/pdf/nature13992.pdf http://www.nature.com/nature/journal/v515/n7527/pdf/nature13972.pdf http://www.nature.com/nature/journal/v515/n7527/pdf/nature13985.pdf http://www.nature.com/nature/journal/v515/n7527/pdf/nature13986.pdf gpuccio

gpuccio I agree that the TAD concept is fascinating. I appreciate that you brought it up to my attention. Also thank you for all the references to interesting papers you just provided. I'm looking into them, but at a much slower pace than you. :) Mile grazie! Dionisio

@754 Gary S. Gaulin RE: #749-751

I’m not exactly sure who to ask. But I do know that it would have to be an impartial observer or a representative from the Darwinian camp.

I'm neither one. :) I'm just a student. That's why I ask so many questions, because I want to learn, and don't have much time for it. When I take breaks, I look into some of the threads in this site. Most discussions are high above my pay grade. :) If you want to know what exactly I'm studying, 700+ posts in this thread can give you an idea. But I look at all that from an information technology perspective, as if I were writing a program based on those papers, i.e. using those papers as programming specs. It ain't easy, but it's very exciting. :) Dionisio

Dionisio: This 2012 paper is probably the start of it. They identify about 2200 TADs in the mammalian genome. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356448/pdf/nihms366885.pdf gpuccio

Dionisio:

Are you sure you are addressing the right person?

No. I'm not exactly sure who to ask. But I do know that it would have to be an impartial observer or a representative from the Darwinian camp. Gary S. Gaulin

Dionisio: "Usually I try to dissect a complex text and reduce the ideas in it to a series of “if (…) then {…}” statements and/or a set of interconnected decision tables. Also include “while (…)” loops. Sometimes a bunch of interconnected logic gates may appear in the description too. That way it may be more understandable to me." Maybe you need some "Turing oracle", to make the concept computable! :) Yes, being a student is the best thing there is. I am fascinated by the TAD concept. A couple of things that make it really interesting: a) TADs seem to be grossly constant (as a topological unit) in all cells of one organism, in different stages and pathways of differentiation. That makes them a very useful "functional unit" in the genome. b) ON the other hand, they change their state (more or less active) in different conditions. c) Finally, they remain however somewhat flexible (see the possible shift of boundaries). Another interesting thing is that they are topological units which reflect, in some way, the 3D aggregation of genes, promoters, enhancers and TFs, including loops, and they are constantly modified by the other epigenetic layers (methylome, histone modifications, and so on). SO, I think they are a good starting point to make some clarity in the dark wood of the procedures... gpuccio

gpuccio 746

All the “magic ‘n-D e’ formula” in less than two pages!

That was impressive especially since page one said nothing about the magic formula. That was reserved for a paragraph on page 2. The magic occurs when "genomes merge and co-exist in the same nucleus", then they can conduct evolutionary "experiments" to create new, functional genetic information. It all works quite nicely! There's only a slight problem ...

Many questions remain though: how do the genomes remain their identities after entering in the same nucleus? How do the regulatory networks re-organize after the merger of two separate genomes

The researchers only gave us a taste with two of the "many questions". Silver Asiatic

@744 Gary S. Gaulin #750 addendum Maybe the quote in the OP of this thread is somehow related to your questions too? Dionisio

@744 Gary S. Gaulin #749 addendum I can use any help I could get. But maybe kf can help you with your questions? Perhaps ba77 can pitch in some information too? You may want to ask them directly. Dionisio

@744 Gary S. Gaulin

Since you are an expert in Darwinian theory...

Are you sure you are addressing the right person? You may want to double check and see if you had someone else in mind. Or maybe you saw another Dionisio in another blog? I'm not an expert in anything, as far as I'm aware of. Not even in the field I dedicated a number of years to: engineering design software development, which is a grandiose name for my work as a simple computer programmer. As my colleagues used to say, we were plankton in the corporate ladder. :) Sorry for not being able to help you. I wish I could. These days I'm just a student. Perhaps gpuccio can help you with your questions. He has been very helpful explaining difficult concepts to many folks here, including myself. He seems very intelligent and has shown to possess the gift of patience, which I lack. Dionisio

gpuccio Wow! "The Evolution of Genome Structure" in less than two pages! That's quite an impressive level of 'compact writing' skills! Just six paragraphs! However, it's high above my level of understanding. After reading it, I have more questions than I had before. Usually I try to dissect a complex text and reduce the ideas in it to a series of "if (...) then {...}" statements and/or a set of interconnected decision tables. Also include "while (...)" loops. Sometimes a bunch of interconnected logic gates may appear in the description too. That way it may be more understandable to me. But an over-compacted text like that paper generates too many question marks. In such cases I don't know how to proceed and I get overwhelmed by so many unanswered questions. Not a very encouraging situation to be in. However, that's a sign of my ignorance, hence I should keep studying and learning. :) Dionisio

gpuccio You've found very interesting papers! Thank you for posting the references here! Also, thank you for the clear explanation responding my question. Let's hope other readers can learn from your insightful comments too. As you indicated, "the new high throughput techniques are revealing new layers of knowledge". It's very exciting to watch all that happening these days. :) However, it's going to take me a little while to 'chew' and 'digest' all that 'food for thoughts' but I like that kind of 'learning' challenge. It feels good to be a student! :) Mile grazie! Dionisio

Dionisio: More recent papers about prokaryote nucleoid organization: http://nar.oxfordjournals.org/content/early/2011/10/05/nar.gkr779.full.pdf http://jb.asm.org/content/195/6/1109.full.pdf However, if you wonder about how all those things originated, don't worry: everything is explained here: http://scitechnol.com/2324-8548/2324-8548-1-e105.pdf All the "magic ‘n-D e’ formula" in less than two pages! :) gpuccio

Dionisio: Your questions are always extremely good! I believe that the functional 3d organization of DNA is essential at all levels. Here, for example, is a paper about prokaryotes: http://genesdev.cshlp.org/content/18/14/1766.full.pdf However, eukaryotes and especially metazoa are certainly more complex in that respect, and there are many recent studies about this exciting new aspects of their organization, especially since the new high throughput techniques are revealing new layers of knowledge. The concept of TADs seems specially important and solid. Here is another good free review: http://www.cell.com/molecular-cell/pdf/S1097-2765(13)00139-1.pdf No Italian here, just to show that I am not biased! :) I will go on digging... gpuccio

Dionisio, all day long I was hoping to get an answer from wd400 to this question in regards to Darwinian (evolutionary) theory:

Could you please in around one paragraph explain the premise, systematics, requirements and necessary variables in “the theory” that “has changed a lot since Darwin’s” time, and without confusing it with other theories such as Cell Theory, Gene Theory and all others?

Since you are an expert in Darwinian theory your answer would be useful for determining what you actually have after removing theories that for the most part already existed and stand on their own, are not the private property of the Darwinian world-view. Gary S. Gaulin

Advances in synapse formation: forging connections DOI: 10.1002/wdev.165 Synapse formation is the quintessential process by which neurons form specific connections with their targets to enable the development of functional circuits. Over the past few decades, intense research efforts have identified thousands of proteins that localize to the pre? and postsynaptic compartments. Genetic dissection has provided important insights into the nexus of the molecular and cellular network, and has greatly advanced our knowledge about how synapses form and function physiologically. Moreover, recent studies have highlighted the complex regulation of synapse formation with the identification of novel mechanisms involving cell interactions from non?neuronal sources. In this review, we cover the conserved pathways required for synaptogenesis and place specific focus on new themes of synapse modulation arising from studies in Caenorhabditis elegans. http://wires.wiley.com/WileyCDA/WiresArticle/wisId-WDEV165.html Dionisio

gpuccio, The authors of the paper work at a French institute, but their names sound Italian, right? :) Dionisio

gpuccio, Yes, I agree, this paper you found is very interesting indeed. Thank you for sharing it. As usual, this paper has much learning material for me. My level of understanding in this area still is relatively low. But I'm trying my best to learn as much as I can. :) I highlighted a few parts of the abstract of the paper:

Metazoan genomes are highly organized inside the cell nucleus. Topologically associating domains (TADs) represent the building blocks of genome organization, but their linear modularity does not explain alone their spatial organization. Indeed, the chromatin type adorning a TAD can shape its structure and drives its nuclear positioning and its function. Genome-wide association studies revealed mainly four chromatin types: active chromatin, Polycomb-repressed chromatin, null chromatin and constitutive heterochromatin.

That shows the amazing power of the magic 'n-D e' formula RV+NS+T :) Are you aware of any available description of the genome organization before the metazoan? Perhaps my question makes no sense, but I know you're a forgiving person. :) Dionisio

Dionisio: This paper is IMO very good: http://www.sciencedirect.com/science/article/pii/S0022283614005129 It is an unusually clear review of what is known about chromatin organization in metazoa. Very interesting. :) gpuccio

Signaling pathways regulating ectodermal cell fate choices doi:10.1016/j.yexcr.2013.08.002 Although embryonic patterning and early development of the nervous system have been studied for decades, our understanding of how signals instruct ectodermal derivatives to acquire specific identities has only recently started to form a coherent picture. In this mini-review, we summarize recent findings and models of how a handful of well-known secreted signals influence progenitor cells in successive binary decisions to adopt various cell type specific differentiation programs. http://www.sciencedirect.com/science/article/pii/S0014482713003303 Dionisio

Transcriptional mechanisms of cell fate decisions revealed by single cell expression profiling DOI: 10.1002/bies.201300102 Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene expression in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. http://onlinelibrary.wiley.com/doi/10.1002/bies.201300102/full Dionisio

Regulatory network decoded from epigenomes of surface ectoderm-derived cell types doi:10.1038/ncomms6442 Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts, to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network. http://www.nature.com/ncomms/2014/141125/ncomms6442/full/ncomms6442.html Dionisio

Decoding the role of chromatin architecture in development: coming closer to the end of the tunnel doi: 10.3389/fpls.2014.00374 Form and function in biology are intimately related aspects that are often difficult to untangle. While the structural aspects of chromatin organization were apparent from early cytological observations long before the molecular details of chromatin functions were deciphered, the extent to which genome architecture may impact its output remains unclear. A major roadblock to resolve this issue is the divergent scales, both temporal and spatial, of the experimental approaches for examining these facets of chromatin biology. Recent advances in high-throughput sequencing and informatics to model and monitor genome-wide chromatin contact sites provide the much-needed platform to close this gap. This mini-review will focus on discussing recent efforts applying new technologies to elucidate the roles of genome architecture in coordinating global gene expression output. Our discussion will emphasize the potential roles of differential genome 3-D structure as a driver for cell fate specification of multicellular organisms. An integrated approach that combines multiple new methodologies may finally have the necessary temporal and spatial resolution to provide clarity on the roles of chromatin architecture during development. http://journal.frontiersin.org/Journal/10.3389/fpls.2014.00374/abstract Dionisio

Regulation of cell fate determination doi: 10.3389/fpls.2014.00368 Building a multicellular organism, like a plant, from a single cell requires the coordinated formation of different cell types in a spatiotemporal arrangement. How different cell types arise in appropriate places and at appropriate times is one of the most intensively investigated questions in modern plant biology. Using models such as trichome formation, root hair formation, and stomatal development in Arabidopsis, scientists have begun to discover some of the answers, including the importance of transcriptional regulatory networks, intrinsic signals such as plant hormones, and extrinsic signals such as environmental stimuli. This research topic aimed to summarize the research progress in cell fate determination in plants. http://journal.frontiersin.org/Journal/10.3389/fpls.2014.00368/full Dionisio

Microtubule nucleation remote from centrosomes may explain how asters span large cells doi: 10.1073/pnas.1418796111 A major challenge in cell biology is to understand how nanometer-sized molecules can organize micrometer-sized cells in space and time. One solution in many animal cells is a radial array of microtubules called an aster, which is nucleated by a central organizing center and spans the entire cytoplasm. Frog (here Xenopus laevis) embryos are more than 1 mm in diameter and divide with a defined geometry every 30 min. Like smaller cells, they are organized by asters, which grow, interact, and move to precisely position the cleavage planes. It has been unclear whether asters grow to fill the enormous egg by the same mechanism used in smaller somatic cells, or whether special mechanisms are required. We addressed this question by imaging growing asters in a cell-free system derived from eggs, where asters grew to hundreds of microns in diameter. By tracking marks on the lattice, we found that microtubules could slide outward, but this was not essential for rapid aster growth. Polymer treadmilling did not occur. By measuring the number and positions of microtubule ends over time, we found that most microtubules were nucleated away from the centrosome and that interphase egg cytoplasm supported spontaneous nucleation after a time lag. We propose that aster growth is initiated by centrosomes but that asters grow by propagating a wave of microtubule nucleation stimulated by the presence of preexisting microtubules. How the cell cytoplasm is spatially organized is of fundamental interest. In ordinary animal cells the cytoplasm is organized by a radial array of microtubules, called an aster. Aster microtubules are nucleated by the centrosome and elongate to the periphery. We investigated how asters grow in an extremely large cell, the frog egg, using microscopy of an extract system. Asters were initially nucleated at centrosomes, but then additional microtubules nucleated far from the centrosome, apparently stimulated by preexisting microtubules. The resulting growth process allows asters to scale to the size of huge egg cells while maintaining a high density of microtubules at the periphery. Microtubule-stimulated microtubule nucleation might be a general principle for organizing large cells. http://www.pnas.org/content/early/2014/12/02/1418796111.abstract?sid=627174eb-28f3-46ff-803f-daf8c83d8a9d Dionisio

Physical basis of spindle self-organization doi: 10.1073/pnas.1409404111 The cytoskeleton forms a variety of steady-state, subcellular structures that are maintained by continuous fluxes of molecules and energy. Understanding such self-organizing structures is not only crucial for cell biology but also poses a fundamental challenge for physics, since these systems are active materials that behave drastically differently from matter at or near equilibrium. Active liquid crystal theories have been developed to study the self-organization of cytoskeletal filaments in in vitro systems of purified components. However, it has been unclear how relevant these simplified approaches are for understanding biological structures, which can be composed of hundreds of distinct proteins. Here we show that a suitably constructed active liquid crystal theory produces remarkably accurate predictions of the behaviors of metaphase spindles—the cytoskeletal structure, composed largely of microtubules and associated proteins, that segregates chromosomes during cell division. The spindle segregates chromosomes during cell division and is composed of microtubules and hundreds of other proteins, but the manner in which these molecular constituents self-organize to form the spindle remains unclear. Here we use a holistic approach, based on quantitative measurements in spindles of the spatiotemporal correlation functions of microtubule density, orientation, and stresses, to identify the key processes responsible for spindle self-organization. We show that microtubule turnover and the collective effects of local microtubule interactions, mediated via motor proteins and cross-linkers, can quantitatively account for the dynamics and the structure of the spindle. We thus reveal the physical basis of spindle self-organization and provide a framework that may be useful for understanding cytoskeletal function in vivo. http://www.pnas.org/content/early/2014/12/02/1409404111.abstract?sid=627174eb-28f3-46ff-803f-daf8c83d8a9d Dionisio

The (r)evolution of gene regulatory networks controlling Arabidopsis plant reproduction: a two-decade history doi: 10.1093/jxb/eru233 Successful plant reproduction relies on the perfect orchestration of singular processes that culminate in the product of reproduction: the seed. The floral transition, floral organ development, and fertilization are well-studied processes and the genetic regulation of the various steps is being increasingly unveiled. Initially, based predominantly on genetic studies, the regulatory pathways were considered to be linear, but recent genome-wide analyses, using high-throughput technologies, have begun to reveal a different scenario. Complex gene regulatory networks underlie these processes, including transcription factors, microRNAs, movable factors, hormones, and chromatin-modifying proteins. Here we review recent progress in understanding the networks that control the major steps in plant reproduction, showing how new advances in experimental and computational technologies have been instrumental. As these recent discoveries were obtained using the model species Arabidopsis thaliana, we will restrict this review to regulatory networks in this important model species. However, more fragmentary information obtained from other species reveals that both the developmental processes and the underlying regulatory networks are largely conserved, making this review also of interest to those studying other plant species. http://jxb.oxfordjournals.org/content/65/17/4731.abstract Dionisio

Science + fairy tale terminology = pseudoscience speculation Here's an example: Molecular Evolution Constraints in the Floral Organ Specification Gene Regulatory Network Module across 18 Angiosperm Genomes doi: 10.1093/molbev/mst223 The gene regulatory network of floral organ cell fate specification of Arabidopsis thaliana is a robust developmental regulatory module. Although such finding was proposed to explain the overall conservation of floral organ types and organization among angiosperms, it has not been confirmed that the network components are conserved at the molecular level among flowering plants. Using the genomic data that have accumulated, we address the conservation of the genes involved in this network and the forces that have shaped its evolution during the divergence of angiosperms. We recovered the network gene homologs for 18 species of flowering plants spanning nine families. We found that all the genes are highly conserved with no evidence of positive selection. We studied the sequence conservation features of the genes in the context of their known biological function and the strength of the purifying selection acting upon them in relation to their placement within the network. Our results suggest an association between protein length and sequence conservation, evolutionary rates, and functional category. On the other hand, we found no significant correlation between the strength of purifying selection and gene placement. Our results confirm that the studied robust developmental regulatory module has been subjected to strong functional constraints. However, unlike previous studies, our results do not support the notion that network topology plays a major role in constraining evolutionary rates. We speculate that the dynamical functional role of genes within the network and not just its connectivity could play an important role in constraining evolution. http://mbe.oxfordjournals.org/content/31/3/560.abstract Dionisio

STEM CELLS AND REGENERATION Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network doi: 10.1242/dev.109678 During blastocyst formation, inner cell mass (ICM) cells differentiate into either epiblast (Epi) or primitive endoderm (PrE) cells, labeled by Nanog and Gata6, respectively, and organized in a salt-and-pepper pattern. Previous work in the mouse has shown that, in absence of Nanog, all ICM cells adopt a PrE identity. Moreover, the activation or the blockade of the Fgf/RTK pathway biases cell fate specification towards either PrE or Epi, respectively. We show that, in absence of Gata6, all ICM cells adopt an Epi identity. Furthermore, the analysis of Gata6+/? embryos reveals a dose-sensitive phenotype, with fewer PrE-specified cells. These results and previous findings have enabled the development of a mathematical model for the dynamics of the regulatory network that controls ICM differentiation into Epi or PrE cells. The model describes the temporal dynamics of Erk signaling and of the concentrations of Nanog, Gata6, secreted Fgf4 and Fgf receptor 2. The model is able to recapitulate most of the cell behaviors observed in different experimental conditions and provides a unifying mechanism for the dynamics of these developmental transitions. The mechanism relies on the co-existence between three stable steady states (tristability), which correspond to ICM, Epi and PrE cells, respectively. Altogether, modeling and experimental results uncover novel features of ICM cell fate specification such as the role of the initial induction of a subset of cells into Epi in the initiation of the salt-and-pepper pattern, or the precocious Epi specification in Gata6+/? embryos. http://dev.biologists.org/content/141/19/3637.short Dionisio

Signals from the surface modulate differentiation of human pluripotent stem cells The fate decisions of human pluripotent stem (hPS) cells are governed by soluble and insoluble signals from the microenvironment. Many hPS cell differentiation protocols use Matrigel, a complex and undefined substrate that engages multiple adhesion and signaling receptors. Using defined surfaces programmed to engage specific cell-surface ligands (i.e., glycosaminoglycans and integrins), the contribution of specific matrix signals can be dissected. For ectoderm and motor neuron differentiation, peptide-modified surfaces that can engage both glycosaminoglycans and integrins are effective. In contrast, surfaces that interact selectively with glycosaminoglycans are superior to Matrigel in promoting hPS cell differentiation to definitive endoderm and mesoderm. The modular surfaces were used to elucidate the signaling pathways underlying these differences. Matrigel promotes integrin signaling, which in turn inhibits mesendoderm differentiation. The data indicate that integrin-activating surfaces stimulate Akt signaling via integrin-linked kinase (ILK), which is antagonistic to endoderm differentiation. The ability to attribute cellular responses to specific interactions between the cell and the substrate offers new opportunities for revealing and controlling the pathways governing cell fate. http://www.ncbi.nlm.nih.gov/pubmed/25422477 Pretty simple. Piece of cake, isn't it? Dionisio

MICRORNAs IN ER STRESS: DIVERGENT ROLES IN CELL FATE DECISIONS. MicroRNAs are small noncoding RNAs which regulate protein expression post-transcriptionally. They respond to changes in a cells environment and can promote cell death or cell survival depending on the context. Recent studies have linked microRNAs to the unfolded protein response pathway. This pathway is activated in the endoplasmic reticulum by conditions which interfere with the normal function of the endoplasmic reticulum. The cell fate outcomes consequent to the activation of the unfolded protein response are binary, either cell survival or cell death. MicroRNAs can regulate multiple components of this pathway to tip the cell towards either fate. Interestingly, inositol requiring enzyme 1 alpha, a canonical unfolded protein response sensor and mediator, has inherent endoribonuclease activity. Recently, it has been demonstrated that it can target microRNAs in addition to its previously known targets. This review highlights key papers in this rapidly emerging field. http://www.ncbi.nlm.nih.gov/pubmed/25419494 Dionisio

Unraveling liver complexity from molecular to organ level: challenges and perspectives. doi: 10.1016/j.pbiomolbio.2014.11.005 Biological responses are determined by information processing at multiple and highly interconnected scales. Within a tissue the individual cells respond to extracellular stimuli by regulating intracellular signaling pathways that in turn determine cell fate decisions and influence the behavior of neighboring cells. As a consequence the cellular responses critically impact tissue composition and architecture. Understanding the regulation of these mechanisms at different scales is key to unravel the emergent properties of biological systems. In this perspective, a multidisciplinary approach combining experimental data with mathematical modeling is introduced. We report the approach applied within the Virtual Liver Network to analyze processes that regulate liver functions from single cell responses to the organ level using a number of examples. By facilitating interdisciplinary collaborations, the Virtual Liver Network studies liver regeneration and inflammatory processes as well as liver metabolic functions at multiple scales, and thus provides a suitable example to identify challenges and point out potential future application of multi-scale systems biology. http://www.ncbi.nlm.nih.gov/pubmed/25433231 Dionisio

Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast. doi: 10.1038/ncomms6538 Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Nonetheless, ES cells can seemingly acquire TS-like characteristics upon manipulation of lineage-determining transcription factors or activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Here we have interrogated the progression of reprogramming in ES cell models with regulatable Oct4 and Cdx2 transgenes or conditional Erk1/2 activation. Although trans-differentiation into TS-like cells is initiated, lineage conversion remains incomplete in all models, underpinned by the failure to demethylate a small group of TS cell genes. Forced expression of these non-reprogrammed genes improves trans-differentiation efficiency, but still fails to confer a stable TS cell phenotype. Thus, even ES cells in ground-state pluripotency cannot fully overcome the boundaries that separate the first cell lineages but retain an epigenetic memory of their ES cell origin. http://www.ncbi.nlm.nih.gov/pubmed/25423963 Dionisio

Kinetochore-driven outgrowth of microtubules is a central contributor to kinetochore fiber maturation doi: 10.1091/mbc.E14-01-0008 We use liquid crystal polarized light imaging to record the life histories of single kinetochore (K-) fibers in living crane-fly spermatocytes, from their origins as nascent K-fibers in early prometaphase to their fully matured form at metaphase, just before anaphase onset. Increased image brightness due to increased retardance reveals where microtubules are added during K-fiber formation. Analysis of experimentally generated bipolar spindles with only one centrosome, as well as of regular, bicentrosomal spindles, reveals that microtubule addition occurs at the kinetochore-proximal ends of K-fibers, and added polymer expands poleward, giving rise to the robust K-fibers of metaphase cells. These results are not compatible with a model for K-fiber formation in which microtubules are added to nascent fibers solely by repetitive "search and capture" of centrosomal microtubule plus ends. Our interpretation is that capture of centrosomal microtubules-when deployed-is limited to early stages in establishment of nascent K-fibers, which then mature through kinetochore-driven outgrowth. When kinetochore capture of centrosomal microtubules is not used, the polar ends of K-fibers grow outward from their kinetochores and usually converge to make a centrosome-free pole. http://www.ncbi.nlm.nih.gov/pubmed/24574457 Dionisio

A morphometric screen identifies specific roles for microtubule-regulating genes in neuronal development of P19 stem cells. doi: 10.1371/journal.pone.0079796 The first morphological change after neuronal differentiation is the microtubule-dependent initiation of thin cell protrusions called neurites. Here we performed a siRNA-based morphometric screen in P19 stem cells to evaluate the role of 408 microtubule-regulating genes during this early neuromorphogenesis step. This screen uncovered several novel regulatory factors, including specific complex subunits of the microtubule motor dynein involved in neurite initiation and a novel role for the microtubule end-binding protein EB2 in attenuation of neurite outgrowth. Epistasis analysis suggests that competition between EB1 and EB2 regulates neurite length, which links its expression to neurite outgrowth. We propose a model that explains how microtubule regulators can mediate cellular morphogenesis during the early steps of neuronal development by controlling microtubule stabilization and organizing dynein-generated forces. http://www.ncbi.nlm.nih.gov/pubmed/24260302 Dionisio

Chaperone machines for protein folding, unfolding and disaggregation doi:10.1038/nrm3658 Molecular chaperones are diverse families of multidomain proteins that have evolved to assist nascent proteins to reach their native fold, protect subunits from heat shock during the assembly of complexes, prevent protein aggregation or mediate targeted unfolding and disassembly. Their increased expression in response to stress is a key factor in the health of the cell and longevity of an organism. Unlike enzymes with their precise and finely tuned active sites, chaperones are heavy-duty molecular machines that operate on a wide range of substrates. The structural basis of their mechanism of action is being unravelled (in particular for the heat shock proteins HSP60, HSP70, HSP90 and HSP100) and typically involves massive displacements of 20–30 kDa domains over distances of 20–50 Å and rotations of up to 100°. http://www.nature.com/nrm/journal/v14/n10/full/nrm3658.html Dionisio

Molecular chaperones in protein folding and proteostasis doi:10.1038/nature10317 Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance. http://www.nature.com/nature/journal/v475/n7356/full/nature10317.html Dionisio

DnaK Functions as a Central Hub in the E. coli Chaperone Network DOI: http://dx.doi.org/10.1016/j.celrep.2011.12.007 Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity. Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL. Quantitative proteomics revealed that DnaK interacts with at least ?700 mostly cytosolic proteins, including ?180 relatively aggregation-prone proteins that utilize DnaK extensively during and after initial folding. Upon deletion of TF, DnaK interacts increasingly with ribosomal and other small, basic proteins, while its association with large multidomain proteins is reduced. DnaK also functions prominently in stabilizing proteins for subsequent folding by GroEL. These proteins accumulate on DnaK upon GroEL depletion and are then degraded, thus defining DnaK as a central organizer of the chaperone network. Combined loss of DnaK and TF causes proteostasis collapse with disruption of GroEL function, defective ribosomal biogenesis, and extensive aggregation of large proteins. http://www.cell.com/cell-reports/abstract/S2211-1247(11)00017-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124711000179%3Fshowall%3Dtrue Dionisio

The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner doi: 10.1074/jbc.M113.532333 The cancer-associated, centrosomal adaptor protein TACC3 (transforming acidic coiled-coil 3) and its direct effector, the microtubule polymerase chTOG (colonic and hepatic tumor overexpressed gene), play a crucial function in centrosome-driven mitotic spindle assembly. It is unclear how TACC3 interacts with chTOG. Here, we show that the C-terminal TACC domain of TACC3 and a C-terminal fragment adjacent to the TOG domains of chTOG mediate the interaction between these two proteins. Interestingly, the TACC domain consists of two functionally distinct subdomains, CC1 (amino acids (aa) 414–530) and CC2 (aa 530–630). Whereas CC1 is responsible for the interaction with chTOG, CC2 performs an intradomain interaction with the central repeat region of TACC3, thereby masking the TACC domain before effector binding. Contrary to previous findings, our data clearly demonstrate that Aurora-A kinase does not regulate TACC3-chTOG complex formation, indicating that Aurora-A solely functions as a recruitment factor for the TACC3-chTOG complex to centrosomes and proximal mitotic spindles. We identified with CC1 and CC2, two functionally diverse modules within the TACC domain of TACC3 that modulate and mediate, respectively, TACC3 interaction with chTOG required for spindle assembly and microtubule dynamics during mitotic cell division. http://www.jbc.org/content/289/1/74.abstract Dionisio

Csi1p recruits alp7p/TACC to the spindle pole bodies for bipolar spindle formation doi: 10.1091/mbc.E14-03-0786 Accurate chromosome segregation requires timely bipolar spindle formation during mitosis. The transforming acidic coiled-coil (TACC) family proteins and the ch-TOG family proteins are key players in bipolar spindle formation. They form a complex to stabilize spindle microtubules, mainly dependent on their localization to the centrosome (the spindle pole body [SPB] in yeast). The molecular mechanism underlying the targeting of the TACC–ch-TOG complex to the centrosome remains unclear. Here we show that the fission yeast Schizosaccharomyces pombe TACC orthologue alp7p is recruited to the SPB by csi1p. The csi1p-interacting region lies within the conserved TACC domain of alp7p, and the carboxyl-terminal domain of csi1p is responsible for interacting with alp7p. Compromised interaction between csi1p and alp7p impairs the localization of alp7p to the SPB during mitosis, thus delaying bipolar spindle formation and leading to anaphase B lagging chromosomes. Hence our study establishes that csi1p serves as a linking molecule tethering spindle-stabilizing factors to the SPB for promoting bipolar spindle assembly. http://www.molbiolcell.org/content/25/18/2750.abstract Dionisio

TACC3 Protein Regulates Microtubule Nucleation by Affecting ?-Tubulin Ring Complexes doi: 10.1074/jbc.M114.575100 Centrosome-mediated microtubule nucleation is essential for spindle assembly during mitosis. Although ?-tubulin complexes have primarily been implicated in the nucleation process, details of the underlying mechanisms remain poorly understood. Here, we demonstrated that a member of the human transforming acidic coiled-coil (TACC) protein family, TACC3, plays a critical role in microtubule nucleation at the centrosome. In mitotic cells, TACC3 knockdown substantially affected the assembly of microtubules in the astral region and impaired microtubule nucleation at the centrosomes. The TACC3 depletion-induced mitotic phenotype was rescued by expression of the TACC3 C terminus predominantly consisting of the TACC domain, suggesting that the TACC domain plays an important role in microtubule assembly. Consistently, experiments with the recombinant TACC domain of TACC3 demonstrated that this domain possesses intrinsic microtubule nucleating activity. Co-immunoprecipitation and sedimentation experiments revealed that TACC3 mediates interactions with proteins of both the ?-tubulin ring complex (?-TuRC) and the ?-tubulin small complex (?-TuSC). Interestingly, TACC3 depletion resulted in reduced levels of ?-TuRC and increased levels of ?-TuSC, indicating that the assembly of ?-TuRC from ?-TuSC requires TACC3. Detailed analyses suggested that TACC3 facilitates the association of ?-TuSC-specific proteins with the proteins known to be involved in the assembly of ?-TuRC. Consistent with such a role for TACC3, the suppression of TACC3 disrupted localization of ?-TuRC proteins to the centrosome. Our findings reveal that TACC3 is involved in the regulation of microtubule nucleation at the centrosome and functions in the stabilization of the ?-tubulin ring complex assembly. http://www.jbc.org/content/289/46/31719.abstract Dionisio

Coordination of adjacent domains mediates TACC3–ch-TOG–clathrin assembly and mitotic spindle binding doi: 10.1083/jcb.201211127 A complex of transforming acidic coiled-coil protein 3 (TACC3), colonic and hepatic tumor overexpressed gene (ch-TOG), and clathrin has been implicated in mitotic spindle assembly and in the stabilization of kinetochore fibers by cross-linking microtubules. It is unclear how this complex binds microtubules and how the proteins in the complex interact with one another. TACC3 and clathrin have each been proposed to be the spindle recruitment factor. We have mapped the interactions within the complex and show that TACC3 and clathrin were interdependent for spindle recruitment, having to interact in order for either to be recruited to the spindle. The N-terminal domain of clathrin and the TACC domain of TACC3 in tandem made a microtubule interaction surface, coordinated by TACC3–clathrin binding. A dileucine motif and Aurora A–phosphorylated serine 558 on TACC3 bound to the “ankle” of clathrin. The other interaction within the complex involved a stutter in the TACC3 coiled-coil and a proposed novel sixth TOG domain in ch-TOG, which was required for microtubule localization of ch-TOG but not TACC3–clathrin. http://jcb.rupress.org/content/202/3/463 Dionisio

An RNAi screen identifies KIF15 as a novel regulator of the endocytic trafficking of interim doi: 10.1242/?jcs.137281 Currently, very little is known about the mechanism that regulates the cell-surface expression and trafficking of ?2?1 integrin. http://jcs.biologists.org/content/127/11/2433.abstract Dionisio

Multifunctional low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) recognizes and internalizes a large number of diverse ligands, including LDL and factor VIII. However, little is known about the regulation of LRP1 endocytosis. http://jcb.rupress.org/content/204/3/395 Dionisio

Junctionally restricted RhoA activity is necessary for apical constriction during phase 2 inner ear placode invalidation doi:10.1016/j.ydbio.2014.08.022 After induction, the inner ear is transformed from a superficially located otic placode into an epithelial vesicle embedded in the mesenchyme of the head. Invagination of this epithelium is biphasic: phase 1 involves the expansion of the basal aspect of the otic cells, and phase 2, the constriction of their apices. Apical constriction is important not only for otic invagination, but also the invagination of many other epithelia; however, its molecular basis is still poorly understood. Here we show that phase 2 otic morphogenesis, like phase 1 morphogenesis, results from the activation of myosin-II. However unlike the actin depolymerising activity observed basally, active myosin-II results in actomyosin contractility. Myosin-II activation is triggered by the accumulation of the planar cell polarity (PCP) core protein, Celsr1 in apical junctions (AJ). Apically polarized Celsr1 orients and recruits the Rho Guanine exchange factor (GEF) ArhGEF11 to apical junctions, thus restricting RhoA activity to the junctional membrane where it activates the Rho kinase ROCK. We suggest that myosin-II and RhoA activation results in actomyosin dependent constriction in an apically polarised manner driving otic epithelium invagination. http://www.sciencedirect.com/science/article/pii/S0012160614004138 Dionisio

Phenotype–Genotype Integrator (PheGenI): synthesizing genome-wide association study (GWAS) data with existing genomic resources doi:10.1038/ejhg.2013.96 Rapidly accumulating data from genome-wide association studies (GWASs) and other large-scale studies are most useful when synthesized with existing databases. To address this opportunity, we developed the Phenotype–Genotype Integrator (PheGenI), a user-friendly web interface that integrates various National Center for Biotechnology Information (NCBI) genomic databases with association data from the National Human Genome Research Institute GWAS Catalog and supports downloads of search results. Here, we describe the rationale for and development of this resource. Integrating over 66?000 association records with extensive single nucleotide polymorphism (SNP), gene, and expression quantitative trait loci data already available from the NCBI, PheGenI enables deeper investigation and interrogation of SNPs associated with a wide range of traits, facilitating the examination of the relationships between genetic variation and human diseases. http://www.nature.com/ejhg/journal/v22/n1/full/ejhg201396a.html Dionisio

large-scale genotype–phenotype association analyses doi: 10.1093/bib/bbt061 Modern molecular biotechnology generates a great deal of intermediate information, such as transcriptional and metabolic products in bridging DNA and complex traits. In genome-wide linkage analysis and genome-wide association study, regression analysis for large-scale correlated phenotypes is applied to map genes for those by-products that are regarded as quantitative traits. For a single trait, least absolute shrinkage and selection operator with coordinate descent step can be employed to efficiently shrink sparse non-zero genetic effects of quantitative trait loci (QTLs). However, regression analyses in a trait-by-trait basis do not take account of the correlations among the analyzed traits. In this study, conditional phenotype of each trait is defined, given other traits. Large-scale genotype–phenotype association analyses are therefore transformed to separate genotype-conditional phenotype ones. Meanwhile, the correlation architecture between each trait and other traits can also be provided by shrinkage estimation for each conditional phenotype. Simulation demonstrates that the proposed conditional mapping method is generally identical to joint mapping method based on multivariate analysis in terms of statistical detection power and parameter estimation. Application of the method is provided to locate eQTL in yeast. http://intl-bib.oxfordjournals.org/content/15/5/814 Dionisio

Genotype–Phenotype Correlation — Promiscuity in the Era of Next-Generation Sequencing DOI: 10.1056/NEJMp1400788 Newly cost-effective next-generation sequencing has led to an explosion of discoveries of novel genetic mutations that reveal the rampant “promiscuity” of genotype–phenotype relationships. Such discoveries should ultimately revolutionize clinical care. http://www.nejm.org/doi/full/10.1056/NEJMp1400788 Dionisio

RNAi Synthetic Logic Circuits for Sensing, Information Processing, and Actuation DOI: 10.1002/3527600906.mcb.20130003 Noncoding small RNAs regulate gene expression through complex RNA interference (RNAi) signaling networks. The elucidation of molecular mechanisms underlying RNAi and the discovery of commonly occurring transcriptional and post-transcriptional motifs have enabled the construction of RNAi-based sensors and devices used for engineering genetic modules and logic circuits that offer sophisticated control of biological systems. In this chapter, recent progress in the design and implementation of RNAi-based logic circuits for the sensing and processing of multiple molecular signals to generate programmed biological actuation is discussed. http://onlinelibrary.wiley.com/doi/10.1002/3527600906.mcb.20130003/abstract Dionisio

Machine Learning in Computational Biology (MLCB) 2014 @ Montreal The field of computational biology has seen dramatic growth over the past few years, in terms of new available data, new scientific questions, and new challenges for learning and inference. In particular, biological data are often relationally structured and highly diverse, well-suited to approaches that combine multiple weak evidence from heterogeneous sources. These data may include sequenced genomes of a variety of organisms, gene expression data from multiple technologies, protein expression data, protein sequence and 3D structural data, protein interactions, gene ontology and pathway databases, genetic variation data (such as SNPs), cell images, and an enormous amount of textual data in the biological and medical literature. New types of scientific and clinical problems require the development of novel supervised and unsupervised learning methods that can use these growing resources. Furthermore, next generation sequencing technologies are yielding terabyte scale data sets that require novel algorithmic solutions. The goal of this workshop is to present emerging problems and machine learning techniques in computational biology. We invite contributed talks on novel learning approaches in computational biology. We encourage contributions describing either progress on new bioinformatics problems or work on established problems using methods that are substantially different from standard approaches. Kernel methods, graphical models, feature selection, and other techniques applied to relevant bioinformatics problems would all be appropriate for the workshop. The targeted audience are people with interest in learning and applications to relevant problems from the life sciences. http://mlcb.org/ Dionisio

Multiple haplotype-resolved genomes reveal population patterns of gene and protein diplotypes doi:10.1038/ncomms6569 To fully understand human biology and link genotype to phenotype, the phase of DNA variants must be known. Here we present a comprehensive analysis of haplotype-resolved genomes to assess the nature and variation of haplotypes and their pairs, diplotypes, in European population samples. We use a set of 14 haplotype-resolved genomes generated by fosmid clone-based sequencing, complemented and expanded by up to 372 statistically resolved genomes from the 1000 Genomes Project. We find immense diversity of both haploid and diploid gene forms, up to 4.1 and 3.9 million corresponding to 249 and 235 per gene on average. Less than 15% of autosomal genes have a predominant form. We describe a ‘common diplotypic proteome’, a set of 4,269 genes encoding two different proteins in over 30% of genomes. We show moreover an abundance of cis configurations of mutations in the 386 genomes with an average cis/trans ratio of 60:40, and distinguishable classes of cis- versus trans-abundant genes. The diplotypic nature of the human genome and its potential functional implications have [...] barely been addressed. This work identifies key features characterizing the diplotypic nature of human genomes and provides a conceptual and analytical framework, rich resources and novel hypotheses on the functional importance of diploidy. http://www.nature.com/ncomms/2014/141126/ncomms6569/full/ncomms6569.html Dionisio

Cell Fate: Journeys to Specialization https://www.youtube.com/embed/Qd4ysCpoOVg?rel=0 Dionisio

Autonomous Cell Fate Specification DOI: 10.1002/9780470015902.a0001148.pub3 Autonomous cell fate specification is a form of embryonic specification in which a developing cell is able to differentiate (become a cell carrying out a specialised function) without receiving external signals. This property is enabled by cytoplasmic determinants (cytoplasmic regulatory factors necessary for specification) that are deposited in different regions of the ovum during oogenesis. These cytoplasmic determinants are partitioned into individual cells during embryonic cleavage, and thus endow these cells with the ability to form specific cell types. If an autonomously specified cell is removed from the embryo during early development and cultured in isolation, that cell will produce the descendants that it would have normally produced in the undisturbed embryo. Frequently, the embryo from which the cell was removed lacks the structures normally made by the missing cell. Autonomous cell fate specification is often used during patterning of invertebrate embryos such as ctenophores, annelids, molluscs, echinoderms and tunicates. http://www.els.net/WileyCDA/ElsArticle/refId-a0001148.html Dionisio

The function of chromatin modifiers in lineage commitment and cell fate specification DOI: 10.1111/febs.13132 Proteins that modify the structure of chromatin are known to be important for various aspects of metazoan biology including development, disease and possibly ageing. Yet functional details of why these proteins are important, i.e. how their action influences a given biological process, are lacking. While it is now possible to describe the biochemistry of how these proteins remodel chromatin, their chromatin binding profiles in cell lines, or gene expression changes upon loss of a given protein, in very few cases has this easily translated into an understanding of how the function of that protein actually influences a developmental process. Given that many chromatin modifying proteins will largely exert their influence through control of gene expression, it is useful to consider developmental processes as changes in the gene regulatory network (GRN), with each cell type exhibiting a unique gene expression profile. In this essay we consider the impact of two abundant and highly conserved chromatin modifying complexes, namely the nucleosome remodelling and deacetylation (NuRD) complex and the polycomb repressive complex 2 (PRC2), on the change in GRNs associated with lineage commitment during early mammalian development. We propose that while the NuRD complex limits the stability of cell states and defines the developmental trajectory between two stable states, PRC2 activity is important for stabilizing a new GRN once established. Although these two complexes display different biochemical activities, chromatin binding profiles and mutant phenotypes, we propose a model to explain how they cooperate to facilitate the transition through cell states that is development. http://onlinelibrary.wiley.com/doi/10.1111/febs.13132/abstract Dionisio

Tension on the linker gates the ?ATP-dependent release of ?dynein from microtubules doi:10.1038/ncomms5587 Cytoplasmic ?dynein is a dimeric motor that transports intracellular cargoes towards the minus end of microtubules (MTs). In contrast to other processive motors, stepping of the ?dynein motor domains (heads) is not precisely coordinated. Therefore, the mechanism of ?dynein processivity remains unclear. Here, by engineering the mechanical and catalytic properties of the motor, we show that ?dynein processivity minimally requires a single active head and a second inert MT-binding domain. Processivity arises from a high ratio of MT-bound to unbound time, and not from interhead communication. In addition, nucleotide-dependent microtubule release is gated by tension on the linker domain. Intramolecular tension sensing is observed in ?dynein’s stepping motion at high interhead separations. On the basis of these results, we propose a quantitative model for the stepping characteristics of ?dynein and its response to chemical and mechanical perturbation. http://www.nature.com/ncomms/2014/140811/ncomms5587/full/ncomms5587.html Dionisio

Autoregulatory mechanism for dynactin control of processive and diffusive dynein transport doi:10.1038/ncb3063 Dynactin is the longest known cytoplasmic dynein regulator, with roles in dynein recruitment to subcellular cargo and in stimulating processive dynein movement. The latter function was thought to involve the N-terminal microtubule-binding region of the major dynactin polypeptide ?p150Glued, although recent results disputed this. To understand how dynactin regulates dynein we generated recombinant fragments of the N-terminal half of ?p150Glued. We find that the dynein-binding coiled-coil ?-helical domain CC1B is sufficient to stimulate dynein processivity, which it accomplishes by increasing average dynein step size and forward-step frequency, while decreasing lateral stepping and microtubule detachment. In contrast, the immediate upstream coiled-coil domain, CC1A, activates a surprising diffusive dynein state. CC1A interacts physically with CC1B and interferes with its effect on dynein processivity. We also identify a role for the N-terminal portion of ?p150Glued in coordinating these activities. Our results reveal an unexpected form of long-range allosteric control of dynein motor function by internal ?p150Glued sequences, and evidence for ?p150Glued autoregulation. http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3063.html The latter function was thought to involve [...] although recent results disputed this. Our results reveal an unexpected [...] Why 'unexpected'? What else did they expect? Why? Dionisio

gpuccio

let’s remind that the heavy chains of dynein are more than 4000 AAs long.

Oh, that's quite a long chain, isn't it? :) Thank you for such a good and timely reminder. BTW, I've enjoyed reading your very insightful comments in your latest thread. Also, I've learned a few things from what you've written there. That thread has provoked long discussions that have produced a large number of posts, as usually occurs with your interesting OPs. Again, you have taught me a lesson on patience while explaining complex concepts to your difficult interlocutors. :) Thank you. Dionisio

Dionisio: Thank you, as always, for the good work. Just in passing, let's remind that the heavy chains of dynein are more than 4000 AAs long. :) gpuccio

Cytoplasmic dynein transports cargos via load-sharing between the heads http://www.nature.com/ncomms/2014/141126/ncomms6544/full/ncomms6544.html Cytoplasmic dynein is a motor protein that walks along microtubules (MTs) and performs mechanical work to power a variety of cellular processes. It remains unclear how a dynein dimer is able to transport cargos against load without coordinating the stepping cycles of its two heads. Here by using a DNA-tethered optical trapping geometry, we find that the force-generating step of a head occurs in the MT-bound state, while the ‘primed’ unbound state is highly diffusional and only weakly biased to step towards the MT-minus end. The stall forces of the individual heads are additive, with both heads contributing equally to the maximal force production of the dimer. On the basis of these results, we propose that the heads of dynein utilize a ‘load-sharing’ mechanism, unlike kinesin and myosin. This mechanism may allow dynein to work against hindering forces larger than the maximal force produced by a single head. http://www.nature.com/ncomms/2014/141126/ncomms6544/full/ncomms6544.html Dionisio

Quantum Stickiness of Molecules Not Quite as Expected? http://www.genengnews.com/gen-news-highlights/quantum-stickiness-of-molecules-not-quite-as-expected/81250647/ Dionisio

Mechanotransduction channels? Maybe there's hope for you, after all. I found that a cheap (or free by scrounging parts) way to make electric hairs/whiskers is: using scissors cut a metal piezo speaker diaphragm into thin wedges, carefully solder fine wire to each side, attach base of piezo wedge to insulated support that has a (can be lighted) plastic fiber optic inner conductor as a whisker also attached to it, to connect the sharp tip of the wedge to without shorting out the two sides of the piezo transducer. Vibration of the whisker is transmitted to the transducer tip producing an AC wave, which can be amplified by a transistor or op amp to a DC signal to power an LED and/or connect to any addressing pin of a RAM chip (with separate address and data bus pins). Gary S. Gaulin

New Piece of a Mysterious Channel Researchers have nailed down yet another component of the mechanotransduction complex responsible for relaying signals from hair cells in the ear. http://www.the-scientist.com//?articles.view/articleNo/41527/title/New-Piece-of-a-Mysterious-Channel/ TMIE Is an Essential Component of the Mechanotransduction Machinery of Cochlear Hair Cells DOI: http://dx.doi.org/10.1016/j.neuron.2014.10.041 Hair cells are the mechanosensory cells of the inner ear. Mechanotransduction channels in hair cells are gated by tip links. The molecules that connect tip links to transduction channels are not known. Here we show that the transmembrane protein TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell’s mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea’s tonotopic axis. http://www.cell.com/neuron/abstract/S0896-6273(14)00961-1 Dionisio

Peer Review Manipulation? BioMed Central says about 50 manuscripts in its systems may have been erroneously considered or accepted as a result of foul play. http://www.the-scientist.com//?articles.view/articleNo/41534/title/Peer-Review-Manipulation-/ Retraction Watch Tracking retractions as a window into the scientific process Publisher discovers 50 manuscripts involving fake peer reviewers http://retractionwatch.com/2014/11/25/publisher-discovers-50-papers-accepted-based-on-fake-peer-reviews/ Dionisio

#694 follow-up The results of this research, as in many other cases in the examples posted in this thread, show how many things could go wrong in the biological processes. That makes it more amazing that so many things could go wrong but many times we don't end as messed up as it would be expected, despite the hostile conditions our bodies are exposed to in our daily careless lifestyles. Definitely much stuff to investigate and learn from. :) Dionisio

NR5A1 prevents centriole splitting by inhibiting centrosomal DNA-PK activation and beta-catenin accumulation doi:10.1186/s12964-014-0055-9 Adrenogonadal cell growth and differentiation are controlled by nuclear receptor NR5A1 (Ad4BP/SF-1) that regulates the expression of adrenal and gonadal genes. In addition, SF-1 also resides in the centrosome and controls centrosome homeostasis by restricting the activity of centrosomal DNA-PK and CDK2/cyclin A. Here we show that SF-1 depletion resulted in centriole splitting and amplification due to aberrant activation of DNA-PK in the centrosome of mouse adrenocortical Y1 cells. In the absence of SF-1, GSK3? was aberrantly phosphorylated during G1 phase and ?-catenin was accumulated in the centrosome, but not in the nucleus. DNA-PK inhibitor vanillin reversed these phenomena. SF-1 overexpression led to inhibition of centrosomal DNA-PK activation caused by SF-1 depletion. Both full-length SF-1 and truncated SF-1 devoid of its DNA-binding domain rescued the multiple centrosome phenotype caused by SF-1 depletion, indicating that the effect of SF-1 in the centrosome is not contributed by its DNA-binding domain. Furthermore, SF-1 interacted with cyclin A in the centrosome, but not in the nucleus. Depletion of SF-1 also resulted in centriole splitting, genomic instability and reduced growth of mouse testicular Leydig MA10 cells. Centrosomal DNA-PK signaling triggers the accumulation of ?-catenin, leading to centrosome over-duplication and centriole splitting. This cascade of centrosomal events results in genomic instability and reduced cell numbers. http://www.biosignaling.com/content/12/1/55/abstract Dionisio

#690 error correction The following references were incorrect:

G: 733 G: 734 G: 735 G: 736

Here are the correct references:

D: 733 D: 734 D: 735 D: 736

Sorry for my mistake. BTW, by the time I noticed the error, the editing timer still had 8 minutes left, but said the editing time had elapsed. (?) Dionisio

690 addendum The onlookers/lurkers may read the referenced posts in the indicated sequence and arrive at their own conclusions. :) Dionisio

Here's my short summary: https://uncommondescent.com/intelligent-design/an-attempt-at-computing-dfsci-for-english-language/#comment-532354 Gary S. Gaulin

FTR: here's a summary of my (D) brief discussion with Gary S. Gaulin (GSG) in another thread moderated by gpuccio (G): https://uncommondescent.com/intelligent-design/an-attempt-at-computing-dfsci-for-english-language/#comment-530373 D: 648 GSG: 668 D: 690 D: 693 G: 706 GSG: 732 G: 733 G: 734 G: 735 G: 736 GSG: 737 D: 738 D: 739 GSG: 740 GSG: 741 D: 742 D: 743 FMM: 744 D: 749 GSG: 772 D: 775 GSG: 776 D: 778 D: 783 D: 785 Then GSG decided to move the discussion to this 'third way' thread: GSG: 686 D: 687 GSG: 688 GSG: 689 Note: FMM stands for fifthmonarchyman who volunteered his comments on the discussion. Dionisio

Dionisio:

Are you upset? Why? Did I ask you inconvenient questions?

For the sake of science (and myself) I'm not going to play your games. You should by now know what is scientifically required for you to be considered a credible judge of theory pertaining to things that are "intelligent". Only thing you accomplished was to show how you dismissed yourself from needing to know what you're talking about by making yourself look smart by quoting a pile of science papers. Gary S. Gaulin

News:

Sounds interesting.

But be careful. The word "evolution" is operationally defined by Darwinian theory, therefore in the best case scenario the only thing you get is another Darwinian theory added to the (way more than 3) clutter of Darwinian variations that already exist. That happening is a reason Biblical creationists gave up on ID. They saw it as a siding with the devil, instead of speaking up for Genesis and explaining our Adam and Eve moment, trinity, how we could be in our creators image/likeness and other (Genesis related but still science) detail. As science sees it a theory that qualifies as a "A third way of evolution" cannot be ID. To be scientifically in spirit with the premise of ID the phenomenon to explain is "intelligent cause" (that first requires the word "intelligent" to be operationally defined by a simple as possible model to experiment with) and nothing else. I know that in everyday conversation the word "evolution" is a common generalization, but when wording a scientific theory using the word once requires operationally defining a generalization that then needs the "evo-devo" generalization to make it to the word "development" that ID explains without generalizing. It's important to be specific as to which level of development is being discussed by saying something like "development of human molecular intelligence (which was estimated to have in all taken some 4 billion years)" or "development of human multicellular intelligence (a brain made of neural components not molecular components)". Being as precise as science requires elimination of "evo" generalizations. They only lead to evermore confusion that is best left to the Darwinian camp to on their own deal with, be muddled by. In at least my case I expect discussion of biological "development" only. Talking about "evolution" changes the subject to a concept that is left up to the imagination of the critics. Before long the buzz-words make it seem like even what was discovered under modern microscopes (as human technology improved) was all made possible thanks to Darwinian theory. Gary S. Gaulin

#686 Gary S. Gaulin

I showed you what I have. It’s now you’re turn to show everyone what YOU have for a minimal code (Occam’s razor) model that is required for you to be taken seriously, in real-science.

When you wrote "you're turn" did you mean "your turn"? Is English your first language? My first language is Spanish. I try to learn English grammar and vocabulary when reading books, journals, online commentaries, etc. Still have a long way to go before I can claim that I know this language well enough to communicate correctly. I thought the expression "you're" was equivalent to "you are" or "you were" depending on the context. Did you notice they have here in UD a new editing feature that can be used up to 20 minutes after posting your comments? BTW, I don't have any minimal code model to show to anyone. I'm studying biology. That's all buddy. Are you upset? Why? Did I ask you inconvenient questions? Please, take it easy. You don't have to answer my questions, specially if you're so busy and/or don't know how to answer my questions. I write also for the onlookers/lurkers out there who visit this blog. :) As far as I'm concerned, our discussion is over. I appreciate the time you took to explain your ideas. I wish the best to you. :) Dionisio

Dionisio, the "theory of intelligent design" requires explaining how "intelligence" and "intelligent cause" works:

The theory of intelligent design holds that certain features of the universe and of living things are best explained by an intelligent cause, not an undirected process such as natural selection.

The only thing you posted are dozens of moving goalposts, and I have better things to do than tire myself out chasing red-herrings. I showed you what I have. It's now you're turn to show everyone what YOU have for a minimal code (Occam's razor) model that is required for you to be taken seriously, in real-science. Gary S. Gaulin

Engineering Cell Fate and Function http://www.keystonesymposia.org/14Z3 Dionisio

Cell Fate Transition in Mammalian Embryonic Stem Cells DOI: http://dx.doi.org/10.1016/j.stem.2014.09.019 N6-methyl-adenosine (m6A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m6A by mapping the m6A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. m6A is enriched over 3? untranslated regions at defined sequence motifs and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m6A methylases, led to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC exit from self-renewal toward differentiation into several lineages in vitro and in vivo. Thus, m6A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages. http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00451-2 Dionisio

execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation doi: 10.1101/gad.247163.114 Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell self-renewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a?/? mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision. http://genesdev.cshlp.org/content/28/20/2219.short?rss=1 Dionisio

Glucose uptake in brown fat cells is dependent on mTOR complex 2–promoted GLUT1 translocation doi: 10.1083/jcb.201403080 Brown adipose tissue is the primary site for thermogenesis and can consume, in addition to free fatty acids, a very high amount of glucose from the blood, which can both acutely and chronically affect glucose homeostasis. Here, we show that mechanistic target of rapamycin (mTOR) complex 2 has a novel role in ?3-adrenoceptor–stimulated glucose uptake in brown adipose tissue. We show that ?3-adrenoceptors stimulate glucose uptake in brown adipose tissue via a signaling pathway that is comprised of two different parts: one part dependent on cAMP-mediated increases in GLUT1 transcription and de novo synthesis of GLUT1 and another part dependent on mTOR complex 2–stimulated translocation of newly synthesized GLUT1 to the plasma membrane, leading to increased glucose uptake. Both parts are essential for ?3-adrenoceptor–stimulated glucose uptake. Importantly, the effect of ?3-adrenoceptor on mTOR complex 2 is independent of the classical insulin–phosphoinositide 3-kinase–Akt pathway, highlighting a novel mechanism of mTOR complex 2 activation. http://jcb.rupress.org/content/207/3/365 Dionisio

Cell division and the maintenance of epithelial order doi: 10.1083/jcb.201408044 Epithelia are polarized layers of adherent cells that are the building blocks for organ and appendage structures throughout animals. To preserve tissue architecture and barrier function during both homeostasis and rapid growth, individual epithelial cells divide in a highly constrained manner. Building on decades of research focused on single cells, recent work is probing the mechanisms by which the dynamic process of mitosis is reconciled with the global maintenance of epithelial order during development. These studies reveal how symmetrically dividing cells both exploit and conform to tissue organization to orient their mitotic spindles during division and establish new adhesive junctions during cytokinesis. http://jcb.rupress.org/content/207/2/181.short?rss=1&ssource=mfr Dionisio

The cell biology of planar cell polarity doi: 10.1083/jcb.201408039 Planar cell polarity (PCP) refers to the coordinated alignment of cell polarity across the tissue plane. Key to the establishment of PCP is asymmetric partitioning of cortical PCP components and intercellular communication to coordinate polarity between neighboring cells. Recent progress has been made toward understanding how protein transport, endocytosis, and intercellular interactions contribute to asymmetric PCP protein localization. Additionally, the functions of gradients and mechanical forces as global cues that bias PCP orientation are beginning to be elucidated. Together, these findings are shedding light on how global cues integrate with local cell interactions to organize cellular polarity at the tissue level. http://jcb.rupress.org/content/207/2/171.short?rss=1&ssource=mfr Dionisio

A molecular chain gang at work in maturing ribosomes Study finds interconnected molecules that reorganize preribosomes. doi: 10.1083/jcb.2074if A motor protein on immature ribosomes connects to a network of other molecules within the nascent organelles, Baßler et al. reveal (1). The motor might help an assembling ribosome get into shape by tugging some of its components into position. A ribosome contains four types of rRNA and around eighty kinds of proteins, so piecing together a working molecular machine from these raw materials is a tricky task. Roughly two hundred different proteins collaborate to orchestrate ribosome assembly and maturation (2). Not only do they have to construct the two main ribosome components, the 60S and 40S subunits, but they have to shape features such as the peptidyl transferase center (PTC), where transfer RNAs hand off their amino acids to the growing peptide chain. The functions of many of these assembly and maturation factors remain a mystery. One protein that scientists have made some headway on is Rea1, a motor protein related to dynein. Rea1 sits on the immature 60S subunit, and researchers initially speculated that it might help move the partly completed ribosome out of the nucleus. Instead, they found that Rea1’s power stroke tugs another protein, Rsa4, out of the ribosome (3, 4). However, it wasn’t clear whether removing Rsa4 caused additional changes to the ribosome’s organization. http://jcb.rupress.org/content/207/4/481.abstract Dionisio

Wait! Don’t throw away those proteins! Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration doi: 10.1083/jcb.201406026 Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. However, the mechanisms by which synaptic proteins turn over remain elusive. In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. In fly sky mutants, synaptic vesicles traveled excessively to endosomes. Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average, suggesting that older proteins are more efficiently degraded. Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking, controlled by the homotypic fusion and vacuole protein sorting (HOPS) complex, rescued the neurotransmission and neurodegeneration defects in sky mutants. Consistently, synaptic vesicle proteins were older in HOPS complex mutants, and these mutants also showed reduced neurotransmission. Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans. http://jcb.rupress.org/content/207/4/453.abstract Dionisio

#676 follow-up

We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex. [really? how?]

Some folks out there might want to consider pursuing a very succe$$ful career as writers of fiction books. Those guys seem to possess quite a creative imagination. :) Dionisio

DNA replication and spindle checkpoints cooperate during S phase to delay mitosis and preserve genome integrity doi: 10.1083/jcb.201306023 Deoxyribonucleic acid (DNA) replication and chromosome segregation must occur in ordered sequence to maintain genome integrity during cell proliferation. Checkpoint mechanisms delay mitosis when DNA is damaged or upon replication stress, but little is known on the coupling of S and M phases in unperturbed conditions. To address this issue, we postponed replication onset in budding yeast so that DNA synthesis is still underway when cells should enter mitosis. This delayed mitotic entry and progression by transient activation of the S phase, G2/M, and spindle assembly checkpoints. Disabling both Mec1/ATR- and Mad2-dependent controls caused lethality in cells with deferred S phase, accompanied by Rad52 foci and chromosome missegregation. Thus, in contrast to acute replication stress that triggers a sustained Mec1/ATR response, multiple pathways cooperate to restrain mitosis transiently when replication forks progress unhindered. We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex. [really? how?] http://jcb.rupress.org/content/204/2/165 Dionisio

Damage control: cellular mechanisms of plasma membrane repair DOI: http://dx.doi.org/10.1016/j.tcb.2014.07.008 When wounded, eukaryotic cells reseal in a few seconds. Ca2+ influx induces exocytosis of lysosomes, a process previously thought to promote repair by ‘patching’ wounds. New evidence suggests that resealing involves direct wound removal. Exocytosis of lysosomal acid sphingomyelinase (ASM) triggers endocytosis of lesions followed by intracellular degradation. Characterization of injury-induced endosomes revealed a role for caveolae, sphingolipid-enriched plasma membrane invaginations that internalize toxin pores and are abundant in mechanically stressed cells. These findings provide a novel mechanistic explanation for the muscle pathology associated with mutations in caveolar proteins. Membrane remodeling by the ESCRT complex was also recently shown to participate in small-wound repair, emphasizing that cell resealing involves previously unrecognized mechanisms for lesion removal that are distinct from the patch model. Dionisio

Lysosome: regulator of lipid degradation pathways DOI: http://dx.doi.org/10.1016/j.tcb.2014.06.006 Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal–autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family. In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting. Dionisio

How chemistry supports cell biology: the chemical toolbox at your service DOI: http://dx.doi.org/10.1016/j.tcb.2014.07.002 Chemical biology is a young and rapidly developing scientific field. In this field, chemistry is inspired by biology to create various tools to monitor and modulate biochemical and cell biological processes. Chemical contributions such as small-molecule inhibitors and activity-based probes (ABPs) can provide new and unique insights into previously unexplored cellular processes. This review provides an overview of recent breakthroughs in chemical biology that are likely to have a significant impact on cell biology. We also discuss the application of several chemical tools in cell biology research. Dionisio

Mitochondria: from cell death executioners to regulators of cell differentiation DOI: http://dx.doi.org/10.1016/j.tcb.2014.08.005 Most, if not all mitochondrial functions, including adenosine-5?-triphosphate (ATP) production and regulation of apoptosis and Ca2+ homeostasis, are inextricably linked to mitochondrial morphology and dynamics, a process controlled by a family of GTP-dependent dynamin related ‘mitochondria-shaping’ proteins. Mitochondrial fusion and fission directly influence mitochondrial metabolism, apoptotic and necrotic cell death, autophagy, muscular atrophy and cell migration. In this review, we discuss the recent evidence indicating that mitochondrial dynamics influence complex signaling pathways, affect gene expression and define cell differentiation. These findings extend the importance of mitochondria to developmental biology, far beyond their mere bioenergetic role. Dionisio

RanBP1 Governs Spindle Assembly by Defining Mitotic Ran-GTP Production DOI: http://dx.doi.org/10.1016/j.devcel.2014.10.014 Accurate control of the Ras-related nuclear protein (Ran) GTPase cycle depends on the regulated activity of regulator of chromosome condensation 1 (RCC1), Ran’s nucleotide exchange factor. RanBP1 has been characterized as a coactivator of the Ran GTPase-activating protein RanGAP1. RanBP1 can also form a stable complex with Ran and RCC1, although the dynamics and function of this complex remain poorly understood. Here, we show that formation of the heterotrimeric RCC1/Ran/RanBP1 complex in M phase Xenopus egg extracts controls both RCC1’s enzymatic activity and partitioning between the chromatin-bound and soluble pools of RCC1. This mechanism is critical for spatial control of Ran-guanosine triphosphate (GTP) gradients that guide mitotic spindle assembly. Moreover, phosphorylation of RanBP1 drives changes in the dynamics of chromatin-bound RCC1 pools at the metaphase-anaphase transition. Our findings reveal an important mitotic role for RanBP1, controlling the spatial distribution and magnitude of mitotic Ran-GTP production and thereby ensuring accurate execution of Ran-dependent mitotic events. Dionisio

Arrested Detachment: A DEPDC1B-Mediated De-adhesion Mitotic Checkpoint DOI: http://dx.doi.org/10.1016/j.devcel.2014.11.008 Mitotic cell rounding is accompanied by changes in the actin cytoskeleton, de-adhesion, and an increase in cortical rigidity. In this issue, Marchesi et al. (2014) describe an adhesion-dependent mitotic checkpoint and identify DEPDC1B as the factor responsible for coordinating de-adhesion with the ability of cells to enter mitosis. Dionisio

Calcium-Dependent Neuroepithelial Contractions Expel Damaged Cells from the Developing Brain DOI: http://dx.doi.org/10.1016/j.devcel.2014.10.012 Both developing and adult organisms need efficient strategies for wound repair. In adult mammals, wounding triggers an inflammatory response that can exacerbate tissue injury and lead to scarring. In contrast, embryonic wounds heal quickly and with minimal inflammation, but how this is achieved remains incompletely understood. Using in vivo imaging in the developing brain of Xenopus laevis, we show that ATP release from damaged cells and subsequent activation of purinergic receptors induce long-range calcium waves in neural progenitor cells. Cytoskeletal reorganization and activation of the actomyosin contractile machinery in a Rho kinase-dependent manner then lead to rapid and pronounced apical-basal contractions of the neuroepithelium. These contractions drive the expulsion of damaged cells into the brain ventricle within seconds. Successful cell expulsion prevents the death of nearby cells and an exacerbation of the injury. Cell expulsion through neuroepithelial contraction represents a mechanism for rapid wound healing in the developing brain. Dionisio

Theoretical Analysis of Microtubule Dynamics at All Times DOI: 10.1021/jp507206f Microtubules are biopolymers consisting of tubulin dimer subunits. As a major component of cytoskeleton they are essential for supporting most important cellular processes such as cell division, signaling, intracellular transport and cell locomotion. The hydrolysis of guanosine triphosphate (GTP) molecules attached to each tubulin subunit supports the nonequilibrium nature of microtubule dynamics. One of the most spectacular properties of microtubules is their dynamic instability when their growth from continuous attachment of tubulin dimers stochastically alternates with periods of shrinking. Despite the critical importance of this process to all cellular activities, its mechanism remains not fully understood. We investigated theoretically microtubule dynamics at all times by analyzing explicitly temporal evolution of various length clusters of unhydrolyzed subunits. It is found that the dynamic behavior of microtubules depends strongly on initial conditions. Our theoretical findings provide a microscopic explanation for recent experiments which found that the frequency of catastrophes increases with the lifetime of microtubules. It is argued that most growing microtubule configurations cannot transit in one step into a shrinking state, leading to a complex overall temporal behavior. Theoretical calculations combined with Monte Carlo computer simulations are also directly compared with experimental observations, and good agreement is found. http://pubs.acs.org/doi/abs/10.1021/jp507206f Dionisio

Cell Cycle In Development “ This Book Focuses On The Intersection Between Cell Cycle Regulation And Embryo Development. Specific Modifications Of The Canonical Cell Cycle Occur Throughout The Whole Period Of Development And Are Adapted To Fulfil Functions Coded By The Developmental Program. Deciphering These Adaptations Is Essential To Comprehending How Living Organisms Develop. The Aim Of This Book Is To Review The Best-known Modifications And Adaptations Of The Cell Cycle During Development. The First Chapters Cover The General Problems Of How The Cell Cycle Evolves, While Consecutive Chapters Guide Readers Through The Plethora Of Such Phenomena. The Book Closes With A Description Of Specific Changes In The Cell Cycle Of Neurons In The Senescent Human Brain. Taken Together, The Chapters Present A Panorama Of Species - From Worms To Humans - And Of Developmental Stages - From Unfertilized Oocyte To Aged Adult. ” http://ebookspdfs.org/download/ebooks/cell-cycle-in-development-pdf Dionisio

Cell Cycle Control: Mechanisms And Protocols A Collection Of New Reviews And Protocols From Leading Experts In Cell Cycle Regulation, Cell Cycle Control: Mechanisms And Protocols, Second Edition Presents A Comprehensive Guide To Recent Technical And Theoretical Advancements In The Field. Beginning With The Overviews Of Various Cell Cycle Regulations, This Title Presents The Most Current Protocols And State-of-the-art Techniques Used To Generate Latest Findings In Cell Cycle Regulation, Such As Protocols To Analyze Cell Cycle Events And Molecules. Written In The Successful Methods In Molecular Biology Series Format, Chapters Include Introductions To Their Respective Topics, Lists Of The Necessary Materials And Reagents, Step-by-step, Readily Reproducible Protocols, And Notes On Troubleshooting And Avoiding Known Pitfalls. Authoritative And Easily Accessible, Cell Cycle Control: Mechanisms And Protocols, Second Edition Will Be A Valuable Resource For A Wide Audience, Ranging From The Experienced Cell Cycle Researchers Looking For New Approaches To The Junior Graduate Students Giving Their First Steps In Cell Cycle Research. http://ebookspdfs.org/download/ebooks/cell-cycle-control-mechanisms-and-protocols-2nd-edition-pdf Dionisio

Extracellular matrix assembly: a multiscale deconstruction doi:10.1038/nrm3902 The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue. http://www.nature.com/nrm/journal/v15/n12/full/nrm3902.html Dionisio

Regulating chromosome segregation doi:10.1038/nrm3809 Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1). CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules. http://www.nature.com/nrm/journal/v15/n6/full/nrm3809.html Dionisio

control proper timing of centrosome separation Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B-type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A-mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers. doi: 10.1038/ncb2952 http://www.ncbi.nlm.nih.gov/pubmed/24776885 Dionisio

Timing Cell-Cycle Exit and Differentiation in Development DOI: 10.1002/0470846666.ch9 During animal development many cells permanently stop dividing and terminally differentiate. For the most part, the mechanisms that control when the cells exit the cell cycle and differentiate are not known. We have been studying the mechanisms in the oligodendrocyte cell lineage. Studies of oligodendrocyte precursor cells (OPCs) in culture suggest that each OPC has a built-in timing mechanism that helps determine when the cell stops dividing and differentiates. This intrinsic timer consists of at least two components – a timing component, which measures elapsed time, and an effector component, which stops cell division and initiates differentiation at the appropriate time. The timer seems to involve both transcriptional and post-transcriptional mechanisms, with some proteins progressively increasing and others progressively decreasing over time. http://onlinelibrary.wiley.com/doi/10.1002/0470846666.ch9/summary Dionisio

Control mechanisms of the cell cycle: role of the spatial arrangement of spindle components in the timing of mitotic events. [very old paper, but still interesting, though more is known now that it was unknown then. But many new unknown issues have appeared as result of the discoveries. As outstanding questions were answered, new questions popped up.] To characterize the control mechanisms for mitosis, we studied the relationship between the spatial organization of microtubules in the mitotic spindle and the timing of mitotic events. Spindles of altered geometry were produced in sea urchin eggs by two methods: (a) early prometaphase spindles were cut into half spindles by micromanipulation or (b) mercaptoethanol was used to indirectly induce the formation of spindles with only one pole. Cells with monopolar spindles produced by either method required an average of 3 X longer than control cells to traverse mitosis. By the time the control cells started their next mitosis, the experimental cells were usually just finishing the original mitosis. In all cases, only the time from nuclear envelope breakdown to the start of telophase was prolonged. Once the cells entered telophase, events leading to the next mitosis proceeded with normal timing. Once prolonged, the cell cycle never resynchronized with the controls. Several types of control experiments showed that were not an artifact of the experimental techniques. These results show that the spatial arrangement of spindle components plays an important role in the mechanisms that control the timing of mitotic events and the timing of the cell cycle as a whole. doi: 10.1083/jcb.97.3.877 http://jcb.rupress.org/content/97/3/877.abstract Dionisio

The cell biology of planar cell polarity doi: 10.1083/jcb.201408039 Planar cell polarity (PCP) refers to the coordinated alignment of cell polarity across the tissue plane. Key to the establishment of PCP is asymmetric partitioning of cortical PCP components and intercellular communication to coordinate polarity between neighboring cells. Recent progress has been made toward understanding how protein transport, endocytosis, and intercellular interactions contribute to asymmetric PCP protein localization. Additionally, the functions of gradients and mechanical forces as global cues that bias PCP orientation are beginning to be elucidated. Together, these findings are shedding light on how global cues integrate with local cell interactions to organize cellular polarity at the tissue level. http://jcb.rupress.org/content/207/2/171.short?rss=1&ssource=mfr Dionisio

mechanisms that regulate the timing and frequency of DNA duplication and cell division. Although we now know much about the regulation of the cell cycle, it is clear that we have a long way to go, particularly in understanding the complexity of the interactions between the vast multitude of proteins already identified. Current research has identified a large number of signaling pathways, many comprising several genes, involved in regulating progression through the cycle. http://www.nature.com/scitable/topic/cell-cycle-and-cell-division-14122649 Dionisio

Timing Mechanism Dependent on Cell Division Is Invoked by Polycomb Eviction in Plant Stem Cells DOI: 10.1126/science.1248559 Plant floral stem cells divide a limited number of times before they stop and terminally differentiate, but the mechanisms that control this timing remain unclear. The precise temporal induction of the Arabidopsis zinc finger repressor KNUCKLES (KNU) is essential for the coordinated growth and differentiation of floral stem cells. We identify an epigenetic mechanism in which the floral homeotic protein AGAMOUS (AG) induces KNU at ~2 days of delay. AG binding sites colocalize with a Polycomb response element in the KNU upstream region. AG binding to the KNU promoter causes the eviction of the Polycomb group proteins from the locus, leading to cell division–dependent induction. These analyses demonstrate that floral stem cells measure developmental timing by a division-dependent epigenetic timer triggered by Polycomb eviction. http://www.sciencemag.org/content/343/6170/1248559 Dionisio

Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration doi: 10.1073/pnas.1318848111 Regulation of adult stem cells (SCs) is fundamental for organ maintenance and tissue regeneration. On the body surface, different ectodermal organs exhibit distinctive modes of regeneration and the dynamics of their SC homeostasis remain to be unraveled. A slow cycling characteristic has been used to identify SCs in hair follicles and sweat glands; however, whether a quiescent population exists in continuously growing nails remains unknown. Using an in vivo label retaining cells (LRCs) system, we detected an unreported population of quiescent cells within the basal layer of the nail proximal fold, organized in a ring-like configuration around the nail root. These nail LRCs express the hair stem cell marker, keratin 15 (K15), and lineage tracing show that these K15-derived cells can contribute to both the nail structure and peri-nail epidermis, and more toward the latter. Thus, this stem cell population is bifunctional. Upon nail plucking injury, the homeostasis is tilted with these SCs dominantly delivering progeny to the nail matrix and differentiated nail plate, demonstrating their plasticity to adapt to wounding stimuli. Moreover, in vivo engraftment experiments established that transplanted nail LRCs can actively participate in functional nail regeneration. Transcriptional profiling of isolated nail LRCs revealed bone morphogenetic protein signaling favors nail differentiation over epidermal fate. Taken together, we have found a previously unidentified ring-configured population of bifunctional SCs, located at the interface between the nail appendage organ and adjacent epidermis, which physiologically display coordinated homeostatic dynamics but are capable of rediverting stem cell flow in response to injury. http://www.pnas.org/content/111/42/15114 Dionisio

At the right place at the right time: novel CENP-A binding proteins shed light on centromere assembly Centromeres, the chromosomal loci that form the sites of attachment for spindle microtubules during mitosis, are identified by a unique chromatin structure generated by nucleosomes containing the histone H3 variant CENP-A. The apparent epigenetic mode of centromere inheritance across mitotic and meiotic divisions has generated much interest in how CENP-A assembly occurs and how structurally divergent centromeric nucleosomes can specify the centromere complex. Although a substantial number of proteins have been implicated in centromere assembly, factors that can bind CENP-A specifically and deliver nascent protein to the centromere were, thus far, lacking. Several recent reports on experiments in fission yeast and human cells have now shown significant progress on this problem. Here, we discuss these new developments and their implications for epigenetic centromere inheritance. http://cat.inist.fr/?aModele=afficheN&cpsidt=21763608 Dionisio

sorting stations for proteins? The epithelium lines the organs of the human body. In the skin and the intestine as well as in the kidney, this cell layer forms a barrier that regulates the exchange of molecules like hormones and nutrients. mechanism by which proteins are transported to the outer membrane in epithelial cells. These cells are polarized: The cell membrane facing outwards, known as the apical membrane, contains different proteins than the basolateral membrane, which faces the interior of organs. It is not well understood how proteins are transported to the appropriate cell pole via tiny membrane containers - so-called vesicles. Cells of an epithelium resemble a shipping port: Substances are delivered, shipped, produced, and sent.. Insights into the organization of the "cellular shipping port" can help to treat diseases in which this transport is impaired. the path of a protein from its synthesis to its arrival at the apical cell membrane. mechanisms and signaling molecules responsible for sorting proteins and transporting them to the apical membrane. Cell membrane proteins are synthesized in the endoplasmic reticulum. They are then sent to the so-called Golgi apparatus and shipped from there to cell compartments or the cell membrane via small vesicles. proteins destined to the apical membrane are, after leaving the Golgi apparatus, also sorted at an additional compartment: the apical recycling endosomes (AREs). The protein Rab11 plays a key role in this process.. After leaving the AREs, the apical proteins are again packaged into vesicles and sent to the target membrane. The protein Rab11 is also involved in the final stage of their journey: The vesicles fuse with the outer membrane, allowing the proteins to reach the apical cell surface. http://phys.org/news/2014-03-imaging-substances-cells-reveals-stations.html#nRlv Dionisio

Cohesin molecule safeguards cell division The ring-shaped cohesin complex ensures that each round of cell division yields two daughter cells with identical sets of chromosomes. The peculiar molecule and its function were discovered in Kim Nasmyth's lab at the IMP in 1997. The conclusions that the researchers drew from their observations back then were unexpected. A molecule shaped like a ring was proposed to hold the two nascent DNA-strands together - much like a rubber band - until the exact moment had arrived for separation. Only then would the ring snap open and release the two copies of chromosomes on which the genetic information is stored. In the following years, this mechanism was not only confirmed but further and far-reaching functions of cohesin were discovered, such as its importance for DNA damage repair and for the structure of chromatin. However, cohesin itself was never seen in action. In the living cell, the opening of the ring is an extremely fast process and doesn't last long enough to be captured. Read more at: http://phys.org/news/2014-11-cohesin-molecule-safeguards-cell-division.html#jCp Dionisio

Membrane proteins: Communicating with the world across the border All living cells are held together by membranes, which provide a barrier to the transport of nutrients. They are also the communication platform connecting the outside world to the cell's interior control centers. Thousands of proteins reside in these cell membranes and control the flow of select chemicals, which move across the barrier and mediate the flux of nutrients and information. Almost all of these pathways work by protein handshakes—one protein "talking" to another in order to, for example, encourage the import of a needed nutrient, to block a compound from accumulating to a toxic level, or to alert the cell's interior to changes in the outside environment. Read more at: http://phys.org/news/2014-05-membrane-proteins-world-border.html#jCp Dionisio

Right place, right time: Cellular transportation compartments Proteins are the machinery that accomplishes almost every task in every cell in every living organism. The instructions for how to build each protein are written into a cell's DNA. But once the proteins are constructed, they must be shipped off to the proper place to perform their jobs. http://phys.org/news/2014-10-cellular-compartments.html Dionisio

Proteins Hey1 and Hey2 Ensure That Inner Ear 'Hair Cells' Are Made at the Right Time, in the Right Place http://www.hopkinsmedicine.org/news/media/releases/proteins_hey1_and_hey2_ensure_that_inner_ear_hair_cells_are_made_at_the_right_time_in_the_right_place Dionisio

Heterogeneity and plasticity of epidermal stem cells doi: 10.1242/dev.104588 The epidermis is an integral part of our largest organ, the skin, and protects us against the hostile environment. It is a highly dynamic tissue that, during normal steady-state conditions, undergoes constant turnover. Multiple stem cell populations residing in autonomously maintained compartments facilitate this task. In this Review, we discuss stem cell behaviour during normal tissue homeostasis, regeneration and disease within the pilosebaceous unit, an integral structure of the epidermis that is responsible for hair growth and lubrication of the epithelium. We provide an up-to-date view of the pilosebaceous unit, encompassing the heterogeneity and plasticity of multiple discrete stem cell populations that are strongly influenced by external cues to maintain their identity and function. http://dev.biologists.org/content/141/13/2559 Dionisio

Regeneration, morphogenesis and self-organization doi: 10.1242/dev.107839 The RIKEN Center for Developmental Biology in Kobe, Japan, hosted a meeting entitled ‘Regeneration of Organs: Programming and Self-Organization’ in March, 2014. Scientists from across the globe met to discuss current research on regeneration, organ morphogenesis and self-organization – and the links between these fields. A diverse range of experimental models and organ systems was presented, and the speakers aptly illustrated the unique power of each. This Meeting Review describes the major advances reported and themes emerging from this exciting meeting. http://dev.biologists.org/content/141/14/2745 Dionisio

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day doi: 10.1242/dev.104851 A biological ‘circadian’ clock conveys diurnal regulation upon nearly all aspects of behavior and physiology to optimize them within the framework of the solar day. From digestion to cardiac function and sleep, both cellular and systemic processes show circadian variations that coincide with diurnal need. However, recent research has shown that this same timekeeping mechanism might have been co-opted to optimize other aspects of development and physiology that have no obvious link to the 24?h day. For example, clocks have been suggested to underlie heterogeneity in stem cell populations, to optimize cycles of cell division during wound healing, and to alter immune progenitor differentiation and migration. http://dev.biologists.org/content/141/16/3105 Dionisio

645 link http://dx.doi.org/10.1242/dev.104471 Dionisio

Out of the niche: exploring unknown pathways doi: 10.1242/dev.110510 In May 2014, approximately 200 stem cell scientists from all over world gathered near Copenhagen in Denmark to participate in ‘The Stem Cell Niche’, part of the Copenhagen Bioscience Conferences series. The meeting covered an array of different stem cell systems from pluripotent stem cells and germ cells to adult stem cells of the lung, liver, muscle, bone and many more. In addition to the stem cell niche, the meeting focused on a number of cutting edge topics such as cell fate transitions and lineage reprogramming, as well as stem cells in ageing and disease, including cancer. This Meeting review describes the exciting work that was presented and some of the themes that emerged from this excellent meeting. http://dev.biologists.org/content/141/18/3441 Dionisio

The T-box gene family: emerging roles in development, stem cells and cancer The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. doi: 10.1242/dev.104471 Dionisio

643 link http://dev.biologists.org/content/141/19/3637 Dionisio

STEM CELLS AND REGENERATION Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network doi: 10.1242/dev.109678 During blastocyst formation, inner cell mass (ICM) cells differentiate into either epiblast (Epi) or primitive endoderm (PrE) cells, labeled by Nanog and Gata6, respectively, and organized in a salt-and-pepper pattern. Previous work in the mouse has shown that, in absence of Nanog, all ICM cells adopt a PrE identity. Moreover, the activation or the blockade of the Fgf/RTK pathway biases cell fate specification towards either PrE or Epi, respectively. We show that, in absence of Gata6, all ICM cells adopt an Epi identity. Furthermore, the analysis of Gata6+/? embryos reveals a dose-sensitive phenotype, with fewer PrE-specified cells. These results and previous findings have enabled the development of a mathematical model for the dynamics of the regulatory network that controls ICM differentiation into Epi or PrE cells. The model describes the temporal dynamics of Erk signaling and of the concentrations of Nanog, Gata6, secreted Fgf4 and Fgf receptor 2. The model is able to recapitulate most of the cell behaviors observed in different experimental conditions and provides a unifying mechanism for the dynamics of these developmental transitions. The mechanism relies on the co-existence between three stable steady states (tristability), which correspond to ICM, Epi and PrE cells, respectively. Altogether, modeling and experimental results uncover novel features of ICM cell fate specification such as the role of the initial induction of a subset of cells into Epi in the initiation of the salt-and-pepper pattern, or the precocious Epi specification in Gata6+/? embryos. [isn't all this really fascinating?] Dionisio

Guiding Light Retinal glial cells acting as optical fibers shuttle longer wavelengths of light to individual cones. http://www.the-scientist.com//?articles.view/articleNo/40996/title/Guiding-Light/ Dionisio

Genetic, Structural, and Molecular Insights into the Function of Ras of Complex Proteins Domains DOI: http://dx.doi.org/10.1016/j.chembiol.2014.05.010 Ras of complex proteins (ROC) domains were identified in 2003 as GTP binding modules in large multidomain proteins from Dictyostelium discoideum. Research into the function of these domains exploded with their identification in a number of proteins linked to human disease, including leucine-rich repeat kinase 2 (LRRK2) and death-associated protein kinase 1 (DAPK1) in Parkinson’s disease and cancer, respectively. This surge in research has resulted in a growing body of data revealing the role that ROC domains play in regulating protein function and signaling pathways. In this review, recent advances in the structural information available for proteins containing ROC domains, along with insights into enzymatic function and the integration of ROC domains as molecular switches in a cellular and organismal context, are explored. Dionisio

639 link http://www.the-scientist.com//?articles.view/articleNo/41483/title/Illuminating-the-Interactome/ Dionisio

Illuminating the Interactome A massive screen yields the most comprehensive map of binary human protein interactions to date. The completion of the human genome sequence more than a decade ago was an indisputable triumph for biomedical research. And more recently, efforts such as the Encyclopedia of DNA Elements (ENCODE) project have sought to expand knowledge of functional elements within the genome. But truly connecting genotype to phenotype will require a comprehensive view of how the protein products of genes operate and interact. “This is a long road, and we’ve never had a human interactome project to go with the Human Genome Project.” “But I think people are starting to appreciate that the genome is the beginning of the story . . . it’s a parts list in an alien language that we’re starting to figure out.” While this latest map is a valuable resource, it provides a static view of the proteome." “Looking at dynamic changes will be another important part of this . . . it would also be useful to look at adaptive responses of the proteome to stresses in the environment.” Dionisio

637 link http://med.stanford.edu/news/all-news/2014/11/of-mice-and-men--researchers-compare-mammals-genomes-to-aid-huma.html Dionisio

Researchers compare mammals’ genomes For years, scientists have considered the laboratory mouse one of the best models for researching disease in humans because of the genetic similarity between the two mammals. Now, researchers at the Stanford University School of Medicine have found that the basic principles of how genes are controlled are similar in the two species, validating the mouse’s utility in clinical research. However, there are important differences in the details of gene regulation that distinguish us as a species. “At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “We are interested in what makes a mouse a mouse and a human a human.” Dionisio

Principles of regulatory information conservation doi:10.1038/nature13985 http://www.nature.com/nature/journal/v515/n7527/full/nature13985.html Dionisio

634 link http://www.pnas.org/content/early/2014/11/19/1413624111 Dionisio

Comparison of transcriptional landscapes doi: 10.1073/pnas.1413624111 Although the similarities between humans and mice are typically highlighted, morphologically and genetically, there are many differences. To better understand these two species on a molecular level, we performed a comparison of the expression profiles of 15 tissues by deep RNA sequencing and examined the similarities and differences in the transcriptome for both protein-coding and -noncoding transcripts. Although commonalities are evident in the expression of tissue-specific genes between the two species, the expression for many sets of genes was found to be more similar in different tissues within the same species than between species. These findings were further corroborated by associated epigenetic histone mark analyses. We also find that many noncoding transcripts are expressed at a low level and are not detectable at appreciable levels across individuals. Moreover, the majority lack obvious sequence homologs between species, even when we restrict our attention to those which are most highly reproducible across biological replicates. Overall, our results indicate that there is considerable RNA expression diversity between humans and mice, well beyond what was described previously, likely reflecting the fundamental physiological differences between these two organisms. Dionisio

The art of culture: Developing cell lines DOI: 10.1126/science.346.6212.1013 Immortalized cell lines are critical for biomedical research, but establishing new lines can be tricky and frustrating. Researchers who've succeeded at it recommend a combination of old and new tools and techniques http://www.sciencemag.org/content/346/6212/1013.short Dionisio

A comparative encyclopedia of DNA elements in the mouse genoma doi:10.1038/nature13992 The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases. http://www.nature.com/nature/journal/v515/n7527/full/nature13992.html Dionisio

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Pores of No Return DOI: http://dx.doi.org/10.1016/j.molcel.2014.11.005 In this issue, Bleicken et al. (2014) use double electron-electron resonance (DEER) spectroscopy to propose a new model for the active form of Bax at membranes that differs significantly from those previously proposed. Dionisio

More Division of Labor at the Eukaryotic Replication Fork DOI: http://dx.doi.org/10.1016/j.molcel.2014.11.004 Our understanding of the dynamics of replication fork-associated protein strand specificity is based largely on genetic or in vitro approaches. Yu et al. (2014) present eSPAN, a ChIP approach that reveals differences between protein abundance on nascent leading and lagging strands. Dionisio

Credibility and Reproducibility DOI: http://dx.doi.org/10.1016/j.molcel.2014.11.012 Credibility is everything for science, and it is built over time in both obvious and subtle ways. It is how we interact with colleagues and collaborators. It is how generously and openly we share reagents and how we mentor students and postdocs. It is how we review each other’s papers, and it is how we credit others' work. It is the way we educate and inform the public that funds us. It is the way we document and store our data. And it is the rigor, transparency, and attention we invest in designing, conducting, and reporting experiments. Dionisio

The Two Faces of Receptor Interacting Protein Kinase-1 DOI: http://dx.doi.org/10.1016/j.molcel.2014.11.001 Receptor Interacting Protein Kinase-1 (RIPK1), a key player in inflammation and cell death, assumes opposite functions depending on the cellular context and its posttranslational modifications. Genetic evidence supported by biochemical and cellular biology approaches sheds light on the circumstances in which RIPK1 promotes or inhibits these processes. Dionisio

Transcribing through the nucleosome DOI: http://dx.doi.org/10.1016/j.tibs.2014.10.004 •Nucleosomes are non-uniform, context specific barriers that affect RNA Polymerase II (Pol II) transit. •Pol II transit affects stability and dynamics of transcribed nucleosomes. •Chromatin modifiers and histone variants modulate the barrier strength. •Transcription-generated torsional stress mediates nucleosome dynamics. The packaging of DNA into chromatin limits sequence accessibility, which affects all DNA-based processes including transcription. Indeed, the fundamental unit of chromatin, the nucleosome, presents a strong barrier to transcription in vitro. Since the discovery of the nucleosome barrier, the question of how the RNA polymerase II (Pol II) machinery overcomes nucleosomes at high speeds in vivo has remained a central question in chromatin biology. In this review, we discuss the nature of the nucleosomal barrier to transcription and highlight recent findings that provide new insights into the mechanism of transcription through nucleosomes. Dionisio

#620 follow-up

these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy.

Dionisio

Centrosome dynamics as a source of chromosomal instability DOI: http://dx.doi.org/10.1016/j.tcb.2014.10.002 •The relationship between centrosome separation and chromosome mis-segregation has historically been overlooked. •Gene mutations that delay or accelerate centrosome separation cause spindle malformation, merotely, aneuploidy, and cancer. •Cyclin B2 and p53 play a central role in centrosome separation. •Centrosome separation defects may be a frequent source of chromosomal instability in human cancers. Accurate segregation of duplicated chromosomes between two daughter cells depends on bipolar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi-orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics – that is, centrosome disjunction and poleward movement of duplicated centrosomes – as a central target for deregulation of bi-orientation in cancer cells. Dionisio

Bacterial microcompartments and the modular construction of microbial metabolism DOI: http://dx.doi.org/10.1016/j.tim.2014.10.003 Bacterial microcompartments (BMCs) are protein-bound organelles predicted to be present across 23 bacterial phyla. BMCs facilitate carbon fixation as well as the aerobic and anaerobic catabolism of a variety of organic compounds. These functions have been linked to ecological nutrient cycling, symbiosis, pathogenesis, and cardiovascular disease. Within bacterial cells, BMCs are metabolic modules that can be further dissociated into their constituent structural and functional protein domains. Dionisio

Molecular regulation of effector and memory T cell differentiation Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy. doi:10.1038/ni.3031 http://www.nature.com/ni/journal/v15/n12/full/ni.3031.html Dionisio

UPF1 dictates stem cell fate a well-known protein has a new function: It acts in a biological circuit to determine whether an immature neural cell remains in a stem-like state or proceeds to become a functional neuron. The findings illuminate a fundamental but still poorly understood cellular act. in concert with a special class of RNAs called microRNA, UPF1 acts as a molecular switch to determine when immature (non-functional) neural cells differentiate into non-dividing (functional) neurons. Specifically, UPF1 triggers the decay of a particular mRNA that encodes for a protein in the TGF-? signaling pathway that promotes neural differentiation. By degrading that mRNA, the encoded protein fails to be produced and neural differentiation is prevented. http://www.stemcellsfreak.com/2014/02/UPF1-stem-cell-fate.html Dionisio

#613 Edward That's an interesting observation you've made. Thank you. Note that this thread was started by an OP about a group of scientists who are critical of the neo-Darwinian narrative, but also reject the ID theory. They have created a third party in the ongoing OOL debate. However, many posts in this thread illustrate how most serious researchers are busy trying to figure out how the observed biological systems work and what effect they produce. Apparently those scientists don't have enough time to spend on OOL issues. First things first. :) Dionisio

Symposium Title Index A chemical approach to controlling cell fate S. Ding University of California San Francisco, USA Thursday, 11 December 2014: Sheng Ding, Gladstone Institute, University of California, San Francisco, USA | A chemical approach to controlling cell fate [INV18] - 14:00-14:30 a metabolic switch critical for muscle stem cell fate H.M. Blau, Nora Yucel* Stanford University, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 A mitochondrial switch promotes tumor metastasis P.E. Porporato*1, V.L. Payen1, J. Pérez-Escuredo1, C.J. De Saedeleer1, P. Danhier1,2, O. Feron1, C. Michiels3, B. Gallez2, P. Sonveaux1 1Institute of Experimental and Clinical Research (IREC), University of Louvain (UCL) Medical School, Brussels, Belgium., Belgium, 2Louvain Drug Research Institute (LDRI), Laboratory of Magnetic Resonance Imaging (REMA), University of Louvain (UCL) Medical School, Brussels, Belgium., Belgium, 3URBC-NARILIS, University of Namur, Namur 5000, Belgium, Belgium Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Abrogation of tumorigenicity through direct reprogramming of human lung cancers C.M. Kong*, D. Mahalingam, L. Jason, X. Wang National University of Singapore, Singapore Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Age-related stem cell dysfunction: Lessons from Drosophila A. Ayyaz, H. Li, L. Wang, L. Guo, H. Deng, J. Karpac, H. Jasper* Buck Institute for Research on Aging, USA Wednesday, 10 December 2014: Heinrich Jasper, Buck Institute for Research on Aging, USA | Age-related stem cell dysfunction: Lessons from Drosophila [INV08] - 11:30-12:00 Aging and insulin signaling differentially control normal and tumorous germline stem cell division cycles C-Y. TSENG*1,2, S-H. KAO1, H-Y. JHUANG1,2, H-J. HSU1 1Institue of Cellular and Organismic Biology, Academia Sinica, Taiwan, 2Graduate Institute of Life Sciences, National Defense Medical Center, Taiwan Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Aging provokes a decrease of adult Neural Stem Cells proliferation associated with metabolic changes M. Daynac*2,1, J.R. Pineda1, A. Chicheportiche1, L.R. Gauthier1, L. Morizur1, M. Ruat2, F.D. Boussin1, M-A. Mouthon1 1CEA FAR, France, 2CNRS, France Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 AMPK confers metabolic stress resistance to AML-initiating cells D. Nakada Baylor College of Medicine, USA Tuesday, 09 December 2014: Daisuke Nakada, Baylor College of Medicine, USA | AMPK confers metabolic stress resistance to AML-initiating cells [ST01] - 17:30-17:45 Autophagic Regulation of Hematopoietic Stem Cell Function E. Passegue University of California,, USA Wednesday, 10 December 2014: Emmanuelle Passegue, University of California, San Francisco, USA | Autophagic Regulation of Hematopoietic Stem Cell Function [INV10] - 15:00-15:30 Autophagy is essential for the survival and regenerative potential of hematopoietic stem cells T.T. Ho*, M.R. Warr, J. Debnath, E. Passegué University of California San Francisco, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Calorie restriction does not restore brain mitochondrial function in P301L tau mice, but it does decrease F0F1-ATPase activity V. Delic*, M. Brownlow, A. Joly-Amado, S. Zivkovic, K. Noble, T. Phan, Y. Zhang, C. Kurien, D. Morgan, P.C. Bradshaw et al University of South Florida, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation and resist glucose deprivation A. Pasto*1, C. Bellio1, G. Pilotto1, V. Ciminale1,2, M. Silic-Benussi2, G. Guzzo3, A. Rasola3, C. Frasson4, G. Nardo2, E. Zulato2 et al 1Department of Surgery, Oncology, and Gastroenterology, Oncology Section, University of Padova, Italy, 2Istituto Oncologico Veneto-IRCCS (IOV), Padova, Italy, 3Department of Biomedical Sciences, University of Padova, Italy, 4Department of Woman and Child Health, Laboratory of Hemato-Oncology, University of Padova, Italy Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Canonical Wnt/?-catenin pathway in salivary gland stem cell regulation M. Maimets*1, R. Bron1, M. Huch3, H. Clevers3, R.G.J. Vries3, R. van Os2, R.P. Coppes1 1University Medical Centre Groningen, The Netherlands, 2European Research Institute for the Biology of Aging, The Netherlands, 3Hubrecht Institute for Developmental Biology and Stem Cell Research, The Netherlands Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis Y-H Wang*1, W. Israelson4, D. Lee1, V. Yu1, N. Jeanson1, C. Clish2, L. Cantley3, M. Vander Heiden4, D. Scadden1 1Harvard Stem Cell Institute, Massachusetts General Hospital, Harvard University, USA, 2Broad Institute, USA, 3Weil-Cornell Medical College, USA, 4Koch Institute, Massachusetts Institute of Technology, USA Tuesday, 09 December 2014: David Scadden, Harvard University Department of Stem Cell and Regenerative Biology/Massachusetts General Hospital, USA | Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis [INV02] - 16:30-17:00 Cellular senescence of stromal cells produces soluble factors that promote proliferation and potency of neighboring stem cells. Z. Shahab1, A.R. Middleton1, A. Meilan1, D.T. Madden*1,2 1Touro University California, USA, 2Buck Institute for Research on Aging, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Change of regional stem cell identity leads to age-related metaplasia in the gastrointestinal tract of Drosophila H.L. Li*, Y.Q. Qi, H.J. Jasper Buck institute for research on aging, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Chemical approaches for induced pluripotency and liver regeneration S.Y. Zhu*, S. Ding The J. David Gladstone Institute, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Computational analysis predicts imbalanced IDH1/2 expression associate with 2-HG-inactivating ?-oxygenation pathway in colorectal cancer J. Koseki*, H. Colvin, T. Fukusumi, N. Nishida, M. Konno, K. Kawamoto, K. Tsunekuni, Y. Doki, M. Mori, H. Ishii Graduate School of Medicine, Osaka University, Japan Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Controling stem cell fates by energetics from a dynamical models perspective V. Olariu2, C. Peterson*1 1Lund University, Sweden, 2The Niels Bohr Institute, Denmark Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Crif1 modulates PKA/CREB signal pathway promoting adipogenic differentiation in bone marrow mesenchymal stem cells after irradiation damage L.X. Xiang1, X. Zhang1, Q. Ran1, Y. Liu1, Y. Xiang1, L. Chen1, F.J. Li1, J.F. Zhong2, Z.J. Li*1 1The Second Affiliated Hospital, Third Military Medical University, China, 2University of Southern California, Keck School of Medicine, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Critical roles for mitochondrial localization of GASZ in nuage formation and MFN-mediated mitofusion during germ cell development J. Zhang, Q. Wang, M. Wang, Y. Sun, J. Wang, Y. Wang* East China Normal University, China Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 DCAF12 regulates proliferative homeostasis in the Drosophila intestinal epithelium by controlling mitotic exit in the intestinal stem cell lineage J. Kim*1, D. Hwangbo2, H. Jasper1 1The Buck Institute for Research on Aging, USA, 2University of Rochester, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Determining stem cell dynamics in human colonic crypts: An in vivo lineage tracing study using mtDNA mutations as clonal evolution markers C. Stamp*1, A. Zupanic2,5, D. Shanley2, J.C. Mathers3,4, T.B.L. Kirkwood2, D.M. Turnbull1,4, L.C. Greaves1,4 1Newcastle University, UK, 2Centre for Integrated Systems Biology of Ageing and Nutrition, Newcastle University, UK, 3Human Nutrition Research Centre, Newcastle University, UK, 4nstitute for Ageing and Health, The Medical School, UK, 5Swiss Federal Institute of Aquatic Science and Technology, Switzerland Thursday, 11 December 2014: Craig Stamp, Newcastle University, UK | Determining stem cell dynamics in human colonic crypts: An in vivo lineage tracing study using mtDNA mutations as clonal evolution markers [ST07] - 10:45-11:00 Direct measurement of local oxygen concentration in the bone marrow of live animals by two-photon phosphorescence quenching method J.A. Spencer1,2 et al 1Massachusetts General Hospital, USA, 2Harvard Medical School, USA, 3Harvard Stem Cell Institute, USA, 4Harvard University, USA, 5University of Pennsylvania, USA, 6King Saud University, Saudi Arabia, 7Laval University, Canada Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Direct Mitochondrial Transfer by Photothermal Nanoblade T-H Wu, E. Sagullo, D. Case, X. Zheng, Y. Li, J. Hong, D. Braas, C.M. Koehler, T. Graeber, P-Y Chiou, M. Teitell* University of California, USA Thursday, 11 December 2014: Mike Teitell, University of California, Los Angeles, USA | Direct Mitochondrial Transfer by Photothermal Nanoblade [INV16] - 11:00-11:30 Distinct blood vessels differentially regulate bone marrow hematopoiesis T. Itkin*1, J.A. Spencer2, A. Schajnovitz2, S.K. Ramasamy3, J.M. Butler4, S. Rafii4, R.H. Adams3, C.P. Lin2, D.T. Scadden2, T. Lapidot1 et al 1The Weizmann Institute of Science, Israel, 2Harvard Medical School, USA, 3Max Planck Institute for Molecular Biomedicine, Germany, 4Weill Cornell Medical College, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 DNA methylation directs metabolic reprogramming during development for the establishment of pancreatic beta cell function. S. Dhawan*1, S.I. Tschen1, C. Zeng1, T. Guo2, M. Hebrok2, A. Matveyenko1, A. Bhushan1 1University of California, Los Angeles, USA, 2University of California, San Francisco, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Effect of HIFs in normal and leukemic stem cell regulation D. Bonnet London Research Institute, UK Tuesday, 09 December 2014: Dominique Bonnet, Cancer Research UK, London Research Institute, UK | Effect of HIFs in normal and leukemic stem cell regulation [INV04] - 18:30-19:00 Effect of mitochondrial protection on neural progenitor cell proliferation and differentiation L.A. Voloboueva*, Y.B. Ouyang, X.Y. Sun, R.G. Giffard Stanford University, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Effects of bone marrow warm ischemia on hematopoietic stem cells E. Necas*, K. Faltusova, M. Molik, F. Savvulidi Charles University in Prague, First Faculty of Medicine, Czech Republic Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Effects of Pulsed Electromagnetic Fields on the Precursor Cells of Osteoclasts and Osteoblasts W.Q. Xu*, F.J. Yang, J. Zhao Institute of Radiation Medicine & Chinese Academy of Medical Sciences, China Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Enhancement of hepatocyte differentiation from hESC by Chinese medicine J.M. Chen*1,2, Y.Y. Duan1, P. Liu2, M. Zern1 et al 1Institute for Regenerative Cures, University of California Davis Medical Center, USA, 2Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, China Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Environmental stress-induced autophagy alters skeletal progenitor cell fate through upregulation of SOX9 N. van Gastel*, S. Torrekens, P. Agostinis, G. Carmeliet KU Leuven, Belgium Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Epigenetic and metabolic regulation of aging stem cells A, Brunet Department of Genetics, Stanford University, USA Thursday, 11 December 2014: Anne Brunet, Stanford University, USA | Epigenetic and metabolic regulation of aging stem cells [INV19] - 14:30-15:00 Excessive cellular proliferation negatively impacts reprogramming efficiency of human fibroblasts M.K. Gupta*1,3, A.K.K. Teo1,3, T.N. Rao1,2, S. Bhatt1,3, A. Kleinridders1,3, D.F. Jesus1,3, R. Windmueller1,3, A.J. Wagers1,2, R.N. Kulkarni1,3 1Joslin Diabetes Center, Harvard Medical School, Boston, USA, 2Howard Hughes Medical Institute, Cambridge, USA, 3Brigham and Women’s Hospital, Harvard Medical School, Boston, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Expression of the system A amino acid transporters suggests a role for amino acids in the regulation of embryo development and pluripotency B.S.N. Tan2, D.K. Gardner2, P.D. Rathjen1, J. Rathjen*1 1Menzies Research Institute Tasmania, Australia, 2University of Melbourne, Australia Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Genetic basis of how stem cells protect themselves against genotoxic metabolites KJ Patel MRC Laboratory of Molecular Biology, UK Wednesday, 10 December 2014: KJ Patel, MRC Laboratory of Molecular Biology, Cambridge, UK | Genetic basis of how stem cells protect themselves against genotoxic metabolites [INV12] - 16:45-17:15 Glial lipid droplets protect neural stem cells from oxidative stress in Drosophila A.P. Bailey*1, G. Koster3, C. Guillermier2,4, A.D. Postle3, C. Lechene3,4, A.P. Gould1 1National Institute for Medical Research, UK, 2Brigham and Women's Hospital, Harvard Medical School, USA, 3University of Southampton, UK, 4National Resource for Imaging Mass Spectrometry, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. V.L. Payen*, C.J. De Saedeleer, P.E. Porporato, T. Copetti, J. Pérez-Escuredo, L. Brisson, O. Feron, P. Sonveaux Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCL), Brussels, Belgium Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Hematopoietic stem cell niche: Hypoxia and ROS T. Suda1 1Keio University School of Medicine, Japan, 2Cancer Science Institute, National University of Singapore, Singapore Wednesday, 10 December 2014: Toshio Suda, Keio University, Japan | Hematopoietic stem cell niche: Hypoxia and ROS [INV05] - 09:00-09:30 HSC functionality in response to an extensive proliferative stress S. Rojas-Sutterlin, T. Hoang* Institute for Research in Immunology and Cancer, Canada Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells M. Popowski*1, I. Ismailoglu1, Q. Chen2, L. Yang2, S. Gross2, A.H. Brivanlou1 1The Rockefeller University, USA, 2Weill Cornell College of Medicine, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes that enhance survival and promote cell retention in vivo J. Beegle1, K. Lakatos2, J.A. Nolta1, F.A. Fierro*1 1University of California Davis, USA, 2Semmelweis University, Hungary Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Identification of metabolic control points for stem cell differentiation using systems-based metabolic flux analysis H. Zhang, M.G. Badur, C.M. Metallo* University of California, San Diego, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Identification of the metabolic fuel requirements of adult neural stem cells E.A. Stoll*1, R. Makin1, I.R. Sweet2, S. Miwa1, A. Trevelyan1, P.J. Horner2, D.M. Turnbull1 1Newcastle University, UK, 2University of Washington, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 In vitro cultivation under adipogenic and osteogenic stimulation causes changes in the energy metabolism of human adipose tissue-derived mesenchymal stem cells J. Meyer*1, G. Kamp2, A. Salamon1, S. Adam1, J. Rychly1, K. Peters1 1Rostock University Medical Center, Germany, 2AMP-Lab GmbH, Germany Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis Y. Jiang*, D.C. Berry, J. Graff ut southwestern medical center, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Insulin Resistance in Human iPS Cells Decreases Mitochondrial Function and Size A. Burkart*, S. Iovino, K. Tan, L. Warren, K.J. Hughes, C.R. Kahn, M-E. Patti Joslin Diabetes Center, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Integration of UPRER and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation L-W. Wang*1, X-Z. Zeng3, H.D.R. Ryoo2, H-J. Jasper1 1Buck Institute for Research on Aging, USA, 2Department of Cell Biology, New York University School of Medicine, USA, 3Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Intermediary metabolite precursor dimethyl-2-ketoglutarate enables the acquisition of a breast cancer stem cell-like phenotype C-Y. Kuo*1, C-T. Cheng1,2, Y-P. Lin3, H. Ma1, W. Li4, H-J. Kung3, D.K. Ann1,2 1Department of Pharmacology, Beckman Research Institute, City of Hope, USA, 2Irell & Manella Graduate School of Biological Sciences, City of Hope, USA, 3Integrated laboratory, Center of Translational Medicine, Taipei Medical University, Taiwan, 4Department of Dermatology, Keck School of Medicine, University of Southern California, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Interplay of ROS and cytokine signaling instructs hematopoietic stem and progenitor cell fate decisions A. Hinge, E. Moose, J. Gu, B. Arronow, M-D. Filippi* Cincinnati Children's Research Foundation, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Intestinal stem cells are regulated by nutritional status and PTEN C.A. Richmond*, L. Deary, B.N. Brandt, R.K. Montgomery, H. Thomas, M.S. Shah, D. Ambruzs, A. Tovaglieri, D.L. Carlone, D.T. Breault Boston Children's Hospital, USA Wednesday, 10 December 2014: Camilla Richmond, Boston Children's Hospital, USA | Intestinal stem cells are regulated by nutritional status and PTEN [ST05] - 16:30-16:45 Intracellular production of ?-ketoglutarate maintains the pluripotency of embryonic stem cells L.W.S. Finley*1, B.W. Carey2, C.D. Allis2, C.B. Thompson1 1Memorial Sloan Kettering Cancer Center, USA, 2The Rockefeller University, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 LIN28 paralogs in reprogramming and stem cell metabolism J. Zhang*1, S. Ratanasirintrawoot1, Z. Wu1, S. Ficarro2, D. Cacchiarelli3, M. Seligson1, G. Shinoda1, W. Xie1, Q. Xia1, G. Daley1 et al 1Boston Children's Hospital, USA, 2Dana-Farber Cancer Institute, USA, 3The Broad Institute of MIT and Harvard, USA, 4Mayo Clinic, USA, 5Israel Deaconess Medical Center, USA, 6Weill Cornell Medical College, USA, 7Boston University, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Linking an endocytic protein to lipid metabolism in haematopoietic stem cells S. Rhost1, N. Lee1, S. Ghotb1, R. Meex2, M. Watt2, S. Ting*1,3 1Monash University, Division of Blood Cancers, ACBD, Melbourne, Australia, 2Monash University, Biology of Lipid Metabolism Laboratory, Melbourne, Australia, 3Alfred Health, Department of Haematology, Melbourne, Australia Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Local and systemic regulators of aging phenotypes in mammalian tissues A. Wagers Harvard University, USA Wednesday, 10 December 2014: Amy Wagers, Harvard University, Boston, USA | Local and systemic regulators of aging phenotypes in mammalian tissues [INV06] - 09:30-10:00 Long-living cord blood mesenchymal stem cells and their metabolism. M. Barilani, V. Parazzi*, E. Ragni, V. Begni, C. Lavazza, M. Vigano', T. Montemurro, R. Giordano, L. Lazzari Cell Factory, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Loss of ATM accelerates pancreatic cancer formation and Epithelial-Mesenchymal-Transition R. Russell*1, L. Perkhofer1, Q. Lin2, A. Lechel1, M. Zenke1, J.K. Lennerz1, T. Seufferlein1, M. Wagner1, A. Kleger1 1Ulm University Hospital, Germany, 2RWTH Aachen Univerity, Germany Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Low doses of ?-radiation lead to long-term defects of hematopoietic stem cells functions S.R.M. Moreira*, D.L. Lewandowski, F.H. Hoffschir, S.M. Moreno, N.G. Gault, P.H.R. Romeo Commissariat de l'Energie Atomique, France Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Macrophage-like Hemocytes Control Stem Cell Activity in Drosophila Intestine A. Ayyaz*, H. Li, H. Jasper Buck Institute for Research on Aging, Novato, CA, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Mammalian Cdk7-kinase submodule of transcription factor II H in global transcription and adipocyte differentiation Y. Yang*, K. Helenius, H. Hakala, T.P. Makela University of Helsinki, Finland Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Matrix assisted transplantation of functional brown adipose-like tissue K.M.T. Tharp*1, A.K.J. Jha1, J.K. Kraiczy1, A.Y. Yesian1, G.K. Karateev2, R.S. Sinisi2, E.D. Dubikovskaya1, K.E.H. Healy1, A.S. Stahl1 1UC Berkeley, USA, 2EPFL, Switzerland Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Metabolic fuels for histone methylation in human pluripotent stem cells S.C. Ng*1, G.Q. Daley2, L.C. Cantley3 et al 1Genome Institute of Singapore, Singapore, 2Harvard Medical School, USA, 3Weill-Cornell Medical College, USA Thursday, 11 December 2014: Shyh-Chang Ng, Genome Institute of Singapore, Singapore | Metabolic fuels for histone methylation in human pluripotent stem cells [ST10] - 16:00-16:15 Metabolic impact on intestinal stem cell division mode A. Aliluev*1,2, A. Böttcher1,2, M. Sterr1,2, M. Irmler3, S. Sass4, F. Theis4, I. Burtscher1,2, H. Lickert1,2 1Institute of Stem Cell Research, Helmholtz Zentrum München, Germany, 2Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany, 3Institute of Experimental Genetics, Helmholtz Zentrum München, Germany, 4Institute of Computational Biology, Helmholtz Zentrum München, Germany Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Metabolic regulation of nucleotide biosynthesis conditions hematopoietic stem cell lineage specification L. Oburoglu*1, S. Tardito2, S.C. de Barros1, V. Fritz1, P. Merida1, N. Mohandas3, E. Gottlieb2, M. Sitbon1, S. Kinet1, N. Taylor1 et al 1Institut de Genetique Moleculaire de Montpellier, France, 2Beatson Institute, UK, 3New York Blood Center, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Metabolic remodeling during oligodendrocyte precursor cell differentiation A.I. Amaral*1, J. Tavares1, U. Sonnewald2, M.R. Kotter1 1University of Cambridge, UK, 2Norwegian University of Science and Technology, Norway Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Metabolic Reprogramming in Stem Cell Fate T. Folmes*, A. Terzic Mayo Clinic, USA Wednesday, 10 December 2014: Andre Terzic, Mayo Clinic, USA | Metabolic Reprogramming in Stem Cell Fate [INV09] - 14:30-15:00 Metabolic reprogramming of human pluripotent stem cells in chemically defined medium H. Zhang*, M. Badur, C. Metallo University of California San Diego, Department of Bioengineering, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 MicroRNAs in the stem cell niche ¬- the key for cellular immortality M. Volin*, O. Gonen, H. Toledano University of Haifa, Israel Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 MiR-369 regulate pyruvate kinase splicing form by stabilizing translation of splicing factors M. Konno*1, N. Nishida1, K. Kawamoto1,2, J. Koseki3, Y. Doki2, M. Mori2, H. Ishii1,3 1Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Japan, 2Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Japan, 3Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Japan Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Mitigation of a newly discovered phenomenon, extra physiologic oxygen shock/stress (ephoss), mediated by the mitochondria permeability transition pore, greatly improves stem cell collection and transplantation C.R. Mantel, H.A. O'Leary, H.E. Broxmeyer* et al Indiana University School of Medicine, Indianapolis, IN, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Mitochondria-dependent stratification of nuclear reprogramming efficiency. C.D.L. Folmes*, S. Oommen, A. Behfar, T.J. Nelson, A. Terzic Mayo Clinic, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Mitochondrial DNA mutagenesis modifies reprogramming kinetics and pluripotent stem cell function. R.H. Hämäläinen*1, K. Ahlqvist1, P. Ellonen4, M.P. Murphy2, T.A. Prolla3, T. Otonkoski1, A. Suomalainen1 1University of Helsinki, Finland, 2MRC Mitochondrial Biology Unit, UK, 3University of Wisconsin Madison, USA, 4Institute for Molecular Medicine Finland, Finland Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Mitochondrial dynamics in the regulation of stem cell self-renewal and cell fate decisions M. Khacho*, A. Clark, D.S. Svoboda, C. Meghaizel, D. Lagace, D.S. Park, R.S. Slack University of Ottawa, Canada Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Mitochondrial dynamics modulation during mesenchymal stem cell differentiation M.F. Forni*, J. Peloggia, A.J. Kowaltowski Universidade de São Paulo, Brazil Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Mitochondrial dynamics regulates Drosophila intestinal stem cell differentiation H.D. DENG*1, S.T. TAKASHIMA2, V.H. HARTENSTEIN2, M.G. GUO2 1Buck research institute on aging, USA, 2University of California, Los Angeles, Molecular biology institute, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Mitochondrial gene replacement in human pluripotent stem cells and neural progenitors for understanding genetics of mitochondrial diseases during early development H.E. Grace2, F. West2, E.J. Lesnefsky1, R.R. Rao1, S. Iyer*1 1Virginia Commonwealth University, USA, 2University of Georgia, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Mitochondrial metabolism is necessary for cellular differentiation N.S. Chandel Northwestern University, USA Thursday, 11 December 2014: Navdeep Chandel, Northwestern University, Chicago, USA | Mitochondrial metabolism is necessary for cellular differentiation [INV17] - 11:30-12:00 Mitochondrial metabolism, the achilles heel of human cancer stem cells P. Sancho, E. Burgos, A. Tavera, R. Campos-Olivas, O. Grana, B. Sainz Jr, C. Heeschen* et al Spanish National Cancer Research Centre, Spain Thursday, 11 December 2014: Christopher Heeschen, Spanish National Cancer Research Centre, Spain | Mitochondrial metabolism, the achilles heel of human cancer stem cells [ST06] - 10:30-10:45 Mitochondrial remodeling in hepatic differentiation and dedifferentiation : opposite transitions in reverse processes A. Wanet*1, N. Remacle1, M. Najar2, L. Lagneaux2, E. Sokal3, T. Arnould1, M. Najimi3, P. Renard1 1University of Namur, Belgium, 2Université Libre de Bruxelles, Belgium, 3Université Catholique de Louvain, Belgium Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Murine insulinoma cell-conditioned medium with ?ETA2/NeuroD1 transduction efficiently induces the differentiation of adipose-derived mesenchymal stem cells into ?-like cells both in vitro and in vivo K. Kawamoto*1, M. Konno2, N. Nishida2, J. Koseki3, S. Yabe4, H. Nagano1, Y. Doki1, H. Okochi4, M. Mori1, H. Ishii3 et al 1Department of Surgery, Graduate School of Medicine, Osaka University, Japan, 2Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Japan, 3Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Japan, 4Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Japan Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Neuroblasts from adult mouse brain dedifferentiate in vitro into stem cell-like cells under hypoxia A. CHICHEPORTICHE*, M. DAYNAC, J.R. PINEDA, M.A. MOUTHON, F.D. BOUSSIN CEA-INSERM U967, France Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Non-coding RNAs control OGT expression N. Nishida*1, J. Ferdin2, X. Wu3, Y. Doki1, M. Mori1, T. Kunej2, M. Ivan3, G. Calin4, H. Ishii1 et al 1Osaka University, Japan, 2University of Ljubljana, Slovenia, 3Indiana University School of Medicine, USA, 4The University of Texas, M. D. Anderson Cancer Center, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Nrf2 modulates neural stem cell function during aging M.J. Corenblum, S. Ray, L. Min, B. Harder, D.D. Zhang, C.A. Barnes, L. Madhavan* University of Arizona, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism G. Daley1 1Boston Children’s Hospital and Dana Farber Cancer Institute, USA, 2Harvard Medical School, USA Tuesday, 09 December 2014: George Daley, Children’s Hospital Boston, Harvard Medical School, USA | Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism [INV01] - 16:00-16:30 Oxygen availability, embryonic development, and stem cell function C. Simon University of Pennsylvania, USA Thursday, 11 December 2014: Celeste Simon, University of Pennsylvania, USA | Oxygen availability, embryonic development, and stem cell function [INV15] - 09:30-10:00 Oxygen tension regulates human mesenchymal stem cell paracrine functions J. PAQUET*1, M. DESCHEPPER1, A. Moya1, D. LOGEART-AVRAMOGLOU1, C. BOISSON-VIDAL2, H. PETITE1 1Laboratoire de bioingénierie et bioimagerie ostéoarticulire, UMR 7052, France, 2UMR 1140, France Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Patterns of mitochondrial metabolism in human pluripotent stem cells before and during differentiation T. TeSlaa*, J. Zhang, S. Iman, E. Nuebel, M. Nili, K. Miyata, C.M. Koehler, M.A. Teitell University of California, Los Angeles, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Prdm16 regulates mitochondrial dynamics and hematopoietic stem cell function L.L. Luchsinger*, H.W. Snoeck Columbia Univeristy, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Pulsed electromagnetic fields effect on hematopoietic stem cell niche F.J. Yang*, W.Q. Xu, J.J. Huang The Institute of Radiation Medicine & Chinese Academy of Medical Sciences, China Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Radioluminescence imaging of head and neck cancer stem cell glucose metabolism D. Sengupta*, Y. Lee, J. Sunwoo, G. Pratx Stanford University, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Rapid activation of adipocyte precursor cells at the onset of obesity E. Jeffery*, C.D. Church, M.S. Rodeheffer Yale University, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Regenerative medicine and mitochondrial diseases: Cure and prevention J.C. Izpisua Belmonte*, A. Ocampo, P. Reddy Salk Institute for Biological Studies, USA Wednesday, 10 December 2014: Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies, USA and Center of Regenerative Medicine in Barcelona, Spain | Regenerative medicine and mitochondrial diseases: Cure and prevention [INV13] - 17:15-17:45 Regulation of cardiac stem cell metabolism and proliferation J. Salabei, P.K. Lorkiewicz, C.R. Holden, Q. Li, R. Bolli, A. Bhatnagar, B.G. Hill* University of Louisville, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Regulation of Drosophila stem cell maintenance and tissue homeostasis by PINK1 and Parkin C.L. Koehler*, D.L. Jones University of California Los Angeles, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Regulation of growth by the mTOR pathway D. Sabatini Whitehead Institute, MIT, USA Tuesday, 09 December 2014: David Sabatini, Whitehead Institute/Massachusetts Institute of Technology, USA | regulation of growth by the mTOR pathway [INV03] - 18:00-18:30 Reversible metabolic changes in human melanoma cells enable distant metastasis in vivo S. Morrison*, E Piskounova University of Texas Southwestern Medical Center, USA Tuesday, 09 December 2014: Keynote speaker | Sean Morrison, UT Southwestern, Texas, USA | Reversible metabolic changes in human melanoma cells enable distant metastasis in vivo [KEY01] - 15:10-16:00 Secreted phospholipase A2 is a stem cell niche factor in intestinal homeostasis, inflammation and cancer M. Schewe*1, P. Franken1, A. Sacchetti1, R. Joosten1, N. Webb2, S. Vermeire3, R. Cormier4, G. Lambeau5, R. Fodde1 1Erasmus MC, The Netherlands, 2University of Kentucky, USA, 3KU Leuven, Belgium, 4University of Duluth, USA, 5University of Nice, France Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Serum deprivation preconditioning enhances human mesenchymal stem cell long term survival in near anoxia without impairing cell functionality. A.M. Moya*, N.L. Larochette, J.P. Paquet, M.D. Deschepper, M.B. Bensidhoum, H.P. Petite, D.L. Logeart–Avramoglou CNRS Paris Diderot University, France Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 STAT3 signaling controls satellite cell expansion and skeletal muscle repair M. Tierney*, F. Boscolo Sesillo, A. Gromova, A. Sacco Sanford-Burnham Medical Research Institute, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Stem cell activation depends on the induction of autophagy T.A. Rando Stanford University School of Medicine, USA Wednesday, 10 December 2014: Tom Rando, Stanford University, USA | Stem cell activation depends on the induction of autophagy [INV07] - 11:00-11:30 Stem cells compete to initiate differentiation by comparing relative levels PI3K/mTOR signalling M. Amoyel*, K-H. Hillion, S.R. Margolis, E.A. Bach NYU School of Medicine, USA Wednesday, 10 December 2014: Marc Amoyel, NYU School of Medicine, USA | Stem cells compete to initiate differentiation by comparing relative levels PI3K/mTOR signaling [ST04] - 10:15-10:30 Systems Biology in the study of cancer cell metabolism with novel computational paradigms G. Jaime-Munoz*1,2, C. Gonzalez-Torres1,2, O. Resendis-Antonio1 1National Autonomous University of Mexico, Mexico, 2National Institute for Genomic Medicine, Mexico Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Targeting Metabolic Pathways In Small Intestine Organoids M.J. Rodriguez-Colman*, M. Meerlo, B.M.T. Burgering UMC Utrecht, The Netherlands Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 TBA G. Draetta The University of Texas MD Anderson Cancer Center, USA Thursday, 11 December 2014: Giulio F. Draetta, The University of Texas MD Anderson Cancer Center, USA | Tackling mechanisms of resistance in pancreatic cancer [INV14] - 09:00-09:30 Temperature-dependent regulation of stem cell recruitment in limb regeneration. M. Khurgel*, M.O. Cullip Bridgewater College, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 The cell cycle regulator p107 controls the bioenergetic state of mesenchymal stem cells D.P. Porras, J.S. Grewal, C.G.R. Perry, A. Scimè* York University, Canada Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 The CREB-SIRT1-HES1 axis mediates neural stem cell (NSC) response to glucose availability S. Fusco, L. Leone, S.A. Barbati, D. Samengo, R. Piacentini, G. Toietta, G. Maulucci, G. Pani, C. Grassi* Università Cattolica Medical School, Italy Wednesday, 10 December 2014: Salvatore Fusco, Università Cattolica Medical School, Italy | The CREB-SIRT1-HES1 axis mediates neural stem cell (NSC) response to glucose availability [ST03] - 10:00-10:15 The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition H. Ruohola-Baker*, H. Sperber, J. Mathieu et al University of Washington, USA Thursday, 11 December 2014: Hannele Ruohola-Baker, University of Washington, USA | The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition [ST09] - 15:45-16:00 The phosphatase Shp2 modulates tissue homeostasis and lifespan in Drosophila L.R. Ruzzi*, M.R. Pagani Instituto de Fisiología y Biofísica Bernardo Houssay. UBA-CONICET, Argentina Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 The role of fasting-refeeding conditions on lymphoid lineage commitment during aging and in disease models C-W. Cheng*, V.D. Longo University of Southern California, Dept. of Gerontology, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 The Role of Glutamine Metabolism in Human Embryonic Stem Cells G. Marsboom1, G-F. Zhang2, N. Pohl-Avila1, Y. Zhang1, A.B. Malik1, J. Rehman*1 1University of Illinois at Chicago, USA, 2Case Western Reserve University, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 The role of mitophagy in pluripotency and differentiation V. Nikoletopoulou*, N. Tavernarakis Institute of Molecular Biology and Biotechnology (IMBB), Greece Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Tis11 mediated mRNA decay regulates intestinal stem cell quiescence L. McClelland*1, H. Jasper2, B. Biteau2 1The Buck Institute for Research on Aging, USA, 2University of Rochester Medical Center, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Transient glycolysis enables mitochondrial fusion and stimulates S phase entry – the role of FoxO3a S. Tudzarova-Trajkovska*1, S. Moncada1 1University College London, UK, 2University of Manchester, UK Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Tuned Transition of Cardiac Stem Cells: Intersection of Signaling Pathways and Metabolic States M. Xaymardan*1,2, A. Asli1,2, R.P. Harvey1 1University of Sydney, Australia, 2Victor Chang Cardiac Research Institute, Australia Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Ubiquitylation of N-myc is essential for quiescence and lymphoid fate specification in hematopoietic stem cells B. King*1, K.M. Cruisio1, J. Wang1, A. Lasorella3, I. Aifantis1,2 1NYU School of Medicine, USA, 2Howard Hughes Medical Institute, USA, 3Columbia University Medical Center, USA Thursday, 11 December 2014: Poster session 02 - 12:30-14:00 Unique and unexpected aspects of the metabolic signaling activities of hematopoietically active cytokines truncated by dipeptidylpeptidase-4 (DPP4) H.A. O'Leary*, C.R. Mantel, M.R. Lee, X. Lai, S. Cooper, G. Hangoc, X. Wu, H.S. Boswell, H.E. Broxmeyer Indiana University School of Medicine, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Using extracellular acidification to measure glycolytic rate and ATP supply S.A. Mookerjee*1,2, R.L.S. Goncalves2, A.A. Gerenscer1,2, M.D. Brand1,2 1Touro University California, USA, 2Buck Institute for Research on Aging, USA Tuesday, 09 December 2014: Poster Session 01 + Drinks reception - 19:00-20:30 Vitamin C modulates repressive epigenetic programs in stem cells during development M. Ramalho-Santos University of California, USA Thursday, 11 December 2014: Miguel Ramalho-Santos, University of California, San Francisco, USA | Vitamin C modulates repressive epigenetic programs in stem cells during development [INV20] - 16:15-16:45 http://www.cell-symposia-stem-cell-energetics.com/conference-program/default.asp Copyright © 2014 Elsevier Limited Dionisio

#614 tentative selection Metabolic Reprogramming in Stem Cell Fate Mitochondrial metabolism is necessary for cellular differentiation A chemical approach to controlling cell fate Dionisio

#614 addendum http://www.cell-symposia-stem-cell-energetics.com/conference-program/default.asp Dionisio

Growing evidence shows that cellular metabolism underlies stem cell fate, including pluripotency, differentiation and reprogramming. In addition to generating ATP, through oxidative phosphorylation, mitochondrial metabolism provides the building blocks to support biomass, such as amino acid and lipids, and is involved in cell signaling in determining stem cell fate. Altered stem cell metabolism has been implicated in aging and diseases, such as cancer, and serves as a potential target for therapeutic intervention. Discussion topics: •Metabolic regulation of stem cell self renewal •Niche influence on stem cell metabolism •Energetics of stem cell flux •Mitochondria regulation of stem cell fate •Metabolites in stem cell epigenetics and reprogramming •Altered stem cell metabolism in aging and disease Reversible metabolic changes in human melanoma cells enable distant metastasis in vivo Metabolic Regulation of Stem Cell Self Renewal Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis AMPK confers metabolic stress resistance to AML-initiating cells Characterizing intrinsic metabolic differences in adult stem cell populations using cutting-edge in vivo probes regulation of growth by the mTOR pathway Effect of HIFs in normal and leukemic stem cell regulation Niche Influence on Stem Cell Metabolism Hematopoietic stem cell niche: Hypoxia and ROS Local and systemic regulators of aging phenotypes in mammalian tissues The CREB-SIRT1-HES1 axis mediates neural stem cell (NSC) response to glucose availability Stem cells compete to initiate differentiation by comparing relative levels PI3K/mTOR signaling Stem cell activation depends on the induction of autophagy Age-related stem cell dysfunction: Lessons from Drosophila Energetics of Stem Cell Flux Metabolic Reprogramming in Stem Cell Fate Autophagic Regulation of Hematopoietic Stem Cell Function Regulation of cellular stress response during cancer initiation and progression Intestinal stem cells are regulated by nutritional status and PTEN Genetic basis of how stem cells protect themselves against genotoxic metabolites Regenerative medicine and mitochondrial diseases: Cure and prevention Tackling mechanisms of resistance in pancreatic cancer Oxygen availability, embryonic development, and stem cell function Mitochondrial metabolism, the achilles heel of human cancer stem cells Determining stem cell dynamics in human colonic crypts: An in vivo lineage tracing study using mtDNA mutations as clonal evolution markers Direct Mitochondrial Transfer by Photothermal Nanoblade Mitochondrial metabolism is necessary for cellular differentiation Metabolites in stem cell epigenetics and reprogramming A chemical approach to controlling cell fate Epigenetic and metabolic regulation of aging stem cells Transcriptome and epigenetic profiling of young and aged hematopoietic stem cells The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition Metabolic fuels for histone methylation in human pluripotent stem cells Vitamin C modulates repressive epigenetic programs in stem cells during development Copyright © 2014 Elsevier Limited. Dionisio

If it's a given that: "Biology can't be understood without Darwinian principles", I'm always surprised that virtually noone dissects or simplifies the examples you post on this thread using Darwinian pricples. Imagine the educational value that's beeing passed up. Edward

Forget the coin flipping. Let's get real. :) See the below questions, based on an interesting commentary gpuccio posted before:

can we regard the constant flux of information between epigenome-genome-epigenome as the only possible way to correctly describe cell differentiation? Is that flux ever interrupted, from the zygote to the adult being to a new zygote? Which of the following levels does the information reside? 1 - genome, both coding and non coding 2 - genome methylation 3 - histone modifications 4 - chromatin modifications 5 - transcription factors network 6 - regulatory RNAs (all the various forms) 7 - post-translational modifications 8 - asymmetric mytosis 9 - cell to cell signaling 10- all of the above 11- none of the above how do those different strata interact? are they independent, parallel networks which ensure a supreme redundancy and robustness, or do they work, at least in part, in sequences?

Dionisio

Amazing technical refinements in mouse genetics, imaging, in utero manipulation, and slice culture methods have led to the discovery of a large number of genes that regulate MP migration, axonogenesis, and direction of movement. Many of the genes have been subjected to epistasis analysis, implying causal relationships and sequences of contingent events. Some protein activities are regulated by external signals, while others may be “hard-wired” by cell intrinsic mechanisms or transcription changes. Despite dramatic progress, it is still unclear how these different processes fit together. We have limited understanding of how different pathways interact and exactly when and where in the cell signaling occurs. Analysis is extremely challenging given the asynchrony of the cell population, the small size of the cells, and the difficulties of imaging signaling events within living tissue. However, given the continuous development of new technology, we can be optimistic that these obstacles will be overcome. Molecules and mechanisms that regulate multipolar migration in the intermediate zone doi: 10.3389/fncel.2014.00386 http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00386/abstract

Dionisio

Molecules and mechanisms that regulate multipolar migration in the intermediate zone doi: 10.3389/fncel.2014.00386 Most neurons migrate with an elongated, “bipolar” morphology, extending a long leading process that explores the environment. However, when immature projection neurons enter the intermediate zone (IZ) of the neocortex they become “multipolar”. Multipolar cells extend and retract cytoplasmic processes in different directions and move erratically—sideways, up and down. Multipolar cells extend axons while they are in the lower half of the IZ. Remarkably, the cells then resume radial migration: they reorient their centrosome and Golgi apparatus towards the pia, transform back to bipolar morphology, and commence locomotion along radial glia (RG) fibers. This reorientation implies the existence of directional signals in the IZ that are ignored during the multipolar stage but sensed after axonogenesis. In vivo genetic manipulation has implicated a variety of candidate directional signals, cell surface receptors, and signaling pathways, that may be involved in polarizing multipolar cells and stabilizing a pia-directed leading process for radial migration. Other signals are implicated in starting multipolar migration and triggering axon outgrowth. Here we review the molecules and mechanisms that regulate multipolar migration, and also discuss how multipolar migration affects the orderly arrangement of neurons in layers and columns in the developing neocortex. http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00386/abstract Dionisio

The big data challenges of connectomics doi:10.1038/nn.3837 The structure of the nervous system is extraordinarily complicated because individual neurons are interconnected to hundreds or even thousands of other cells in networks that can extend over large volumes. Mapping such networks at the level of synaptic connections, a field called connectomics, began in the 1970s with a the study of the small nervous system of a worm and has recently garnered general interest thanks to technical and computational advances that automate the collection of electron-microscopy data and offer the possibility of mapping even large mammalian brains. However, modern connectomics produces 'big data', unprecedented quantities of digital information at unprecedented rates, and will require, as with genomics at the time, breakthrough algorithmic and computational solutions. Here we describe some of the key difficulties that may arise and provide suggestions for managing them. http://www.nature.com/neuro/journal/v17/n11/pdf/nn.3837.pdf Dionisio

#607 bornagain77 Yes, that's a very good idea. Thank you. I'm looking into this. A friend suggested using online Mind Meister in combination with hierarchically connected blogs grouping topics and subtopics with their own categories within each of them. Also exploring, with my wife's help, free online access database (cloud based), which allows sorting by DOI and category tags. Will provide a link to that when ready for review, so that we can adjust it while it grows. Dionisio

Dionisio, there is veritable gold mine of information here. It would be wonderful if you could format all this information into a 'easily accessible' hierarchy of some type. Perhaps others on UD, who have organized other things on UD, can help with some suggestions as in how to properly organize it so as to be of ready use on UD.,,, kf, gppucio, any thoughts? bornagain77

#579 bornagain77 Thought about your suggestion and decided to continue posting here some of the materials for review. Thank you. Dionisio

Bivalent histone modifications during tooth development doi: 10.1038/ijos.2014.60 Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation. Dionisio

Molecular regulation of effector and memory T cell differentiation doi:10.1038/ni.3031 Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy. Dionisio

"The holy grail of cell biology is a ‘complete’ description of the structure and function of an organelle, cell, tissue, or even of an organism, at molecular resolution." Systems biology in 3D space – enter the morphome John M. Lucocq1, Terry M. Mayhew 2, Yannick Schwab 3, Anna M. Steer 3, and Christian Hacker1 1 School of Medicine, University of St Andrews, St Andrews KY16 9TF, UK 2 School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK 3 Electron Microscopy Core Facility, Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1,69117 Heidelberg, Germany Trends in Cell Biology xx (2014) 1–6 1 0962-8924/ 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tcb.2014.09.008 Dionisio

regulation of size, pattern and alignment of tissues doi: http://dx.doi.org/10.1242/dev.109603 Dionisio

Edward

Always amazing. Too bad that I understand so little in the cited articles, but they are still interesting.

"Too bad that I understand so little in the cited articles..." Join the club! :) Honesty and humility are very rare virtues listed in the endangered species catalog. Blessed are those very few who still have it. :) "Always amazing" By humbly recognizing how amazing all that is, you're far ahead of many folks out there who look arrogantly at that amazing stuff through rose-colored reductionist glasses and loudly proclaim it ain't as amazing as it seems to be. Dionisio

Always amazing. Too bad that I understand so little in the cited articles, but they are still interesting. Edward

*********************************************************** *********************************************************** *********************************************************** Very interesting summary written by gpuccio:

Indeed, what we see in research about cell differentiation and epigenomics is a growing mass of detailed knowledge (and believe me, it is really huge and daily growing) which seems to explain almost nothing. What is really difficult to catch is how all that complexity is controlled. Please note, at this level there is almost no discussion about how the complexity arose: we have really non idea of how it is implemented, and therefore any discussion about its origin is almost impossible. Now, there must be information which controls the flux. It is a fact that cellular differentiation happens, that it happens with very good order and in different ways in different species, different tissues, and so on. That cannot happen without a source of information. And yet, the only information that we understand clearly is then protein sequence information. Even the regulation of protein transcription at the level of promoters and enhancers by the transcription factor network is of astounding complexity. Please, look at this paper: Uncovering Enhancer Functions Using the ?-Globin Locus. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199490/pdf/pgen.1004668.pdf In particular Fig. 2. And this is only to regulate the synthesis of alpha globin in red cells, a very straightforward differentiation task. So, I see that, say, 15 TFs are implied in regulating the synthesis of one protein, I want to know why, and what controls the 15 TFs, and what information guides that control. My general idea is that, unless we find some completely new model, information that guides a complex process, like differentiation, in a reliable, repetitive way must be written, in some way, somewhere. That’s what I want to know: where that information is written, how it is written, how does it work, and, last but not least, how did it originate? --- gpuccio

*********************************************************** *********************************************************** *********************************************************** Dionisio

Intrinsic genetic programs...? Specification of neuronal subtypes by different levels of Hunchback doi: http://dx.doi.org/10.1242/dev.113381 During the development of the central nervous system, neural progenitors generate an enormous number of distinct types of neuron and glial cells by asymmetric division. Intrinsic genetic programs define the combinations of transcription factors that determine the fate of each cell, but the precise mechanisms by which all these factors are integrated at the level of individual cells are poorly understood. Dionisio

Closing in??? Receptor signaling: Closing in on a mechanism for activation DOI: http://dx.doi.org/10.7554/eLife.04909 Nevertheless, precisely how these small proteins activate their receptors is still something of a mystery. This is essentially the opposite mechanism to that proposed by Kavran et al. Further work is needed to resolve these conflicting models of activation. Other key questions remain unanswered. The nature of this steric constraint is unknown. Thus, the juxtamembrane regions of the IGF1 receptor and insulin receptor hold mechanistic secrets yet to be revealed. Dionisio

A Competitive Cell Fate Switch DOI: http://dx.doi.org/10.1016/j.devcel.2014.10.016 Whereas tissue development and homeostasis depend on stem cell self-renewal and differentiation, the mechanisms that balance these processes remain incompletely understood. Pan et al. (2014) now show that competitive protein-protein interactions between Bam and COP9 signalosome components regulate cell fate decisions within the Drosophila ovarian germline stem cell lineage. Dionisio

Systems biology in 3D space – enter the morphome DOI: http://dx.doi.org/10.1016/j.tcb.2014.09.008 Systems-based understanding of living organisms depends on acquiring huge datasets from arrays of genes, transcripts, proteins, and lipids. These data, referred to as ‘omes’, are assembled using ‘omics’ methodologies. Currently a comprehensive, quantitative view of cellular and organellar systems in 3D space at nanoscale/molecular resolution is missing. We introduce here the term ‘morphome’ for the distribution of living matter within a 3D biological system, and ‘morphomics’ for methods of collecting 3D data systematically and quantitatively. A sampling-based approach termed stereology currently provides rapid, precise, and minimally biased morphomics. We propose that stereology solves the ‘big data’ problem posed by emerging wide-scale electron microscopy (EM) and can establish quantitative links between the newer nanoimaging platforms such as electron tomography, cryo-EM, and correlative microscopy. •We define the morphome as the distribution of matter in a 3D object. •Morphomics methods characterize or quantify 3D data at ground truth level. •Stereology is the most efficient and precise archetypal morphomics method. •Stereology can be applied to solve the big data problem in serial EM. •Stereology can be applied to make quantitative links between nanoscale imaging modes. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00166-4 Dionisio

#590 gpuccio

cell regulation across different cells and species seems to be a very strange mix of conservation, divergence and flexibility! Wonderful indeed.

Agree. Although, perhaps Wonderful is an understatement. :) Dionisio

correction to post #592: "infer something beyond information and matter; something that coordinates it and gives it meaning." Box

Gpuccio: Thank you, I can certainly agree. But I would like to be able to detect the effect of non material components in material observables.

Gpuccio, thank you for your kind open response. I did not expect that ... I wonder if it will ever be possible to scientifically detect things like "harmony" or "unity" and infer something beyond information. Maybe there is no other way than to just 'see' it. Box

Box: Thank you, I can certainly agree. But I would like to be able to detect the effect of non material components in material observables. Indeed, design detection is a first step. The essence itself of design is that the specific form is outputted from a conscious representation to a material object. And that is done purposefully. So, in the act of design we have at the same time cognition (the meaning of the information) and felling, desire, love (the purpose which has to be attained by the information itself). I am convinced that design theory is a new paradigm for science, which in time will allow a new, and much better, map of reality. Certainly more holistic, but also able to explain better what we observe in material things. gpuccio

Dionisio: "Those elaborate choreographic networks at different levels sometimes seem to increase the robustness of the whole system, sometimes they seem to be independent, sometimes they seem to depend on one another, sometimes they seem to operate parallel and sometimes sequentially. " I think you have caught exactly the point: cell regulation across different cells and species seems to be a very strange mix of conservation, divergence and flexibility! Wonderful indeed. Ottimo lavoro! gpuccio

A holistic position is an interesting model, but how do you envision it? I am completely open to all suggestions, because this is really something that we at present do not understand.

Let me give it a try. I hold that there must be at least one non-material component - other than information - present in life. This component has a encompassing, harmonizing and orchestrating role. Let's call it 'love' - to be understood in a general way; not necessarily the romantic kind. An important ground for my proposal is the notion that reason is empty without 'love'; just empty words. And why would it be any different for information? - If I speak in the tongues of men or of angels, but do not have love, I am only a resounding gong or a clanging cymbal. Box

586 gpuccio eccellente mio caro Dottore!!! simply excellent!!! that's exactly it. Io sono en completo accordo. (?) mille grazie! :) Dionisio

gpuccio I think your excellent question resides exactly at the core of this whole informational puzzle that fascinate us so strongly, as you well stated. At this point of my ignorance this seems to be a blurry 'all of the above' type of answers. As you wrote, the amount of information on this subject seems to increase at a fast pace lately. It's simply overwhelming to me. But as you said, that's good. I like it this way. :) Those elaborate choreographic networks at different levels sometimes seem to increase the robustness of the whole system, sometimes they seem to be independent, sometimes they seem to depend on one another, sometimes they seem to operate parallel and sometimes sequentially. As you know, I have a substantial disadvantage studying this, due to my poor knowledge of the subject. This is why I highly appreciate your insightful comments on this subject. This is at the center of my current autodidact studies. The increasing complexity of this enormous puzzle has forced me to consider different software tools to organize the whole thing in order to make it easier for me to chew and digest it. :) Lately I've been playing with the mind mapping tool Mind Meister. However, already have encountered some frustrating difficulties associated with what you just wrote in your posts 583 and 584 here. As you can see, reading your comments have given me some relief because now I see that the difficulties I've encountered are seen by more educated folks like you. :) Thank you. Have a good weekend. Dionisio

Box: What you say is very interesting. Indeed, what we see in research about cell differentiation and epigenomics is a growing mass of detailed knowledge (and believe me, it is really huge and daily growing) which seems to explain almost nothing. What is really difficult to catch is how all that complexity is controlled. Please note, at this level there is almost no discussion about how the complexity arose: we have really non idea of how it is implemented, and therefore any discussion about its origin is almost impossible. Now, there must be information which controls the flux. It is a fact that cellular differentiation happens, that it happens with very good order and in different ways in different species, different tissues, and so on. That cannot happen without a source of information. And yet, the only information that we understand clearly is then protein sequence information. Even the regulation of protein transcription at the level of promoters and enhancers by the transcription factor network is of astounding complexity. Please, look at this paper: Uncovering Enhancer Functions Using the ?-Globin Locus. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199490/pdf/pgen.1004668.pdf In particular Fig. 2. And this is only to regulate the synthesis of alpha globin in red cells, a very straightforward differentiation task. Now, a holistic position is very interesting, but it must be clearly formulated, and it must explain in some way the analytic details that we observe. Facts are fact: no theory can cancel them. So, I see that, say, 15 TFs are implied in regulating the synthesis of one protein, I want to know why, and what controls the 15 TFs, and what information guides that control. My general idea is that, unless we find some completely new model, information that guides a complex process, like differentiation, in a reliable, repetitive way must be written, in some way, somewhere. That's what I want to know: where that information is written, how it is written, how does it work, and, last but not least, how did it originate? A holistic position is an interesting model, but how do you envision it? I am completely open to all suggestions, because this is really something that we at present do not understand. gpuccio

Gpuccio, I don't mean to annoy you (or Dionisio) with my holistic ideas, and please say so if I do, but isn't it true that all these interactions between different strata point towards an top-down orchestration from the level of the whole? From what we see, isn't it most likely that there isn't a bottom-up explanation for the goings on in life? - - p.s. Do you think that there is a way to scientifically prove a holistic position? Box

Dionisio: I forgot cell to cell signaling! :) gpuccio

Dionisio: I believe that we are both fascinated and amazed at the huge information that is being gathered about cell development. I have been reading scientific papers almost daily, in the last few months, about the subject, and I have growing questions, rather than growing answers. Maybe that is good. I wanted to ask your opinion on what is maybe my biggest question. I have come to regard the constant flux of information between epigenome-genome-epigenome as the only possible way to correctly describe cell differentiation. Indeed, that flux is never interrupted, from the zygote to the adult being to a new zygote. As the information seems to reside on multiple levels: - genome, both coding and non coding - genome methylation - histone modifications - chromatin modifications - transcription factors network - regulatory RNAs (all the various forms) - post-translational modifications - asymmetric mytosis and probably others, my greatest difficulty is to get some clues about how those different strata interact: IOWs, are they independent, parallel networks which ensure a supreme redundancy and robustness, or do they work, at least in part, in sequences? What do you think? I have found really little about that, in the literature. gpuccio

Here's a brief chat with a technical journal, after reading a very interesting article they published today. Part of the article is quoted here:

GEN News Highlights Nov 5, 2014 Critical Mass of Stem Cells Sets Off Embryonic Development in the Lab ...researchers at the University of Cambridge have managed to reconstruct the early stages of mammalian development using [...] embryonic stem cells, showing that a critical mass of cells—not too few, but not too many—is needed for the cells to begin self-organizing into the correct structure for an embryo to form. By manipulating the signals that the cells see at a particular time, the researchers were able to influence what type of cell they become and how they are organized. ...activation of a particular signal at the correct time elicits the appearance of the mesoderm, endoderm, and ectoderm—the precursors of all cell types—with a spatial organization similar to that of an embryo. http://www.genengnews.com/gen-news-highlights/critical-mass-of-stem-cells-sets-off-embryonic-development-in-the-lab/81250559/

I posted a few comments with some of these questions:

What exactly makes that 'critical mass' to work? What fails when the number of SCs is less than the critical mass number? What goes wrong when the number of SCs is greater than the critical mass number? What mechanisms determine which particular signal is activated in vivo? What mechanisms determine the correct time for the given signal to be activated in vivo?

there are more questions, but these are enough for now. The journal nicely responded:

Posted 11/05/2014 by Patrice Bartell Here is some information provided by the University of Cambridge press office: The researchers show that if the number of cells aggregated initially is similar to that of a mouse embryo, the cells generate a single axis and this serves as a template for a sequence of events that mimics those of the early embryo. By manipulating the signals that the cells see at a particular time, the researchers were able to influence what type of cell they become and how they are organized. In one of the experiments, for example, activation of a particular signal at the correct time elicits the appearance of the mesoderm, endoderm and ectoderm. The abstract adds that: The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. So, to be more correct, there’s more involved than simply having the right number of cells. Signal manipulation, too, comes into play. For more, you’ll need to access the full article: S. C. van den Brink, P. Baillie-Johnson, T. Balayo, A.-K. Hadjantonakis, S. Nowotschin, D. A. Turner, A. Martinez Arias. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development, 2014; 141 (22): 4231 DOI: 10.1242/dev.113001 http://dev.biologists.org/content/141/22/4231

Next I plan to read the original paper and contact the authors with my questions, if I can't find the answer. :) Dionisio

Found scrawled on the bathroom wall at the University of Chicago:

There once was a third-wayer from Nantucket Inspite of darwindian thoughts and other theories sought couldn't explain why cells kick the bucket.

Edward

BA77 Yes, as per your request, will try to share a link to the information I'm gathering, sorting and reviewing. It's a mix of online information mapping (using Mind Meister) connected to multiple Wordpress blogs for separate topics and subtopics. But this whole process is very time-consuming and it requires a good deal of dedicated work. Now took a break to stop by UD and see what's going on here. Noticed quite a bit of heated discussions in some new threads and a few new names among the commenters. Still appreciate your posts loaded with interesting information. Good job! Keep it up! curious lurker

Dionisio, If you do organize into a file please do share the link. bornagain77

It was fun to post in this thread for almost 5 months, but time is up to move on. I may continue to review and organize these materials using online tools like Mind Meister. Ciao amici! Dionisio

Regulation of patterning, cell fate specification, and neurocircuitry in the developing cerebral cortex The cerebral cortex, the seat of our highest cognitive and perceptual functions, arises from a simple sheet of neuroepithelial tissue. Creating this structure poses an extraordinary developmental challenge. Transcription factor Lhx2 plays a fundamental role, acting as a “selector gene” for cortical fate. Lhx2-null cells cannot become cortex, but instead differentiate into an adjacent type of tissue, the hem, that functions as a signaling center in the brain. Using wild-type and Lhx2-null embryonic stem cell chimeras, we created embryos with ectopic hems, each of which patterned the adjacent cortex into an ectopic hippocampus. These results provide insight not only into how cortical fate is specified, but also into how specific cortical structures are positioned in the brain by the action of organizing centers. Lhx2 plays additional spatio-temporally distinct roles in the developing brain. After the critical period for its cortical selector function has ended, it plays a necessary and sufficient role in regulating the neuron-glia cell fate switch in the hippocampus. In the neocortex, it regulates neurocircuitry in the somatosensory cortex, such that the barrels do not form in the absence of cortical Lhx2 function. Lhx2 is therefore a central regulator of cortical development, with multiple roles at fundamental steps – patterning, cell fate specification, and the formation of neurocircuitry. http://ist.ac.at/de/veranstaltungen/vorlesungen-vortraege/seminar-talks/2014/09/regulation-of-patterning-cell-fate-specification-and-neurocircuitry-in-the-developing-cerebral-cortex/date/157/ Dionisio

Cell fate specification in early embryogenesis The main goal of our research is to identify molecular mechanisms underlying the establishment of the basic body organization in the Arabidopsis early embryo. The asymmetric division of the zygote generates a small apical (embryogenic) cell and a large basal (extra-embryogenic) cell that differ from one another in gene expression, cell division pattern and developmental fate. How these differences are initially set up is analyzed from several perspectives. One approach makes use of fluorescent markers that are differentially expressed between the two cell lineages and enables sorting of nuclei followed by expression profiling. This is to yield inventories of genes that are specifically expressed in the embryonic or extra-embryonic lineages, and to eventually lead to the identification and functional analysis of relevant transcriptional regulators. Another approach focuses on the role of auxin response in early embryogenesis, notably in cell-communication resulting in cell fate specification events. A well known example is the interaction of ARF transcription factor MP and its AUX/IAA inhibitor BDL in the embryonic lineage. This interaction regulates auxin transport via the efflux carrier PIN1 to the future basal pole and activates the expression of a mobile transcription factor TMO7, both of which together mediate the specification of the founder cell for the root stem-cell system (Schlereth et al., 2010). A different auxin-response machinery acts in the basal lineage, and one of the challenges is to analyze how the two systems are initially set up and how they might be interrelated. Finally, the goal is to determine when and how the initial apical-basal polarity of the embryo is established http://www.eb.tuebingen.mpg.de/research/departments/cell-biology/cell-fate-specification-in-early-embryogenesis.html Dionisio

Minireview: pioneer transcription factors in cell fate specification doi: 10.1210/me.2014-1084. The specification of cell fate is critical for proper cell differentiation and organogenesis. In endocrine tissues, this process leads to the differentiation, often a multistep process, of hormone-producing cells. This process is driven by a combination of transcription factors (TFs) that includes general factor, tissue-restricted, and/or cell-restricted factors. The last 2 decades have seen the discovery of many TFs of restricted expression and function in endocrine tissues. These factors are typically critical for expression of hormone-coding genes as well as for differentiation and proper function of hormone-producing cells. Further, genes encoding these tissue-restricted TFs are themselves subject to mutations that cause hormone deficiencies. Although the model that emerged from these 2 decades is one in which a specific combination of TFs drives a unique cell specification and genetic program, recent findings have led to the discovery of TFs that have the unique property of being able to remodel chromatin and thus modify the epigenome. Most importantly, such factors, known as pioneer TFs, appear to play critical roles in programming the epigenome during the successive steps involved in cell specification. This review summarizes our current understanding of the mechanisms for pioneer TF remodeling of chromatin. Currently, very few TFs that have proven pioneer activity are known, but it will be critical to identify these factors and understand their mechanisms of action if we are to harness the potential of regenerative therapies in endocrinology. http://www.ncbi.nlm.nih.gov/pubmed/24825399 Dionisio

Querius Yes, agree, that's a very good report. Dionisio

(About the mitochondria, of course!) Querius

Astounding! Thank you, -Q Querius

Shaking up cell biology: Researchers focus in on decades-old mitochondrial mystery The mitochondria also appear to synchronize their movements not only in an individual cell but, quite unexpectedly, into a linked network of oscillators vibrating throughout the tissue. "You look through the microscope, and it almost looks like a synchronized dance," said Weigert. "The synchronization, to borrow an old cliché, tells us that we need to differentiate the forest from the trees—and vice versa—when studying mitochondria. It may be that the forest holds the key to understanding how mitochondria function in human health and disease." The mitochondrion (the singular of mitochondria) is of one of several distinct compartments, or organelles, in the cell cytoplasm. Although mitochondria are jacks of many biochemical trades, they are best known as the power plants of the cell. They generate a continuous supply of the molecule ATP that, like bits of coal, serve as the cell's main source of energy to power the heart to beat, muscles to stretch, and virtually every movement that the body makes. To keep cells fully charged, mitochondria operate four biochemical production lines that coalesce with oxygen molecules from normal respiration to produce ATP. One of these production lines starts with processing the molecule nicotinamide adenine dinucleotide, or NADH. Weigert and colleagues recognized that they could use their high-magnificati on microscope to visualize NADH as it naturally emits electrons as part of the ATP production process. The powerful optics allowed the scientists to visualize the oscillations in their native milieu and to puzzle over their cause. Based on a series of subsequent experiments and observations, the researchers discovered that the oscillations are linked to the production of reactive oxygen species, a chemically interactive byproduct of making ATP. This finding suggests that the oscillations likely are not inherent to mitochondria but a response to conditions in their environment. "These findings emphasize how important it is scientifically to study biology on its own terms, not under artificial laboratory conditions," said Natalie Porat-Shliom, an NIDCR scientist and lead author on the paper. "We saw things in live animals that you don't see in cell culture. The reasons, in this case, very well may be that the mitochondria continue to receive an influx of signals from the blood vessels, the nervous system, and their surrounding environment. The entire system can't be reassembled in cell culture." http://phys.org/print333097232.html Dionisio

Wow!, finally, they figured it out! Research Yields Possible Precursor to Life How did life originate? And can scientists create life? These questions not only occupy the minds of scientists interested in the origin of life, but also researchers working with technology of the future. If we can create artificial living systems, we may not only understand the origin of life, we can also revolutionize the future of technology. http://www.laboratoryequipment.com/news/2014/10/research-yields-possible-precursor-life?et_cid=4220068&et_rid=653535995&type=cta Dionisio

Genomic Control Process Genomic Control Process explores the biological phenomena around genomic regulatory systems that control and shape animal development processes, and which determine the nature of evolutionary processes that affect body plan. Unifying and simplifying the descriptions of development and evolution by focusing on the causality in these processes, it provides a comprehensive method of considering genomic control across diverse biological processes. This book is essential for graduate researchers in genomics, systems biology and molecular biology seeking to understand deep biological processes which regulate the structure of animals during development. Covers a vast area of current biological research to produce a genome oriented regulatory bioscience of animal life Places gene regulation, embryonic and postembryonic development, and evolution of the body plan in a unified conceptual framework Provides the conceptual keys to interpret a broad developmental and evolutionary landscape with precise experimental illustrations drawn from contemporary literature Includes a range of material, from developmental phenomenology to quantitative and logic models, from phylogenetics to the molecular biology of gene regulation, from animal models of all kinds to evidence of every relevant type Demonstrates the causal power of system-level understanding of genomic control process Contents 1. The Genome in Development 2. Gene Regulatory Networks 3. Genomic Strategies for Embryonic Development 4. Genomic Control Processes in Adult Body Part Formation 5. Genomic Strategies for Cell Fate Determination 6. Predictive Gene Regulatory Network Models 7. Evolution of Bilaterian Animals: Processes of Change and Stasis in Hierarchical Developmental GRNs Let's wait and see... Dionisio

Computational Systems Biology http://www.sciencedirect.com/science/book/9780124059269 Dionisio

#565 addendum Transcriptional Switches During Development The general concepts of transcriptional regulation are now well established, a major challenge resides in understanding the logic and physical elements implementing these regulatory interactions within a given cell in a developing organism. A central problem to be addressed is how transcriptional programs are set up and then modified throughout the successive steps of embryonic development. The book Transcriptional Switches during Development provides a broad range of insights into the molecular determinants of such transcriptional switches during development. It summarizes efforts to tackle this question in various model systems, each with their advantages and limitations. These contributions also show that different scales of analysis are required together to solve the problem of gene expression control during development. It is believed that the combination of both genome-wide approaches (experimental or predictive) and functional analyses scrutinizing the intimate details of each element is the most promising way to unravel the control of terminal differentiation and its evolutionary diversification. Dionisio

Sertoli Cell Biology http://www.sciencedirect.com/science/book/9780126477511 Dionisio

Transcriptional Switches During Development http://www.elsevier.com/books/transcriptional-switches-during-development/unknown/978-0-12-386499-4 Dionisio

Structural Biology Research Members of Princeton's vibrant structural biology community—students, postdocs, and faculty—make use of a wide array of cutting-edge methods to gain insight into biological structure and mechanism. Some examples of the approaches being used, and in some cases developed, at Princeton include x-ray crystallography, electron microscopy, mass spectrometry, NMR spectroscopy, super-resolution optical microscopy, single-molecule methods, and computational modeling. These tools are being applied to biological problems ranging from protein folding and design, to signal transduction, to intracellular trafficking. Structural biology is an intrinsically interdisciplinary activity; Princeton provides a supportive and exceptionally collegial environment for students to receive training in these areas while, at the same time, contributing to fundamental discoveries about form and function in the biological world. http://molbio.princeton.edu/faculty/research/structural-biology Dionisio

Structural biology seeks to provide a complete and coherent picture of biological phenomena at the molecular and atomic level. The goals of structural biology include developing a comprehensive understanding of the molecular shapes and forms embraced by biological macromolecules and extending this knowledge to understand how different molecular architectures are used to perform the chemical reactions that are central to life. In addition, structural biologists are interested in understanding related processes such as protein folding, protein dynamics, molecular modeling, drug design, and computational biology. Central tools used in this research include X-ray diffraction, NMR, electron microscopy, other spectroscopies and biophysical methods, protein expression, bio-physical and bio-organic chemistry, computer science and bioengineering. https://biology.mit.edu/research/structural_biology Dionisio

Structural Choreography of Cellular Self-Digestion http://www.mskcc.org/events/seminar/Structural-Choreography-Cellular-Self-Digestion Dionisio

Stem Cell Peaks Yet Unscaled http://www.genengnews.com/gen-articles/stem-cell-peaks-yet-unscaled/5319/?page=1 Dionisio

Illuminating the Multifaceted Roles of Neurotransmission in Shaping Neuronal Circuitry DOI: http://dx.doi.org/10.1016/j.neuron.2014.08.029 Across the nervous system, neurons form highly stereotypic patterns of synaptic connections that are designed to serve specific functions. Mature wiring patterns are often attained upon the refinement of early, less precise connectivity. Much work has led to the prevailing view that many developing circuits are sculpted by activity-dependent competition among converging afferents, which results in the elimination of unwanted synapses and the maintenance and strengthening of desired connections. Studies of the vertebrate retina, however, have recently revealed that activity can play a role in shaping developing circuits without engaging competition among converging inputs that differ in their activity levels. Such neurotransmission-mediated processes can produce stereotypic wiring patterns by promoting selective synapse formation rather than elimination. We discuss how the influence of transmission may also be limited by circuit design and further highlight the importance of transmission beyond development in maintaining wiring specificity and synaptic organization of neural circuits. Dionisio

Stem Cells Defy Germ Layer Destiny http://www.genengnews.com/gen-news-highlights/stem-cells-defy-germ-layer-destiny/81250479/ Dionisio

Proteogenomics: Integrating Proteomics and Genomics to Unlock Biological Function http://www.genengnews.com/insight-and-intelligence/proteogenomics-integrating-proteomics-and-genomics-to-unlock-biological-function/77900284/ Dionisio

Information-limiting correlations doi:10.1038/nn.3807 Computational strategies used by the brain strongly depend on the amount of information that can be stored in population activity, which in turn strongly depends on the pattern of noise correlations. In vivo, noise correlations tend to be positive and proportional to the similarity in tuning properties. Such correlations are thought to limit information, which has led to the suggestion that decorrelation increases information. In contrast, we found, analytically and numerically, that decorrelation does not imply an increase in information. Instead, the only information-limiting correlations are what we refer to as differential correlations: correlations proportional to the product of the derivatives of the tuning curves. Unfortunately, differential correlations are likely to be very small and buried under correlations that do not limit information, making them particularly difficult to detect. We found, however, that the effect of differential correlations on information can be detected with relatively simple decoders. http://www.nature.com/neuro/journal/v17/n10/full/nn.3807.html Dionisio

Genome-wide identification and characterization of functional neuronal activity–dependent enhancers doi:10.1038/nn.3808 Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease. http://www.nature.com/neuro/journal/v17/n10/full/nn.3808.html Dionisio

important constraints on models of the neuronal mechanisms underlying cognitive factors Attention can either increase or decrease spike count correlations in visual cortex doi:10.1038/nn.3835 Visual attention enhances the responses of visual neurons that encode the attended location. Several recent studies have shown that attention also decreases correlations between fluctuations in the responses of pairs of neurons (termed spike count correlation or rSC). These results are consistent with two hypotheses. First, attention-related changes in rate and rSC might be linked (perhaps through a common mechanism), with attention always decreasing rSC. Second, attention might either increase or decrease rSC, possibly depending on the role of the neurons in the behavioral task. We recorded simultaneously from dozens of neurons in area V4 while monkeys performed a discrimination task. We found strong evidence in favor of the second hypothesis, showing that attention can flexibly increase or decrease correlations depending on whether the neurons provide evidence for the same or opposite choices. These results place important constraints on models of the neuronal mechanisms underlying cognitive factors. http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3835.html Dionisio

In a biological system so many things can easily mess things up that I'm amazed the whole thing still works so many times. http://www.nature.com/nrc/posters/pathways/index.html Dionisio

Pathways represented as a subway map [kind of old, but still interesting poster] http://www.nature.com/nrc/posters/subpathways/index.html Dionisio

Molecular mechanisms of stem-cell identity and fate Fiona M. Watt and Kevin Eggan Stem cells have been identified and characterized in several mammalian tissues. In addition, pluripotent embryonic stem cells have been derived from pre-implantation embryos in both mice and humans. Whereas the recent advances in stem-cell research have the potential to revolutionize medicine, the critical scientific challenge remains to elucidate the fundamental cellular and molecular controls of stem cells. An understanding of the molecular mechanisms that govern stem-cell fate and the identification of specific stem-cell markers is of fundamental significance in cell and developmental biology. This Poster provides an overview of distinct embryonic and adult stem-cell types and the stem-cell markers that have been used to identify stem cells and cancer-stem-cell-enriched populations. The Poster is freely available thanks to support from Abcam. View this poster as a high-resolution PDF (2,855 KB) http://www.nature.com/nrc/posters/stemcell/index.html Dionisio

Haematopoietic stem cells, niches and differentiation pathways Thomas Graf and Andreas Trumpp Haematopoietic stem cells (HSCs) are characterized by extensive self-renewal capacity and the ability to differentiate into multiple cell lineages of the immune system. Much current research is focused on understanding the nature of HSC niches and the molecular interactions between cells in these niches. The nature of the early stages of HSC development is also a hot topic in the HSC field. This poster provides an overview of HSC niches, including details of the molecules that mediate interactions between HSCs, osteoblasts and CXCL12-expressing reticular cells in these niches. The differentiation pathways of HSC-derived cells of the immune system are also illustrated, including the lineage-instructive factors that mediate each developmental stage. The poster is freely available thanks to support from Abcam. http://www.nature.com/nri/posters/hsc/index.html Dionisio

549 follow-up Anchoring the neural compass: coding of local spatial reference frames in human medial parietal lobe doi:10.1038/nn.3834 The neural systems that code for location and facing direction during spatial navigation have been investigated extensively; however, the mechanisms by which these quantities are referenced to external features of the world are not well understood. To address this issue, we examined behavioral priming and functional magnetic resonance imaging activity patterns while human subjects recalled spatial views from a recently learned virtual environment. Behavioral results indicated that imagined location and facing direction were represented during this task, and multivoxel pattern analyses indicated that the retrosplenial complex (RSC) was the anatomical locus of these spatial codes. Critically, in both cases, location and direction were defined on the basis of fixed elements of the local environment and generalized across geometrically similar local environments. These results suggest that RSC anchors internal spatial representations to local topographical features, thus allowing us to stay oriented while we navigate and retrieve from memory the experience of being in a particular place. http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3834.html Dionisio

Brain’s Compass Relies on Geometric Relationships http://www.biosciencetechnology.com/videos/2014/10/brain%E2%80%99s-compass-relies-geometric-relationships?et_cid=4212828&et_rid=653535995&location=top Dionisio

A Dynamic Microtubule Cytoskeleton Directs Medial Actomyosin Function during Tube Formation DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.023 The cytoskeleton is a major determinant of cell-shape changes that drive the formation of complex tissues during development. Important roles for actomyosin during tissue morphogenesis have been identified, but the role of the microtubule cytoskeleton is less clear. Here, we show that during tubulogenesis of the salivary glands in the fly embryo, the microtubule cytoskeleton undergoes major rearrangements, including a 90° change in alignment relative to the apicobasal axis, loss of centrosomal attachment, and apical stabilization. Disruption of the microtubule cytoskeleton leads to failure of apical constriction in placodal cells fated to invaginate. We show that this failure is due to loss of an apical medial actomyosin network whose pulsatile behavior in wild-type embryos drives the apical constriction of the cells. The medial actomyosin network interacts with the minus ends of acentrosomal microtubule bundles through the cytolinker protein Shot, and disruption of Shot also impairs apical constriction. Dionisio

Neural Stem Cell Differentiation Is Dictated by Distinct Actions of Nuclear Receptor Corepressors and Histone Deacetylases DOI: http://dx.doi.org/10.1016/j.stemcr.2014.07.008 Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear. Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs. The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs. The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression. Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9. Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors. Dionisio

Endoderm Generates Endothelial Cells during Liver Development DOI: http://dx.doi.org/10.1016/j.stemcr.2014.08.009 Organogenesis requires expansion of the embryonic vascular plexus that migrates into developing organs through a process called angiogenesis. Mesodermal progenitors are thought to derive endothelial cells (ECs) that contribute to both embryonic vasculogenesis and the subsequent organ angiogenesis. Here, we demonstrate that during development of the liver, which is an endoderm derivative, a subset of ECs is generated from FOXA2+ endoderm-derived fetal hepatoblast progenitor cells expressing KDR (VEGFR2/FLK-1). Using human and mouse embryonic stem cell models, we demonstrate that KDR+FOXA2+ endoderm cells developing in hepatic differentiation cultures generate functional ECs. This introduces the concept that ECs originate not exclusively from mesoderm but also from endoderm, supported in Foxa2 lineage-tracing mouse embryos by the identification of FOXA2+ cell-derived CD31+ ECs that integrate the vascular network of developing fetal livers. Dionisio

The 3D Genome in Transcriptional Regulation and Pluripotency DOI: http://dx.doi.org/10.1016/j.stem.2014.05.017 It can be convenient to think of the genome as simply a string of nucleotides, the linear order of which encodes an organism’s genetic blueprint. However, the genome does not exist as a linear entity within cells where this blueprint is actually utilized. Inside the nucleus, the genome is organized in three-dimensional (3D) space, and lineage-specific transcriptional programs that direct stem cell fate are implemented in this native 3D context. Here, we review principles of 3D genome organization in mammalian cells. We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked. Dionisio

A Quantitative Framework to Evaluate Modeling of Cortical Development by Neural Stem Cells DOI: http://dx.doi.org/10.1016/j.neuron.2014.05.035 Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease. Dionisio

The promise of organotypic models DOI: http://dx.doi.org/10.1016/j.tibtech.2014.04.006 Advances in the design and assembly of in vitro organotypic liver and gastrointestinal (GI) models can accelerate our understanding of metabolism, nutrient absorption, and the effect of microbial flora. Such models can provide comprehensive information on how of environmental toxins, drugs, and pharmaceuticals interact with and within these organs. Information obtained from such models could elucidate the complicated cascades of signaling mechanisms that occur in vivo. Because experiments on large-scale animal models are expensive and resource intensive, the design of organotypic models has renewed significance. The challenges and approaches to designing liver and GI models are similar. Because these organs are in close proximity and interact continually, we have described recent design considerations to guide future tissue models. Dionisio

Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.021 During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typeI>0 switch is triggered by activation of Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS. Dionisio

How Kinetochores CCAN Resist Force DOI: http://dx.doi.org/10.1016/j.devcel.2014.09.007 Kinetochores orchestrate chromosome segregation during mitosis and must cope with dynamic forces generated by attached microtubules. In this issue of Developmental Cell, Suzuki et al. (2014) demonstrate that the constitutive centromere-associated network (CCAN) displays a complex architecture that plays a crucial role in resisting these forces. Dionisio

Combining Genetic Perturbations and Proteomics to Examine Kinase-Phosphatase Networks DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.027 Connecting phosphorylation events to kinases and phosphatases is key to understanding the molecular organization and signaling dynamics of networks. We have generated a validated set of transgenic RNA-interference reagents for knockdown and characterization of all protein kinases and phosphatases present during early Drosophila melanogaster development. These genetic tools enable collection of sufficient quantities of embryos depleted of single gene products for proteomics. As a demonstration of an application of the collection, we have used multiplexed isobaric labeling for quantitative proteomics to derive global phosphorylation signatures associated with kinase-depleted embryos to systematically link phosphosites with relevant kinases. We demonstrate how this strategy uncovers kinase consensus motifs and prioritizes phosphoproteins for kinase target validation. We validate this approach by providing auxiliary evidence for Wee kinase-directed regulation of the chromatin regulator Stonewall. Further, we show how correlative phosphorylation at the site level can indicate function, as exemplified by Sterile20-like kinase-dependent regulation of Stat92E. Dionisio

The Architecture of CCAN Proteins Creates a Structural Integrity to Resist Spindle Forces and Achieve Proper Intrakinetochore Stretch DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.003 Constitutive centromere-associated network (CCAN) proteins, particularly CENP-C, CENP-T, and the CENP-H/-I complex, mechanically link CENP-A-containing centromeric chromatin within the inner kinetochore to outer kinetochore proteins, such as the Ndc80 complex, that bind kinetochore microtubules. Accuracy of chromosome segregation depends critically upon Aurora B phosphorylation of Ndc80/Hec1. To determine how CCAN protein architecture mechanically constrains intrakinetochore stretch between CENP-A and Ndc80/Hec1 for proper Ndc80/Hec1 phosphorylation, we used super-resolution fluorescence microscopy and selective protein depletion. We found that at bi-oriented chromosomes in late prometaphase cells, CENP-T is stretched ?16 nm to the inner end of Ndc80/Hec1, much less than expected for full-length CENP-T. Depletion of various CCAN linker proteins induced hyper-intrakinetochore stretch (an additional 20–60 nm) with corresponding significant decreases in Aurora B phosphorylation of Ndc80/Hec1. Thus, proper intrakinetochore stretch is required for normal kinetochore function and depends critically on all the CCAN mechanical linkers to the Ndc80 complex. Dionisio

Cutting through the Noise: The Mechanics of Intracellular Transport DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.013 Intracellular transport of organelles and proteins is driven by multiple ATP-dependent processes. Recently in Cell, Guo et al. (2014) developed a technique, force-spectrum microscopy, to measure intracellular forces and demonstrate that large motion of cellular components can be produced by random ATP-dependent fluctuations within the cytoplasm. Dionisio

Regulatory Circuit Controls Lipid Droplet Fusion and Growth DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.005 Rab GTPases, by targeting to specific membrane compartments, play essential roles in membrane trafficking. Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Fsp27 is shown to be required for LD fusion and growth by enriching at LD-LD contact sites. Here, we identify Rab8a as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes. Knockdown of Rab8a in the livers of ob/ob mice results in the accumulation of smaller LDs and lower hepatic lipid levels. Surprisingly, it is the GDP-bound form of Rab8a that exhibits fusion-promoting activity. We further discover AS160 as the GTPase activating protein (GAP) for Rab8a, which forms a ternary complex with Fsp27 and Rab8a to positively regulate LD fusion. MSS4 antagonizes Fsp27-mediated LD fusion activity through Rab8a. Our results have thus revealed a mechanistic signaling circuit controlling LD fusion and fatty liver formation. Dionisio

A Molecular Switch for the Orientation of Epithelial Cell Polarización DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.027 The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a ?1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKC?II phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization. Dionisio

DOI If the provided DOI doesn't start with 'http://' then appending the DOI to the prefix http://dx.doi.org/ should produce a link to the given article. Dionisio

Long Noncoding RNAs in Cell-Fate Programming and Reprogramming DOI: http://dx.doi.org/10.1016/j.stem.2014.05.014 In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of regulators of gene expression. lncRNAs exhibit several distinctive features that confer unique regulatory functions, including exquisite cell- and tissue-specific expression and the capacity to transduce higher-order spatial information. Here we review evidence showing that lncRNAs exert critical functions in adult tissue stem cells, including skin, brain, and muscle, as well as in developmental patterning and pluripotency. We highlight new approaches for ascribing lncRNA functions and discuss mammalian dosage compensation as a classic example of an lncRNA network coupled to stem cell differentiation. Dionisio

Surveillance of Nuclear Pore Complex Assembly by ESCRT-III/Vps4 DOI: http://dx.doi.org/10.1016/j.cell.2014.09.012 The maintenance of nuclear compartmentalization by the nuclear envelope and nuclear pore complexes (NPCs) is essential for cell function; loss of compartmentalization is associated with cancers, laminopathies, and aging. We uncovered a pathway that surveils NPC assembly intermediates to promote the formation of functional NPCs. Surveillance is mediated by Heh2, a member of the LEM (Lap2-emerin-MAN1) family of integral inner nuclear membrane proteins, which binds to an early NPC assembly intermediate, but not to mature NPCs. Heh2 recruits the endosomal sorting complex required for transport (ESCRT)—III subunit Snf7 and the AAA-ATPase Vps4 to destabilize and clear defective NPC assembly intermediates. When surveillance or clearance is compromised, malformed NPCs accumulate in a storage of improperly assembled nuclear pore complexes compartment, or SINC. The SINC is retained in old mothers to prevent loss of daughter lifespan, highlighting a continuum of mechanisms to ensure nuclear compartmentalization. http://www.cell.com/cell/abstract/S0092-8674(14)01161-1 Dionisio

Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes DOI: http://dx.doi.org/10.1016/j.cell.2014.09.030 The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here, we use ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure. •Cohesin ChIA-PET reveals local chromosome structures in the ES cell genome •Super-enhancer-driven cell identity genes occur in insulated chromosome loops •Polycomb-bound lineage-specifying genes occur in insulated chromosome loops •Integrity of insulated neighborhoods is important for normal gene expression Dionisio

ESCRTs Take on a Job in Surveillance DOI: http://dx.doi.org/10.1016/j.cell.2014.09.046 Nuclear pore assembly can go awry, but how the cell handles defective intermediates has been an ongoing question. In this issue, Lusk and colleagues describe a surveillance pathway during nuclear pore assembly and, in doing so, identify a new role for proteins that function at the endosome and plasma membrane. http://www.cell.com/cell/abstract/S0092-8674(14)01234-3 Dionisio

DNA’s security system unveiled As befitting life’s blueprint, DNA is surrounded by an elaborate security system that assures crucial information is imparted without error. In a new study appearing in Cell, Yale Univ. researchers Brant Webster, Patrick Lusk and colleagues describe a key quality control mechanism that protects new cells from inheriting defective NPCs. In the accompanying movie, defective NPCs are sequestered into a specialized compartment (colored red) that is retained in the mother cell, while each daughter inherits functional NPCs. “It is important to understand how these gatekeepers, which are fundamental to cellular function, are built and maintained,” Lusk said. http://www.rdmag.com/videos/2014/10/dna%E2%80%99s-security-system-unveiled?et_cid=4205867&et_rid=653535995&location=top Dionisio

Wired in DOI: http://dx.doi.org/10.1016/j.tibs.2014.08.007 In biochemical research, the wiring diagram is the ubiquitous symbol of a signal transduction pathway. These roadmaps of signaling circuitry reduce complicated protein–protein interaction cascades into simple(r), easy-to-follow summaries. The wiring of any signal transduction pathway ultimately boils down to a few key steps: the detection and transduction of the signal, amplification of that signal, and integration into a response. In this Special Issue, TiBS presents a selection of Reviews that focus on our emerging understanding of the molecular mechanisms involved in each of these key steps, and ultimately how they can be subverted and ‘rewired’ in different physiological contexts such as disease. http://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(14)00150-9 Dionisio

Molecular Machines at Work The next Cell Press Webinar will look at structural biology of macromolecular complexes and how structural insights enable deeper functional understanding. In this webinar, Eva Nogales, Venki Ramakrishnan, and Andrew Ward will discuss some of the most recent successes in solving structures of complex biological systems. This webinar is for anyone interested in learning about the latest in structural biology as well as different ways that researchers are using structural biology to address various questions related to the cellular function of large biomolecular assemblies. The webinar is an excellent opportunity to learn what is possible at the cutting edge of structural biology and how it might impact your own research. http://view6.workcast.net/register?pak=5972149491135649 Dionisio

Transcriptome dynamics and diversity in an early embryo doi: 10.1093/bfgp/elt049 Recent years advances in high-throughput sequencing have improved our understanding of how transcripts regulate early vertebrate development. Here, we review the transcriptome dynamics and diversity during early stages of zebrafish embryogenesis. Transcriptome dynamics is characterized by different patterns of mRNA degradation, activation of dormant transcripts and onset of transcription. Several studies have shown a striking diversity of both coding and non-coding transcripts. However, in the aftermath of this immense increase in data, functional studies of both protein-coding and non-coding transcripts are lagging behind. We anticipate that the forthcoming years will see studies relying on different high-throughput sequencing technologies and genomic tools developed for zebrafish embryos to further pin down yet un-annotated transcript–function relationships. http://bfg.oxfordjournals.org/content/13/2/95.abstract?sid=48f670bc-0e3c-4e83-83a7-353b7a48f096 Dionisio

epigenome reorganization during oocyte differentiation and early embryogenesis doi: 10.1093/bfgp/elu007 In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells. During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization. After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo. Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role. Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear. This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications. http://bfg.oxfordjournals.org/content/13/3/246.abstract?sid=48f670bc-0e3c-4e83-83a7-353b7a48f096 Dionisio

epigenetic mediator expression and function in embryonic blastomeres doi: 10.1093/hmg/ddu212 A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications. Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation. We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level. In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage. Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture. Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation. Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development. http://hmg.oxfordjournals.org/content/23/18/4970.abstract?sid=7cdaaee8-55e5-4baf-8295-636ef6ee92ef Dionisio

Atmin mediates kidney morphogenesis by modulating Wnt signaling doi: 10.1093/hmg/ddu246 The DNA damage protein and transcription factor Atmin (Asciz) is required for both lung tubulogenesis and ciliogenesis. Like the lungs, kidneys contain a tubular network that is critical for their function and in addition, renal ciliary dysfunction has been implicated in the pathogenesis of cystic kidney disease. Using the Atmin mouse mutant Gasping6 (Gpg6), we investigated kidney development and found it severely disrupted with reduced branching morphogenesis, resulting in fewer epithelial structures being formed. Unexpectedly, transcriptional levels of key cilia associated genes were not altered in AtminGpg6/Gpg6 kidneys. Instead, Gpg6 homozygous kidneys exhibited altered cytoskeletal organization and modulation of Wnt signaling pathway molecules, including ?-catenin and non-canonical Wnt/planar cell polarity (PCP) pathway factors, such as Daam2 and Vangl2. Wnt signaling is important for kidney development and perturbation of Wnt signaling pathways can result in cystic, and other, renal abnormalities. In common with other PCP pathway mutants, AtminGpg6/Gpg6 mice displayed a shortened rostral-caudal axis and mis-oriented cell division. Moreover, intercrosses between AtminGpg6/+ and Vangl2Lp/+ mice revealed a genetic interaction between Atmin and Vangl2. Thus we show for the first time that Atmin is critical for normal kidney development and we present evidence that mechanistically, Atmin modifies Wnt signaling pathways, specifically placing it as a novel effector molecule in the non-canonical Wnt/PCP pathway. The identification of a novel modulator of Wnt signaling has important implications for understanding the pathobiology of renal disease. http://hmg.oxfordjournals.org/content/23/20/5303.abstract?sid=00616139-af11-456f-9f89-44c0b2f241c9 Dionisio

Centrosomes A new partner for BRCA1–BARD1 doi:10.1038/nrm3733 In addition to being a key factor for DNA repair, the BRCA1 (breast cancer 1)–BARD1 (BRCA1-associated RING domain 1) heterodimer affects other cellular processes, including centrosome regulation. http://www.nature.com/nrm/journal/v15/n1/full/nrm3733.html Dionisio

Microtubules protect spindle assembly factors doi:10.1038/nrm3759 The spindle assembly factors HURP (hepatoma up-regulated protein), NuSAP (nucleolar and spindle-associated protein) and TPX2 (targeting protein for XKLP2) associate with microtubules to recruit additional regulators of spindle formation, and they are degraded by APC/C (anaphase-promoting complex, also known as the cyclosome)-mediated ubiquitylation when they have fulfilled their mitotic roles. http://www.nature.com/nrm/journal/v15/n3/full/nrm3759.html Dionisio

8Endocycles doi:10.1038/nrm3756 In endoreplication cell cycles, known as endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis and thereby become polyploid. Such cycles, for which there are many variants, are widespread in protozoa, plants and animals. Endocycling cells can achieve ploidies of >200,000 C (chromatin-value); this increase in genomic DNA content allows a higher genomic output, which can facilitate the construction of very large cells or enhance macromolecular secretion. These cells execute normal S phases, using a G1–S regulatory apparatus similar to the one used by mitotic cells, but their capability to segregate chromosomes has been suppressed, typically by downregulation of mitotic cyclin-dependent kinase activity. The various endocycle mechanisms found in nature highlight the versatility of the cell cycle control machinery. http://www.nature.com/nrm/journal/v15/n3/full/nrm3756.html Dionisio

Metabolic requirements for the maintenance of self-renewing stem cells doi:10.1038/nrm3772 A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency. Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal. Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT–mTOR pathway, Gln metabolism and fatty acid metabolism. As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise. http://www.nature.com/nrm/journal/v15/n4/full/nrm3772.html Dionisio

Molecular Modeling at the Atomic Scale: Methods and Applications in Quantitative Biology Developments in molecular modeling from experimental and computational techniques have enabled a wide range of biological applications. This timely summary reflects the recent advances in bridging novel algorithms and high performance computing with characterization of important biological processes, such as folding dynamics of key proteins. It encompasses the perspectives of leading experts on this transformation in molecular biology, illustrating with state of the art examples how molecular modeling approaches are being applied to critical questions in modern quantitative biology. http://www.crcpress.com/product/isbn/9781466562950 Dionisio

Inter-species inference of gene set enrichment in lung epithelial cells from proteomic and large transcriptomic datasets. Translating findings in rodent models to human models has been a cornerstone of modern biology and drug development. However, in many cases, a naive 'extrapolation' between the two species has not succeeded. As a result, clinical trials of new drugs sometimes fail even after considerable success in the mouse or rat stage of development. In addition to in vitro studies, inter-species translation requires analytical tools that can predict the enriched gene sets in human cells under various stimuli from corresponding measurements in animals. Such tools can improve our understanding of the underlying biology and optimize the allocation of resources for drug development. We developed an algorithm to predict differential gene set enrichment as part of the sbv IMPROVER (systems biology verification in Industrial Methodology for Process Verification in Research) Species Translation Challenge, which focused on phosphoproteomic and transcriptomic measurements of normal human bronchial epithelial (NHBE) primary cells under various stimuli and corresponding measurements in rat (NRBE) primary cells. We find that gene sets exhibit a higher inter-species correlation compared with individual genes, and are potentially more suited for direct prediction. Furthermore, in contrast to a similar cross-species response in protein phosphorylation states 5 and 25 min after exposure to stimuli, gene set enrichment 6 h after exposure is significantly different in NHBE cells compared with NRBE cells. In spite of this difference, we were able to develop a robust algorithm to predict gene set activation in NHBE with high accuracy using simple analytical methods. Implementation of all algorithms is available as source code (in Matlab) at http://bhanot.biomaps.rutgers.edu/wiki/codes_SC3_Predicting_GeneSets.zip, along with the relevant data used in the analysis. Gene sets, gene expression and protein phosphorylation data are available on request. © The Author 2014. Published by Oxford University Press. http://www.ncbi.nlm.nih.gov/pubmed/25152231 Dionisio

A crowd-sourcing approach for the construction of species-specific cell signaling networks. Animal models are very important tools in drug discovery and for understanding human biology in general. However many drugs that initially show promising results in rodents fail in later stages of clinical trials. Understanding the commonalities and differences between human and rat cell signaling networks can lead to better experimental designs, improved allocation of resources and ultimately better drugs. The sbv IMPROVER Species-Specific Network Inference challenge was designed to use the power of the crowds to build two species-specific cell signaling networks given phosphoproteomics, transcriptomics and cytokine data generated from NHBE and NRBE cells exposed to various stimuli. A common literature-inspired reference network with 220 nodes and 501 edges was also provided as prior knowledge from which challenge participants could add or remove edges but not nodes. Such a large network inference challenge not based on synthetic simulations but on real data presented unique difficulties in scoring and interpreting the results. Because any prior knowledge about the networks was already provided to the participants for reference, novel ways for scoring and aggregating the results were developed. Two human and rat consensus networks were obtained by combining all the inferred networks. Further analysis showed that major signaling pathways were conserved between the two species with only isolated components diverging, as in the case of ribosomal S6 kinase RPS6KA1. Overall, the consensus between inferred edges was relatively high with the. © The Author(s) 2014. Published by Oxford University Press. http://www.ncbi.nlm.nih.gov/pubmed/25294919 Dionisio

#515 addendum http://www.ncbi.nlm.nih.gov/pubmed/25236459 Dionisio

Understanding the limits of animal models as predictors of human biology Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones, is an essential question in biomedicine. Very often, however, this question cannot be addressed since it is not possible to perform experiments in humans. A reasonable alternative consists of generating responses in animal models and "translating" those results to humans. The limitations of such translation, however, are far from clear, and systematic assessments of its actual potential are urgently needed. sbv IMPROVER ( S: ystems B: iology V: erification for I: ndustrial M: ethodology for PRO: cess VE: rification in R: esearch) was designed as a series of challenges to address translatability between humans and rodents. This collaborative crowd-sourcing initiative invited scientists from around the world to apply their own computational methodologies on a multi-layer systems biology dataset comprised of phosphoproteomics, transcriptomics, and cytokine data derived from normal human and rat bronchial epithelial cells exposed in parallel to 52 different stimuli under identical conditions. Our aim was to understand the limits of species-to-species translatability at different levels of biological organization: signaling, transcriptional, and release of secreted factors (such as cytokines). Participating teams submitted 49 different solutions across the sub-challenges; two-thirds of which were statistically significantly better than random. Additionally, similar computational methods were found to range widely in their performance within the same challenge, and no single method emerged as a clear winner across all sub-challenges. Finally, computational methods were able to effectively translate some specific stimuli and biological processes in the lung epithelial system, such as DNA synthesis, cytoskeleton and extracellular matrix (ECM), translation, immune/inflammation, and growth factor/proliferation pathways, better than the expected response similarity between species. © The Author(s) 2014. Published by Oxford University Press. Dionisio

Tech meets bio doi:10.1038/nm0810-844 IBM computers and Microsoft software have been mainstays of biomedical studies for years. But, in the past decade, software and technology companies have increasingly been taking a more active role in biological research. http://www.nature.com/nm/journal/v16/n8/full/nm0810-844.html Dionisio

Biology has arrived at an interesting juncture. The last decade has seen an unprecedented explosion in the amount of information generated by the biological research community, and a concomitant rise in the challenges of sharing, archiving, integrating and analyzing it. This is particularly acute in genomics, where next generation sequencing technologies are accelerating faster than Moore's Law. Serendipitously, this explosion of biological data has come at the same time that computer scientists have developed scalable data management solutions for handling the vastness of the internet; solutions including distributed file systems, cloud computing, and algorithms for efficient data-intensive computation across multiple machines. This 2014 conference brought together biologists and computer scientists from industry and academia to discuss the challenges and trends in this quickly evolving field. The goals included: * Surveying data and computation challenges in the fields of genomics, medical genetics, neuroinformatics, biological imaging and agronomics. * Identifying critical bottlenecks in distributing biological data to the community. * Discussing solutions to growing problem of data sets that are "too big to download." * Debating the tension between community access to personal genomic data sets (e.g. cancer genomes) and potential impact on patient privacy. What made this conference unique is that it examined a common problem, "How do we handle big data?" across multiple research specialties that rarely interact. We brought together plant scientists, medical geneticists, genomicists, microscopists and neurobiologists. The expected outcome is a greater understanding of the challenges each field faces, and the solutions that they have found. http://www.keystonesymposia.org/index.cfm?e=web.Meeting.Program&meetingid=1274 Dionisio

Prime movers: the mechanochemistry of mitotic kinesis doi:10.1038/nrm3768 Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation. http://www.nature.com/nrm/journal/v15/n4/full/nrm3768.html Dionisio

A safety net for successful mitosis doi:10.1038/nrm3777 The spindle assembly checkpoint (SAC) delays anaphase until all kinetochores are bound by microtubules on the mitotic spindle, to ensure accurate chromosome segregation during mitosis. New research published in Cell now describes that cells can also transduce SAC signals during interphase to provide a secondary level of cell cycle control. http://www.nature.com/nrm/journal/v15/n4/full/nrm3777.html Dionisio

Advances in whole-embryo imaging: a quantitative transition is underway doi:10.1038/nrm3786 With the advent of imaging probes and live microscopy, developmental biologists have markedly extended our understanding of the molecular and cellular details of embryonic development. To fully comprehend the complex mechanistic framework that forms the developing organism, quantitative studies with high fidelity in space and time are now required. We discuss how integrating established, newly introduced and future imaging tools with quantitative analysis will ensure that imaging can fulfil its promise to elucidate how new life begins. http://www.nature.com/nrm/journal/v15/n5/full/nrm3786.html Dionisio

Regulating chromosome segregation doi:10.1038/nrm3809 Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1). CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules. http://www.nature.com/nrm/journal/v15/n6/full/nrm3809.html Dionisio

Polo-like kinases: structural variations lead to multiple functions doi:10.1038/nrm3819 Members of the polo-like kinase (PLK) family are crucial regulators of cell cycle progression, centriole duplication, mitosis, cytokinesis and the DNA damage response. PLKs undergo major changes in abundance, activity, localization and structure at different stages of the cell cycle. They interact with other proteins in a tightly controlled spatiotemporal manner as part of a network that coordinates key cell cycle events. Their essential roles are highlighted by the fact that alterations in PLK function are associated with cancers and other diseases. Recent knowledge gained from PLK crystal structures, evolution and interacting molecules offers important insights into the mechanisms that underlie their regulation and activity, and suggests novel functions unrelated to cell cycle control for this family of kinases. http://www.nature.com/nrm/journal/v15/n7/full/nrm3819.html Dionisio

Making the spindle checkpoint strong doi:10.1038/nrm3828 Spindle checkpoint signals (generated by checkpoint proteins, including MAD1 and the RZZ (Rod–Zw10–Zwilch) complex) arrest mitosis until all kinetochores are correctly attached to spindle microtubules, whereupon checkpoint proteins are removed in a dynein-dependent manner. http://www.nature.com/nrm/journal/v15/n7/full/nrm3828.html Dionisio

Bidirectional cargo transport: moving beyond tug of war doi:10.1038/nrm3853 Vesicles, organelles and other intracellular cargo are transported by kinesin and dynein motors, which move in opposite directions along microtubules. This bidirectional cargo movement is frequently described as a 'tug of war' between oppositely directed molecular motors attached to the same cargo. However, although many experimental and modelling studies support the tug-of-war paradigm, numerous knockout and inhibition studies in various systems have found that inhibiting one motor leads to diminished motility in both directions, which is a 'paradox of co-dependence' that challenges the paradigm. In an effort to resolve this paradox, three classes of bidirectional transport models — microtubule tethering, mechanical activation and steric disinhibition — are proposed, and a general mathematical modelling framework for bidirectional cargo transport is put forward to guide future experiments. http://www.nature.com/nrm/journal/v15/n9/full/nrm3853.html Dionisio

The maintenance of chromosome structure: positioning and functioning of SMC complexes doi:10.1038/nrm3857 Structural maintenance of chromosomes (SMC) complexes, which in eukaryotic cells include cohesin, condensin and the Smc5/6 complex, are central regulators of chromosome dynamics and control sister chromatid cohesion, chromosome condensation, DNA replication, DNA repair and transcription. Even though the molecular mechanisms that lead to this large range of functions are still unclear, it has been established that the complexes execute their functions through their association with chromosomal DNA. A large set of data also indicates that SMC complexes work as intermolecular and intramolecular linkers of DNA. When combining these insights with results from ongoing analyses of their chromosomal binding, and how this interaction influences the structure and dynamics of chromosomes, a picture of how SMC complexes carry out their many functions starts to emerge. http://www.nature.com/nrm/journal/v15/n9/full/nrm3857.html Dionisio

Signalling dynamics in the spindle checkpoint response doi:10.1038/nrm3888 The spindle checkpoint ensures proper chromosome segregation during cell division. Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation. New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin. In contrast to the traditional view of a binary checkpoint response — either completely on or off — new findings indicate that the checkpoint response strength is variable. This revised perspective provides insight into how checkpoint bypass can lead to aneuploidy and informs strategies to exploit these errors for cancer treatments. http://www.nature.com/nrm/journal/vaop/ncurrent/full/nrm3888.html Dionisio

Cell polarization in early embryos doi: 10.1083/jcb.201407064 Polarization of early embryos along cell contact patterns—referred to in this paper as radial polarization—provides a foundation for the initial cell fate decisions and morphogenetic movements of embryogenesis. Although polarity can be established through distinct upstream mechanisms in Caenorhabditis elegans, Xenopus laevis, and mouse embryos, in each species, it results in the restriction of PAR polarity proteins to contact-free surfaces of blastomeres. In turn, PAR proteins influence cell fates by affecting signaling pathways, such as Hippo and Wnt, and regulate morphogenetic movements by directing cytoskeletal asymmetries. http://jcb.rupress.org/content/206/7/823.abstract Dionisio

How mitosis keeps itself in order Researchers describe how multiple mechanisms ensure that mitotic proteins are degraded in the correct sequence. doi: 10.1083/jcb.2071if Cells progress through mitosis by switching protein activities on and off in a clearly defined order. The ubiquitin ligase APC/C deactivates mitotic proteins by targeting them for degradation by the proteasome. The APC/C is activated by two different subunits that recognize short sequence motifs, known as D and KEN boxes, in the target proteins. In early mitosis, once the spindle assembly checkpoint (SAC) has been satisfied, the APC/C partners with the activating subunit Cdc20 to promote the cell’s entry into anaphase. The APC/C then pairs up with Cdh1 to degrade a different set of substrates and promote the cell’s exit from mitosis. CBut even substrates targeted by the same activating subunit are degraded in a specific sequence http://jcb.rupress.org/content/early/2014/09/30/jcb.2071if Dionisio

chromosome attachments http://www.fredhutch.org/en/news/spotlight/imports/mad1-checks-in-on-chromosome-attachments.html Dionisio

Sister kinetochores are mechanically fused during meiosis DOI: 10.1126/science.1256729 Production of healthy gametes requires a reductional meiosis I division in which replicated sister chromatids comigrate, rather than separate as in mitosis or meiosis II. Fusion of sister kinetochores during meiosis I may underlie sister chromatid comigration in diverse organisms, but direct evidence for such fusion has been lacking. We used laser trapping and quantitative fluorescence microscopy to study native kinetochore particles isolated from yeast. Meiosis I kinetochores formed stronger attachments and carried more microtubule-binding elements than kinetochores isolated from cells in mitosis or meiosis II. The meiosis I–specific monopolin complex was both necessary and sufficient to drive these modifications. Thus, kinetochore fusion directs sister chromatid comigration, a conserved feature of meiosis that is fundamental to Mendelian inheritance. http://www.sciencemag.org/content/346/6206/248.abstract Dionisio

Lysosome: regulator of lipid degradation pathways DOI: http://dx.doi.org/10.1016/j.tcb.2014.06.006 •Lipophagy is a transcriptionally regulated process. •The lysosome as a sensor of lipophagy induction. •Nuclear receptors link lipophagy to lipid catabolism. Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal–autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family. In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00103-2 Dionisio

A perspective on proteomics in cell biology DOI: http://dx.doi.org/10.1016/j.tcb.2013.10.010 Proteomic strategies facilitate system-wide analyses of protein complexes. •Isotope labelling allows quantitative measurement of protein properties, not only their identification. •There is a major need to organise effective community sharing of the proteomic data mountain. •The integration of proteomic data with other online data repositories must be improved. During the past 15 years mass spectrometry (MS)-based analyses have become established as the method of choice for direct protein identification and measurement. Owing to the remarkable improvements in the sensitivity and resolution of MS instruments, this technology has revolutionised the opportunities available for the system-wide characterisation of proteins, with wide applications across virtually the whole of cell biology. In this article we provide a perspective on the current state of the art and discuss how the future of cell biology research may benefit from further developments and applications in the field of MS and proteomics, highlighting the major challenges ahead for the community in organising the effective sharing and integration of the resulting data mountain. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(13)00191-8 Dionisio

Specification of sensory neurons occurs through diverse developmental programs functioning in the brain and spinal cord DOI: 10.1002/dvdy.24184 Vertebrates possess two populations of sensory neurons located within the central nervous system (CNS): Rohon-Beard (RB) and mesencephalic trigeminal nucleus (MTN) neurons. RB neurons are transient spinal cord neurons whilst MTN neurons are the proprioceptive cells that innervate the jaw muscles. It has been suggested that MTN and RB neurons share similarities and may have a common developmental program, but it is unclear how similar or different their development is. We have dissected RB and MTN neuronal specification in zebrafish. We find that RB and MTN neurons express a core set of genes indicative of sensory neurons, but find these are also expressed by adjacent diencephalic neurons. Unlike RB neurons, our evidence argues against a role for the neural crest during MTN development. We additionally find that neurogenin1 function is dispensable for MTN differentiation, unlike RB cells and all other sensory neurons. Finally, we demonstrate that, although Notch signalling is involved in RB development, it is not involved in the generation of MTN cells. Our work reveals fundamental differences between the development of MTN and RB neurons and suggests that these populations are non-homologous and thus have distinct developmental and, probably, evolutionary origins. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc. http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24184/abstract Dionisio

Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems doi:10.1038/nsmb.2876 Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments. These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications. Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors. Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies. Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation. http://www.nature.com/nsmb/journal/v21/n9/full/nsmb.2876.html Dionisio

Protein dynamics during presynaptic-complex assembly on individual single-stranded DNA molecules doi:10.1038/nsmb.2886 Homologous recombination is a conserved pathway for repairing double-stranded breaks, which are processed to yield single-stranded DNA overhangs that serve as platforms for presynaptic-complex assembly. Here we use single-molecule imaging to reveal the interplay between Saccharomyces cerevisiae RPA, ?Rad52 and ?Rad51 during presynaptic-complex assembly. We show that ?Rad52 binds RPA–ssDNA and suppresses RPA turnover, highlighting an unanticipated regulatory influence on protein dynamics. ? Rad51 binding extends the ssDNA, and ?Rad52–RPA clusters remain interspersed along the presynaptic complex. These clusters promote additional binding of RPA and ?Rad52. Our work illustrates the spatial and temporal progression of the association of RPA and ?Rad52 with the presynaptic complex and reveals a new RPA–?Rad52–?Rad51–ssDNA intermediate, with implications for how the activities of ?Rad52 and RPA are coordinated with ?Rad51 during the later stages of recombination. http://www.nature.com/nsmb/journal/v21/n10/full/nsmb.2886.html http://www.nature.com/nsmb/journal/v21/n10/full/nsmb.2886.html Dionisio

The vertebrate corneal epithelium: From early specification to constant renewal DOI: 10.1002/dvdy.24179 The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function. Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult. Recent progress in the molecular and stem cell biology of corneal morphogenesis and renewal shows that it can serves as a paradigm for epithelial /mesenchymal organ biology. This review will synthesize historical knowledge together with recent data to present a consistent overview of cornea specification, formation, maturation, and maintenance. This should be of interest not only to developmental biologists but also ophthalmologists, as several human vision problems are known to be rooted in defects in corneal development. Developmental Dynamics 243:1226–1241, 2014. © 2014 Wiley Periodicals, Inc. http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24179/abstract Dionisio

Event timing at the single-cell level doi: 10.1093/bfgp/els057 The timing of a cellular event often hides critical information on the process leading to the event. Our ability to measure event times in single cells along with other quantities allow us to learn about the drivers of the timed process and its downstream effects. In this review, we cover different types of events that have been timed in single cells, methods to time such events and types of analysis that have been applied to event timings. We show how different timing distributions suggest different natures for the process. The statistical relations between the timing of different events may reveal how their respective processes are related biologically: Do they occur in sequence or in parallel? Are they independent or inter-dependent? Finally, quantifying morphological and molecular variables may help assess their contribution to the timing of an event and its related process. http://bfg.oxfordjournals.org/content/12/2/90.abstract?sid=867f189b-6067-49f0-9931-2d7b980de051 Dionisio

488 addendum 2 Here's a separate source to the same article where the controversial term is used: http://onlinelibrary.wiley.com/doi/10.1002/embj.201387637/full Dionisio

490 addendum Here's some information about the scientist who apparently wrote the original article containing the controversial term: http://www.dzne.de/en/sites/goettingen/forschergruppen/fischer.html Dionisio

488 addendum Here's the link to the referred article: http://emboj.embopress.org/content/early/2014/04/09/embj.201387637 Dionisio

Functional roles of nucleosome stability and dynamics doi: 10.1093/bfgp/elu038 Nucleosome is a histone–DNA complex known as the fundamental repeating unit of chromatin. Up to 90% of eukaryotic DNA is wrapped around consecutive octamers made of the core histones H2A, H2B, H3 and H4. Nucleosome positioning affects numerous cellular processes that require robust and timely access to genomic DNA, which is packaged into the tight confines of the cell nucleus. In living cells, nucleosome positions are determined by intrinsic histone–DNA sequence preferences, competition between histones and other DNA-binding proteins for genomic sequence, and ATP-dependent chromatin remodelers. We discuss the major energetic contributions to nucleosome formation and remodeling, focusing especially on partial DNA unwrapping off the histone octamer surface. DNA unwrapping enables efficient access to nucleosome-buried binding sites and mediates rapid nucleosome removal through concerted action of two or more DNA-binding factors. High-resolution, genome-scale maps of distances between neighboring nucleosomes have shown that DNA unwrapping and nucleosome crowding (mutual invasion of nucleosome territories) are much more common than previously thought. Ultimately, constraints imposed by nucleosome energetics on the rates of ATP-dependent and spontaneous chromatin remodeling determine nucleosome occupancy genome-wide, and shape pathways of cellular response to environmental stresses. http://bfg.oxfordjournals.org/content/early/2014/09/30/bfgp.elu038.abstract?sid=2577a409-206e-4c49-96f4-59581de47e66 Dionisio

Epigenetic memory: the Lamarckian brain Andre Fischer DOI 10.1002/embj.201387637 | Published online 09.04.2014 The EMBO Journal (2014) embj.201387637 Memory formation via gene expression control

The human brain has about 100 billion neurons that are interconnected via synapses, and this is believed to provide the basis for the encoding, consolidation and retrieval of memories. How the brain achieves such miraculous tasks is one of the greatest remaining mysteries of our time.

Is the bold word politically correct? Dionisio

Cell-to-cell expression variability + signal reinforcement lead to early lineage segregation. doi: 10.1038/ncb2881. It is now recognized that extensive expression heterogeneities among cells precede the emergence of lineages in the early mammalian embryo. To establish a map of pluripoten epiblast (EPI) versus primitive endoderm (PrE) lineage segregation within the inner cell mass (ICM) of the mouse blastocyst, we characterized the gene expression profiles of individual ICM cells. Clustering analysis of the transcriptomes of 66 cells demonstrated that initially they are non-distinguishable. Early in the segregation, lineage-specific marker expression exhibited no apparent correlation, and a hierarchical relationship was established only in the late blastocyst. Fgf4 exhibited a bimodal expression at the earliest stage analysed, and in its absence, the differentiation of PrE and EPI was halted, indicating that Fgf4 drives, and is required for, ICM lineage segregation. These data lead us to propose a model where stochastic cell-to-cell expression heterogeneity followed by signal reinforcement underlies ICM lineage segregation by antagonistically separating equivalent cells. http://www.ncbi.nlm.nih.gov/pubmed/24292013 Dionisio

Regulatory Principles of Pluripotency: From the Ground State Up DOI: http://dx.doi.org/10.1016/j.stem.2014.09.015 Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism. This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease. Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform “ground state” of pluripotency, which more closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states. http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00406-8?elsca1=etoc&elsca2=email&elsca3=1934-5909_20141002_15_4_&elsca4=Cell%20Press Dionisio

A series of fortuitous genetic events? If I had this creative imagination I could easily become a famous bestselling author in the fiction genre: http://www.the-scientist.com//?articles.view/articleNo/41055/title/The-Rainbow-Connection/ Dionisio

The Oct4 protein: more than a magic stemness marker The Oct4 protein, encoded by the Pou5f1 gene was the very first master gene, discovered 25 years ago, to be absolutely required for the stemness properties of murine and primate embryonic stem cells. This transcription factor, which has also been shown to be essential for somatic cell reprogrammation, displays various functions depending upon its level of expression and has been quoted as a "rheostat" gene. Oct4 protein is in complexes with many different partners and its activity depends upon fine post-translational modifications. This review aims at revisiting some properties of this protein, which has not yet delivered all its potentialities. http://www.ncbi.nlm.nih.gov/pubmed/25232507 Dionisio

close look at the mammalian blastocyst: epiblast and primitive endoderm formation. During early development, the mammalian embryo undergoes a series of profound changes that lead to the formation of two extraembryonic tissues--the trophectoderm and the primitive endoderm. These tissues encapsulate the pluripotent epiblast at the time of implantation. The current model proposes that the formation of these lineages results from two consecutive binary cell fate decisions. The first controls the formation of the trophectoderm and the inner cell mass, and the second controls the formation of the primitive endoderm and the epiblast within the inner cell mass. While early mammalian embryos develop with extensive plasticity, the embryonic pattern prior to implantation is remarkably reproducible. Here, we review the molecular mechanisms driving the cell fate decision between primitive endoderm and epiblast in the mouse embryo and integrate data from recent studies into the current model of the molecular network regulating the segregation between these lineages and their subsequent differentiation. doi: 10.1007/s00018-014-1630-3. Epub 2014 May 4. http://www.ncbi.nlm.nih.gov/pubmed/24794628 Dionisio

Challenging bioinformatics, imaging, computational biology issues http://www.ncbi.nlm.nih.gov/pubmed/24672759 Dionisio

Formation of a polarised primitive endoderm layer in embryoid bodies requires fgfr/erk signalling. The primitive endoderm arises from the inner cell mass during mammalian pre-implantation development. It faces the blastocoel cavity and later gives rise to the extraembryonic parietal and visceral endoderm. Here, we investigate a key step in primitive endoderm development, the acquisition of apico-basolateral polarity and epithelial characteristics by the non-epithelial inner cell mass cells. Embryoid bodies, formed from mouse embryonic stem cells, were used as a model to study this transition. The outer cells of these embryoid bodies were found to gradually acquire the hallmarks of polarised epithelial cells and express markers of primitive endoderm cell fate. Fgf receptor/Erk signalling is known to be required for specification of the primitive endoderm, but its role in polarisation of this tissue is less well understood. To investigate the function of this pathway in the primitive endoderm, embryoid bodies were cultured in the presence of a small molecule inhibitor of Mek. This inhibitor caused a loss of expression of markers of primitive endoderm cell fate and maintenance of the pluripotency marker Nanog. In addition, a mislocalisation of apico-basolateral markers and disruption of the epithelial barrier, which normally blocks free diffusion across the epithelial cell layer, occurred. Two inhibitors of the Fgf receptor elicited similar phenotypes, suggesting that Fgf receptor signalling promotes Erk-mediated polarisation. This data shows that primitive endoderm cells of the outer layer of embryoid bodies gradually polarise, and formation of a polarised primitive endoderm layer requires the Fgf receptor/Erk signalling pathway. doi: 10.1371/journal.pone.0095434. eCollection 2014 http://www.ncbi.nlm.nih.gov/pubmed/24752320 Dionisio

Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis The preimplantation period of early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast. During this period two cell fate decisions are made while cells gradually lose their totipotency. The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper. Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo. Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed. doi: 10.1002/dvg.22368 http://www.ncbi.nlm.nih.gov/pubmed/23349011 Dionisio

There yet? nope, but close... :) How the circadian clock regulates the timing of sleep is poorly understood. The protein machinery that regulates asymmetric cell division (ACD) has been identified in Drosophila, but how this machinery acts to allow the establishment of differential cell fates is not entirely understood. Over the past years, a conserved protein machinery for ACD has been identified, but how this machinery connects to the organism architecture is less clear. The process of ACD involves the establishment of a polarity axis, the orientation of the mitotic spindle, the polarized distribution of cell fate determinants, and, ultimately, the establishment of different daughter cell fates. Further experiments will be needed to address these issues and clarify the instructive role of Bnd in establishing cell asymmetry ... Why Bnd is also found at centrosomes and at the spindle is harder to explain. these studies may therefore be relevant for a variety of biological processes in higher organisms as well The molecular pathways by which the circadian clock modulates the timing of sleep are unknown. http://www.sdbonline.org/sites/fly/genebrief/banderuola.htm Dionisio

BA77, I see what you mean. Thank you. I pray that the interlocutor gets pulled out from that fantasyland daydreaming addiction before it's too late. Anyway, they ain't seen nothing yet. The best part (for us) in this debate is still ahead. Let's just wait and see. :) Dionisio

Well Dionisio, my experience with people who prefer to live in a fantasy land, i.e. drug addicts and alcoholics, is that they will either ignore you or lash out at the people who even mention that they may have a problem. Fortunately, reality itself has a way of intruding on their dream world and waking them from their denialism. bornagain77

BA77 RE: your questions posted on #454, #456 and #458. Any hope you'll get a reply from our interlocutor? :) Dionisio

generation of a remarkable diversity of cell types from a surprisingly small set of precursor cells? Surprisingly? Why surprised? What else did they expect? :) Control of neural stem cell self-renewal and differentiation in drosophila. The neural stem cells called neuroblasts, have the ability to self-renew and at the same time produce many different types of neurons and glial cells. In the central brain and ventral ganglia, neuroblasts are specified and delaminate from the neuroectoderm during embryonic development under the control of proneural and neurogenic genes. In contrast, in the optic lobes, neuroepithelial cells are transformed into neuroblasts postembryonically by a spatial wave of proneural gene expression. Central brain and ventral nerve cord neuroblasts manifest a short embryonic proliferation period followed by a stage of quiescence and then undergo a prolonged postembryonic proliferation period during which most of the differentiated neurons of the adult CNS are generated. While most neuroblasts belong to a type I class that produces neuronal lineages through non-self-renewing ganglion mother cells, a small subset of type II neuroblasts generates exceptionally large neuronal lineages through self-renewing intermediate progenitor cells that have a transit amplifying function. All neuroblasts in the CNS generate their neural progeny through an asymmetric cell division mode in which the interplay of apical complex and basal complex molecules in the mitotically active progenitor results in the segregation of cell fate determinants into the smaller more differentiated daughter cell. Defects in this molecular control of asymmetric cell division in neuroblasts can result in brain tumor formation. Proliferating neuroblast lineages in the developing CNS utilize transcription factor cascades as a generic mechanism for temporal patterning and birth order-dependent determination of differential neural cell fate. This contributes to the generation of a remarkable diversity of cell types in the developing CNS from a surprisingly small set of neural stem cell-like precursors. http://www.ncbi.nlm.nih.gov/pubmed/24902665 Dionisio

Addendum to posts #463 and #464 As science gets deeper into the nature of Nature, the revealed elaborate complexity is a more convincing evidence that leads to... Dionisio

Any news from The Third Way front yet? Any progress there? ;-) Dionisio

#471 misspelling error correction

Effects of geometry and chemistry on hydrophobic solvation

The word 'solvation' in the title of the post #471 was misspelled by the autocorrect feature of the word processing software. BTW, I'm not aware of that concept 'hydrophobic salvation' but I'm aware of the most important 'salvation' by faith alone. :) Dionisio

Effects of geometry and chemistry on hydrophobic salvation [time to remodel?] doi: 10.1073/pnas.1406080111 Significance The solvation free energy of a molecule includes the free energy required to remove solvent from what will become the molecular interior and the free energy gained from dispersive interactions between the solute and solvent. Traditionally, these free energies have been assumed to be proportional to the surface area of the molecule. However, we computed these free energies for a series of alkanes and four configurations of decaalanine and showed that although these free energies were linear in the surface area for each set of molecules, each atom’s contributions to these energies depended on correlations with its surrounding atoms. The atomic contributions to these energies were therefore not additive. This finding suggests that most current hydrophobic models are unsatisfactory. [oops!] Abstract Inserting an uncharged van der Waals (vdw) cavity into water disrupts the distribution of water and creates attractive dispersion interactions between the solvent and solute. This free-energy change is the hydrophobic solvation energy (?Gvdw). Frequently, it is assumed to be linear in the solvent-accessible surface area, with a positive surface tension (?) that is independent of the properties of the molecule. However, we found that ? for a set of alkanes differed from that for four configurations of decaalanine, and ? = ?5 was negative for the decaalanines. These findings conflict with the notion that ?Gvdw favors smaller A. We broke ?Gvdw into the free energy required to exclude water from the vdw cavity (?Grep) and the free energy of forming the attractive interactions between the solute and solvent (?Gatt) and found that ? ?rep and ?att < 0. Additionally, ?att and ?rep for the alkanes differed from those for the decaalanines, implying that none of ?Gatt, ?Grep, and ?Gvdw can be computed with a constant surface tension. We also showed that ?Gatt could not be computed from either the initial or final water distributions, implying that this quantity is more difficult to compute than is sometimes assumed. Finally, we showed that each atom’s contribution to ?rep depended on multibody interactions with its surrounding atoms, implying that these contributions are not additive. These findings call into question some hydrophobic models. http://www.pnas.org/content/early/2014/09/24/1406080111.abstract.html?etoc Dionisio

Evidence for close side-chain packing in an early protein folding intermediate previously assumed to be a molten globule doi: 10.1073/pnas.1410630111 Significance Molten globules—defined as compact protein conformations with significant secondary structure but only loosely packed tertiary structure—have been hypothesized to be general folding intermediates. In this work we investigate one folding intermediate long thought to be a molten globule and find significant evidence that it likely has a well-folded region, with closely packed tertiary structure. These results suggest that the evidence for moltenness in other protein folding intermediates should be revisited and that even for fairly simple, small proteins, exclusion of water can occur before the rate-limiting step to folding. The molten globule, a conformational ensemble with significant secondary structure but only loosely packed tertiary structure, has been suggested to be a ubiquitous intermediate in protein folding. However, it is difficult to assess the tertiary packing of transiently populated species to evaluate this hypothesis. Escherichia coli RNase H is known to populate an intermediate before the rate-limiting barrier to folding that has long been thought to be a molten globule. We investigated this hypothesis by making mimics of the intermediate that are the ground-state conformation at equilibrium, using two approaches: a truncation to generate a fragment mimic of the intermediate, and selective destabilization of the native state using point mutations. Spectroscopic characterization and the response of the mimics to further mutation are consistent with studies on the transient kinetic intermediate, indicating that they model the early intermediate. Both mimics fold cooperatively and exhibit NMR spectra indicative of a closely packed conformation, in contrast to the hypothesis of molten tertiary packing. This result is important for understanding the nature of the subsequent rate-limiting barrier to folding and has implications for the assumption that many other proteins populate molten globule folding intermediates. http://www.pnas.org/content/early/2014/09/24/1410630111.abstract.html?etoc Dionisio

Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium doi: 10.1369/0022155412451582 Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration. Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration. The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate. Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development. Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2. Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells. These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area. http://jhc.sagepub.com/content/60/9/675.abstract Dionisio

Numb is Required for the Production of Terminal Asymmetric Cell Divisions in the Developing Retina doi: 10.1523/JNEUROSCI.4127-12.2012 In the developing nervous system, cell diversification depends on the ability of neural progenitor cells to divide asymmetrically to generate daughter cells that acquire different identities. While much work has recently focused on the mechanisms controlling self-renewing asymmetric divisions producing a differentiating daughter and a progenitor, little is known about mechanisms regulating how distinct differentiating cell types are produced at terminal divisions. Here we study the role of the endocytic adaptor protein Numb in the developing mouse retina. Using clonal numb inactivation in retinal progenitor cells (RPCs), we show that Numb is required for normal cell-cycle progression at early stages, but is dispensable for the production of self-renewing asymmetric cell divisions. At late stages, however, Numb is no longer required for cell-cycle progression, but is critical for the production of terminal asymmetric cell divisions. In the absence of Numb, asymmetric terminal divisions that generate a photoreceptor and a non-photoreceptor cell are decreased in favor of symmetric terminal divisions generating two photoreceptors. Using live imaging in retinal explants, we show that a Numb fusion protein is asymmetrically inherited by the daughter cells of some late RPC divisions. Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions. http://www.jneurosci.org/content/32/48/17197.abstract Dionisio

DNA asymmetry and cell fate regulation in stem cells DOI: 10.1016/j.semcdb.2013.05.008 Highlights • Cell divisions can be invariant, or stochastic where they can potentially alternate between symmetric and asymmetric divisions. • We propose that all cell divisions are de facto asymmetric in nature, and that symmetric divisions do not seize this opportunity to generate distinct cell fates. • Segregation of chromatids containing oldest DNA strands to only one daughter cell has been linked to cell fate choice. • The coupling of transcription and pre- or post-replication events in S-phase could mark chromatids for future selection and asymmetric segregation during mitosis. Abstract The semi-conservative nature of DNA replication has suggested that identical DNA molecules within chromatids are inherited by daughter cells after cell division. Numerous reports of non-random DNA segregation in prokaryotes and eukaryotes suggest that this is not always the case, and that epigenetic marks on chromatids, if not the individual DNA strands themselves, could have distinct signatures. Their selective distribution to daughter cells provides a novel mechanism for gene and cell fate regulation by segregating chromatids asymmetrically. Here we highlight some examples and potential mechanisms that can regulate this process. We propose that cellular asymmetry is inherently present during each cell division, and that it provides an opportunity during each cell cycle for moderating cell fates. http://www.sciencedirect.com/science/article/pii/S1084952113000748 Dionisio

Biased segregation of DNA and centrosomes — moving together or drifting apart? doi:10.1038/nrm2784 Old and newly synthesized centrosomes have different microtubule nucleating abilities and they contribute to cell polarity when they migrate to opposite poles during cell division. The asymmetric localization of epigenetic marks and kinetochore proteins could lead to the differential recognition of sister chromatids and the biased segregation of DNA strands to daughter cells during cell division. We propose that this asymmetric localization is linked to biased chromatid segregation, which might also be related to the acquisition of distinct cell fates after mitosis. http://www.nature.com/nrm/journal/v10/n11/full/nrm2784.html Dionisio

Mechanisms regulating stem cell polarity and the specification of asymmetric divisiones The ability of cells to divide asymmetrically to produce two different cell types provides the cellular diversity found in every multicellular organism. Asymmetric localization of cell-cell junctions and/or intrinsic cell fate determinants and position within specific environment (“niche”) are examples of mechanisms used to specify cell polarity and direct asymmetric divisions. During development, asymmetric divisions provide the basis for establishment of the body axis and cell fate determination in a range of processes. Subsequently, asymmetric cell divisions play a critical role in maintaining adult stem cell populations, while at the same time generating an adequate number of differentiating daughter cells to maintain tissue homeostasis and repair. Loss of cell polarity, and consequently the potential for asymmetric divisions, is often linked to excessive stem cell self-renewal and tumorigenesis. Here we will discuss multiple factors and mechanisms that imbue cells with polarity to facilitate an asymmetric outcome to stem cell divisions, assuring self-renewal and maintenance of the stem cell pool. Asymmetric division is a property of stem cells that leads to the generation of two cells that can adopt different fates. One has the potential to renew stem cell identity and continue to divide in an asymmetric manner, whereas the other cell will differentiate along a specific lineage. In some cases, factors within the dividing mother cell lead to the differential segregation of cell fate determinants to give two distinct daughters upon division.[intrinsic asymmetry] In others, however, establishment of different fates is reinforced through signaling from neighboring cells. [extrinsic asymmetry] Ultimately, asymmetric divisions are regulated directly by genes that control the process of asymmetric cell division itself or determine the distinct cell fates of the two daughter cells. http://www.stembook.org/node/562 Dionisio

#463 addendum Important clarification by KF in another thread:

D: FSCO/I is the general form, which needs not be in digitally coded strings — cf the exploded view of a fishing reel in the OP, which can be reduced to a set of coded strings by using something like AutoCAD etc. What GP and I both call dFSCI is the latter, coded strings. DNA is an explicit code, RNA is transcribed from it, proteins are assembled based on translating the code and themselves embed the code in their amino acid sequences. So, analysis on strings is without loss of generality, WLOG. Of course, the funciton of protein strings is quite remote from the DNA code, it requires a lot of nanomachinery to transcribe, edit, transfer, set up the Ribosome, and assemble the protein, That hen needs to fold or be folded in a chaperone machine, then perhaps be augmented with enabling species and/or clustered to build a structure, etc. We have not yet touched on the post office despatch system using the intracellular highway and vesicles moved about with walking trucks — yes, walking trucks. This stuff is astonishing, awe-inspiring indeed. We have a long way to go to get near that sophistication. And as for the molecular nanotech involved, sheer genius that. KF

Here's the link to the above quoted KF's post:

https://uncommondescent.com/atheism/ftr-answering-es-po-mo-antics-with-the-semantics-of-function/#comment-517080

Dionisio

Clarification: In the many research examples we see in this thread, one can note elaborate cellular and molecular choreographies associated with what KF calls FSCO/I and GP refers to as dFCSI. As one could note in most of these posts, serious scientists are very busy trying to figure out how those complex processes work. They don’t have time to think about how they appeared to begin with. IOW, OOL discussions are irrelevant to resolve their research issues at this point. Every new discovery reveals more FSCO/I and dFCSI that demand explanation. Any question about how an intelligent agent does his work seems kind of premature, in light of our lack of detailed information about the actual functioning of the observed processes. One might have to wait quite a while for an answer to such a question. First things first. Dionisio

Chromosome length and perinuclear attachment constrain resolution of DNA intertwines doi: 10.1083/jcb.201404039 To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication. How this process extends to the full genome is not well understood. In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase. In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II–dependent segregation. Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells. Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes. Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope. We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase. http://jcb.rupress.org/content/206/6/719 Dionisio

Facing a strong challenge to their weak belief? The journal Biosemiotics provides a platform for exceptional peer-reviewed papers that is as broad as the rapidly growing discipline for which it is named. Its coverage spans a range of disciplines, bridging biology, philosophy, linguistics and the communication sciences. Conceived in the insight that the genetic code is a language as old as life itself, and grounded in the study of signs, of communication and of information in organisms, biosemiotics is evolving today toward the challenge of naturalizing not only biological information but also biological meaning, in the belief that signs and codes are fundamental components of the living world.[???] Biosemiotics offers an advanced forum for the exchange of ideas on this exciting new area of biological theory. It serves a readership comprising biosemioticians themselves, along with interested researchers in disciplines from social semiotics to community ecology, from communication science to artificial intelligence. http://link.springer.com/journal/12304 Here are the articles posted in this journal: http://link.springer.com/search?sortOrder=newestFirst&facet-content-type=Article&facet-journal-id=12304 Definitely they have a very difficult task ahead. Perhaps it might be interesting to watch how they handle it and what arguments they present to support their beliefs. Dionisio

#454 bornagain77 You asked:

But AVS, would it not be far more reasonable to suppose that the person who said such unfathomed complexity arose by accidental processes (as you do), instead of by purposeful intent, was the one on drugs?

Here's what AVS wrote on March 31, 2014:

we don’t know a lot about how things are happening in cells currently, this makes putting together a picture of the evolution of these biological systems extremely difficult. https://uncommondescent.com/intelligent-design/jonathan-wells-far-from-being-all-powerful-dna-does-not-wholly-determine-biological-form/#comment-494560

Would that comment give us an idea about a possible answer to your question? :) Dionisio

#454 bornagain77 Exactly! :) I could not have said it better. Thank you. BTW, I'm surprised that the 'drug' reference came from no other than the same person who posted the below comments in this old thread: https://uncommondescent.com/intelligent-design/jonathan-wells-far-from-being-all-powerful-dna-does-not-wholly-determine-biological-form/ 49 AVS March 31, 2014 at 9:06 pm

Dionisio [...] your IT background puts you at an extreme disadvantage. We are talking about the living world here in biology, while at the surface it may seem similar to the computer world, there are a vast amount of differences. The best way I can sum it up is the fact that biology is concerned with living things, to which there is no real comparison in the non-living world.

50 AVS March 31, 2014 at 9:18 pm

Dionisio, on the off chance that you are being sincere in your request I will explain: Asking for a complete description of all the process that occur in the first week of development and how they evolved is absolutely absurd. Not only do we not know exactly how a lot of these things work, but what we do know would fill stacks and stacks of books. In fact they do. That’s part of what the problem is with teaching you guys about evolution; we don’t know a lot about how things are happening in cells currently, this makes putting together a picture of the evolution of these biological systems extremely difficult. Anyway here are some terms you can look up to get you on your path to knowledge: transcription factors, cell determination, cell differentiation, fate maps, ectoderm, endoderm, and mesoderm, gastrulation, mitosis, hox genes, and morphogens Wiki is a good resource, goodluck

56 AVS March 31, 2014 at 9:52 pm

Dionisio, if you really want to learn about biology, take some classes at an accredited university. Definitely do not rely on UD as a source for information on how biology works. As you can see from this page alone it would seem none of the regulars here at UD have the slightest of knowledge as to molecular biology.

72. AVS March 31, 2014 at 10:53 pm

Dionisio, do everyone a favor and stick to computer engineering. You are absolutely clueless.

Dionisio

So you refuse to honestly answer the question as to if you are on drugs? Now I'm really starting to get suspicious! bornagain77

Well first of all it's a loaded question, BA. You are assuming to know what I do and do not believe in, something mr. news just did in another post. Also, how can we imitate something we don't fully understand? Of course we're going to have trouble doing this. The question was obviously meant to be funny/ridiculous and the fact that you are pushing me to answer it still shows how little respect you give and therefore how little respect you deserve. I shouldn't even be responding to you, you're not worth the effort. AVS

AVS, So your response is to ignore my question to you? Let me ask again,, Is the reason that you believe accidental processes can produces complexity that far exceeds man's ability to imitate because you on drugs? Admitting you have a problem is the first step in recovery AVS! bornagain77

Dio has been copying and pasting the summaries of random scientific papers here for four months now. Not holding a conversation with anyone or anything of the sort, just mindlessly copying and pasting. I wish I had that much time on my hands, and was entertained by such simplicity. AVS

AVS, so your response to all of Dionisio's hard work in documenting the astonishing complexity in the cell, complexity that far exceeds man's ability to imitate, is to ask if he is on drugs??? But AVS, would it not be far more reasonable to suppose that the person who said such unfathomed complexity arose by accidental processes (as you do), instead of by purposeful intent, was the one on drugs? bornagain77

#451 AVS

What drugs are you on Dio? I want some of that.

Here it is:

"Delight yourself in the Lord, and He will give you the desires of your heart." [Psalm 37:4 (ESV)]

Go for it! Enjoy it too! It's for everyone who wants it! And it's free! Someone paid it all, so you and I don't have to pay it. Isn't that great? :) Don't wait longer... go for it, now!

We must make God our heart’s delight and then we shall have our heart’s desire. We must not only depend upon God, but solace ourselves in Him. We must be well pleased that there is a God, that He is such a One as He has revealed Himself to be, and that He is our God in covenant. We must delight ourselves in His beauty, bounty, and benignity; our souls must return to Him, and repose in Him, as their rest, and their portion for ever. And even this pleasant duty of delighting in God has a promise annexed to it, which is very full and precious, enough to recompense the hardest services: He shall give thee the desires of thy heart. He has not promised to gratify all the appetites of the body and the humours of the fancy, but to grant all the desires of the heart, all the cravings of the renewed sanctified soul. What is the desire of the heart of a good man? It is this, to know, and love, and live to God, to please Him and to be pleased in Him. [Matthew Henry's Commentary]

:) Dionisio

Topoisomerase II has to work late Chromatid-untangling enzyme takes longer than expected to complete job. Without the enzyme topoisomerase II (topo II), sister chromatids can’t separate during mitosis. Contrary to conventional wisdom, however, the enzyme is still unraveling tangled DNA molecules during anaphase in budding yeast. Animal chromosomes are typically longer than their yeast counterparts, though, and the impact of length on sister chromatid intertwines (SCI) resolution is unclear. doi: 10.1083/jcb.2066if http://jcb.rupress.org/content/206/6/691.full?sid=08ffece3-427a-4d6d-be1f-15285c19d79e Dionisio

What drugs are you on Dio? I want some of that. AVS

Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN doi: 10.1083/jcb.201405060 Oriented cell divisions are necessary for the development of epithelial structures. Mitotic spindle orientation requires the precise localization of force generators at the cell cortex via the evolutionarily conserved LGN complex. However, polarity cues acting upstream of this complex in vivo in the vertebrate epithelia remain unknown. In this paper, we show that Dlg1 is localized at the basolateral cell cortex during mitosis and is necessary for planar spindle orientation in the chick neuroepithelium. Live imaging revealed that Dlg1 is required for directed spindle movements during metaphase. Mechanistically, we show that direct interaction between Dlg1 and LGN promotes cortical localization of the LGN complex. Furthermore, in human cells dividing on adhesive micropatterns, homogenously localized Dlg1 recruited LGN to the mitotic cortex and was also necessary for proper spindle orientation. We propose that Dlg1 acts primarily to recruit LGN to the cortex and that Dlg1 localization may additionally provide instructive cues for spindle orientation. http://jcb.rupress.org/content/206/6/707.abstract?sid=08ffece3-427a-4d6d-be1f-15285c19d79e Dionisio

Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival doi: 10.1083/jcb.201402002 Unless mitigated, external and physiological stresses are detrimental for cells, especially in mitosis, resulting in chromosomal missegregation, aneuploidy, or apoptosis. Heat shock proteins (Hsps) maintain protein homeostasis and promote cell survival. Hsps are transcriptionally regulated by heat shock factors (HSFs). Of these, HSF1 is the master regulator and HSF2 modulates Hsp expression by interacting with HSF1. Due to global inhibition of transcription in mitosis, including HSF1-mediated expression of Hsps, mitotic cells are highly vulnerable to stress. Here, we show that cells can counteract transcriptional silencing and protect themselves against proteotoxicity in mitosis. We found that the condensed chromatin of HSF2-deficient cells is accessible for HSF1 and RNA polymerase II, allowing stress-inducible Hsp expression. Consequently, HSF2-deficient cells exposed to acute stress display diminished mitotic errors and have a survival advantage. We also show that HSF2 expression declines during mitosis in several but not all human cell lines, which corresponds to the Hsp70 induction and protection against stress-induced mitotic abnormalities and apoptosis. http://jcb.rupress.org/content/206/6/735.abstract?sid=418b8b98-6771-4b78-adde-71b69b5d83c0 Dionisio

Enzyme helps fold the spindle assembly checkpoint (SAC) doi: 10.1083/jcb.2067iti1 phosphatase that helps shut down the spindle assembly checkpoint (SAC) when chromosomes are correctly attached to the spindle. The SAC prevents cells from entering anaphase until they have verified the connections between spindle microtubules and the chromosomes. The checkpoint forms when the enzyme Mps1 phosphorylates the kinetochore protein Knl1, and this alteration attracts other SAC proteins such as Bub1 and BubR1 to kinetochores. Once all the chromosome–spindle links check out, cells remove the phosphates from Knl1, and the checkpoint shuts down as Bub1 and other components disperse. In yeast, the phosphatase PP1, a member of the phosphoprotein phosphatase (PPP) family, dephosphorylates Knl1, but researchers weren’t sure which enzyme performs the task in mammalian cells. http://jcb.rupress.org/content/early/2014/09/16/jcb.2067iti1.full?sid=418b8b98-6771-4b78-adde-71b69b5d83c0 Dionisio

Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II [Say what?] :) In mitosis, the Greatwall kinase (called microtubule-associated serine/threonine kinase like [Mastl] in mammals) is essential for prometaphase entry or progression by suppressing protein phosphatase 2A (PP2A) activity. PP2A suppression in turn leads to high levels of Cdk1 substrate phosphorylation. We have used a mouse model with an oocyte-specific deletion of Mastl to show that Mastl-null oocytes resume meiosis I and reach metaphase I normally but that the onset and completion of anaphase I are delayed. Moreover, after the completion of meiosis I, Mastl-null oocytes failed to enter meiosis II (MII) because they reassembled a nuclear structure containing decondensed chromatin. Our results show that Mastl is required for the timely activation of anaphase-promoting complex/cyclosome to allow meiosis I exit and for the rapid rise of Cdk1 activity that is needed for the entry into MII in mouse oocytes. doi: 10.1083/jcb.201406033 http://jcb.rupress.org/content/early/2014/09/16/jcb.201406033.abstract?sid=418b8b98-6771-4b78-adde-71b69b5d83c0 Dionisio

spindle assembly checkpoint silencing doi: 10.1083/jcb.201406109 The spindle assembly checkpoint (SAC) monitors correct attachment of chromosomes to microtubules, an important safeguard mechanism ensuring faithful chromosome segregation in eukaryotic cells. How the SAC signal is turned off once all the chromosomes have successfully attached to the spindle remains an unresolved question. Mps1 phosphorylation of Knl1 results in recruitment of the SAC proteins Bub1, Bub3, and BubR1 to the kinetochore and production of the wait-anaphase signal. SAC silencing is therefore expected to involve a phosphatase opposing Mps1. Here we demonstrate in vivo and in vitro that BubR1-associated PP2A-B56 is a key phosphatase for the removal of the Mps1-mediated Knl1 phosphorylations necessary for Bub1/BubR1 recruitment in mammalian cells. SAC silencing is thus promoted by a negative feedback loop involving the Mps1-dependent recruitment of a phosphatase opposing Mps1. Our findings extend the previously reported role for BubR1-associated PP2A-B56 in opposing Aurora B and suggest that BubR1-bound PP2A-B56 integrates kinetochore surveillance and silencing of the SAC. http://jcb.rupress.org/content/early/2014/09/16/jcb.201406109.abstract?sid=418b8b98-6771-4b78-adde-71b69b5d83c0 Dionisio

Chromosome length and perinuclear attachment constrain resolution of DNA intertwines doi: 10.1083/jcb.201404039 To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication. How this process extends to the full genome is not well understood. In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase. In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II–dependent segregation. Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells. Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes. Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope. We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase. http://jcb.rupress.org/content/206/6/719 Dionisio

Unraveling cell division: Process of mitosis more clear, thanks to new research At this very moment thousands of our body's cells are duplicating and dividing. This is the mechanism by which the body repairs damaged tissues and regenerates others like skin and hair. It involves a fairly complex process known as "mitosis," during which the cell duplicates its genetic material and separates it into two identical halves, which are then split apart. It is crucially important that this process works well each and every time it takes place, as otherwise it could give rise to mutations that might trigger diseases such as cancer. http://www.sciencedaily.com/releases/2014/09/140916101958.htm Dionisio

Garbage In = Garbage Out? Complex Biological Sample Preparation for Omics Studies http://www.genengnews.com/webinars/garbage-in-garbage-out-complex-biological-sample-preparation-for-omics-studies/232/ Dionisio

#438 the bystander The belief that the design agent of OOL is the God of the Bible is not provided by science, including ID, but by God Himself through His special revelation (His word). Nature is God's general revelation. It makes us wonder, for example it makes ID proponents wonder about the origin of functional complex specified information. But it does not reveal the many details about God that we find in the Bible. Dionisio

A molecular mechanism of mitotic centrosome assembly DOI: http://dx.doi.org/10.7554/eLife.03399 Centrosomes comprise a pair of centrioles surrounded by pericentriolar material (PCM). The PCM expands dramatically as cells enter mitosis, but it is unclear how this occurs. In this study, we show that the centriole protein Asl initiates the recruitment of DSpd-2 and Cnn to mother centrioles; both proteins then assemble into co-dependent scaffold-like structures that spread outwards from the mother centriole and recruit most, if not all, other PCM components. In the absence of either DSpd-2 or Cnn, mitotic PCM assembly is diminished; in the absence of both proteins, it appears to be abolished. We show that DSpd-2 helps incorporate Cnn into the PCM and that Cnn then helps maintain DSpd-2 within the PCM, creating a positive feedback loop that promotes robust PCM expansion around the mother centriole during mitosis. These observations suggest a surprisingly simple mechanism of mitotic PCM assembly in flies. - See more at: http://elifesciences.org/content/3/e03399#sthash.CtR3AWaS.dpuf Dionisio

Myosin VIII associates with microtubule ends and together with actin plays a role in guiding plant cell division DOI: http://dx.doi.org/10.7554/eLife.03498 Plant cells divide using the phragmoplast, a microtubule-based structure that directs vesicles secretion to the nascent cell plate. The phragmoplast forms at the cell center and expands to reach a specified site at the cell periphery, tens or hundreds of microns distant. The mechanism responsible for guiding the phragmoplast remains largely unknown. Here, using both moss and tobacco, we show that myosin VIII associates with the ends of phragmoplast microtubules and together with actin plays a role in guiding phragmoplast expansion to the cortical division site. Our data lead to a model whereby myosin VIII links phragmoplast microtubules to the cortical division site via actin filaments. Myosin VIII's motor activity along actin provides a molecular mechanism for steering phragmoplast expansion. http://elifesciences.org/content/3/e03498/abstract-1 Dionisio

#438 the bystander But we could benefit from knowing well how this complex stuff works. Most serious biology scientists study current mechanisms, current structures, not OOL. They are too busy trying to figure out how things work, hence don't have time to think about OOL issues. To Christians, the OOL discussion is irrelevant, because, although we don't know how it happened, we know the agent. ID proponents in general don't know who the design agent is. That question is not part of ID. Anyway, it is fascinating to study this puzzle. :) Dionisio

I too hold the view that both ID and Evolution are inadequate in explaining origin of life and evolution of various species. The 3rd explanation is not satisfactory either. I think we may never know how life started and spread. It is a futile search. the bystander

Making the spindle checkpoint strong doi:10.1038/nrm3828 Spindle checkpoint signals (generated by checkpoint proteins) arrest mitosis until all kinetochores are correctly attached to spindle microtubules, whereupon checkpoint proteins are removed in a dynein-dependent manner. http://www.nature.com/nrm/journal/v15/n7/full/nrm3828.html Dionisio

An agent-based model for mRNA export through the nuclear pore complex doi: 10.1091/mbc.E14-06-1065 mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood. The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known. It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the NPC. Using previously published biophysical and biochemical parameters of mRNA export, we implemented a 3D coarse-grained agent- based model of mRNA export in the nanosecond regime to gain insight into these questions. On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA, and that there is a rate- limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel. Notably, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport. This has implications for future experimental design to study mRNA transport dynamics. http://www.molbiolcell.org/content/early/2014/09/22/mbc.E14-06-1065.abstract?sid=5c21adaa-c062-4f9d-b1e1-63ab2fc7bad6 Dionisio

LIM proteins in actin cytoskeleton mechanoresponse DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.009 The actin cytoskeleton assembles into branched networks or bundles to generate mechanical force for critical cellular processes such as establishment of polarity, adhesion, and migration. Stress fibers (SFs) are contractile actomyosin structures that physically couple to the extracellular matrix through integrin-based focal adhesions (FAs), thereby transmitting force into and across the cell. Recently, LIN-11, Isl1, and MEC-3 (LIM) domain proteins have been implicated in mediating this cytoskeletal mechanotransduction. Among the more well-studied LIM domain adapter proteins is zyxin, a dynamic component of both FAs and SFs. Here we discuss recent research detailing the mechanisms by which SFs adjust their structure and composition to balance mechanical forces and suggest ways that zyxin and other LIM domain proteins mediate mechanoresponse. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00074-9?elsca1=etoc&elsca2=email&elsca3=0962-8924_201410_24_10_&elsca4=Cell%20Press Dionisio

Physiological roles of long noncoding RNAs DOI: http://dx.doi.org/10.1016/j.tcb.2014.06.003 Long noncoding RNAs (lncRNAs) are a pervasive and recently recognized class of genes. lncRNAs have been proposed to modulate gene expression and nuclear architecture, but their physiological functions are still largely unclear. Several recent efforts to inactivate lncRNA genes in mouse models have shed light on their functions. Different genetic strategies have yielded specific lessons about the roles of lncRNA transcription, the lncRNA transcript itself, and underlying sequence elements. Current results indicate important functions #for lncRNAs in organ development, immunity, organismal viability, and in human diseases. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00100-7?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0962892414001007%3Fshowall%3Dtrue Dionisio

Secretory cargo sorting at the trans-Golgi network DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.007 Sorting of proteins for secretion from cells is crucial for normal physiology and the regulation of key cellular events. Although the sorting of lysosomal hydrolases at the trans-Golgi network (TGN) for delivery to pre-lysosomes is well characterized, the corresponding mechanism by which secreted proteins are sorted for plasma-membrane delivery remains poorly understood. Recent discoveries have revealed a novel sorting mechanism that requires the linkage between the cytoplasmic actin cytoskeleton to the membrane-anchored Ca2+ ATPase, SPCA1 (secretory pathway calcium ATPase 1), and the luminal 45?kDa Ca2+-binding protein, Cab45, for successful sorting of a subset of proteins at the TGN. We review progress in understanding these processes. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00072-5?elsca1=etoc&elsca2=email&elsca3=0962-8924_201410_24_10_&elsca4=Cell%20Press Dionisio

The machinery of mitosis: Kinetechores, centrioles and chromosome pumps At the cellular level, the mitotic spindle apparatus is arguably the most complicated piece of machinery in existence. Its basic function is to isolate and separate the chromosomes during cell division. A group of researchers at the University of North Carolina have been piecing together a model of the spindle and associated proteins which provides a way to visualize in detail exactly what might be going on. The group chose to simulate budding yeast cells because their entire spindle is comprised of only around 40 microtubules (MTs), compared to 100 times that amount in mammalian cells. Over the years the group has contributed to an emerging mechanical picture of the spindle wherein the MTs provide the compression elements, pericentric chromatin the elastic tension elements, and a proteinaceous kinetochore bridges the two polymers together. Their most recent paper, published in Current Biology, provides a new and detailed 3d map of the kinetochore region of the chromosome, and seeks to provides answers to the origins of the seemingly mysterious force that organizes the dividing cell. http://phys.org/news/2013-10-machinery-mitosis-kinetechores-centrioles-chromosome.html Dionisio

What makes cell division accurate? Cell division is helped along by a complex of more than 90 proteins, called a kinetochore, interacting with scaffolding-like structural fibers called microtubules. Together the kinetochore and microtubules provide the structure and force that pull the two duplicate halves of the chromosome apart and direct them to each daughter cell. The study of mitosis has focused on microtubules and kinetochores, the most prominent structure that researchers observe. This work demonstrates the importance of expanding the scope of study to include other cellular components because this is critical to achieving an in depth understanding of the mechanisms underlying chromosome alignment in preparation for dividing the DNA into two new cells http://phys.org/news/2014-01-cell-division-accurate.html Dionisio

Faithful cell division requires tightly controlled protein placement at the centromeres From fertilized egg to adult, the cells of the human body go through an astronomical number of divisions. During division of any of the body's roughly 30 trillion cells, DNA from the initial cell must be split precisely between the two resulting cells. Critical to successful cell division is the integrity of the centromere—a region of DNA on each chromosome where the cell division machinery attaches to segregate the chromosomes. http://phys.org/news/2014-07-faithful-cell-division-requires-tightly.html Dionisio

Cells simply avoid chromosome confusion: Reproductive cell division has a mechanical safeguard against errors Reproductive cell division has evolved a simple, mechanical solution to avoid chromosome sorting errors, researchers report in the Sept. 11 Science Express. This natural safeguard prevents incorrect chromosome counts and misalignments that lead to infertility, miscarriage, or congenital conditions. Meiosis occurs, for example, to create sperm or egg cells. The reduction allows offspring to inherit half their chromosomes from their father, and half from their mother. "During cell division, chromosomes must be precisely sorted in an elaborate choreography where chromosomes pair up and then part in a sequence." However, the arrangement gets complicated during the early stages of reproductive cell division. Instead of just pairs of chromosomes, the spindle-like apparatus in cells that pulls chromosomes apart has to deal with quartets. Each contains two 'sister chromatids' coming from the mother linked to two coming from the father A chromatid is either of the two strands formed when a chromosome is duplicated; sister chromatids are identical copies. http://phys.org/news/2014-09-cells-simply-chromosome-reproductive-cell.html Dionisio

New technique reveals a role for histones in cell division Proteins known as histones give structure to DNA, which coils around them like string on spools. But as is so often the case in biology, it turns out there is more to these structures than meets the eye. Scientists already know histones play a part in controlling the expression of genes, and more recently they have accumulated evidence that certain aspects of cell division depend on these proteins. But this last suspicion has proven difficult to test. Now a new technique developed at Rockefeller University in Hironori Funabiki's Laboratory of Chromosome and Cell Biology allows researchers to examine histones' role in crucial cell division processes that revolve around DNA, such as the segregation of chromosomes and the construction of the cell's nucleus. Hooray for histones: Researchers found that beads covered with histones and DNA (top) attracted a protein called lamin B3 (green) that supports the membrane around a new cell's nucleus. Beads with only DNA (bottom) did not attract lamins. http://phys.org/news/2014-09-technique-reveals-role-histones-cell.html Dionisio

ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes doi: 10.1101/gad.246579.114 Genes & Dev. 2014. 28: 2013-2026 ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes ?10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes. http://genesdev.cshlp.org/content/28/18/2013.abstract?sid=49f4d053-4a47-4c9a-8a82-a96cc7782dcf Dionisio

Regulation of pre-mRNA alternative splicing DOI: http://dx.doi.org/10.1182/blood-2013-12-542209 The scope and roles of regulated isoform gene expression during erythroid terminal development are poorly understood. We identified hundreds of differentiation-associated isoform changes during terminal erythropoiesis. Sequences surrounding cassette exons of skipped exon events are enriched for motifs bound by the Muscleblind-like (MBNL) family of splicing factors. Knockdown of Mbnl1 in cultured murine fetal liver erythroid progenitors resulted in a strong block in erythroid differentiation and disrupted the developmentally regulated exon skipping of Ndel1 mRNA, which is bound by MBNL1 and critical for erythroid terminal proliferation. These findings reveal an unanticipated scope of the alternative splicing program and the importance of Mbnl1 during erythroid terminal differentiation. http://www.bloodjournal.org/content/124/4/598.abstract Dionisio

spindle orientation and neurogenesis doi: 10.1242/?bio.20147807 Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. [...] we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis. http://bio.biologists.org/content/3/6/475.abstract Dionisio

mitosis and mitotic spindle organization doi: 10.1093/hmg/ddt436 Heterozygous LIS1 mutations are responsible for the human neuronal migration disorder lissencephaly. Mitotic functions of LIS1 have been suggested from many organisms throughout evolution. However, the cellular functions of LIS1 at distinct intracellular compartments such as the centrosome and the cell cortex have not been well defined especially during mitotic cell division. Here, we used detailed cellular approaches and time-lapse live cell imaging of mitosis from Lis1 mutant mouse embryonic fibroblasts to reveal critical roles of LIS1 in mitotic spindle regulation. We found that LIS1 is required for the tight control of chromosome congression and segregation to dictate kinetochore–microtubule (MT) interactions and anaphase progression. In addition, LIS1 is essential for the establishment of mitotic spindle pole integrity by maintaining normal centrosome number. Moreover, LIS1 plays crucial roles in mitotic spindle orientation by increasing the density of astral MT plus-end movements toward the cell cortex, which enhances cortical targeting of LIS1–dynein complex. Overexpression of NDEL1–dynein and MT stabilization rescues spindle orientation defects in Lis1 mutants, demonstrating that mouse LIS1 acts via the LIS1–NDEL1–dynein complex to regulate astral MT plus-ends dynamics and establish proper contacts of MTs with the cell cortex to ensure precise cell division. http://hmg.oxfordjournals.org/content/23/2/449.abstract?sid=d4f74c0e-7eb4-4320-9d01-c4f7063022fb Dionisio

epigenetic mediator expression and function in embryonic blastomeres doi: 10.1093/hmg/ddu212 A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications. Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation. We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level. In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage. Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture. Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation. Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development. http://hmg.oxfordjournals.org/content/23/18/4970.abstract?sid=d4f74c0e-7eb4-4320-9d01-c4f7063022fb Dionisio

Enhancing togetherness: kinetochores and cohesion Kinetochore–microtubule attachments. Chromosomes are shown in blue, centromeres in yellow, microtubules in black, and spindle poles in green. (A) Amphitelic attachment: Each kinetochore is attached to microtubules from opposing spindle poles. (B) Syntelic attachment: Both sister kinetochores are attached to microtubules from the same spindle pole. (C) Monotelic attachment: One kinetochore is attached to a microtubule from a spindle pole and the other kinetochore is not attached to a microubule. (D) Activation of the spindle checkpoint can occur via a tension defect or an attachment defect. http://genesdev.cshlp.org/content/21/3/238/F1.large.jpg Dionisio

Structural and functional elements of the centromere region The centromere/inner kinetochore, outer kinetochore, centric heterochromatin and chromosome arms, and associated functions, are shown. http://www.nature.com/nrg/journal/v2/n8/fig_tab/nrg0801_584a_F1.html Dionisio

A transcriptome-wide atlas of RNP composition reveals diverse classes of mRNAs and lncRNAs A transcriptome-wide analysis shows that different classes of mRNAs and lncRNAs are characterized by distinct mechanisms of 3? end formation and RNP complexes, explaining how cells distinguish among these otherwise similar RNAs. http://www.wcb.ed.ac.uk/paper/transcriptome-wide-atlas-rnp-composition-reveals-diverse-classes-mrnas-and-lncrnas Dionisio

Shugoshin biases chromosomes for biorientation through condensin recruitment to the pericentromere During cell division the chromosomes line up in a way that increases the chances that the daughter cells will each inherit one copy of each chromosome after cell division. This study shows that proteins known as shugoshins assemble a "hub" on a region of the DNA called the pericentromere that monitors the lining up of chromosome for accurate cell division. http://www.wcb.ed.ac.uk/paper/shugoshin-biases-chromosomes-biorientation-through-condensin-recruitment-pericentromere Dionisio

The dynamic kinetochore-microtubule interface http://jcs.biologists.org/content/117/23/5461/F1.large.jpg Dionisio

Interaction of the mitotic checkpoint complex (MCC) with the anaphase promoting complex/cyclosome (APC/C) http://www.fli-leibniz.de/groups/hp_diekmann_interaction_en.php Dionisio

The human centromere/kinetochore complex http://www.fli-leibniz.de/groups/hp_diekmann_hk_en.php Dionisio

Kinetochores require oligomerization of Dam1 complex to maintain microtubule attachments against tension and promote biorientation doi:10.1038/ncomms5951 Kinetochores assemble on centromeric DNA and present arrays of proteins that attach directly to the dynamic ends of microtubules. Kinetochore proteins coordinate at the microtubule interface through oligomerization, but how oligomerization contributes to kinetochore function has remained unclear. Here, using a combination of biophysical assays and live-cell imaging, we find that oligomerization of the Dam1 complex is required for its ability to form microtubule attachments that are robust against tension in vitro and in vivo. An oligomerization-deficient Dam1 complex that retains wild-type microtubule binding activity is primarily defective in coupling to disassembling microtubule ends under mechanical loads applied by a laser trap in vitro. In cells, the oligomerization-deficient Dam1 complex is unable to support stable bipolar alignment of sister chromatids, indicating failure of kinetochore–microtubule attachments under tension. We propose that oligomerization is an essential and conserved feature of kinetochore components that is required for accurate chromosome segregation during mitosis. http://www.nature.com/ncomms/2014/140919/ncomms5951/full/ncomms5951.html Dionisio

Upright BiPed Glad to know you like it! :) I'm just posting links to interesting papers. Anyone could do this. Thank God that I can do it too. :) This is a fascinating time to watch what's going on in serious biological research. I'm attracted to understanding cell fate specification and determination mechanisms, from a functional information processing perspective. That includes the elaborate choreographies found in the intrinsic asymmetric mitosis. This is why many posts in this thread have to do with this subject. However, I'm also interested in other related biological processes. Now, don't forget to constantly remind yourself that all these wonderful things we observe are the product of the powerful magic 'n-D e' formula RV+NS+T! Agree? ;-) Dionisio

I love this thread Dio. Thank You. Upright BiPed

Sending sisters their separate ways Repair protein helps resolve entanglements between sister chromatids doi: 10.1083/jcb.2041if Sister chromatids are often reluctant to separate during mitosis, but apparently a protein involved in DNA replication and repair helps eliminate lingering connections that can hold sister chromatids together. http://jcb.rupress.org/content/204/1/3.full Dionisio

DNA anaphase bridges are a potential source of genome instability that may lead to chromosome breakage or nondisjunction during mitosis doi: 10.1083/jcb.201305157 TopBP1/Dpb11 prevents accumulation of anaphase bridges via stimulation of the Mec1/ATR kinase and suppression of homologous recombination. http://jcb.rupress.org/content/204/1/45.abstract?sid=a087542e-4a34-4066-81be-1602de12ee3e Dionisio

Dynamics of the DNA damage response: insights from live-cell imaging Briefings in Functional Genomics (2013) 12 (2): 109-117. doi: 10.1093/bfgp/els059 All organisms have to safeguard the integrity of their genome to prevent malfunctioning and oncogenic transformation. Sophisticated DNA damage response mechanisms have evolved to detect and repair genomic lesions. With the emergence of live-cell microscopy of individual cells, we now begin to appreciate the complex spatiotemporal kinetics of the DNA damage response and can address the causes and consequences of the heterogeneity in the responses of genetically identical cells. Here, we highlight key discoveries where live-cell imaging has provided unprecedented insights into how cells respond to DNA double-strand breaks and discuss the main challenges and promises in using this technique. http://bfg.oxfordjournals.org/content/12/2/109.abstract?sid=877d480f-b910-403a-b1da-0c541ef81a34 Dionisio

The Kinetochore doi: 10.1101/cshperspect.a015826 A critical requirement for mitosis is the distribution of genetic material to the two daughter cells. The central player in this process is the macromolecular kinetochore structure, which binds to both chromosomal DNA and spindle microtubule polymers to direct chromosome alignment and segregation. This review will discuss the key kinetochore activities required for mitotic chromosome segregation, including the recognition of a specific site on each chromosome, kinetochore assembly and the formation of kinetochore–microtubule connections, the generation of force to drive chromosome segregation, and the regulation of kinetochore function to ensure that chromosome segregation occurs with high fidelity. http://cshperspectives.cshlp.org/content/6/7/a015826.abstract Dionisio

Kinetochore: Structure, Function DOI: 10.1002/9780470015902.a0006237.pub2 Duplicated eukaryotic chromosomes are segregated into daughter cells through cell division. Faithful chromosome segregation depends on kinetochores, which are specialized macromolecular structures built upon centromeric chromatin. The dynamic kinetochore structures connect chromosomes with spindle microtubules, power chromosome movement, and signal the activation and silencing of the spindle assembly checkpoint (SAC). Molecular analyses of the components and architecture of kinetochores have advanced rapidly in recent years. A human kinetochore contains approximately 200 proteins, many of which are evolutionarily conserved in other organisms. A histone H3 variant, CENP?A and associated constitutive centromere proteins lay the foundation for kinetochore build?up. Multiple kinetochore?localised microtubule?binding proteins including the Ndc80 complex help regulate chromosome movement. The SAC signalling originates from kinetochores and contributes to the fidelity of chromosome segregation. Many fascinating properties remain to be elucidated about the kinetochore as a fundamental machinery to maintain genomic stability. Key Concepts: •Chromosome segregation in eukaryotic cells depends upon connecting spindle microtubules with special macromolecular structures on chromosomes called kinetochores. •The centromere is the chromosomal locus where a kinetochore is built. •Laying the foundation for kinetochore assembly at centromeres are CENP?A (a histone H3 variant) containing nucleosomes and a group of CENP?A associated proteins (termed constitutive centromere proteins). •There are multiple microtubule motors and nonmotor microtubule?binding proteins localised at kinetochores to coordinate chromosome movement. •A 10 protein complex called KMN network is currently thought to provide the primary end?on microtubule?binding activity. •The spindle assembly checkpoint (SAC) monitors the kinetochore–microtubule attachment and signals the delay of the metaphase?to?anaphase transition when defects are detected. •Conformational change of MAD2 and assembly of the mitotic checkpoint complex (MCC) are the key events to activate the SAC. •Comparative studies of similar and distinct kinetochore composition, structure and function in different species and during mitosis or meiosis have provided evolutionary perspectives on mechanisms regulating chromosome segregation. http://www.els.net/WileyCDA/ElsArticle/refId-a0006237.html Dionisio

Microtubule attachment and spindle assembly checkpoint signalling at the kinetochores doi:10.1038/nrm3494 In eukaryotes, chromosome segregation during cell division is facilitated by the kinetochore, a multiprotein structure that is assembled on centromeric DNA. The kinetochore attaches chromosomes to spindle microtubules, modulates the stability of these attachments and relays the microtubule-binding status to the spindle assembly checkpoint (SAC), a cell cycle surveillance pathway that delays chromosome segregation in response to unattached kinetochores. Recent studies are shaping current thinking on how each of these kinetochore-centred processes is achieved, and how their integration ensures faithful chromosome segregation, focusing on the essential roles of kinase–phosphatase signalling and the microtubule-binding KMN protein network. http://www.nature.com/nrm/journal/v14/n1/full/nrm3494.html Dionisio

Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint doi:10.1038/ncomms5795 The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle. Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment. Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules towards spindle poles. Here we incorporate this streaming behavior into a theoretical model that accounts for the robustness of checkpoint silencing. Poleward streams are integrated at spindle poles, but are diverted by any unattached kinetochore; consequently, accumulation of checkpoint components at spindle poles increases markedly only when every kinetochore is properly attached. This step change robustly triggers checkpoint silencing after, and only after, the final kinetochore-spindle attachment. Our model offers a conceptual framework that highlights the role of spatiotemporal regulation in mitotic spindle checkpoint signaling and fidelity of chromosome segregation. http://www.nature.com/ncomms/2014/140912/ncomms5795/abs/ncomms5795.html Dionisio

A blueprint for kinetochores — new insights into the molecular mechanics of cell division doi:10.1038/nrm3133 Kinetochores are large proteinaceous complexes that physically link centromeric DNA to the plus ends of spindle microtubules. Stable kinetochore–microtubule attachments are a prerequisite for the accurate and efficient distribution of genetic material over multiple generations. In the past decade, concerted research has resulted in the identification of the individual kinetochore building blocks, the characterization of critical microtubule-interacting components, such as the NDC80 complex, and the development of an approximate model of the architecture of this sophisticated biological machine. http://www.nature.com/nrm/journal/v12/n7/full/nrm3133.html Dionisio

Structural basis for microtubule recognition by the human kinetochore Ska complex doi:10.1038/ncomms3964 The ability of kinetochores (KTs) to maintain stable attachments to dynamic microtubule structures (‘straight’ during microtubule polymerization and ‘curved’ during microtubule depolymerization) is an essential requirement for accurate chromosome segregation. Here we show that the kinetochore-associated Ska complex interacts with tubulin monomers via the carboxy-terminal winged-helix domain of Ska1, providing the structural basis for the ability to bind both straight and curved microtubule structures. This contrasts with the Ndc80 complex, which binds straight microtubules by recognizing the dimeric interface of tubulin. The Ska1 microtubule-binding domain interacts with tubulins using multiple contact sites that allow the Ska complex to bind microtubules in multiple modes. Disrupting either the flexibility or the tubulin contact sites of the Ska1 microtubule-binding domain perturbs normal mitotic progression, explaining the critical role of the Ska complex in maintaining a firm grip on dynamic microtubules. http://www.nature.com/ncomms/2014/140113/ncomms3964/full/ncomms3964.html Dionisio

The Code of codes At one level, the human body is an Enigma– a code machine. All day long they run: informing, creating, conducting. There’s the genetic code, sure. Then there’s the histone code, the sugar code, the signal transduction code, the ubiquitin code, the adhesive code, the splicing code, the tubulin code, the metabolic code, and so on and so forth. Michael Mark's blog: http://embracingforever.com/2014/09/17/the-christ-code/ Dionisio

The tubulin code: Molecular components, readout mechanisms, and functions doi: 10.1083/jcb.201406055 Microtubules are cytoskeletal filaments that are dynamically assembled from ?/?-tubulin heterodimers. The primary sequence and structure of the tubulin proteins and, consequently, the properties and architecture of microtubules are highly conserved in eukaryotes. Despite this conservation, tubulin is subject to heterogeneity that is generated in two ways: by the expression of different tubulin isotypes and by posttranslational modifications (PTMs). Identifying the mechanisms that generate and control tubulin heterogeneity and how this heterogeneity affects microtubule function are long-standing goals in the field. Recent work on tubulin PTMs has shed light on how these modifications could contribute to a “tubulin code” that coordinates the complex functions of microtubules in cells. http://jcb.rupress.org/content/206/4/461 Dionisio

Regulation of microtubule motors by tubulin isotypes and post-translational modifications doi:10.1038/ncb2920 The ‘tubulin-code’ hypothesis proposes that different tubulin genes or post-translational modifications (PTMs), which mainly confer variation in the carboxy-terminal tail (CTT), result in unique interactions with microtubule-associated proteins for specific cellular functions. However, the inability to isolate distinct and homogeneous tubulin species has hindered biochemical testing of this hypothesis. tubulin isotypes and PTMs can govern motor velocity, processivity and microtubule depolymerization rates, with substantial changes conferred by even single amino acid variation. different molecular motors recognize distinctive tubulin ‘signatures’, which supports the premise of the tubulin-code hypothesis. http://www.nature.com/ncb/journal/v16/n4/full/ncb2920.html Dionisio

Towards elucidating the tubulin code doi:10.1038/ncb2938 Genetically encoded and post-translationally generated variations of tubulin C-terminal tails give rise to extensive heterogeneity of the microtubule cytoskeleton. The generation of different tubulin variants now demonstrates how single amino-acid differences or post-translational modifications can modulate the behaviour of selected molecular motors. http://www.nature.com/ncb/journal/v16/n4/full/ncb2938.html Dionisio

The dynamics of microtubule minus ends in the human mitotic spindle doi:10.1038/ncb2996 During mitotic spindle assembly, ?-tubulin ring complexes (?TuRCs) nucleate microtubules at centrosomes, around chromosomes, and, by interaction with augmin, from pre-existing microtubules. How different populations of microtubules are organized to form a bipolar spindle is poorly understood, in part because we lack information on the dynamics of microtubule minus ends. Here we show that ?TuRC is associated with minus ends of non-centrosomal spindle microtubules. Recruitment of ?TuRC to spindles occurs preferentially at pole-distal regions, requires nucleation and/or interaction with minus ends, and is followed by sorting of minus-end-bound ?TuRC towards the poles. Poleward movement of ?TuRC exceeds k-fibre flux, involves the motors dynein, ?HSET (also known as ?KIFC1; a kinesin-14 family member) and ?Eg5 (also known as ?KIF11; a kinesin-5 family member), and slows down in pole-proximal regions, resulting in the accumulation of minus ends. Thus, in addition to nucleation, ?TuRC actively contributes to spindle architecture by organizing microtubule minus ends. http://www.nature.com/ncb/journal/v16/n8/full/ncb2996.html Dionisio

Sliding filaments and mitotic spindle organization doi:10.1038/ncb3019 Mitosis depends upon the action of the mitotic spindle, a subcellular machine that uses microtubules (MTs) and motors to assemble itself and to coordinate chromosome segregation. Recent work illuminates how the motor-driven poleward sliding of MTs — nucleated at centrosomes, chromosomes and on pre-existing MTs — contributes to spindle assembly and length control. http://www.nature.com/ncb/journal/v16/n8/full/ncb3019.html Dionisio

The biogenesis of chromosome translocations doi:10.1038/ncb2941 Chromosome translocations are catastrophic genomic events and often play key roles in tumorigenesis. Yet the biogenesis of chromosome translocations is remarkably poorly understood. Recent work has delineated several distinct mechanistic steps in the formation of translocations, and it has become apparent that non-random spatial genome organization, DNA repair pathways and chromatin features, including histone marks and the dynamic motion of broken chromatin, are critical for determining translocation frequency and partner selection. http://www.nature.com/ncb/journal/v16/n4/full/ncb2941.html Dionisio

Mitotic spindle multipolarity without centrosome amplification doi:10.1038/ncb2958 Mitotic spindle bipolarity is essential for faithful segregation of chromosomes during cell division. Multipolar spindles are often seen in human cancers and are usually associated with supernumerary centrosomes that result from centrosome overduplication or cytokinesis failure. A less-understood path to multipolar spindle formation may arise due to loss of spindle pole integrity in response to spindle and/or chromosomal forces. Here we discuss the different routes leading to multipolar spindle formation, focusing on spindle multipolarity without centrosome amplification. We also present the distinct and common features between these pathways and discuss their therapeutic implications. http://www.nature.com/ncb/journal/v16/n5/full/ncb2958.html Dionisio

The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification doi:10.1038/ncb2965 The precise relationship of embryonic stem cells (ESCs) to cells in the embryo remains controversial. We present transcriptional and functional data to identify the embryonic counterpart of ESCs. Marker profiling shows that ESCs are distinct from early inner cell mass (ICM) and closely resemble pre-implantation epiblast. A characteristic feature of mouse ESCs is propagation without ERK signalling. Single-cell culture reveals that cell-autonomous capacity to thrive when the ERK pathway is inhibited arises late during blastocyst development and is lost after implantation. The frequency of deriving clonal ESC lines suggests that all E4.5 epiblast cells can become ESCs. We further show that ICM cells from early blastocysts can progress to ERK independence if provided with a specific laminin substrate. These findings suggest that formation of the epiblast coincides with competence for ERK-independent self-renewal in vitro and consequent propagation as ESC lines. http://www.nature.com/ncb/journal/v16/n6/full/ncb2965.html Dionisio

Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport doi:10.1038/ncb3029 Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. http://www.nature.com/ncb/journal/v16/n9/full/ncb3029.html Dionisio

NIH Single Cell Analysis Challenge: Follow That Cell Many biological experiments are performed under the assumption that all cells of a particular “type” are identical. However, recent data suggest that individual cells within a single population may differ quite significantly and these differences can drive the health and function of the entire cell population. Single cell analysis comprises a broad field that covers advanced optical, electrochemical, mass spectrometry instrumentation, and sensor technology, as well as separation and sequencing techniques. Although the approaches currently in use can offer snapshots of single cells, the methods are often not amenable to longitudinal studies that monitor changes in individual cells in situ. https://www.innocentive.com/ar/challenge/9933618?cc=Nature9933618&utm_source=nature&utm_medium=pavilion&utm_campaign=challenges Dionisio

Embryonic stem cell identity grounded in the embryo doi:10.1038/ncb2984 Pluripotent embryonic stem cells (ESCs) can be derived from blastocyst-stage mouse embryos. However, the exact in vivo counterpart of ESCs has remained elusive. A combination of expression profiling and stem cell derivation identifies epiblast cells from late-stage blastocysts as the source, and functional equivalent, of ESCs. http://www.nature.com/ncb/journal/v16/n6/full/ncb2984.html Dionisio

Relative quiescence and self renewal are defining features of adult stem cells, but their potential coordination remains unclear. doi:10.1038/nn.3545 http://www.nature.com/neuro/journal/v16/n11/full/nn.3545.html Maintenance mechanism prevents stem cells from aging research may shed light on the maintenance of stem cells in the adult brain, and their activity to produce new neurons throughout life. http://www.sciencedaily.com/releases/2013/10/131010091553.htm Dionisio

Researchers apply brainpower to understanding neural stem cell differentiation Researchers explain how neural stem and progenitor cells differentiate into neurons and related cells called glia. Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step towards harnessing this therapeutic potential. http://www.sciencedaily.com/releases/2013/10/131024121450.htm Dionisio

Signaling in Adult Brain Determines Neural Stem Cell (NSC)Positional Identity the mechanism of adult NSC positional specification remains unknown DOI: http://dx.doi.org/10.1016/j.neuron.2011.05.018 Signal explains why site of origin affects fate of postnatal neural stem cells New research may help to explain why the location of postnatal neural stem cells in the brain determines the type of new neurons that are generated. The research demonstrates that a signaling pathway which plays a key role in development also actively regulates the fate of neural stem cells in the adult brain. http://www.sciencedaily.com/releases/2011/07/110727121550.htm Dionisio

Cell fate specification in the mammalian telencephalon DOI: 10.1016/j.pneurobio.2007.02.009 A fundamental feature of neural development in vertebrates is that different cell types are generated in a precise temporal sequence, first neurons, followed by oligodendrocytes and astrocytes. The mechanisms underlying these remarkable changes in progenitor fate during development are not well understood, but are thought to include both changes in the intrinsic properties of neural progenitors and changes in their signaling environment. I discuss the mechanisms that control the specification of neuronal, astroglial and oligodendroglial fates, focusing on the mammalian telencephalon, one of the most extensively used models to study neural specification mechanisms in vertebrates. I first consider the multiple extracellular signals that have been implicated in neural fate specification. Their roles are often complex, with the same signals having different effects at different developmental stages, and different signaling pathways interacting extensively. The selection of a particular cell fate ultimately results from the integration of multiple signals. Signaling pathways regulate cell fates by modulating the expression and activity of numerous transcription factors in neural stem cells. I discuss how transcription factors also act in a combinatorial manner to determine progenitor fates, with individual factors promoting the generation of one or two cell types and repressing alternative fate(s). Finally, I discuss the many levels of regulation involved in preventing premature astrocyte differentiation during neurogenesis, and later on in controlling the transition from neurogenesis to gliogenesis. http://www.sciencedirect.com/science/article/pii/S0301008207000512 Dionisio

#376 gpuccio I thank God for allowing an ignorant like me to find all these recent references to interesting scientific research papers that I can use in my current studies and also share with others in this blog. Also I appreciate the help you provided with explaining some terminologies and concepts, as well as suggesting potential sources of information, when I started to ask what others considered dumb or silly questions. Trying to understand the cell fate specification and determination mechanisms sometimes seems like resolving a huge complex puzzle, where many tiny pieces are all over a large table and many more are hidden somewhere out there beneath the night sky. At this point a good friend of mine -who was my boss at work years ago- has suggested that I try this tool "Mind Meister" in order to map and organize the thoughts along with the reference materials in a way that is easier to access any required information. I'm starting to try using this tool. That same friend has also suggested that I try hard to describe the 'mysterious' spatiotemporal mechanisms for cell fate specification, determination, differentiation and migration, in a way that is easier for nonscientists like my friend and myself to understand. I like his idea and am considering it very seriously now. However, this is a very difficult task for me. Again, thank you for your encouraging comments. Maybe someday (Dios mediante) I can meet you personally to tell you: Mile grazie mio caro amico Dottore! and then share a delicious Italian meal while singing: Lasciatemi cantare con la chitarra in mano Lasciatemi cantare una canzone piano piano :) Now let's get back to work. Ciao! Dionisio

Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation. PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types. Currently, the mechanism of PGC specification in mammals is best understood from studies in mice. Following implantation, the epiblast cells develop as an egg cylinder while the extra-embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder. However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates. This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells. Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro. http://link.springer.com/article/10.1007/s12522-014-0184-2 Dionisio

Cell fate control in the developing central nervous system DOI: 10.1016/j.yexcr.2013.10.003 Highlights • Similar mechanisms regulate cell fate in different CNS cell types and structures. • Cell fate regulators operate in a spatial–temporal manner. • Different neural cell types rely on the generation of a diversity of progenitor cells. • Cell fate decision is dictated by the integration of intrinsic and extrinsic signals. Abstract The principal neural cell types forming the mature central nervous system (CNS) are now understood to be diverse. This cellular subtype diversity originates to a large extent from the specification of the earlier proliferating progenitor populations during development. Here, we review the processes governing the differentiation of a common neuroepithelial cell progenitor pool into mature neurons, astrocytes, oligodendrocytes, ependymal cells and adult stem cells. We focus on studies performed in mice and involving two distinct CNS structures: the spinal cord and the cerebral cortex. Understanding the origin, specification and developmental regulators of neural cells will ultimately impact comprehension and treatments of neurological disorders and diseases. http://www.sciencedirect.com/science/article/pii/S0014482713004205 Dionisio

Plant biology examples of cell fate specification and determination mechanisms. Mechanisms to control bundle sheath cell fate and function. Bundle sheath (BS) cells form a single cell layer surrounding the vascular tissue in leaves. DOI: 10.1111/tpj.12470 The molecular basis of BS cell-fate specification remains unclear. Certain transcription factors are expressed specifically in the BS cells and act redundantly in BS cell-fate specification, but their expression pattern and function diverge at later stages of leaf development. http://onlinelibrary.wiley.com/doi/10.1111/tpj.12470/abstract Dionisio

Fez family transcription factors: Controlling neurogenesis and cell fate in the developing nervous system DOI: 10.1002/bies.201400039 Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types. http://onlinelibrary.wiley.com/doi/10.1002/bies.201400039/abstract Dionisio

Neural development Tracing interneuron roots doi:10.1038/nrn3628 Interneurons make up 25% of human cortical neurons, but their developmental origins remain mysterious. http://www.nature.com/nrn/journal/v14/n12/full/nrn3628.html Dionisio

Development Branched for function doi:10.1038/nrn3579 Unique combinations of transcription factors are known to distinguish neuronal fates, but the downstream mechanisms that specify neuronal morphology are poorly understood. http://www.nature.com/nrn/journal/v14/n9/full/nrn3579.html Dionisio

Sophisticated genetic methods for cell type identification have increased our understanding of cell fate acquisition during development. doi:10.1038/nrn3751 http://www.nature.com/nrn/journal/v15/n6/full/nrn3751.html Dionisio

A cell’s lineage describes the developmental history of a cell from its birth until its final division and differentiation into a particular cell type, which is known as its cell fate. Cell fate is determined by the actions of numerous cell intrinsic and extrinsic factors. Cell fate The patterns of fate doi:10.1038/nrn3643 The mechanisms determining neural progenitor cell (NPC) fate choices remain incompletely understood. NPC differentiation is associated with the sustained, dominant expression of particular transcription factors, whereas the proliferation of NPCs is associated with oscillating patterns of expression of several factors. http://www.nature.com/nrn/journal/v14/n12/full/nrn3643.html Dionisio

Neural Crest: Origin, Migration and Differentiation DOI: 10.1002/9780470015902.a0000786.pub2 The neural crest is a population of cells that emigrates from the dorsal neural tube during early embryogenesis and migrates extensively to give rise to a myriad of cell types. Patterns of migration are controlled largely by extracellular cues in the environment. Neural crest cells are initially multipotent. Cell fate specification – the selection of an individual cell fate from all the possibilities available to a multipotent progenitor – is likely to involve a series of steps, in which cells become progressively restricted to individual fates, a process that is likely to begin while still in the dorsal neural tube, but which then is usually completed during, or even after migration. Extracellular cues in the migratory and postmigratory environment act together with intrinsic transcription factors to ensure that specific fates are chosen. Together, these result in expression of one or more transcription factors that activate or cement a gene regulatory network that establishes and maintains expression of the differentiated phenotype. http://www.els.net/WileyCDA/ElsArticle/refId-a0000786.html Dionisio

gpuccio Thank you for encouraging me to stick to biology when someone visiting this blog earlier this year suggested that I better get out of this blog and go back to my previous engineering work. Do you remember that incident? The learning process hasn't ben easy for me, but now I understand a little more than I did 6 months ago. BTW, have you used Mind Meister to organize research documents? Dionisio

Dionisio: Thank you so much for your continuing effort in giving us such precious references from the scientific literature. You really find the important things! I hope that many others, like me, will read those papers and reflect on them. gpuccio

Cell Fate Specification by Localized Cytoplasmic Determinants and Cell Interactions DOI: 10.1016/S0074-7696(08)61612-5 how the fate of each blastomere becomes specified during development interesting features concerning cellular mechanisms responsible for the fate specification During embryogenesis, the developmental fate of a blastomere is specified by one of three different mechanisms: -localized maternal cytoplasmic determinants, -inductive interactions, or -lateral inhibition in an equivalence cell group http://www.sciencedirect.com/science/article/pii/S0074769608616125 Dionisio

An embryonic cell's fate is sealed by the speed of a signal When embryonic cells get the signal to specialize the call can come quickly. Or it can arrive slowly. Now, new research from Rockefeller University suggests the speed at which a cell in an embryo receives that signal has an unexpected influence on that cell's fate. Until now, only concentration of the chemical signals was thought to matter in determining if the cell would become, for example, muscle, skin, brain or bone. "It turns out that if ramped up slowly enough an otherwise potent signal elicits no response from the receiving cells. Meanwhile, a pulsing, on-off signal appears to have a stronger effect than a constant one," http://www.ecnmag.com/news/2014/08/embryonic-cells-fate-sealed-speed-signal Dionisio

(In)sights Into Pluripotency, Cell Fate Specification, and Tissue Formation http://www.mskcc.org/events/ski-talks/insights-pluripotency-cell-fate-specification-and-tissue-formation Dionisio

Cell fate specification and determination During development, cells are undergoing differentiation. Often, cells are discussed in terms of their terminal differentiation state. During development, fates of cells may be specified at certain times. When referring to developmental fate or cell fate, one is talking about everything that happens to that cell and its progeny after that point in development. The process of a cell to be committed to a certain state can be divided into two stages: specification and determination. Specification is not a permanent stage and cells can be reversed based upon different cues. In contrast, determination refers to when cells are irreversibly committed to a particular fate. The state of commitment of a cell is also known as its developmental potential. When the developmental potential is less than or equal to the developmental fate, the cell is exhibiting mosaic behavior. When the developmental potential is greater than the developmental fate, the cell is exhibiting regulative behavior. Embryos can use a combination of methods and exhibit a combination of behaviors throughout its development. Types of specification There are three major ways that developmental fates become specified: autonomous specification, conditional specification and syncytial specification. Autonomous specification This type of specification results from cell-intrinsic properties; it gives rise to mosaic development. The cell-intrinsic properties arise from a cleavage of a cell with asymmetric cytoplasmic determinants or morphogenetic determinants. Thus, the fate of the cell depends on factors segregated into the cytoplasm during cleavage. Early examples of autonomous specification came from the work of Whittaker in tunicate embryos. Conditional specification In contrast to the autonomous specification, this type of specification is a cell-extrinsic process that relies on cues and interactions between cells or from concentration-gradients of morphogens. These interactions can be either stimulatory or inhibitory. This type of specification was discovered from the result of transplantation experiments and isolation experiments. Syncytial specification This type of a specification is a hybrid of the autonomous and conditional that occurs in insects. This method involves the action of morphogen gradients within the syncytium. As there are no cell boundaries in the syncytium, these morphogens can influence nuclei in a concentration-dependent manner. http://www.bionity.com/en/encyclopedia/Cell_fate_determination.html Dionisio

Stem Cell Activation and Cell Fate Specification Cell communication between tissue stem cells and their cellular microenvironment within so-called stem cell niches is critical for stem cell self-renewal, differentiation and thus overall tissue homeostasis. But how these specialized niche cells acquire their inductive properties generally remains unknown. http://research.mssm.edu/rendl/research.html Dionisio

Polarized Wnt Signaling Regulates Ectodermal Cell Fate doi:10.1016/j.devcel.2014.03.015 How cells convert polarity cues into cell fate specification is incompletely understood https://www.gene-tools.com/content/polarized-wnt-signaling-regulates-ectodermal-cell-fate-xenopus Dionisio

Diverse patterns of genomic targeting by transcriptional regulators doi: 10.1101/gr.168807.113. http://www.ncbi.nlm.nih.gov/pubmed/24985916 Dionisio

Chromatin stretch enhancer states drive cell-specific gene regulation doi: 10.1073/pnas.1317023110 Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (? 3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. http://www.ncbi.nlm.nih.gov/pubmed/24127591 Dionisio

Enhancers: emerging roles in cell fate specification. doi: 10.1038/embor.2012.52. Enhancers are regulatory DNA elements that dictate the spatial and temporal patterns of gene expression during development. Recent evidence suggests that the distinct chromatin features of enhancer regions provide the permissive landscape required for the differential access of diverse signalling molecules that drive cell-specific gene expression programmes. The epigenetic patterning of enhancers occurs before cell fate decisions, suggesting that the epigenetic information required for subsequent differentiation processes is embedded within the enhancer element. Lineage studies indicate that the patterning of enhancers might be regulated by the intricate interplay between DNA methylation status, the binding of specific transcription factors to enhancers and existing histone modifications. In this review, we present insights into the mechanisms of enhancer function, which might ultimately facilitate cell reprogramming strategies for use in regenerative medicine. http://www.ncbi.nlm.nih.gov/pubmed/22491032 Dionisio

Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification. doi: 10.1242/dev.101709. The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs). Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers. Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities. Furthermore, clustering the top-scoring classifier sequence features identified novel cardiac and cell type-specific regulatory motifs. For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions. In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities. Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks. http://www.ncbi.nlm.nih.gov/pubmed/24496624 Dionisio

Pioneer Transcription Factors in Cell Fate Specification DOI: http://dx.doi.org/10.1210/me.2014-1084 The specification of cell fate is critical for proper cell differentiation and organogenesis. http://press.endocrine.org/doi/full/10.1210/me.2014-1084 Dionisio

Autonomous Cell Fate Specification DOI: 10.1002/9780470015902.a0001148.pub3 Autonomous cell fate specification is a form of embryonic specification in which a developing cell is able to differentiate (become a cell carrying out a specialized function) without receiving external signals. This property is enabled by cytoplasmic determinants (cytoplasmic regulatory factors necessary for specification) that are deposited in different regions of the ovum during oogenesis. These cytoplasmic determinants are partitioned into individual cells during embryonic cleavage, and thus endow these cells with the ability to form specific cell types. If an autonomously specified cell is removed from the embryo during early development and cultured in isolation, that cell will produce the descendants that it would have normally produced in the undisturbed embryo. Frequently, the embryo from which the cell was removed lacks the structures normally made by the missing cell. Autonomous cell fate specification is often used during patterning of invertebrate embryos such as ctenophores, annelids, molluscs, echinoderms and tunicates. http://www.els.net/WileyCDA/ElsArticle/refId-a0001148.html Dionisio

Specification of epidermal cell fate in plant shoots Land plants have a single layer of epidermal cells, which are characterized by mostly anticlinal cell division patterns, formation of a waterproof coat called cuticle, and unique cell types such as stomatal guard cells and trichomes. The shoot epidermis plays important roles not only to protect plants from dehydration and pathogens but also to ensure their proper organogenesis and growth control. Extensive molecular genetic studies in Arabidopsis and maize have identified a number of genes that are required for epidermal cell differentiation. However, the mechanism that specifies shoot epidermal cell fate during plant organogenesis remains largely unknown. Particularly, little is known regarding positional information that should restrict epidermal cell fate to the outermost cell layer of the developing organs. Recent studies suggested that certain members of the HD-ZIP class IV homeobox genes are possible master regulators of shoot epidermal cell fate. Here, we summarize the roles of the regulatory genes that are involved in epidermal cell fate specification and discuss the possible mechanisms that limit the expression and/or activity of the master transcriptional regulators to the outermost cell layer in plant shoots. doi: 10.3389/fpls.2014.00049 http://journal.frontiersin.org/Journal/10.3389/fpls.2014.00049/full Dionisio

lymphatic cell fate specification pathways doi: 10.1242/dev.105031 http://www.ncbi.nlm.nih.gov/pubmed/24523456 Dionisio

Insights into the geometry of genetic coding

When proteins are produced in cells based on the "genetic code" of codons, there is a precise process under which molecules called transfer RNA (tRNA) bind to specific amino acids and then transport them to cellular factories called ribosomes where the amino acids are placed together, step by step, to form a protein. Mistakes in this process, which is mediated by enzymes called synthetases, can be disastrous, as they can lead to improperly formed proteins. Thankfully, the tRNA molecules are matched to the proper amino acids with great precision, but we still lack a fundamental understanding of how this selection takes place. [...] have identified a surprising mechanism that allows one of these enzymes, alanyl-tRNA synthetase, to properly assemble a tRNA molecule with its cognate proper amino acid, alanine, allowing cells to accurately translate their genetic code into the proteins that are essential for biological functions. [...] the enzyme precisely identifies the proper tRNA thanks to a geometric feature, an arrangement of a specific base pair in the tRNA molecule that is placed in a "wobble" configuration, allowing tRNA for alanine but not for other amino acids to come into contact with the enzyme's active region. The overall enzyme reaction was 100 times faster in the wild-type tRNA, and it turns out that the key is a configuration change in the tRNA molecule caused by the difference in the single base pair. Thus, this small feature is exploited by the enzyme to make the recognition accurate. [...] this is a fascinating finding that may give us new insights into how living systems can so accurately translate their genetic code through processes that are at their core stochastic or random, using even small structural changes [...] [...] previously unknown mechanism of tRNA recognition [...]

DOI: 10.1038/nature13440 http://www.riken.jp/en/pr/press/2014/20140612_1/ Dionisio

Mature T cells can switch function to better tackle infection Helper cells of the immune system can switch to become killer cells in the gut The fate of mature T lymphocytes might be a lot more flexible than previously thought. http://www.riken.jp/en/pr/press/2013/20130121_1/ Dionisio

system regulates cell fate determination of stem cells DOI: 10.1111/gtc.12126 Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative/electrophilic stress, and Keap1 negatively regulates Nrf2. Emerging works have also suggested a role for Nrf2 as a regulator of differentiation in various cells, but the contribution of Nrf2 to the differentiation of hematopoietic stem cells (HSCs) remains elusive. Clarifying this point is important to understand Nrf2 functions in the development and/or resolution of inflammation. Here, we established two transgenic reporter mouse lines that allowed us to examine Nrf2 expression precisely in HSCs. Nrf2 was abundantly transcribed in HSCs, but its activity was maintained at low levels due to the Keap1-mediated degradation of Nrf2 protein. When we characterized Keap1-deficient mice, their bone marrow cells showed enhanced granulocyte-monocyte differentiation at the expense of erythroid and lymphoid differentiation. @Importantly, Keap1-null HSCs showed lower expression of erythroid and lymphoid genes than did control HSCs, suggesting granulocyte-monocyte lineage priming in Keap1-null HSCs. This abnormal lineage commitment was restored by a concomitant deletion of Nrf2, demonstrating the Nrf2-dependency of the skewing. Analysis of Nrf2-deficient mice revealed that the physiological level of Nrf2 is sufficient to contribute to the lineage commitment. This study unequivocally shows that the Keap1-Nrf2 system regulates the cell fate determination of HSCs. http://onlinelibrary.wiley.com/doi/10.1111/gtc.12126/abstract Dionisio

Influence of the microenvironment on cell fate determination and migration DOI: 10.1152/physiolgenomics.00170.2013 Several critical cell functions are influenced not only by internal cellular machinery but also by external mechanical and biochemical cues from the surrounding microenvironment. Slight changes to the microenvironment can result in dramatic changes to the cell's phenotype; for example, a change in the nutrients or pH of a tumor microenvironment can result in increased tumor metastasis. While cellular fate and the regulators of cell fate have been studied in detail for several decades now, our understanding of the extracellular regulators remains qualitative and far from comprehensive. In this review, we discuss the microenvironment influence on cell fate in terms of adhesion, migration, and differentiation and focus on both developments in experimental and computation tools to analyze cellular fate http://physiolgenomics.physiology.org/content/46/9/309 Dionisio

Involvement of certain proteins in the regulation of cell fate determination DOI: 10.1111/jipb.12221 Cell fate determination is a basic developmental process during the growth of multicellular organisms. Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells of the aerial tissues and roots respectively, and they serve as excellent models for understanding the molecular mechanisms controlling cell fate determination and cell morphogenesis. The regulation of trichome and root hair formation is a complex program that consists of the integration of hormonal signals with a large number of transcriptional factors, including MYB and bHLH transcriptional factors. Studies during recent years have uncovered an important role of C2H2 type zinc finger proteins in the regulation of epidermal cell fate determination. Here in this minireview we briefly summarize the involvement of C2H2 zinc finger proteins in the control of trichome and root hair formation in Arabidopsis http://onlinelibrary.wiley.com/doi/10.1111/jipb.12221/abstract Dionisio

Regulation of cell fate determination Building a multicellular organism from a single cell requires the coordinated formation of different cell types in a spatiotemporal arrangement. How different cell types arise in appropriate places and at appropriate times is one of the most intensively investigated questions in modern biology. doi: 10.3389/fpls.2014.00368 http://journal.frontiersin.org/Journal/10.3389/fpls.2014.00368/full Dionisio

Synthetic biology at the interface of functional genomics Briefings in Functional Genomics (2014) doi: 10.1093/bfgp/elu031 Functional genomics is considered a powerful tool that helps understand the relation between an organism’s genotype and possible phenotypes. Volumes of data generated on several ‘omics’ platforms have revealed the network complexities underlying biological processes. Systems and synthetic biology have garnered much attention because of the ability to infer and comprehend the uncertainties associated with such complexities. Also, part-wise characterization of the network components (e.g. DNA, RNA, protein) has rendered an engineering perspective in life sciences to build modular and functional devices. This approach can be used to combat one of the many concerns of the world, i.e. in the area of biomedical translational research by designing and constructing novel therapeutic devices to intervene network perturbation in a diseased state to transform to a healthy state. http://bfg.oxfordjournals.org/content/early/2014/09/10/bfgp.elu031.abstract?sid=5186b4e3-cbae-4c7f-8e1b-3272d5abe451 Dionisio

Role of lncRNAs in health and disease—size and shape matter Most of the mammalian genome including a large fraction of the non-protein coding transcripts has been shown to be transcribed. Studies related to these non-coding RNA molecules have predominantly focused on smaller molecules like microRNAs. In contrast, long non-coding RNAs (lncRNAs) have long been considered to be transcriptional noise. Accumulating evidence suggests that lncRNAs are involved in key cellular and developmental processes. Several critical questions regarding functions and properties of lncRNAs and their circular forms remain to be answered. Increasing evidence from high-throughput sequencing screens also suggests the involvement of lncRNAs in diseases such as cancer, although the underlying mechanisms still need to be elucidated. Here, we discuss the current state of research in the field of lncRNAs, questions that need to be addressed in light of recent genome-wide studies documenting the landscape of lncRNAs, their functional roles and involvement in diseases. We posit that with the availability of high-throughput data sets it is not only possible to improve methods for predicting lncRNAs but will also facilitate our ability to elucidate their functions and phenotypes by using integrative approaches. Briefings in Functional Genomics (2014) doi: 10.1093/bfgp/elu034 http://bfg.oxfordjournals.org/content/early/2014/09/11/bfgp.elu034.abstract?sid=5186b4e3-cbae-4c7f-8e1b-3272d5abe451 Dionisio

From ‘JUNK’ to Just Unexplored Noncoding Knowledge: the case of transcribed Alus Briefings in Functional Genomics 10 (5): 294-311. doi: 10.1093/bfgp/elr029 Non-coding RNAs (ncRNAs) are increasingly being implicated in diverse functional roles. Majority of these ncRNAs have their origin in the repetitive elements of genome. Significantly, increase in genomic complexity has been correlated with increase in repetitive content of the genome. Of the many possible functional roles of Alu repeats, they have been shown to modulate human transcriptome by virtue of harboring diverse array of functional RNA pol II TFBS, cryptic splice-site-mediated Alu exonization and as probable miRNA targets. Retro-transposition of Alu harboring TFBS has shaped up gene-specific regulatory networks. Alu exonized transcripts are raw material for dsRNA-mediated A–I editing leading to nuclear retention of transcripts and change in miRNA target. miRNA targets within Alu may titrate the effective miRNA or transcript concentration, thus acting as ‘miRNA sponge’. Differential levels of Alu RNA during different conditions of stress also await clear functional understanding. Recent reports of co-localization of pol II and pol III binding sites near the gene and elsewhere in the genome, increase the possibility of dynamic co-ordination between both pol II and pol III determining the ultimate transcriptional outcome. Dynamic and functional Alu repeats seem to be centrally placed to modulate the transcriptional landscape of human genome. http://bfg.oxfordjournals.org/content/10/5/294.full Dionisio

How..., how..., how...??? Epigenetic mechanisms and developmental choice hierarchies in development Briefings in Functional Genomics (2013) 12 (6): 512-524. doi: 10.1093/bfgp/elt027 Three interlocking problems in gene regulation are: how to explain genome-wide targeting of transcription factors in different cell types, how prior transcription factor action can establish an ‘epigenetic state’ that changes the options for future transcription factor action, and how directly a sequence of developmental decisions can be memorialized in a hierarchy of repression structures applied to key genes of the ‘paths not taken’. This review uses the finely staged process of T-cell lineage commitment as a test case in which to examine how changes in developmental status are reflected in changes in transcription factor expression, transcription factor binding distribution across genomic sites, and chromatin modification. These are evaluated in a framework of reciprocal effects of previous chromatin structure features on transcription factor access and of transcription factor binding on other factors and on future chromatin structure. http://bfg.oxfordjournals.org/content/12/6/512.abstract?sid=3feeaa33-6f30-4ed9-b1c2-ed73957d97ea Dionisio

epigenome reorganization during oocyte differentiation and early embryogenesis Briefings in Functional Genomics (2014) 13 (3): 246-253. doi: 10.1093/bfgp/elu007 In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells. During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization. After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo. Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role. Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear. This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications. http://bfg.oxfordjournals.org/content/13/3/246.abstract?sid=3feeaa33-6f30-4ed9-b1c2-ed73957d97ea Dionisio

The past decades have revealed an unexpected yet prominent role of so-called ‘junk DNA’ in the regulation of gene expression, thereby challenging our view of the mechanisms underlying phenotypic evolution. In particular, several mechanisms through which transposable elements (TEs) participate in functional genome diversity have been depicted, bringing to light the ‘TEs bright side’. However, the relative contribution of those mechanisms and, more generally, the importance of TE-based polymorphisms on past and present phenotypic variation in crops species remain poorly understood. Briefings in Functional Genomics (2014) 13 (4): 276-295. doi: 10.1093/bfgp/elu002 http://bfg.oxfordjournals.org/content/13/4/276.abstract?sid=1f60197a-e09c-4299-b115-39cfe19c039c Dionisio

Restoring totipotency through epigenetic reprogramming Briefings in Functional Genomics (2013) 12 (2): 118-128. doi: 10.1093/bfgp/els042 Epigenetic modifications are implicated in the maintenance and regulation of transcriptional memory by marking genes that were previously transcribed to facilitate transmission of these expression patterns through cell division. During germline specification and maintenance, extensive epigenetic modifications are acquired. Yet somehow at fertilization, the fusion of the highly differentiated sperm and egg results in formation of the totipotent zygote. This massive change in cell fate implies that the selective erasure and maintenance of epigenetic modifications at fertilization may be critical for the re-establishment of totipotency. In this review, we discuss recent studies that provide insight into the extensive epigenetic reprogramming that occurs around fertilization and the mechanisms that may be involved in the re-establishment of totipotency in the embryo. http://bfg.oxfordjournals.org/content/12/2/118.abstract?sid=e91a60f8-3139-41d8-98cf-fe0998e03ceb Dionisio

Do they mention how new functionality arises? Interspecific Variation in Rx1 Expression Controls Opsin Expression and Causes Visual System Diversity in African Cichlid Fisches Mol Biol Evol (2014) 31 (9): 2297-2308. doi: 10.1093/molbev/msu172 The mechanisms underlying natural phenotypic diversity are key to understanding evolution and speciation. Cichlid fishes are among the most speciose vertebrates and an ideal model for identifying genes controlling species differences. Cichlids have diverse visual sensitivities that result from species expressing subsets of seven cichlid cone opsin genes. We previously identified a quantitative trait locus (QTL) that tunes visual sensitivity by varying SWS2A (short wavelength sensitive 2A) opsin expression in a genetic cross between two Lake Malawi cichlid species. Here, we identify Rx1 (retinal and anterior neural fold homeobox) as the causative gene for the QTL using fine mapping and RNAseq in retinal transcriptomes. Rx1 is differentially expressed between the parental species and correlated with SWS2A expression in the F2 progeny. Expression of Rx1 and SWS2A is also correlated in a panel of 16 Lake Malawi cichlid species. Association mapping in this panel identified a 413-bp deletion located 2.5-kb upstream of the Rx1 translation start site that is correlated with decreased Rx1 expression. This deletion explains 62% of the variance in SWS2A expression across 53 cichlid species in 29 genera. The deletion occurs in both the sand and rock-dwelling cichlid clades, suggesting that it is an ancestral polymorphism. Our finding supports the hypothesis that mixing and matching of ancestral polymorphisms can explain the diversity of present day cichlid phenotypes. Dionisio

Transmission of a signal that synchronizes cell movements doi: 10.1073/pnas.1411925111 PNAS September 9, 2014 vol. 111 no. 36 13105-13110 Multicellular organisms, by necessity[?], form highly organized structures. The mechanisms required to construct these often dynamic structures are a challenge to understand. Myxococcus xanthus, a soil bacterium, builds two large structures: growing swarms and fruiting bodies. Because the cells are genetically identical, they rely on regulating protein activity and the levels of gene expression. Moreover, the long, flexible, rod-shaped cells modify each others’ behavior when they collide. By examining development of a Myxococcus swarm, testable rules can be proposed that rely only on cell behavior and cell–cell contact signaling. The mechanisms used by this prokaryote to form complex, dynamic multicellular structures might have been adapted for Hedgehog and Wnt morphogenetic signaling in animals.[how?] ----- We offer evidence for a signal that synchronizes the behavior of hundreds of Myxococcus xanthus cells in a growing swarm. Swarms are driven to expand by the periodic reversing of direction by members. By using time-lapse photomicroscopy, two organized multicellular elements of the swarm were analyzed: single-layered, rectangular rafts and round, multilayered mounds. Rafts of hundreds of cells with their long axes aligned in parallel enlarge as individual cells from the neighborhood join them from either side. Rafts can also add a second layer piece by piece. By repeating layer additions to a raft and rounding each layer, a regular multilayered mound can be formed. About an hour after a five-layered mound had formed, all of the cells from its top layer descended to the periphery of the fourth layer, both rapidly and synchronously. Following the first synchronized descent and spaced at constant time intervals, a new fifth layer was (re)constructed from fourth-layer cells, in very close proximity to its old position and with a number of cells similar to that before the “explosive” descent. This unexpected series of changes in mound structure can be explained by the spread of a signal that synchronizes the reversals of large groups of individual cells. http://www.pnas.org/content/111/36/13105.abstract.html?etoc Dionisio

Custos controls ?-catenin to regulate head development during vertebrate embryogenesis doi: 10.1073/pnas.1414437111 PNAS September 9, 2014 vol. 111 no. 36 13099-13104 Canonical Wnt pathway is essential for primary axis formation and establishment of basic body pattern during embryogenesis. Defects in Wnt signaling have also been implicated in tumorigenesis and birth defect disorders. Here we characterize a novel component of canonical Wnt signaling termed Custos and show that this protein binds to and modulates ?-catenin nuclear translocation in the canonical Wnt signal transduction cascade. Our functional characterization of Custos further shows that this protein has a conserved role in development, being essential for organizer formation and subsequent anterior development in the Xenopus and zebrafish embryo. These studies unravel a new layer of regulation of canonical Wnt signaling that might provide insights into mechanisms by which deregulated Wnt signaling results in pathological disorders. ----- Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders. A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of ?-catenin, a process that remains incompletely understood. Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelled–interacting protein. Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis. Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer. In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited ?-catenin/TCF-dependent transcription. Custos binds to ?-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of ?-catenin. This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling. The function of Custos is conserved as loss-of-function and gain-of-function studies in zebrafish also demonstrate a role for Custos in anterior head development. Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-?-catenin signal transduction cascade. http://www.pnas.org/content/111/36/13099.abstract.html?etoc Dionisio

Three-dimensional cell body shape dictates the onset of traction force generation and growth of focal adhesions doi: 10.1073/pnas.1411785111 PNAS September 9, 2014 vol. 111 no. 36 13075-13080 Living cells interact with their environment through surface receptors. In particular, adhesion molecules form complexes that anchor cells to each other and to the extracellular matrix. These complexes ensure mechanical integrity of tissues and control cell function through specific biochemical signaling. This dual role is due to the ability of adhesion complexes to grow and change their composition and activity in response to mechanical forces. Here, we show how cell spreading, by modifying cell shape, controls the distribution of internal tension over adhesion complexes, inducing their growth above a well-defined spread area. Because such a threshold area was reported for many cell functions, our findings shed a new light on the possible mechanisms behind the geometric control of cell fate. ----------- Cell shape affects proliferation and differentiation, which are processes known to depend on integrin-based focal adhesion (FA) signaling. Because shape results from force balance and FAs are mechanosensitive complexes transmitting tension from the cell structure to its mechanical environment, we investigated the interplay between 3D cell shape, traction forces generated through the cell body, and FA growth during early spreading. Combining measurements of cell-scale normal traction forces with FA monitoring, we show that the cell body contact angle controls the onset of force generation and, subsequently, the initiation of FA growth at the leading edge of the lamella. This suggests that, when the cell body switches from convex to concave, tension in the apical cortex is transmitted to the lamella where force-sensitive FAs start to grow. Along this line, increasing the stiffness resisting cell body contraction led to a decrease of the lag time between force generation and FA growth, indicating mechanical continuity of the cell structure and force transmission from the cell body to the leading edge. Remarkably, the overall normal force per unit area of FA increased with stiffness, and its values were similar to those reported for local tangential forces acting on individual FAs. These results reveal how the 3D cell shape feeds back on its internal organization and how it may control cell fate through FA-based signaling. http://www.pnas.org/content/111/36/13075.abstract?sid=bd3bc8c2-0f0c-4ae9-b2d7-ad122cab965b Dionisio

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate doi: 10.1073/pnas.1410977111 Multipotent cells, such as mesenchymal stromal cells (MSCs), have the capacity to differentiate into cartilage-forming cells. Chondrocytes derived from MSCs obtain an epiphyseal cartilage-like phenotype, which turns into bone upon implantation via endochondral ossification. Here, we report that the chondrogenic fate of MSCs can be metabolically programmed by low oxygen tension to acquire an articular chondrocyte-like phenotype via mechanisms that resemble natural development. Our study identifies metabolic programming of stem cells by oxygen tension as a powerful tool to control cell fate, which may have broad applications for the way in which stem cells are now prepared for clinical use. ------------ Actively steering the chondrogenic differentiation of mesenchymal stromal cells (MSCs) into either permanent cartilage or hypertrophic cartilage destined to be replaced by bone has not yet been possible. During limb development, the developing long bone is exposed to a concentration gradient of oxygen, with lower oxygen tension in the region destined to become articular cartilage and higher oxygen tension in transient hypertrophic cartilage. Here, we prove that metabolic programming of MSCs by oxygen tension directs chondrogenesis into either permanent or transient hyaline cartilage. Human MSCs chondrogenically differentiated in vitro under hypoxia (2.5% O2) produced more hyaline cartilage, which expressed typical articular cartilage biomarkers, including established inhibitors of hypertrophic differentiation. In contrast, normoxia (21% O2) prevented the expression of these inhibitors and was associated with increased hypertrophic differentiation. Interestingly, gene network analysis revealed that oxygen tension resulted in metabolic programming of the MSCs directing chondrogenesis into articular- or epiphyseal cartilage-like tissue. This differentiation program resembled the embryological development of these distinct types of hyaline cartilage. Remarkably, the distinct cartilage phenotypes were preserved upon implantation in mice. Hypoxia-preconditioned implants remained cartilaginous, whereas normoxia-preconditioned implants readily underwent calcification, vascular invasion, and subsequent endochondral ossification. In conclusion, metabolic programming of MSCs by oxygen tension provides a simple yet effective mechanism by which to direct the chondrogenic differentiation program into either permanent articular-like cartilage or hypertrophic cartilage that is destined to become endochondral bone. http://www.pnas.org/content/early/2014/09/08/1410977111.abstract?sid=bd3bc8c2-0f0c-4ae9-b2d7-ad122cab965b Dionisio

Chromosome and Kinetochore in Mitosis video https://www.youtube.com/embed/0JpOJ4F4984?rel=0 Dionisio

Fertilization video https://www.youtube.com/embed/_5OvgQW6FG4?rel=0 Dionisio

on the frenetic hunt for new cytosine modifications Briefings in Functional Genomics (2013) 12 (3): 191-204. doi: 10.1093/bfgp/elt010 http://bfg.oxfordjournals.org/content/12/3/191.abstract?sid=594fa406-9b1d-48cb-bb9d-140a4e37cccc Epigenetic genome marking and chromatin regulation are central to establishing tissue-specific gene expression programs, and hence to several biological processes. Until recently, the only known epigenetic mark on DNA in mammals was 5-methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression. All of a sudden, a host of new actors—novel cytosine modifications and the ten eleven translocation (TET) enzymes—has appeared on the scene, sparking great interest. The challenge is now to uncover the roles they play and how they relate to DNA demethylation. Knowledge is accumulating at a frantic pace, linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis. Here, we review the recent progress in this exciting field, highlighting the TET enzymes as epigenetic DNA modifiers, their physiological roles, and their functions in health and disease. We also discuss the need to find relevant TET interactants and the newly discovered TET–O-linked N-acetylglucosamine transferase (OGT) pathway. Dionisio

Genomics of cardiac electrical function Proper generation and conduction of the cardiac electrical impulse is essential for the continuous coordinated contraction of the heart. Dysregulation of cardiac electrical function may lead to cardiac arrhythmias, which constitute a huge medical and social burden. Identifying the genetic factors underlying cardiac electrical activity serves the double purpose of allowing the early identification of individuals at risk for arrhythmia and discovering new potential therapeutic targets for prevention. The aim of this review is to provide an overview of the genes and genetic loci linked thus far to cardiac electrical function and arrhythmia. These genes and loci have been primarily uncovered through studies on the familial rhythm disorders and through genome-wide association studies on electrocardiographic parameters in large sets of the general population. An overview of all genes and loci with their respective effect is given. Briefings in Functional Genomics (2014) 13 (1): 39-50. doi: 10.1093/bfgp/elt029 http://bfg.oxfordjournals.org/content/13/1/39.abstract?sid=594fa406-9b1d-48cb-bb9d-140a4e37cccc Dionisio

Congenital heart diseases (CHD) represent the most common birth defect in human. The majority of cases are caused by a combination of complex genetic alterations and environmental influences. In the past, many disease-causing mutations have been identified; however, there is still a large proportion of cardiac malformations with unknown precise origin. High-throughput sequencing technologies established during the last years offer novel opportunities to further study the genetic background underlying the disease. In this review, we provide a roadmap for designing and analyzing high-throughput sequencing studies focused on CHD, but also with general applicability to other complex diseases. The three main next-generation sequencing (NGS) platforms including their particular advantages and disadvantages are presented. To identify potentially disease-related genomic variations and genes, different filtering steps and gene prioritization strategies are discussed. In addition, available control datasets based on NGS are summarized. Finally, we provide an overview of current studies already using NGS technologies and showing that these techniques will help to further unravel the complex genetics underlying CHD. Briefings in Functional Genomics (2014) 13 (1): 51-65. doi: 10.1093/bfgp/elt040 http://bfg.oxfordjournals.org/content/13/1/51.abstract?sid=594fa406-9b1d-48cb-bb9d-140a4e37cccc Dionisio

Message control in developmental transitions Briefings in Functional Genomics (2014) 13 (2): 106-120. doi: 10.1093/bfgp/elt045 Now that the sequencing of genomes has become routine, understanding how a given genome is used in different ways to obtain cell type diversity in an organism is the next frontier. How specific transcription programs are established during vertebrate embryogenesis, however, remains poorly understood. Transcription is influenced by chromatin structure, which determines the accessibility of DNA-binding proteins to the genome. Although large-scale genomics approaches have uncovered specific features of chromatin structure that are diagnostic for different cell types and developmental stages, our functional understanding of chromatin in transcriptional regulation during development is very limited. In recent years, zebrafish embryogenesis has emerged as an excellent vertebrate model system to investigate the functional relationship between chromatin organization, gene regulation and development in a dynamic environment. Here, we review how studies in zebrafish have started to improve our understanding of the role of chromatin structure in genome activation and pluripotency and in the potential inheritance of transcriptional states from parent to progeny. http://bfg.oxfordjournals.org/content/13/2/106.abstract?sid=1ac10bae-34e5-41ac-a372-cc7f990bb80b Dionisio

Epigenetic regulation of the genome Briefings in Functional Genomics (2014) 13 (3): 203-216. doi: 10.1093/bfgp/elt047 http://bfg.oxfordjournals.org/content/13/3/203.abstract?sid=1ac10bae-34e5-41ac-a372-cc7f990bb80b Dionisio

embryogenesis is governed by a series of signals that progressively define cell fate and shape the embryo. Nowadays, we know that such signals consist of regulatory mechanisms such as DNA methylation, histone modifications, long non-coding RNA and others. Briefings in Functional Genomics (2014) 13 (3): 189-190. doi: 10.1093/bfgp/elu008 http://bfg.oxfordjournals.org/content/13/3/189.extract?sid=1ac10bae-34e5-41ac-a372-cc7f990bb80b Dionisio

epigenome reorganization during early embryogenesis Briefings in Functional Genomics (2014) 13 (3): 246-253. doi: 10.1093/bfgp/elu007 http://bfg.oxfordjournals.org/content/13/3/246.abstract?sid=1ac10bae-34e5-41ac-a372-cc7f990bb80b In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells. During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization. After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo. Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role. Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear. This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications. Dionisio

epigenetic regulation in development and aging Briefings in Functional Genomics (2014) 13 (3): 223-234. doi: 10.1093/bfgp/elt048 The precise developmental map of the Caenorhabditis elegans cell lineage, as well as a complete genome sequence and feasibility of genetic manipulation make this nematode species highly attractive to study the role of epigenetics during development. Genetic dissection of phenotypical traits, such as formation of egg-laying organs or starvation-resistant dauer larvae, has illustrated how chromatin modifiers may regulate specific cell-fate decisions and behavioral programs. Moreover, the transparent body of C. elegans facilitates non-invasive microscopy to study tissue-specific accumulation of heterochromatin at the nuclear periphery. We also review here recent findings on how small RNA molecules contribute to epigenetic control of gene expression that can be propagated for several generations and eventually determine longevity. http://bfg.oxfordjournals.org/content/13/3/223.abstract?sid=1ac10bae-34e5-41ac-a372-cc7f990bb80b Dionisio

The ability to generate spontaneous motion and stable oscillations is a hallmark of living systems. Cells crawl to heal wounds, and the heart contracts periodically to pump blood through the entire body. Reproducing and understanding this behavior, both theoretically and experimentally, remains one of the great challenges of 21st-century science. http://www.rdmag.com/news/2014/09/physicists-explore-biomimetic-clocks?et_cid=4141771&et_rid=653535995&location=top Dionisio

Single Cell Smashes, Rebuilds Its Own Genome Life can be so intricate and novel that even a single cell can pack a few surprises, according to a study led by Princeton University researchers. http://www.biosciencetechnology.com/news/2014/09/single-cell-smashes-rebuilds-its-own-genome?et_cid=4141951&et_rid=653535995&type=cta Dionisio

In Directing Stem Cells, Study Shows Context Matters Figuring out how blank slate stem cells decide which kind of cell they want to be when they grow up — a muscle cell, a bone cell, a neuron — has been no small task for science. http://www.biosciencetechnology.com/news/2014/09/directing-stem-cells-study-shows-context-matters?et_cid=4141951&et_rid=653535995&location=top Dionisio

A Gene Regulatory Network Controls the Binary Fate Decision of Rod and Bipolar Cells in the Vertebrate Retina DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.018 Gene regulatory networks (GRNs) regulate critical events during development. In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types. Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron. The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision. We identified a cis-regulatory module (CRM), B108, that mimics Blimp1 expression. Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1. Otx2 and ROR? were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells. Dionisio

Local CRH Signaling Promotes Synaptogenesis and Circuit Integration of Adult-Born Neurons DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.001 Neural activity either enhances or impairs de novo synaptogenesis and circuit integration of neurons, but how this activity is mechanistically relayed in the adult brain is largely unknown. Neuropeptide-expressing interneurons are widespread throughout the brain and are key candidates for conveying neural activity downstream via neuromodulatory pathways that are distinct from classical neurotransmission. With the goal of identifying signaling mechanisms that underlie neuronal circuit integration in the adult brain, we have virally traced local corticotropin-releasing hormone (CRH)-expressing inhibitory interneurons with extensive presynaptic inputs onto new neurons that are continuously integrated into the adult rodent olfactory bulb. Local CRH signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation, and integration of new neurons in the adult brain. Dionisio

The Centromere: Chromatin Foundation for the Kinetochore Machinery DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.016 Since discovery of the centromere-specific histone H3 variant CENP-A, centromeres have come to be defined as chromatin structures that establish the assembly site for the complex kinetochore machinery. In most organisms, centromere activity is defined epigenetically, rather than by specific DNA sequences. In this review, we describe selected classic work and recent progress in studies of centromeric chromatin with a focus on vertebrates. We consider possible roles for repetitive DNA sequences found at most centromeres, chromatin factors and modifications that assemble and activate CENP-A chromatin for kinetochore assembly, plus the use of artificial chromosomes and kinetochores to study centromere function. Dionisio

The surprising dynamics of scaffolding proteins The function of scaffolding proteins is to bring together two or more proteins in a relatively stable configuration, hence their name. Numerous scaffolding proteins are found in nature, many having multiple protein–protein interaction modules. Over the past decade, examples of scaffolding complexes long thought to be stable have instead been found to be surprisingly dynamic. These studies are scattered among different biological systems, and so the concept that scaffolding complexes might not always represent stable entities and that their dynamics can be regulated has not garnered general attention. We became aware of this issue in our studies of a scaffolding protein in microvilli, which forced us to reevaluate its contribution to their structure. The purpose of this Perspective is to draw attention to this phenomenon and discuss why complexes might show regulated dynamics. We also wish to encourage more studies on the dynamics of “stable” complexes and to provide a word of caution about how functionally important dynamic associations may be missed in biochemical and proteomic studies. doi: 10.1091/mbc.E14-04-0878 http://www.molbiolcell.org/content/25/16/2315.abstract?sid=5ab41a9c-7549-4acf-982f-f62e6bfedd87 Dionisio

Kinetochore–microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin Centromere protein E (CENP-E) is a highly elongated kinesin that transports pole-proximal chromosomes during congression in prometaphase. During metaphase, it facilitates kinetochore–microtubule end-on attachment required to achieve and maintain chromosome alignment. In vitro CENP-E can walk processively along microtubule tracks and follow both growing and shrinking microtubule plus ends. Neither the CENP-E–dependent transport along microtubules nor its tip-tracking activity requires the unusually long coiled-coil stalk of CENP-E. The biological role for the CENP-E stalk has now been identified through creation of “Bonsai” CENP-E with significantly shortened stalk but wild-type motor and tail domains. We demonstrate that Bonsai CENP-E fails to bind microtubules in vitro unless a cargo is contemporaneously bound via its C-terminal tail. In contrast, both full-length and truncated CENP-E that has no stalk and tail exhibit robust motility with and without cargo binding, highlighting the importance of CENP-E stalk for its activity. Correspondingly, kinetochore attachment to microtubule ends is shown to be disrupted in cells whose CENP-E has a shortened stalk, thereby producing chromosome misalignment in metaphase and lagging chromosomes during anaphase. Together these findings establish an unexpected role of CENP-E elongated stalk in ensuring stability of kinetochore–microtubule attachments during chromosome congression and segregation. doi: 10.1091/mbc.E14-01-0698 http://www.molbiolcell.org/content/25/15/2272.abstract?sid=acc89c2f-771d-4c69-a65f-9c4d441b9017 Dionisio

Mathematical model with spatially uniform regulation explains long-range bidirectional transport of early endosomes In many cellular contexts, cargo is transported bidirectionally along microtubule bundles by dynein and kinesin-family motors. Upstream factors influence how individual cargoes are locally regulated, as well as how long-range transport is regulated at the whole-cell scale. Although the details of local, single-cargo bidirectional switching have been extensively studied, it remains to be elucidated how this results in cell-scale spatial organization. Here we develop a mathematical model of early endosome transport in Ustilago maydis. We demonstrate that spatiotemporally uniform regulation, with constant transition rates, results in cargo dynamics that is consistent with experimental data, including data from motor mutants. We find that microtubule arrays can be symmetric in plus-end distribution but asymmetric in binding-site distribution in a manner that affects cargo dynamics and that cargo can travel past microtubule ends in microtubule bundles. Our model makes several testable predictions, including secondary features of dynein and cargo distributions. doi: 10.1091/mbc.E14-03-0826 http://www.molbiolcell.org/content/25/16/2408.abstract?sid=acc89c2f-771d-4c69-a65f-9c4d441b9017 Dionisio

Cdk1 promotes cytokinesis in fission yeast through activation of the septation initiation network In Schizosaccharomyces pombe, late mitotic events are coordinated with cytokinesis by the septation initiation network (SIN), an essential spindle pole body (SPB)–associated kinase cascade, which controls the formation, maintenance, and constriction of the cytokinetic ring. It is not fully understood how SIN initiation is temporally regulated, but it depends on the activation of the GTPase Spg1, which is inhibited during interphase by the essential bipartite GTPase-activating protein Byr4-Cdc16. Cells are particularly sensitive to the modulation of Byr4, which undergoes cell cycle–dependent phosphorylation presumed to regulate its function. Polo-like kinase, which promotes SIN activation, is partially responsible for Byr4 phosphorylation. Here we show that Byr4 is also controlled by cyclin-dependent kinase (Cdk1)–mediated phosphorylation. A Cdk1 nonphosphorylatable Byr4 phosphomutant displays severe cell division defects, including the formation of elongated, multinucleate cells, failure to maintain the cytokinetic ring, and compromised SPB association of the SIN kinase Cdc7. Our analyses show that Cdk1-mediated phosphoregulation of Byr4 facilitates complete removal of Byr4 from metaphase SPBs in concert with Plo1, revealing an unexpected role for Cdk1 in promoting cytokinesis through activation of the SIN pathway. doi: 10.1091/mbc.E14-04-0936 http://www.molbiolcell.org/content/25/15/2250.abstract?sid=f4f15ab3-1982-4b14-9f5b-4f6979c5409e Dionisio

Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm. Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs. The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear. Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations. Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin ?– and Nup153-binding domains. However, Nup50 dynamics are independent of importin ?, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility. Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes. Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC. doi: 10.1091/mbc.E14-04-0865 http://www.molbiolcell.org/content/25/16/2472.abstract?sid=f4f15ab3-1982-4b14-9f5b-4f6979c5409e Dionisio

Integration of biological data by kernels on graph nodes allows prediction of new genes involved in mitotic chromosome condensation The advent of genome-wide RNA interference (RNAi)–based screens puts us in the position to identify genes for all functions human cells carry out. However, for many functions, assay complexity and cost make genome-scale knockdown experiments impossible. Methods to predict genes required for cell functions are therefore needed to focus RNAi screens from the whole genome on the most likely candidates. Although different bioinformatics tools for gene function prediction exist, they lack experimental validation and are therefore rarely used by experimentalists. To address this, we developed an effective computational gene selection strategy that represents public data about genes as graphs and then analyzes these graphs using kernels on graph nodes to predict functional relationships. To demonstrate its performance, we predicted human genes required for a poorly understood cellular function—mitotic chromosome condensation—and experimentally validated the top 100 candidates with a focused RNAi screen by automated microscopy. Quantitative analysis of the images demonstrated that the candidates were indeed strongly enriched in condensation genes, including the discovery of several new factors. By combining bioinformatics prediction with experimental validation, our study shows that kernels on graph nodes are powerful tools to integrate public biological data and predict genes involved in cellular functions of interest. doi: 10.1091/mbc.E13-04-0221 Dionisio

Do Endothelial Cells Dream of Eclectic Shape? Endothelial cells (ECs) exhibit dramatic plasticity of form at the single- and collective-cell level during new vessel growth, adult vascular homeostasis, and pathology. Understanding how, when, and why individual ECs coordinate decisions to change shape, in relation to the myriad of dynamic environmental signals, is key to understanding normal and pathological blood vessel behavior. However, this is a complex spatial and temporal problem. In this review we show that the multidisciplinary field of Adaptive Systems offers a refreshing perspective, common biological language, and straightforward toolkit that cell biologists can use to untangle the complexity of dynamic, morphogenetic systems. DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.019 Dionisio

A Dynamic Microtubule Cytoskeleton Directs Medial Actomyosin Function during Tube Formation The cytoskeleton is a major determinant of cell-shape changes that drive the formation of complex tissues during development. Important roles for actomyosin during tissue morphogenesis have been identified, but the role of the microtubule cytoskeleton is less clear. Here, we show that during tubulogenesis of the salivary glands in the fly embryo, the microtubule cytoskeleton undergoes major rearrangements, including a 90° change in alignment relative to the apicobasal axis, loss of centrosomal attachment, and apical stabilization. Disruption of the microtubule cytoskeleton leads to failure of apical constriction in placodal cells fated to invaginate. We show that this failure is due to loss of an apical medial actomyosin network whose pulsatile behavior in wild-type embryos drives the apical constriction of the cells. The medial actomyosin network interacts with the minus ends of acentrosomal microtubule bundles through the cytolinker protein Shot, and disruption of Shot also impairs apical constriction. DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.023 Dionisio

High-Resolution Temporal Analysis Reveals a Functional Timeline for the Molecular Regulation of Cytokinesis To take full advantage of fast-acting temperature-sensitive mutations, thermal control must be extremely rapid. We developed the Therminator, a device capable of shifting sample temperature in ?17 s while simultaneously imaging cell division in vivo. Applying this technology to six key regulators of cytokinesis, we found that each has a distinct temporal requirement in the Caenorhabditis elegans zygote. Specifically, myosin-II is required throughout cytokinesis until contractile ring closure. In contrast, formin-mediated actin nucleation is only required during assembly and early contractile ring constriction. Centralspindlin is required to maintain division after ring closure, although its GAP activity is only required until just prior to closure. Finally, the chromosomal passenger complex is required for cytokinesis only early in mitosis, but not during metaphase or cytokinesis. Together, our results provide a precise functional timeline for molecular regulators of cytokinesis using the Therminator, a powerful tool for ultra-rapid protein inactivation. DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.009 Dionisio

Mother Centrioles Do a Cartwheel to Produce Just One Daughter In this issue of Developmental Cell, Fong et al. (2014) present evidence for a model of centriole duplication whereby the cartwheel—the starting building block in centriole biogenesis—assembles within the lumen of the mother centriole before templating the daughter centriole to ensure a single duplication event per cell cycle. DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.013 Dionisio

A Self-Organizing miR-132/Ctbp2 Circuit Regulates Bimodal Notch Signals and Glial Progenitor Fate Choice during Spinal Cord Maturation Radial glial progenitors play pivotal roles in the development and patterning of the spinal cord, and their fate is controlled by Notch signaling. How Notch is shaped to regulate their crucial transition from expansion toward differentiation remains, however, unknown. miR-132 in the developing zebrafish dampens Notch signaling via a cascade involving the transcriptional corepressor Ctbp2 and the Notch suppressor Sirt1. At early embryonic stages, high Ctbp2 levels sustain Notch signaling and radial glial expansion and concomitantly induce miR-132 expression via a double-negative feedback loop involving Rest inhibition. The changing balance in miR-132 and Ctbp2 interaction gradually drives the switch in Notch output and radial glial progenitor fate as part of the larger developmental program involved in the transition from embryonic to larval spinal cord. DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.006 Dionisio

unsuspected role of Notch signaling? The regulatory inputs that drive lineage-restricted expression and how they relate to cell position are largely unknown? Notch and Hippo Converge on Cdx2 to Specify the Trophectoderm Lineage? The first lineage choice in mammalian embryogenesis is that between the trophectoderm, which gives rise to the trophoblast of the placenta, and the inner cell mass, from which is derived the embryo proper and the yolk sac. The establishment of these lineages is preceded by the inside-versus-outside positioning of cells in the early embryo and stochastic expression of key transcription factors, which is then resolved into lineage-restricted expression. The regulatory inputs that drive this restriction and how they relate to cell position are largely unknown. Here, we show an unsuspected role of Notch signaling in regulating trophectoderm-specific expression of Cdx2 in cooperation with TEAD4. Notch activity is restricted to outer cells and is able to influence positional allocation of blastomeres, mediating preferential localization to the trophectoderm. Our results show that multiple signaling inputs at preimplantation stages specify the first embryonic lineages. DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.019 Dionisio

Long Noncoding RNAs Bind Active Chromatin Sites Mechanistic roles for many lncRNAs are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess. Using a method to purify endogenous RNAs and their associated factors, we mapped the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. We also identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process. DOI: http://dx.doi.org/10.1016/j.molcel.2014.07.012 Dionisio

Absence of a simple code: how transcription factors read the genome •TFs recognize their genomic target sites by using mechanisms at multiple levels. •Models of DNA sequence and shape can capture the in vitro TF binding specificity. •Cofactors, cooperativity, chromatin, and other factors affect in vivo TF binding. •No simple code combines all the various determinants of TF binding specificity. Transcription factors (TFs) influence cell fate by interpreting the regulatory DNA within a genome. TFs recognize DNA in a specific manner; the mechanisms underlying this specificity have been identified for many TFs based on 3D structures of protein–DNA complexes. More recently, structural views have been complemented with data from high-throughput in vitro and in vivo explorations of the DNA-binding preferences of many TFs. Together, these approaches have greatly expanded our understanding of TF–DNA interactions. However, the mechanisms by which TFs select in vivo binding sites and alter gene expression remain unclear. Recent work has highlighted the many variables that influence TF–DNA binding, while demonstrating that a biophysical understanding of these many factors will be central to understanding TF function. DOI: http://dx.doi.org/10.1016/j.tibs.2014.07.002 Dionisio

How chemistry supports cell biology: the chemical toolbox at your service Chemical biology is a young and rapidly developing scientific field. In this field, chemistry is inspired by biology to create various tools to monitor and modulate biochemical and cell biological processes. Chemical contributions such as small-molecule inhibitors and activity-based probes (ABPs) can provide new and unique insights into previously unexplored cellular processes. Overview of recent breakthroughs in chemical biology that are likely to have a significant impact on cell biology. Application of several chemical tools in cell biology research. DOI: http://dx.doi.org/10.1016/j.tcb.2014.07.002 Dionisio

Lighting Up pre-mRNA Recognition Systematic analyses, by UV crosslinking, of the precise binding sites for 23 different proteins across the yeast pre-mRNA population have given insights into the in vivo assembly of, and interactions between, pre-mRNA processing, packaging, and transport complexes. DOI: http://dx.doi.org/10.1016/j.molcel.2014.08.021 Dionisio

Protein Simulations 23—24 October 2014 Protein and enzyme function is determined by both structure and dynamic flexibility in solution. Molecular simulations provide insight into conformational transitions that play a critical role in biological activity. ?Theoretical aspects of molecular dynamics simulations ?Preparation of a protein system for molecular dynamics simulations ?Practical aspects of running a simulation ?Output of simulations and analysis of trajectories ?Steered molecular dynamics http://www.biochemistry.org/Conferences/AllConferences/tabid/379/Filter/0%20BSTD/MeetingNo/TD004/view/Conference/Default.aspx Dionisio

#303, 304, 308 follow-up Conference explores complex world of the dynamic cell From mitosis to motors and microtubules - the latest in science's understanding of the dynamic cell will be on show at a four-day conference in Cambridge, UK, this September. The Dynamic Cell – a joint Biochemical Society and British Society of Cell Biology (BSCB) conference – will feature more than 40 speakers discussing the latest research into the molecular biology that underpins key cellular processes. "Dynamic cell growth, division and movement are hallmarks of life and are essential for the formation of an organism, yet our understanding of the molecular basis of these processes is far from complete," says BSCB Meetings Secretary Dr Stephen Royle. "Our stellar line-up of speakers from the UK and around the world will showcase the most exciting and topical findings in dynamic cell biology, using different model organisms and both in vivo and in vitro approaches." Topics will cover cell migration and the cytoskeleton, cargo sorting in the endocytic and secretory pathways, molecular control of chromosome segregation and mitosis, membrane dynamics during cytokinesis, and in vitro analysis of molecular motors. http://www.eurekalert.org/pub_releases/2014-06/bs-cec062314.php Dionisio

OT

Beyond the Blueprint In addition to serving as a set of instructions to build an individual, the genome can influence neighboring organisms and, potentially, entire ecosystems. The relationship between an individual’s phenotype and genotype has been fundamental to the genetic analysis of traits and to models of evolutionary change for decades. Of course, scientists have long recognized that phenotype responds to nongenetic factors, such as environmental variation in nutrient availability or the presence of other, competing species. But by assuming that the genetic component of a particular trait is confined to your genes and only yours, scientists overlooked another important input: the genes of your neighbors. http://www.the-scientist.com//?articles.view/articleNo/40870/title/Beyond-the-Blueprint/

Check this comment:

Evolutionary models lack experimental evidence of evolutionary events that are required to link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man. It is time to examine evidence that attests to the biologically-based cause of cell type differences in all cells of all tissues in all organs of all organisms and to stop claiming that the differences in morphological and behavioral phenotypes "evolved." Ecological variation leads to nutrient-dependent pheromone-controlled ecological adaptations manifested in biodiversity. There are too many model organisms that exemplify that fact. Evolutionary models must either include events associated with cell type differentiation or the models will only continue to add theories to theories all the while the evolutionary models dismiss experimental evidence of biologically-based cause and effect.

Dionisio

#303 correction Sorry, forgot to include the link http://www.jointbscbbs.org/ Dionisio

#306 follow-up Sorry, forgot to add the link http://app.aaas-science.org/e/es?s=1906&e=92805&elq=201102ca2ca54886acf39f9275a23527 Dionisio

OT Big data should get much bigger - the info avalanche coming from research keeps increasing: As next generation sequencing (NGS) platforms advance in their speed, ease-of-use, and cost-effectiveness, many researchers are transitioning from microarrays to RNA sequencing (or RNA-seq) for their gene expression analysis needs. RNA-seq goes beyond differential gene expression to provide fundamental insights into how genomes are organized and regulated. Some RNA-seq platforms also offer higher sensitivity, increased sample number flexibility, and the ability to analyze highly degraded or rare samples from as little as 10 ng of input RNA. During this webinar, our expert speakers will discuss how NGS and RNA-seq can be broadly applied, including for the analysis of gene regulation through allelic expression and long non-coding RNAs, particularly in pharmacogenomics; for identification of novel microRNAs and transcript isoforms in stem cells; or for the discovery of new tumor biomarkers in archived formalin-fixed, paraffin-embedded samples. During the webinar, viewers will: • Hear about current approaches using RNA-seq for biomarker discovery • Discover novel techniques using NGS for differential gene expression • Learn what bioinformatics tools are being used in RNA-seq applications • Have their questions answered live by our expert panel! Dionisio

Separate to operate: control of centrosome positioning and separation The centrosome is the main microtubule (MT)-organizing centre of animal cells. It consists of two centrioles and a multi-layered proteinaceous structure that surrounds the centrioles, the so-called pericentriolar material. Centrosomes promote de novo assembly of MTs and thus play important roles in Golgi organization, cell polarity, cell motility and the organization of the mitotic spindle. To execute these functions, centrosomes have to adopt particular cellular positions. Actin and MT networks and the association of the centrosomes to the nuclear envelope define the correct positioning of the centrosomes. Another important feature of centrosomes is the centrosomal linker that connects the two centrosomes. The centrosome linker assembles in late mitosis/G1 simultaneously with centriole disengagement and is dissolved before or at the beginning of mitosis. Linker dissolution is important for mitotic spindle formation, and its cell cycle timing has profound influences on the execution of mitosis and proficiency of chromosome segregation. In this review, we will focus on the mechanisms of centrosome positioning and separation, and describe their functions and mechanisms in the light of recent findings. doi: 10.1098/rstb.2013.0461 http://rstb.royalsocietypublishing.org/content/369/1650/20130461.abstract Dionisio

#303 follow-up that conference seems really loaded with very juicy material! I'm drooling already :) All their papers must be up to date, with the latest and greatest info on the subjects, right? Let's keep an eye on this. :) Dionisio

gpuccio, check this conference, which is scheduled to start this week in the UK: The Dynamic Cell Molecular Control of Chromosome Segregation

The Ran-GTP Gradient Spatially Regulates the Activity of XCTK2 within the Spindle Protein complexes responsible for centrosome segregation in mitosis Temporal control of cell division: switches, refractory periods and feedback control Sharpening the anaphase switch Regulation of the chromosomal passenger complex in cancer The spindle checkpoint regulates Cdc20 activity and turnover to control mitotic progression A mitotic exit ubiquitome from human cells Cell cycle dynamics in Bacillus subtitles

Cargo Sorting in the Endocytic Pathway

Endocytic cargo selection and clathrin coat assembly The how and why early endosomes move: Lessons from a fungal model system CLIP-170 spatially modulates receptor tyrosine kinase localization to coordinate cell migration A membrane-driven conformational switch in AP2 activates clathrin recruitment Adaptor protein complexes Endosomal sorting orchestrated by retromer Ysc84 is a novel, PI(4,5)P2 regulated, actin - capping protein functioning in early stages of yeast endocytosis

In-Vitro Analysis of Molecular Motors

The structure and mechanisms of dynein Reconstitution of a hierarchical +TIP interaction network controlling microtubule end tracking of human dynein. Myosin Va and dynamic actin oppose microtubules to drive long-range organelle transport. Molecular mechanisms of myosin function Cut7-driven microtubule sliding reverses direction depending on motor density The Myosin Family of Molecular Motors: Nature's Exquisite Nanomachines New insights into aneuploidy in mammalian eggs

Membrane Dynamics during Cytokinesis

Precision timing mechanisms for anaphase onset and cytokinesis in human cells Plant cytokinesis – a tale of membrane traffic and fusion Essential role of ESCRT-III-associated kinase in the regulation of abscission timing Dividing cells regulate their lipid composition and localization Regulation of midbody formation and function by mitotic kinesis The roles of the oncoprotein GOLPH3 in contractile ring assembly and membrane trafficking during cytokinesis.

Cell Migration and the Cytoskeleton

Control of directional cell migration by the microtubule cytoskeleton Role of the actin cytoskeleton in 3D invasive migration Oncogene-like induction of cellular invasion from centrosome amplification Syndecan-4 controls integrin recycling to regulate cell migration and the extracellular microenvironment Pushing with actin: from cells to pathogens Dynamic anisotropies in cytoskeletal organisation induced by ROS and Rho signalling underlie multicellular sensing and spatial patterning in a Drosophila epithelium. Drink or drive: Competition between macropinocytosis and cell migration. A helping hand from enveloped viruses to uncover the final events of cell division

Cargo Sorting in the Secretory Pathway

Parallels between ER-Golgi traffic and AutoPlay Morpho-functional changes in the organisation of the secretory pathway in D. melanogaster upon starvation Protein sorting and glycan biosynthesis Sterol traffic in yeast is mediated by a newly discovered family of StART proteins Mechanism of sorting and export of bulky procollagen VII from the endosplasmic reticulum Regulation of Exocytosis by the Exocyst Complex The small GTPase Arf1 modulates mitochondrial morphology and function

Dionisio

Advances in high throughput and platform technologies in biology present an unprecedented challenge in scale, management, and analysis of biological data. Advances in computing architecture and scale are enabling simulations of complex biological processes at various organizational levels from atomic to cellular and beyond. http://researcher.watson.ibm.com/researcher/view_group.php?id=1080 Dionisio

Science research can use all available help, including computing resources for big data processing, modeling, simulations, analysis, documentation, organization. Microsoft Biology Initiative http://research.microsoft.com/en-us/projects/bio/default.aspx Dionisio

Mung

Nucleic Acid Rain?

Did you mean "amino acid" clouds? http://ghr.nlm.nih.gov/handbook/howgeneswork/protein Dionisio

Nature's design principles? http://wyss.harvard.edu/viewpage/about-us/about-us Dionisio

Nucleic Acid Rain? Mung

Protein Clouds Gather and Disperse, But Why? Blobs. Clouds. Assemblages. All these terms have been applied to poorly defined protein clusters that mysteriously form inside cells and then just as mysteriously disappear. These protein collections might be considered fuzzy outliers. After all, they defy the usual expectations for proteins. Proteins are supposed to assume definite structures that confer highly specific activities. Proteins—we like to think—work with each other and their nonprotein partners in lock-and-key fashion. http://www.genengnews.com/gen-news-highlights/protein-clouds-gather-and-disperse-but-why/81250296/ Dionisio

#295 correction Box, I assume that in post #292 the concept “information in a non conscious system, like a computer,…” includes the microprocessor signaling codes, the operating system, the drivers, the DBMS, the app programs, as well as the engineering design that lead to the hardware where the software operates and the technical specs that preceded all the software development and implementation. Dionisio

Box, I assume that in post #292 the concept "information in a non conscious system, like a computer,..." includes the operating system, drivers, app programs, as well as the engineering design that lead to the hardware where the software operates. Dionisio

Box, gpuccio has responded your good questions much better than I could have done it. The more questions get answered, the clearer the big picture turns, revealing an elaborate information processing system that the best management information systems analysts in the world would drool at the sight of such marvel. Mind-boggling orchestrated choreographies that would make the ballets Swan Lake and The Nutcracker look like bad TV commercials. There's a problem: as outstanding questions get answered, newer questions are posed. Many things remain stubbornly elusive. Now, and this is very important, we must remind ourselves that all that stuff is the result of the powerful magic 'n-D e' formula RV+NS+T and maybe -as gpuccio suggested- some great, great, great luck! ;-) Dionisio

Gpuccio, thank you very much for explaining your position.

Gpuccio: Now, biological information is more similar to a working computer than to a hard drive. This is one of the points that I will try to discuss in my OP. In that sense, it can certainly take “decisions” about many things, which have been in some way (that still eludes us) programmed in it.

Mysterious indeed. There are many examples for context-dependent behaviour of parts of organisms (e.g. mouse hair follicles in Talbott’s article). If this is to be explained by “high level procedural information” [HLPI], one has to wonder where HLPI resides. HLPI must be present at multiple levels. Chimerism is IMHO, among other phenomena, strong indication that there is even an abundance of HLPI residing at the level of the whole organism. What medium does HLPI use? Box

Box: Good questions. I would say that information in a non conscious system, like a computer, possesses decision power for those decisions that have been programmed in the system. That can include situations that were not completely programmed, but that can be dealt in some way by the existing programs. That can even include "learning" (not in a conscious way, obviously). For example, neural networks and similar software can "learn" from inputs and from its elaboration of inputs, but only according to procedures that have been programmed in the original software. Now, biological information is more similar to a working computer than to a hard drive. This is one of the points that I will try to discuss in my OP. In that sense, it can certainly take "decisions" about many things, which have been in some way (that still eludes us) programmed in it. But you ask: can it "create new information"? There are two aspects to that. a) As you probably know, I firmly believe that a non conscious computing system can never "create new information" in the sense of new original dFSCI. IOWs it cannot define a new function and generate complex information to implement that function. As I have said, even systems that "learn" can only learn according to the rules for which they have pre-set definitions. A computing system has no idea of what a function is, because it has no idea of purpose. Therefore, it can never define a really new function, or even simply recognize it, unless it has been in some indirect way already defined in the system. So, lacking the definition of a new function, it cannot certainly compute complexity to implement it. So, in this sense, even the biological information which we find "written" in cells (and which can be compared to a very complex computing system, must share this limitation. That's why new proteins, or body plans, or regulatory networks are proof of a design intervention from outside, and cannot be explained simply as adaptations. b) But I think that you suggest that some processes in the existing beings, different from the evolution of a new species, could be beyond the possibilities of a computational system, however complex. You quote tissue damage repair as an example. Well, if it were true that some of the physiological processes in living beings cannot be explained by computational processes alone, that would mean that some other components (not completely physical and computational) are at work in living beings. IOWs, that would correspond to proposing some form of what I would call "neo-vitalism". Now, I have nothing against that. Frankly, I am often tempted by that perspective. However, before I am labeled by our kind adversaries, at their fascinating sites, as a neo vitalist, with all the inevitable compliments that you can imagine, I must state that I have no explicit scientific arguments, at present, so I am not endorsing the idea as an explicit scientific theory. However, if you are interested in creating a neo vitalism fan club, we can discuss! :) gpuccio

Gpuccio, I'm looking very much forward to your OP on this subject. I'm a big fan of your writings. Though I wonder if “high level procedural information” can fulfill the role of “master-controller”. Does information possess decision power? Or, to use Mung's analogy, can a hard drive control a computer? Also, can a hard drive solve new problems - and in effect create new information?

Stephen Talbott: Scientists can damage tissues in endlessly creative ways that the organism has never confronted in its evolutionary history. Yet, so far as its resources allow, it mobilizes those resources, sets them in motion, and does what it has never done before, all in the interest of restoring a dynamic form and a functioning that the individual molecules and cells certainly cannot be said to “understand” or “have in view”. We can frame the problem of identity and context with this question: Where do we find the context and activity that, in whatever sense we choose to use the phrase, does “have in view” this restorative aim? Not an easy question. Yet the achievement is repeatedly carried through; an ever-adaptive intelligence comes into play somehow, and all those molecules and cells are quite capable of participating in and being caught up in the play. [my emphasis]

Box

Or, as Piotr said some time ago, “it’s just the memory of what worked”.

So he wants us to imagine something like a hard drive, with no means of memory storage, only retrieval, where random changes to the bit values on the drive result in a functioning computer with ever more complex features becoming available. And we call this "the memory of what worked." How does it know what worked and what didn't? Mung

Box: It's a big problem. I have been trying to understand what is known (and, as you can see from Dionisio's many references, it's really a lot), and I am preparing an OP about that. I can certainly anticipate that what you call "the master-controller" (that I would call the "high level procedural information) remains really elusive. As you know, our neo darwinist friends simply avoid the problem of the "master-controller". They are satisfied with detailing the (apparently endless) complexities of the low-level procedures. Probably, they simply believe that all goes well because of some great, great, great luck! Or, as Piotr said some time ago, "it's just the memory of what worked". A very good memory indeed... gpuccio

Dionisio, are they looking for the master-controller? What would that look like? Is such a thing even conceivable? Box

Dionisio #286, What controls the Hox genes? And what controls the controllers of Hox genes? And ... Box

Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis. doi: 10.1242/dev.098731 Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo. http://www.ncbi.nlm.nih.gov/pubmed/24449840 Dionisio

CYLD regulates spindle orientation by stabilizing astral microtubules and promoting dishevelled-NuMA-dynein/dynactin complex formation. doi: 10.1073/pnas.1319341111 Oriented cell division is critical for cell fate specification, tissue organization, and tissue homeostasis, and relies on proper orientation of the mitotic spindle. The molecular mechanisms underlying the regulation of spindle orientation remain largely unknown. Herein, we identify a critical role for cylindromatosis (CYLD), a deubiquitinase and regulator of microtubule dynamics, in the control of spindle orientation. CYLD is highly expressed in mitosis and promotes spindle orientation by stabilizing astral microtubules and deubiquitinating the cortical polarity protein dishevelled. The deubiquitination of dishevelled enhances its interaction with nuclear mitotic apparatus, stimulating the cortical localization of nuclear mitotic apparatus and the dynein/dynactin motor complex, a requirement for generating pulling forces on astral microtubules. These findings uncover CYLD as an important player in the orientation of the mitotic spindle and cell division and have important implications in health and disease. http://www.ncbi.nlm.nih.gov/pubmed/24469800 Dionisio

Need for multi-scale systems to identify spindle orientation regulators doi: 10.3389/fphys.2014.00278 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110440/ During cell division, the mitotic spindle captures chromosomes and segregates them into two equal sets. The orientation and position of the mitotic spindle is important because the spindle equator becomes the plane of cell division. For instance, in a columnar cell with apical and basal polarity, if the spindle pole-to-pole axis orients along the cell's long axis, the cell will divide along its short-axis; however, if the spindle axis orients along the cell's short axis, the cell will divide along its long-axis (Figure ?(Figure1A).1A). Similarly when the spindle is off-centered (mis-positioned), it results in asymmetric cell sizes in the two daughter cells, which is often used to control tissue organization (Figure ?(Figure1B).1B). Thus, errors in the orientation and positioning of the mitotic spindle can cause incorrect plane of cell division leading to incorrect cell size, content and neighborhood of daughter cells (Figures 1A,B). Figure 1 http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=4110440_fphys-05-00278-g0001.jpg (A,B) Fates of incorrect spindle orientation and positioning: Cartoons show mitotic spindle movements relative to the substratum leading to spindle mis-orientation (A) and mis-positioning (B) with cortical bands highlighting polarity differences. In (A), misorientation alters the relative positions and contents of daughter cells, without affecting progenitor cell sizes. In (B), mispositioning affects daughter cell size, relative positions and their contents. Legend describing cell substratum, spindle microtubules, metaphase plate, and spindle movements included. (C) Oncogenic pathways implicated in spindle orientation: The Hippo, PTEN-PI3K, and Wnt tumor suppressor pathway components are marked in pink, blue, and purple, respectively. The oncogenic estrogen receptor (ER) pathway is marked in green. Together, these pathways regulate astral microtubule (marked in bold) function. Red arrows indicate force generation events. The Hippo pathway also influences transcriptional regulation of several genes involved in orientation (marked on chromosomes). Dionisio

Mechanisms of spindle positioning. doi: 10.1083/jcb.201210007 Accurate positioning of spindles is essential for asymmetric mitotic and meiotic cell divisions that are crucial for animal development and oocyte maturation, respectively. The predominant model for spindle positioning, termed "cortical pulling," involves attachment of the microtubule-based motor cytoplasmic dynein to the cortex, where it exerts a pulling force on microtubules that extend from the spindle poles to the cell cortex, thereby displacing the spindle. Recent studies have addressed important details of the cortical pulling mechanism and have revealed alternative mechanisms that may be used when microtubules do not extend from the spindle to the cortex. http://www.ncbi.nlm.nih.gov/pubmed/23337115 Dionisio

Molecular mechanisms in spindle positioning: structures and new concepts. doi: 10.1016/j.ceb.2012.10.005. Coordination of cell cleavage with respect to cell geometry, cell polarity and neighboring tissues is critical for tissue maintenance, malignant transformation and metastasis. The position of the mitotic spindle within the cell determines where cell cleavage occurs. Spindle positioning is often mediated through capture of astral microtubules by motor proteins at the cell cortex. Recently, the core dynein anchor complex has been structurally resolved. Junctional complexes were shown to provide additional capture sites for astral microtubules in proliferating tissues. Finally, latest studies show that signals from centrosomes control spindle positioning and propose novel concepts for generation of centrosome identity. http://www.ncbi.nlm.nih.gov/pubmed/23142476 Dionisio

Epithelial polarity and spindle orientation: intersecting pathways. doi: 10.1098/rstb.2013.0291. During asymmetric stem cell divisions, the mitotic spindle must be correctly oriented and positioned with respect to the axis of cell polarity to ensure that cell fate determinants are appropriately segregated into only one daughter cell. By contrast, epithelial cells divide symmetrically and orient their mitotic spindles perpendicular to the main apical-basal polarity axis, so that both daughter cells remain within the epithelium. Work in the past 20 years has defined a core ternary complex consisting of Pins, Mud and G?i that participates in spindle orientation in both asymmetric and symmetric divisions. As additional factors that interact with this complex continue to be identified, a theme has emerged: there is substantial overlap between the mechanisms that orient the spindle and those that establish and maintain apical-basal polarity in epithelial cells. In this review, we examine several factors implicated in both processes, namely Canoe, Bazooka, aPKC and Discs large, and consider the implications of this work on how the spindle is oriented during epithelial cell divisions. http://www.ncbi.nlm.nih.gov/pubmed/24062590 Dionisio

Spindle orientation and epidermal morphogenesis. doi: 10.1098/rstb.2013.0016. Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stem cells. ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur. During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane. These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions. That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells. Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis. http://www.ncbi.nlm.nih.gov/pubmed/24062586 Dionisio

Oriented divisions, fate decisions. doi: 10.1016/j.ceb.2013.08.003. During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction. Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis. Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively. The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices. http://www.ncbi.nlm.nih.gov/pubmed/24021274 Dionisio

Molecular pathways regulating mitotic spindle orientation in animal cells. doi: 10.1242/dev.087627. Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions. Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity+. Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge. Here, we review both the well-established spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs. http://www.ncbi.nlm.nih.gov/pubmed/23571210 Dionisio

Cell cycle, checkpoints and cancer Maintenance of genomic integrity is a pre-requisite for a safe and long lasting life and prevents development of diseases associated with genomic instability such as cancer. DNA is constantly subjected and damaged by a large variety of chemical and physical agents, thus cells had to set up a number of surveillance mechanisms that constantly monitor the DNA integrity and the cell cycle progression and in the presence of any type of DNA damage activate pathways that lead to cell cycle checkpoints, DNA repair, apoptosis and transcription. In recent years checkpoint pathways have been elucidated as an integral part of the DNA damage response and in fact dysfunctions or mutations of these pathways are important in the pathogenesis of malignant tumors. Understanding the molecular mechanisms regulating the cell cycle progression and checkpoints and how these processes are altered in malignant cells may be crucial to better define the events behind such a complex and devastating desease like cancer... http://atlasgeneticsoncology.org/Deep/CellCycleandCancerID20123.html Dionisio

BioMed Research International Volume 2014 (2014), Article ID 145289, 8 pages http://dx.doi.org/10.1155/2014/145289 An Overview of the Spindle Assembly Checkpoint Status Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer. Deregulated spindle assembly checkpoint (SAC) is thought as one of the mechanisms that drive aneuploidy. In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers. While mutations are rather rare, many tumors show altered expression levels of SAC components. Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown. Yet, our knowledge on the status of SAC components in oral cancer remains sparse. In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20. http://www.hindawi.com/journals/bmri/2014/145289/ Dionisio

CK1 is required for a mitotic checkpoint that delays cytokinesis Failure to accurately partition genetic material during cell division causes aneuploidy and drives tumorigenesis. Cell-cycle checkpoints safeguard cells from such catastrophes by impeding cell-cycle progression when mistakes arise. FHA-RING E3 ligases, including human RNF8 and CHFR and fission yeast Dma1, relay checkpoint signals by binding phosphorylated proteins via their FHA domains and promoting ubiquitination of downstream targets. Upon mitotic checkpoint activation, S. pombe Dma1 concentrates at spindle pole bodies (SPBs) in an FHA-dependent manner and ubiquitinates Sid4, a scaffold of Polo kinase, to suspend cytokinesis. However, the kinase or kinases that phosphoprime Sid4 for Dma1-mediated ubiquitination are unknown. Here, we report that the highly conserved protein kinase CK1 transmits the signal necessary to stall cytokinesis by phosphopriming Sid4 for Dma1-mediated ubiquitination. Like Dma1, CK1 accumulates at SPBs during a mitotic arrest and associates stably with SPB components, including Sid4. Our results establish CK1 as an integral component of a mitotic, ubiquitin-mediated checkpoint pathway. doi: 10.1016/j.cub.2013.07.077. http://www.ncbi.nlm.nih.gov/pubmed/24055157 Dionisio

The spindle checkpoint. DOI: 10.1016/S0959-437X(99)80010-0 Prior to sister-chromatid separation, the spindle checkpoint inhibits cell-cycle progression in response to a signal generated by mitotic spindle damage or by chromosomes that have not attached to microtubules. Recent work has shown that the spindle checkpoint inhibits cell-cycle progression by direct binding of components of the spindle checkpoint pathway to components of a specialized ubiquitin-conjugating system that is responsible for triggering sister-chromatid separation. http://www.researchgate.net/publication/13219220_The_spindle_checkpoint Dionisio

The spindle checkpoint Every mitosis, replicated chromosomes must be accurately segregated into each daughter cell. Pairs of sister chromatids attach to the bipolar mitotic spindle during prometaphase, they are aligned at metaphase, then sisters separate and are pulled to opposite poles during anaphase. Failure to attach correctly to the spindle before anaphase onset results in unequal segregation of chromosomes, which can lead to cell death or disease. The spindle checkpoint is a surveillance mechanism that delays anaphase onset until all chromosomes are correctly attached in a bipolar fashion to the mitotic spindle. The core spindle checkpoint proteins are Mad1, Mad2, BubR1 (Mad3 in yeast), Bub1, Bub3 and Mps1. The Mad and Bub proteins were first identified in budding yeast by genetic screens for mutants that failed to arrest in mitosis when the spindle was destroyed (Taylor et al., 2004). These proteins are conserved in all eukaryotes. Several other checkpoint components, such as Rod, Zw10 and CENP-E, have since been identified in higher eukaryotes but have no yeast orthologues (Karess, 2005; Mao et al., 2003). This reflects a more complex checkpoint regulation in higher eukaryotes where, unlike in yeasts, checkpoint proteins are essential and regulate normal mitotic timing (Meraldi et al., 2004; Taylor et al., 2004). Here, we highlight current understanding of how the spindle checkpoint is activated, how it delays anaphase onset, and how it is silenced. doi: 10.1242/?jcs.03165 http://jcs.biologists.org/content/119/20/4139.full Dionisio

Defining pathways of spindle checkpoint silencing: functional redundancy between Cdc20 ubiquitination and p31comet A general molecular framework for spindle checkpoint inactivation is lacking. The Mad2 inhibitor, p31comet, has roles independent of the ubiquitin-proteasome pathway. This key finding allows the delineation of two partially redundant pathways for mitotic exit. http://biblioteca.universia.net/html_bura/ficha/params/title/defining-pathways-of-spindle-checkpoint-silencing-functional-redundancy-between-cdc20/id/54989039.html Dionisio

The Cell's Surveillance System: Introducing the Cell Cycle Checkpoint Pathways The checkpoint pathways can be thought of as the cell's surveillance systems that function to arrest cell cycle progression in response to detected problems in cell division or chromosome replication. Checkpoint pathways ensure that DNA replication does not commence before all of the components necessary for its completion have been produced. They also ensure that the replication process is not derailed by damaged DNA; that cells do not attempt to divide before genome duplication is complete; and that each daughter cell receives a complete set of chromosomes. Checkpoint pathways are essential for an organism's viability. Although a cell can complete its cycle successfully without them, their absence results in infidelity of chromosome transmission and a greatly raised susceptibility to DNA-damaging agents. The consequence of checkpoint pathway inactivation is genome instability, which inevitably leads to cancer... http://www.evolutionnews.org/2013/08/the_cells_surve075151.html Dionisio

The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction Reviews the elegant design of the mitotic spindle assembly checkpoint pathway, the molecular processes that minimize the risks of improper chromosome segregation during cell division as a consequence of improper microtubule-kinetochore attachment. https://html2-f.scribdassets.com/s1di7nr5s381su8/images/1-05dd0f6fed.jpg Monitoring Spindle-Kinetochore Attachment The precise mechanism by which the spindle checkpoint system detects improper chromatid bi-orientation has not been fully elucidated. http://www.scribd.com/doc/190695766/The-Spindle-Assembly-Checkpoint-Mechanism-and-the-Consequences-of-its-Dysfunction Dionisio

Mad1 contribution to spindle assembly checkpoint signalling goes beyond presenting Mad2 at kinetochores DOI 10.1002/embr.201338114 The spindle assembly checkpoint inhibits anaphase until all chromosomes have become attached to the mitotic spindle. A complex between the checkpoint proteins Mad1 and Mad2 provides a platform for Mad2:Mad2 dimerization at unattached kinetochores, which enables Mad2 to delay anaphase. Here, we show that mutations in Bub1 and within the Mad1 C?terminal domain impair the kinetochore localization of Mad1:Mad2 and abrogate checkpoint activity. Artificial kinetochore recruitment of Mad1 in these mutants co?recruits Mad2; however, the checkpoint remains non?functional. We identify specific mutations within the C?terminal head of Mad1 that impair checkpoint activity without affecting the kinetochore localization of Bub1, Mad1 or Mad2. Hence, Mad1 potentially in conjunction with Bub1 has a crucial role in checkpoint signalling in addition to presenting Mad2. http://embor.embopress.org/content/early/2014/01/28/embr.201338114 Dionisio

Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis DOI: http://dx.doi.org/10.1016/j.stem.2014.07.005 In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy. Dionisio

Supergenomic Network Compression DOI: http://dx.doi.org/10.1016/j.cell.2014.07.011 A central problem in biology is to identify gene function. One approach is to infer function in large supergenomic networks of interactivos and ancestral relationships among genes; however, their analysis can be computationally prohibitive. We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships, and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks. Compression enables global network analysis to computationally harness hundreds of interconnected genomes and to produce functional predictions. As a demonstration, we show that the essential, but functionally uncharacterized Plasmodium falciparum antigen EXP1 is a membrane glutathione S-transferase. EXP1 efficiently degrades cytotoxic hematin, is potently inhibited by artesunate, and is associated with artesunate metabolism and susceptibility in drug-pressured malaria parasites. These data implicate EXP1 in the mode of action of a frontline antimalarial drug. Dionisio

NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane The positioning and the elongation of the mitotic spindle must be carefully regulated. In human cells, the evolutionary conserved proteins LGN/G?i1?3 anchor the coiled?coil protein NuMA and dynein to the cell cortex during metaphase, thus ensuring proper spindle positioning. The mechanisms governing cortical localization of NuMA and dynein during anaphase remain more elusive. Here, we report that LGN/G?i1?3 are dispensable for NuMA?dependent cortical dynein enrichment during anaphase. We further establish that NuMA is excluded from the equatorial region of the cell cortex in a manner that depends on the centralspindlin components CYK4 and MKLP1. Importantly, we reveal that NuMA can directly associate with PtdInsP (PIP) and PtdInsP2 (PIP2) phosphoinositides in vitro. Furthermore, chemical or enzymatic depletion of PIP/PIP2 prevents NuMA cortical localization during mitosis, and conversely, increasing PIP2 levels augments mitotic cortical NuMA. Overall, our study uncovers a novel function for plasma membrane phospholipids in governing cortical NuMA distribution and thus the proper execution of mitosis. DOI 10.15252/embj.201488147 | Published online 04.07.2014 The EMBO Journal (2014) 33, 1815-1830 http://emboj.embopress.org/content/33/16/1815 Dionisio

Cellular and molecular longevity pathways: the old and the new DOI: http://dx.doi.org/10.1016/j.tem.2013.12.003 Human lifespan has been increasing steadily during modern times, mainly due to medical advancements that combat infant mortality and various life-threatening diseases. However, this gratifying longevity rise is accompanied by growing incidences of devastating age-related pathologies. Understanding the cellular and molecular mechanisms that underlie aging and regulate longevity is of utmost relevance towards offsetting the impact of age-associated disorders and increasing the quality of life for the elderly. Several evolutionarily conserved pathways that modulate lifespan have been identified in organisms ranging from yeast to primates. Here we survey recent findings highlighting the interplay of various genetic, epigenetic, and cell-specific factors, and also symbiotic relationships, as longevity determinants. We further discuss outstanding matters within the framework of emerging, integrative views of aging. Dionisio

regulated expression of certain genes during differentiation of some cell types ? [...] Dionisio

Communicating by touch – neurons are not alone DOI: http://dx.doi.org/10.1016/j.tcb.2014.01.003 Long-distance cell–cell communication is essential for organ development and function. Whereas neurons communicate at long distances by transferring signals at sites of direct contact (i.e., at synapses), it has been presumed that the only way other cell types signal is by dispersing signals through extracellular fluid – indirectly. Recent evidence from Drosophila suggests that non-neuronal cells also exchange signaling proteins at sites of direct contact, even when long distances separate the cells. We review here contact-mediated signaling in neurons and discuss how this signaling mechanism is shared by other cell types. Dionisio

Less well understood? A CULLINary ride across the secretory pathway: more than just secretion Mulitmeric cullin-RING ubiquitin ligases (CRLs) represent the largest class of ubiquitin ligases in eukaryotes. However, most CRL ubiquitylation pathways remain uncharacterized. CRLs control a myriad of functions by catalyzing mono- or poly-ubiquitylation of target proteins. Recently, novel CRLs have been identified along the secretory pathway where they modify substrates involved in diverse cellular processes such as vesicle coat assembly and cell cycle progression. This review discusses our current understanding of CRL ubiquitylation within the secretory pathway, with special emphasis on the emerging role of the Golgi as a ubiquitylation platform. CRLs are also implicated in endosome function, where their specific roles are less well understood. DOI: http://dx.doi.org/10.1016/j.tcb.2014.02.001 Dionisio

Surviving change: the metabolic journey of hematopoietic stem cells DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.001 Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that maintain blood production and are uniquely wired to adapt to diverse cellular fates during the lifetime of an organism. Recent studies have highlighted a central role for metabolic plasticity in facilitating cell fate transitions and in preserving HSC functionality and survival. This review summarizes our current understanding of the metabolic programs associated with HSC quiescence, self-renewal, and lineage commitment, and highlights the mechanistic underpinnings of these changing bioenergetics programs. It also discusses the therapeutic potential of targeting metabolic drivers in the context of blood malignancies. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00062-2 Dionisio

How pervasive are circadian oscillations? DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.005 Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems. Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations. Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00069-5 Dionisio

Making connections: interorganelle contacts orchestrate mitochondrial behavior DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.004 Mitochondria are highly dynamic organelles. During their life cycle they frequently fuse and divide, and damaged mitochondria are removed by autophagic degradation. These processes serve to maintain mitochondrial function and ensure optimal energy supply for the cell. It has recently become clear that this complex mitochondrial behavior is governed to a large extent by interactions with other organelles. In this review, we describe mitochondrial contacts with the endoplasmic reticulum (ER), plasma membrane, and peroxisomes. In particular, we highlight how mitochondrial fission, distribution, inheritance, and turnover are orchestrated by inter-organellar contacts in yeast and metazoa. These interactions are pivotal for the integration of the dynamic mitochondrial network into the architecture of eukaryotic cells. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00065-8 Dionisio

A Gene Regulatory Network Controls the Binary Fate Decision of Rod and Bipolar Cells in the Vertebrate Retina Gene regulatory networks (GRNs) regulate critical events during development. In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types. Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron. The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision. We identified a cis-regulatory module (CRM), B108, that mimics Blimp1 expression. Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1. Otx2 and ROR? were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells. DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.018 Dionisio

mitotic spindle geometry and chromosome segregation doi:10.1186/1747-1028-7-19 Assembly of a bipolar mitotic spindle is essential to ensure accurate chromosome segregation and prevent aneuploidy, and severe mitotic spindle defects are typically associated with cell death. Recent studies have shown that mitotic spindles with initial geometric defects can undergo specific rearrangements so the cell can complete mitosis with a bipolar spindle and undergo bipolar chromosome segregation, thus preventing the risk of cell death associated with abnormal spindle structure. Although this may appear as an advantageous strategy, transient defects in spindle geometry may be even more threatening to a cell population or organism than permanent spindle defects. Indeed, transient spindle geometry defects cause high rates of chromosome mis-segregation and aneuploidy. http://www.celldiv.com/content/7/1/19 Dionisio

Cell Fate Decision During each stem cell division, precise mechanisms insure that newly formed cells differentiate into the correct cell type that is required to maintain long-term homeostasis of their resident tissue. http://www.urmc.rochester.edu/labs/biteau-lab/projects/cell_fate_decision Dionisio

Piece of cake - very simple ;-) Planar Cell Polarity Goes Perpendicular DOI: 10.1126/scisignal.2005416 Polarized distribution of signaling molecules followed by asymmetric cell division can restrict the distribution of cell fate determinants to a single daughter cell. The larval skin of the frog is composed mostly of mucus-secreting goblet cells derived from the outer polarized epithelium of the embryonic ectoderm. The skin also contains multiciliated cells, which are derived from a deeper layer of ventral ectoderm cells generated by occasional asymmetric divisions of the outer epithelial cells perpendicular to the epithelial plane. Huang et al. report that the Wnt receptor Lrp6 was enriched in the basolateral domain of the outer epithelial cells and uniformly present on the basal daughters after these cells divided asymmetrically. Wnt signaling through Lrp6 leads to nuclear accumulation of ?-catenin and activation of target genes. By endogenous and reporter gene expression criteria, basal cells showed greater Wnt signaling activity than outer epithelial cells. Inhibiting Wnt signaling reduced the number of ciliated cells, and injecting mRNA encoding ?-catenin promoted the differentiation of supernumerary multiciliated cells. Signaling through the Frizzled-planar cell polarity (Fz-PCP) pathway, which requires Wnt receptors of the Frizzled family, was required for the asymmetric distribution of Lrp6 in the epithelial cells. Dishevelled (Dvl), a multidomain protein involved in both Wnt-?-catenin and Fz-PCP signaling, colocalized with Lrp6 in the basolateral membrane of outer epithelial cells, and embryos lacking Dvl did not show polarized distribution of Lrp6. Polar localization of Lrp6 required domains in Dvl that mediate PCP signaling, but not a domain required only for Wnt-?-catenin signaling. Morpholino-mediated knockdown of Wnt5a, which has been implicated in PCP, or of Fz7 prevented the polarized distribution of both Lrp6 and Dvl in outer epithelial cells and enrichment of Lrp6 in deep cells. These findings indicate that PCP signaling can influence apicobasal polarity in addition to its well-established role in defining polarity within the plane of the epithelium and demonstrate that PCP and Wnt-?-catenin signaling can cooperate to link cell polarity to fate determination. http://stke.sciencemag.org/content/7/324/ec121.abstract Dionisio

Metabolic Determinants of Stem Cell Pluripotency and Cell Fate Commitments The metabolic needs of cells are determined by function and fate. Pluripotent cells must make the choice to either self-renew, or commit to alternative cell fates. What are the changes in metabolic programs and cell bioenergetics associated with this stem cell choice? Do cell fate decisions determine metabolic activity, or do metabolic switches trigger the commitment to alternative cell fates? How do rapidly proliferating cells signal their comprehensive needs for more ATP, reducing equivalents, and biosynthetic intermediates that provide for growth and division? Can small molecules be used to divert stem cells toward expansion of desired lineages for cell-based therapies? Speakers at this symposium will present their latest metabolomic findings on stem cell metabolism vs. lineage commitment — and how this knowledge may be applied for future therapies. http://info.biotech-calendar.com/Science-Researcher-Update/bid/92681/Metabolic-Determinants-of-Stem-Cell-Pluripotency-and-Cell-Fate-Commitments Dionisio

MicroRNAs as Neuronal Fate Determinants doi: 10.1177/1073858413497265 Since the discovery of short, regulatory microRNAs (miRNA) 20 years ago, the understanding of their impact on gene regulation has dramatically increased. Differentiation of cells requires comprehensive changes in regulatory networks at all levels of gene expression. Posttranscriptional regulation by miRNA leads to rapid modifications in the protein level of large gene networks, and it is therefore not surprising that miRNAs have been found to influence the fate of differentiating cells. Several recent studies have shown that overexpression of a single miRNA in different cellular contexts results in forced differentiation of nerve cells. Loss of this miRNA constrains neurogenesis and promotes gliogenesis. This miRNA, miR-124, is probably the most well-documented example of a miRNA that controls nerve cell fate determination. In this review we summarize the recent findings on miR-124, potential molecular mechanisms used by miR-124 to drive neuronal differentiation, and outline future directions. http://nro.sagepub.com/content/early/2013/07/22/1073858413497265.abstract Dionisio

it is currently unclear how the precursors for most Piwi?interacting RNAs (piRNAs) are recognized as substrates by the piRNA processing machinery that resides in cytoplasmic granules called nuage. Primary piRNA biogenesis: caught up in a Maelstrom Radha Raman Pandey, Ramesh S Pillai DOI 10.15252/embj.201489670 | Published online 22.08.2014 The EMBO Journal (2014) embj.201489670 Precursors for most Piwi?interacting RNAs (piRNAs) are indistinguishable from other RNA polymerase II?transcribed long non?coding RNAs. So, it is currently unclear how they are recognized as substrates by the piRNA processing machinery that resides in cytoplasmic granules called nuage. In this issue, Castaneda et al (2014) reveal a role for the nuage component and nucleo?cytoplasmic shuttling protein Maelstrom in mouse piRNA biogenesis. See also: J Castaneda et al Germ cells are entrusted with the task of faithfully transmitting genetic information from one generation to the next. A major threat to germline genome integrity is the activity of mobile genetic elements called transposons, as they have the potential to cause mutations, usually leading to infertility. To counteract this threat, animal germlines have evolved a conserved small RNA?based transposon defense system composed of Piwi proteins and their associated piRNAs (Malone & Hannon, 2009). In their simplest form, piRNAs guide Piwi endonucleases to cleave transposon transcripts resulting in their degradation. More complex systems come into play when nuclear Piwi proteins mediate transcriptional silencing of target transposon loci by recruitment of H3K9me3 chromatin marks and/or DNA methylation as in Drosophila and mice, respectively. While piRNAs targeting transposable elements is a universal feature across the animal kingdom, the mammalian male germline expresses an abundant set of piRNAs http://emboj.embopress.org/content/early/2014/08/22/embj.201489670 Dionisio

the emerging notion that this process may be more complex than previously appreciated. DOI 10.15252/embj.201489490 Following fertilization, activation of a complex developmental program requires the differential expression of key genes. In most metazoa, the prevailing view is that early differential gene expression occurs primarily through post?transcriptional regulation of maternally deposited products in the oocyte. Two novel studies published from the Rajewsky laboratory in this issue of The EMBO Journal add significantly to the emerging notion that this process may be more complex than previously appreciated. See also: M Stoeckius et al (August 2014a) and M Stoeckius et al (August 2014b) In the first study from Rajewsky and co?workers (Stoeckius et al, 2014a), global approaches including metabolic labeling and RNA?seq of 1?cell stage embryos are employed to discover significant deposition of mRNAs and small non?coding RNAs of paternal origin into Caenorhabditis elegans oocytes. In their second paper, the authors comprehensively surveyed transcriptome and proteome changes that occur at one of the earliest steps in animal development: the oocyte?to?embryo transition (OET). The results thus establish a nearly complete inventory of one of the most fundamental transition periods in embryonic development. The most prominent finding here is the discovery of a remarkable wave of mRNA turnover that immediately follows fertilization. They go further to characterize an mRNA clearance mechanism involving a 3? UTR polyC motif that allows coordinated and rapid turnover of maternal mRNAs prior to what is generally considered to be the maternal?to?zygotic transition in C. elegans (Stoeckius et al, 2014b). Taken together, these rather unexpected results offer a glimpse into the role paternal RNAs might play during early developmental decisions. http://emboj.embopress.org/content/33/16/1729 Dionisio

Orchestration of secretory protein folding by ER chaperones doi: 10.1016/j.bbamcr.2013.03.007. The endoplasmic reticulum is a major compartment of protein biogenesis in the cell, dedicated to production of secretory, membrane and organelle proteins. The secretome has distinct structural and post-translational characteristics, since folding in the ER occurs in an environment that is distinct in terms of its ionic composition, dynamics and requirements for quality control. The folding machinery in the ER therefore includes chaperones and folding enzymes that introduce, monitor and react to disulfide bonds, glycans, and fluctuations of luminal calcium. We describe the major chaperone networks in the lumen and discuss how they have distinct modes of operation that enable cells to accomplish highly efficient production of the secretome. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. Copyright © 2013 Elsevier B.V. All rights reserved. http://www.ncbi.nlm.nih.gov/pubmed/23507200 Dionisio

Molecular Chaperone Functions in Protein Folding and Proteostasis Annual Review of Biochemistry Vol. 82: 323-355 (Volume publication date June 2013) DOI: 10.1146/annurev-biochem-060208-092442 The biological functions of proteins are governed by their three-dimensional fold. Protein folding, maintenance of proteome integrity, and protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)folding. Folding occurs upon controlled release of newly synthesized proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation. http://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-060208-092442 Dionisio

Molecular Chaperones in Cellular Protein Folding: The Birth of a Field DOI: http://dx.doi.org/10.1016/j.cell.2014.03.029 The early decades of Cell witnessed key discoveries that coalesced into the field of chaperones, protein folding, and protein quality control. Dionisio

if polyphosphate worked well for protein folding, why did evolution fire it? Why did it hire a team of chaperones to do the work that polyphosphate was doing so well? How did it go from the polyphosphate to the chaperone network? doesn't NS follows the principle that "if ain't broke, don't fix it"? any thoughts on this? http://phys.org/news/2014-02-chemical-chaperones-proteins-jobs-billions.html Dionisio

A better understanding of cell to cell communication http://phys.org/news/2014-08-cell.html#nRlv Dionisio

Molecular high-speed origami: Researchers elucidate important mechanism of protein folding http://phys.org/news/2014-05-molecular-high-speed-origami-elucidate-important.html Dionisio

A whole conference dedicated mainly to protein folding issues, including chaperones. https://secure.faseb.org/FASEB/meetings/summrconf/Programs/11617.pdf Dionisio

Thanks, Dionisio. There were some great moments in that article. This is my favorite:

That may be true for random sequences, but clearly not for evolved proteins, or we wouldn’t be here. “A random sequence would go down a wrong path and have to undo it, go down another wrong path, and have to undo it,” said Wolynes, who in his original paper compared the process to a drunken golfer wandering aimlessly around a golf course. “There would be no overall guidance to the right solution.”

The way they concluded it wasn't a random walk is "we wouldn't be here" otherwise and there would be "no overall guidance to the right solution". It's comical. Silver Asiatic

Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31comet vol. 111 no. 33 > Esther Eytan, 12019–12024, doi: 10.1073/pnas.1412901111 The mitotic checkpoint system has an important role to ensure accurate segregation of chromosomes in mitosis. This system regulates the activity of the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) by the formation of a negatively acting Mitotic Checkpoint Complex (MCC). When the checkpoint is satisfied, MCC is disassembled, but the mechanisms of MCC disassembly are not well understood. We show here that the ATP-hydrolyzing enzyme Thyroid Receptor Interacting Protein 13 (TRIP13), along with the MCC-targeting protein p31comet, promote the disassembly of the mitotic checkpoint complexes and the inactivation of the mitotic checkpoint. The results reveal an important molecular mechanism in the regulation of APC/C by the mitotic checkpoint. The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. When the checkpoint signal is turned off, MCC is disassembled and the checkpoint is inactivated. The mechanisms of the disassembly of MCC are not sufficiently understood. We have previously observed that ATP hydrolysis is required for the action of the Mad2-binding protein p31comet to disassemble MCC. We now show that HeLa cell extracts contain a factor that promotes ATP- and p31comet-dependent disassembly of a Cdc20–Mad2 subcomplex and identify it as Thyroid Receptor Interacting Protein 13 (TRIP13), an AAA-ATPase known to interact with p31comet. The joint action of TRIP13 and p31comet also promotes the release of Mad2 from MCC, participates in the complete disassembly of MCC and abrogates checkpoint inhibition of APC/C. We propose that TRIP13 plays centrally important roles in the sequence of events leading to MCC disassembly and checkpoint inactivation. http://www.pnas.org/content/111/33/12019.abstract?sid=0c989e5a-cafe-4ddb-baa7-221aa0472954 Dionisio

RE: # 238 original papers: http://www.pnas.org/content/early/2014/08/07/1413575111.abstract http://news.rice.edu/2014/08/11/from-eons-to-seconds-proteins-exploit-the-same-forces/ Dionisio

Silver Asiatic @ 239 Excellent detailed review of that article! Thank you for the insightful comments! Dionisio

#238 Fascinating article - all sorts of imaginary, teleological processes at work. "Nature selects" the right things at the right time, "otherwise we wouldn't be here". Evolution is "guided" to solutions. That's just the way evolution works. :-) Of course, if you question this, you're wrong: "The only way to explain the funnel’s existence is to say that sequences are not random, but that they’re the result of evolution." Ok! I didn't realize there was only one just-so story we could use to explain this. :-)

New Rice research shows how the interplay between evolution and physics developed the skills necessary to conserve useful proteins. A Rice team led by biophysicists Peter Wolynes and José Onuchic used computer models to show that the energy landscapes that describe how nature selects viable protein sequences over evolutionary timescales employ essentially the same forces as those that allow proteins to fold in less than a second.

[We know nature selected viable sequences because we're here and therefore evolution works!]

The results offer a look at how nature selects useful, stable proteins.

[Fortunately, nature selects useful and stable proteins. The genius of evolution.]

In addition to showing how evolution works, their study aims to give scientists better ways to predict the structures of proteins, which is critical for understanding disease and for drug design.

[I'm glad we didn't have to worry about mutations in order to understand how evolution works. That would have been far too messy. Instead, we know that nature selects all the right stuff -- and it all happened to be there for selection, right when nature needed it.]

...how much the energy landscape of proteins has guided evolution.

[Of course, energy guided evolution to be successful. We exist, therefore evolution was guided by energy to select us. It makes sense!]

Folding theories developed by Onuchic and Wolynes nearly two decades ago already suggested this connection between evolution and physics. Proteins that start as linear chains of amino acids programmed by genes fold into their three-dimensional native states in the blink of an eye because they have evolved to obey the principle of minimal frustration. According to this principle, the folding process is guided by interactions found in the final, stable form.

[Evolution evolved them to avoid frustration so that they could become the best and most optimal organisms they could truly be. Otherwise, evolution would have failed in its task and that would have been bad. Good job, evolution!]

“The funnel shows that the protein tries things that are mostly positive rather than wasting time with dead ends,” Wolynes said. “That turns out to resolve what was called Levinthal’s paradox.” The paradox said even a relatively short protein of 100 acids, or residues, that tries to fold in every possible way would take longer than the age of the universe to complete the process.

[The protein evolved to find positive solutions, otherwise, the organism would die and evolution would be very sad about that. But we do exist - so evolution must have worked very well indeed!]

That may be true for random sequences, but clearly not for evolved proteins, or we wouldn’t be here. “A random sequence would go down a wrong path and have to undo it, go down another wrong path, and have to undo it,” said Wolynes, who in his original paper compared the process to a drunken golfer wandering aimlessly around a golf course. “There would be no overall guidance to the right solution.”

[ "Proteins evolved through this process. If not, we wouldn't be here." Got it! We exist, therefore we evolved. There's no other answer to it. If it was random, there would be no guidance to the right solution. The wrong solution would be dead organisms and extinction. Thankfully, evolution would not stand for that - it insisted on guiding things to the right solution.]

So the funnel is a useful map of how functional proteins reach their destinations. “The only way to explain the funnel’s existence is to say that sequences are not random, but that they’re the result of evolution. The key idea of the energy landscape (depicted by the funnel) only makes sense in the light of evolution,” he said.

[Right, because the proteins wanted to arrive at the right solution. Energy fields guided evolution so that it would create human beings.]

Only with recent advances in gene sequencing has a sufficiently large and growing library of such information become available to test evolution quantitatively. “If proteins evolved to search for funnel-like sequences, the signature of this evolution will be seen projected on the sequences that we observe,” Knowing how evolution did it should make it much faster for people to design proteins “because we can make a change in sequence and test its effect on folding very quickly,” he said.

Silver Asiatic

Does this article leave some important questions unanswered and raise new questions? Nature’s artistic and engineering skills are evident in proteins, life’s robust molecular machines. For proteins, energy landscapes serve as maps that show the number of possible forms they may take as they fold. http://www.rdmag.com/news/2014/08/eons-seconds-proteins-exploit-same-forces Dionisio

Systems approach to metabolic diseases In order to develop a complete understanding of a biological system, information must cover multiple dimensions. Over the last ten years, we have witnessed decisive advances in bioinformatics, genome sequencing, and high-throughput technologies, that have highlighted the need for approaching biological systems as a whole. Metabolic diseases, including type 2 diabetes and cardiovascular disease, as well as cancer, involve complex genetic, molecular, and environmental interactions, and systems-based approaches have proven to be instrumental in tackling this complexity by integrating genomic, molecular, and physiological data. This meeting will provide a unique opportunity to bring together experts in systems biology and metabolism to discuss how ‘Omics’ approaches can be exploited in an effort to understand the perturbations that take place in the pathogenesis of metabolic diseases. We will discuss novel approaches for studying metabolic alterations in a high-throughput scale and explore how epigenomics, non-coding RNAs, and environmental factors control metabolic pathways in disease settings. Dionisio

The Cep192-Organized Aurora A-Plk1 Cascade Is Essential for Centrosome Cycle and Bipolar Spindle Assembly DOI: http://dx.doi.org/10.1016/j.molcel.2014.06.016 As cells enter mitosis, the two centrosomes separate and grow dramatically, each forming a nascent spindle pole that nucleates a radial array of microtubules. Centrosome growth (and associated microtubule nucleation surge), termed maturation, involves the recruitment of pericentriolar material components via an as-yet unknown mechanism. Here, we show that Cep192 binds Aurora A and Plk1, targets them to centrosomes in a pericentrin-dependent manner, and promotes sequential activation of both kinases via T-loop phosphorylation. The Cep192-bound Plk1 then phosphorylates Cep192 at several residues to generate the attachment sites for the ?-tubulin ring complex and, possibly, other pericentriolar material components, thus promoting their recruitment and subsequent microtubule nucleation. We further found that the Cep192-dependent Aurora A-Plk1 activity is essential for kinesin-5-mediated centrosome separation, bipolar spindle formation, and equal centrosome/centriole segregation into daughter cells. Thus, our study identifies a Cep192-organized signaling cascade that underlies both centrosome maturation and bipolar spindle assembly. http://www.cell.com/molecular-cell/abstract/S1097-2765(14)00524-3?elsca1=etoc&elsca2=email&elsca3=1097-2765_20140821_55_4_&elsca4=Cell%20Press Dionisio

Here's an important biological subsystem that the third way folks could try to research in order to explain its detailed origin. At least now we know more about it than we knew not so long ago.

Capturing the bacterial holo-complex Franck Duong, 4739–4740, doi: 10.1073/pnas.1402139111 Protein transport is a fundamental activity for all living cells and an exciting area for scientific exploration (1, 2). In bacteria, the process depends on the concerted action of at least three membrane-embedded components: the ubiquitous SecYEG complex that forms the polypeptide-conducting membrane pore, the essential YidC insertase that works independently or in cooperation with SecYEG to insert hydrophobic protein segments into the lipid bilayer, and the auxiliary SecDF–yajC complex that associates with both SecYEG and YidC to accelerate the overall process. Depending on specific requirements of the substrate to be transported, SecYEG also associates with the ribosome or the cytosolic ATPase SecA, which mediate the cotranslational and posttranslational mode of translocation, respectively. Over the last decade, our understanding of the bacterial protein transport process has greatly advanced with the determination of structures for almost all of the individual components (3?–5). However, our understanding of the interconnection between these components is still limited because the interactions are weak or transient, and certainly difficult to analyze because they occur in the membrane environment. In PNAS, Schulze et al. (6) report the isolation of a supercomplex that contains all seven subunits: the SecYEG–DFyajC–YidC holo-enzyme aka holo-translocon (HTL). This large membrane assembly of ?250 kDa encompasses 34 transmembrane segments with three large loops exposed on the trans-side of the membrane. The isolation of the HTL is a breakthrough in the field, opening new avenues for investigation; it is also an elegant method that resolves major challenges in membrane … http://www.pnas.org/content/111/13/4739.extract

Dionisio

The dynamic protein Knl1 – a kinetochore rendezvous Journal of Cell Science (Impact Factor: 5.88). 07/2014; DOI: 10.13140/2.1.2196.2881 Knl1 (also known as CASC5, UniProt Q8NG31) is a scaffolding protein that is required for proper kinetochore assembly, spindle assembly checkpoint (SAC) function and chromosome congression. A number of recent reports have confirmed the prominence of Knl1 in these processes and provided molecular details and structural features that dictate Knl1 functions in higher organisms. Knl1 recruits SAC components to the kinetochore and is the substrate of certain protein kinases and phosphatases, the interplay of which ensures the exquisite regulation of the aforementioned processes. In this Commentary, we discuss the overall domain organization of Knl1 and the roles of this protein as a versatile docking platform. We present emerging roles of the protein interaction motifs present in Knl1, including the RVSF, SILK, MELT and KI motifs, and their role in the recruitment and regulation of the SAC proteins Bub1, BubR1, Bub3 and Aurora B. Finally, we explore how the regions of low structural complexity that characterize Knl1 are implicated in the cooperative interactions that mediate binding partner recognition and scaffolding activity by Knl1 Dionisio

Dynein-dependent transport of spindle assembly checkpoint proteins off kinetochores toward spindle poles. DOI: 10.1016/j.febslet.2014.07.011 A predominant mechanism of spindle assembly checkpoint (SAC) silencing is dynein-mediated transport of certain kinetochore proteins along microtubules. There are still conflicting data as to which SAC proteins are dynein cargoes. Using two ATP reduction assays, we found that the core SAC proteins Mad1, Mad2, Bub1, BubR1, and Bub3 redistributed from attached kinetochores to spindle poles, in a dynein-dependent manner. This redistribution still occurred in metaphase-arrested cells, at a time when the SAC should be satisfied and silenced. Unexpectedly, we found that a pool of Hec1 and Mis12 also relocalizes to spindle poles, suggesting KMN components as additional dynein cargoes. The potential significance of these results for SAC silencing is discussed. Dionisio

Kinetic framework of spindle assembly checkpoint signalling. The mitotic spindle assembly checkpoint (SAC) delays anaphase onset until all chromosomes have attached to both spindle poles. Here, we investigated SAC signalling kinetics in response to acute detachment of individual chromosomes using laser microsurgery. Most detached chromosomes delayed anaphase until they had realigned to the metaphase plate. A substantial fraction of cells, however, entered anaphase in the presence of unaligned chromosomes. We identify two mechanisms by which cells can bypass the SAC: first, single unattached chromosomes inhibit the anaphase-promoting complex/cyclosome (APC/C) less efficiently than a full complement of unattached chromosomes; second, because of the relatively slow kinetics of re-imposing APC/C inhibition during metaphase, cells were unresponsive to chromosome detachment up to several minutes before anaphase onset. Our study defines when cells irreversibly commit to enter anaphase and shows that the SAC signal strength correlates with the number of unattached chromosomes. Detailed knowledge about SAC signalling kinetics is important for understanding the emergence of aneuploidy and the response of cancer cells to chemotherapeutics targeting the mitotic spindle. doi: 10.1038/ncb2842 http://www.ncbi.nlm.nih.gov/pubmed/24096243 Dionisio

The spindle assembly checkpoint works like a rheostat rather than a toggle switch. DOI: 10.1038/ncb2855 The spindle assembly checkpoint (SAC) is essential in mammalian mitosis to ensure the equal segregation of sister chromatids. The SAC generates a mitotic checkpoint complex (MCC) to prevent the anaphase-promoting complex/cyclosome (APC/C) from targeting key mitotic regulators for destruction until all of the chromosomes have attached to the mitotic apparatus. A single unattached kinetochore can delay anaphase for several hours, but how it is able to block the APC/C throughout the cell is not understood. Present concepts of the SAC posit that either it exhibits an all-or-nothing response or there is a minimum threshold sufficient to block the APC/C (ref. ). Here, we have used gene targeting to measure SAC activity, and find that it does not have an all-or-nothing response. Instead, the strength of the SAC depends on the amount of MAD2 recruited to kinetochores and on the amount of MCC formed. Furthermore, we show that different drugs activate the SAC to different extents, which may be relevant to their efficacy in chemotherapy. Dionisio

Nuclear pores set the speed limit for mitosis. DOI: 10.1016/j.cell.2014.02.004 The spindle assembly checkpoint prevents separation of sister chromatids until each kinetochore is attached to the mitotic spindle. Rodriguez-Bravo et al. report that the nuclear pore complex scaffolds spindle assembly checkpoint signaling in interphase Dionisio

Coffee or tea? Caffeine stabilizes Cdc25 independently of Rad3 in Schizosaccharomyces pombe contributing to checkpoint override Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both Schizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S.?pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S.?pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. DOI: 10.1111/mmi.12592 http://onlinelibrary.wiley.com/doi/10.1111/mmi.12592/full Dionisio

Sister chromatid cohesion, which depends on cohesin, is essential for the faithful segregation of replicated chromosomes Sororin pre-mRNA splicing is required for proper sister chromatid cohesion in human cells Here, we report that splicing complex Prp19 is essential for cohesion in both G2 and mitosis, and consequently for the proper progression of the cell through mitosis. Inactivation of splicing factors SF3a120 and U2AF65 induces similar cohesion defects to Prp19 complex inactivation. Our data indicate that these splicing factors are all required for the accumulation of cohesion factor Sororin, by facilitating the proper splicing of its pre-mRNA. Finally, we show that ectopic expression of Sororin corrects defective cohesion caused by Prp19 complex inactivation. We propose that the Prp19 complex and the splicing machinery contribute to the establishment of cohesion by promoting Sororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability. DOI: 10.15252/embr.201438640 http://onlinelibrary.wiley.com/doi/10.15252/embr.201438640/abstract Dionisio

Preparing a cell for nuclear envelope breakdown: Spatio-temporal control of phosphorylation during mitotic entry Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin-dependent kinase 1 (Cdk1)-cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo-cytoplasmic transport of critical cell cycle regulators such as Cdk1-cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo-cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis. DOI: 10.1002/bies.201400040 http://onlinelibrary.wiley.com/doi/10.1002/bies.201400040/abstract Dionisio

Human Embryonic Aneuploidy Human embryonic aneuploidy can have a meiotic or a mitotic origin. The majority of meiotic chromosome errors arise during oogenesis. Two main aneuploidy-causing mechanisms have been defined: the first involves the nondisjunction of entire chromosomes and takes place during both meiotic divisions, whereas the second involves the premature division of a chromosome into its two sister chromatids during meiosis I, followed by their random segregation. Mitotic aneuploidy can arise as a consequence of problems such as nondisjunction, endoreduplication and anaphase lag and occurs most often during the first three divisions after fertilisation. The cleavage stage of development is characterised by the highest rates of aneuploidy, after which the incidence of cytogenetic abnormality decreases significantly. A large number of oocytes and embryos have been examined in order to define the spectrum of aneuploidies during the first few days of life and to shed light upon their origins. Various classical and molecular cytogenetic methods have been employed for this purpose, and valuable data of biological and clinical relevance have been obtained. Key Concepts: •Aneuploidy is the most important genetic cause of human reproductive wastage (i.e. the principal reason for embryo implantation failure and miscarriage). •The outcome of assisted reproductive treatments (e.g. in vitro fertilisation (IVF)) and natural reproductive cycles is negatively affected by aneuploidy. •Most meiotically derived abnormalities arise during oogenesis. •There is a strong relationship between advancing female age and increasing aneuploidy rates in oocytes. •Two distinct mechanisms of oocyte chromosome malsegregation have been described, whole chromosome nondisjunction and unbalanced chromatid predivision. •Post-zygotic aneuploidy usually arises during the first few mitotic divisions and leads to mosaicism in the embryo. •There are three main mechanisms responsible for aneuploidy of mitotic origin: anaphase lag, endoreduplication and mitotic nondisjunction. •The cleavage stage of preimplantation development is associated with the highest aneuploidy rates. •The frequency of chromosome abnormalities and mosaicism declines as embryos progress to the blastocyst stage, presumably due to loss of abnormal cells or demise of affected embryos. DOI: 10.1002/9780470015902.a0025706 http://onlinelibrary.wiley.com/doi/10.1002/9780470015902.a0025706/abstract Dionisio

Kinetochore: Structure, Function and Evolution Duplicated eukaryotic chromosomes are segregated into daughter cells through cell division. Faithful chromosome segregation depends on kinetochores, which are specialized macromolecular structures built upon centromeric chromatin. The dynamic kinetochore structures connect chromosomes with spindle microtubules, power chromosome movement, and signal the activation and silencing of the spindle assembly checkpoint (SAC). Molecular analyses of the components and architecture of kinetochores have advanced rapidly in recent years. A human kinetochore contains approximately 200 proteins, many of which are evolutionarily conserved in other organisms. A histone H3 variant, CENP-A and associated constitutive centromere proteins lay the foundation for kinetochore build-up. Multiple kinetochore-localised microtubule-binding proteins including the Ndc80 complex help regulate chromosome movement. The SAC signalling originates from kinetochores and contributes to the fidelity of chromosome segregation. Many fascinating properties remain to be elucidated about the kinetochore as a fundamental machinery to maintain genomic stability. Key Concepts: •Chromosome segregation in eukaryotic cells depends upon connecting spindle microtubules with special macromolecular structures on chromosomes called kinetochores. •The centromere is the chromosomal locus where a kinetochore is built. •Laying the foundation for kinetochore assembly at centromeres are CENP-A (a histone H3 variant) containing nucleosomes and a group of CENP-A associated proteins (termed constitutive centromere proteins). •There are multiple microtubule motors and nonmotor microtubule-binding proteins localised at kinetochores to coordinate chromosome movement. •A 10 protein complex called KMN network is currently thought to provide the primary end-on microtubule-binding activity. •The spindle assembly checkpoint (SAC) monitors the kinetochore–microtubule attachment and signals the delay of the metaphase-to-anaphase transition when defects are detected. •Conformational change of MAD2 and assembly of the mitotic checkpoint complex (MCC) are the key events to activate the SAC. •Comparative studies of similar and distinct kinetochore composition, structure and function in different species and during mitosis or meiosis have provided evolutionary perspectives on mechanisms regulating chromosome segregation. DOI: 10.1002/9780470015902.a0006237.pub2 http://onlinelibrary.wiley.com/doi/10.1002/9780470015902.a0006237.pub2/abstract Dionisio

Quantifying Mitotic Chromosome Dynamics and Positioning The proper organization and segregation of chromosomes during cell division is essential to the preservation of genomic integrity. To understand the mechanisms that spatially control the arrangement and dynamics of mitotic chromosomes requires imaging assays to quantitatively resolve their positions and movements. Here, we will discuss analytical approaches to investigate the position-dependent control of mitotic chromosomes in cultured cells. These methods can be used to dissect the specific contributions of mitotic proteins to the molecular control of chromosome dynamics. J. Cell. Physiol. 229: 1301–1305, 2014. © 2014 Wiley Periodicals, Inc. DOI: 10.1002/jcp.24634 http://onlinelibrary.wiley.com/doi/10.1002/jcp.24634/abstract Dionisio

Link Between DNA Damage and Centriole Disengagement/Reduplication in Untransformed Human Cells The radiation and radiomimetic drugs used to treat human tumors damage DNA in both cancer cells and normal proliferating cells. Centrosome amplification after DNA damage is well established for transformed cell types but is sparsely reported and not fully understood in untransformed cells. We characterize centriole behavior after DNA damage in synchronized untransformed human cells. One hour treatment of S phase cells with the radiomimetic drug, Doxorubicin, prolongs G2 by at least 72?h, though 14% of the cells eventually go through mitosis in that time. By 72?h after DNA damage we observe a 52% incidence of centriole disengagement plus a 10% incidence of extra centrioles. We find that either APC/C or Plk activities can disengage centrioles after DNA damage, though they normally work in concert. All disengaged centrioles are associated with ?-tubulin and maturation markers and thus, should in principle be capable of reduplicating and organizing spindle poles. The low incidence of reduplication of disengaged centrioles during G2 is due to the p53-dependent expression of p21 and the consequent loss of Cdk2 activity. We find that 26% of the cells going through mitosis after DNA damage contain disengaged or extra centrioles. This could produce genomic instability through transient or persistent spindle multipolarity. Thus, for cancer patients the use of DNA damaging therapies raises the chances of genomic instability and evolution of transformed characteristics in proliferating normal cell populations. J. Cell. Physiol. 229: 1427–1436, 2014. © 2014 Wiley Periodicals, Inc. DOI: 10.1002/jcp.24579 http://onlinelibrary.wiley.com/doi/10.1002/jcp.24579/abstract Dionisio

Epigenetic regulation of adult stem cell function Understanding the cellular and molecular mechanisms that specify cell lineages throughout development, and that maintain tissue homeostasis during adulthood, is paramount towards our understanding of why we age or develop pathologies such as cancer. Epigenetic mechanisms ensure that genetically identical cells acquire different fates during embryonic development and are therefore essential for the proper progression of development. How they do so is still a matter of intense investigation, but there is sufficient evidence indicating that they act in a concerted manner with inductive signals and tissue-specific transcription factors to promote and stabilize fate changes along the three germ layers during development. In consequence, it is generally hypothesized that epigenetic mechanisms are also required for the continuous maintenance of cell fate during adulthood. However, in vivo models in which different epigenetic factors have been depleted in different tissues do not show overt changes in cell lineage, thus not strongly supporting this view. Instead, the function of some of these factors appears to be primarily associated with tissue functionality, and a strong causal relationship has been established between their misregulation and a diseased state. In this review, we summarize our current knowledge of the role of epigenetic factors in adult stem cell function and tissue homeostasis. DOI: 10.1111/febs.12946 http://onlinelibrary.wiley.com/doi/10.1111/febs.12946/abstract Dionisio

A CENP-S/X complex assembles at the centromere in S and G2 phases of the human cell cycle The functional identity of centromeres arises from a set of specific nucleoprotein particle subunits of the centromeric chromatin fibre. These include CENP-A and histone H3 nucleosomes and a novel nucleosome-like complex of CENPs -T, -W, -S and -X. Fluorescence cross-correlation spectroscopy and Förster resonance energy transfer (FRET) revealed that human CENP-S and -X exist principally in complex in soluble form and retain proximity when assembled at centromeres. Conditional labelling experiments show that they both assemble de novo during S phase and G2, increasing approximately three- to fourfold in abundance at centromeres. Fluorescence recovery after photobleaching (FRAP) measurements documented steady-state exchange between soluble and assembled pools, with CENP-X exchanging approximately 10 times faster than CENP-S (t1/2 ? 10 min versus 120 min). CENP-S binding to sites of DNA damage was quite distinct, with a FRAP half-time of approximately 160 s. Fluorescent two-hybrid analysis identified CENP-T as a uniquely strong CENP-S binding protein and this association was confirmed by FRET, revealing a centromere-bound complex containing CENP-S, CENP-X and CENP-T in proximity to histone H3 but not CENP-A. We propose that deposition of the CENP-T/W/S/X particle reveals a kinetochore-specific chromatin assembly pathway that functions to switch centromeric chromatin to a mitosis-competent state after DNA replication. Centromeres shuttle between CENP-A-rich, replication-competent and H3-CENP-T/W/S/X-rich mitosis-competent compositions in the cell cycle. doi: 10.1098/rsob.130229 http://rsob.royalsocietypublishing.org/content/4/2/130229.abstract?sid=49b9a010-27a7-4ce5-af1b-bdbc6e9ab40b Dionisio

Insights into the molecular mechanisms underlying diversified wing venation among insects Insect wings are great resources for studying morphological diversities in nature as well as in fossil records. Among them, variation in wing venation is one of the most characteristic features of insect species. Venation is therefore, undeniably a key factor of species-specific functional traits of the wings; however, the mechanism underlying wing vein formation among insects largely remains unexplored. Our knowledge of the genetic basis of wing development is solely restricted to Drosophila melanogaster. A critical step in wing vein development in Drosophila is the activation of the decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signalling pathway during pupal stages. A key mechanism is the directional transport of Dpp from the longitudinal veins into the posterior crossvein by BMP-binding proteins, resulting in redistribution of Dpp that reflects wing vein patterns. Recent works on the sawfly Athalia rosae, of the order Hymenoptera, also suggested that the Dpp transport system is required to specify fore- and hindwing vein patterns. Given that Dpp redistribution via transport is likely to be a key mechanism for establishing wing vein patterns, this raises the interesting possibility that distinct wing vein patterns are generated, based on where Dpp is transported. Experimental evidence in Drosophila suggests that the direction of Dpp transport is regulated by prepatterned positional information. These observations lead to the postulation that Dpp generates diversified insect wing vein patterns through species-specific positional information of its directional transport. Extension of these observations in some winged insects will provide further insights into the mechanisms underlying diversified wing venation among insects. doi: 10.1098/rspb.2014.0264 http://rspb.royalsocietypublishing.org/content/281/1789/20140264.abstract?sid=bf1f02fd-7b85-4565-b719-020fac0be6ef 7 Dionisio

drc466 I think I understood your explanation and see your point. Thank you for the comments. Dionisio

The problem with "The Third Way" is that it is not really an alternative to Creationism/Evolution. It does not offer an explanation of origins, so much as hope to provide license to scientists to discuss how life actually functions without the need to fit it into an Evolutionary storyline. It's an attempt to be able to say "I don't know how it got that way" without being accused of being called a creationist because what they observe doesn't fit the Darwinist fairy tale. Basically, it's an attempt to say "please don't shoot me, I'm not a creationist" while releasing research and experimentation that doesn't fit any current molecules-to-man storyline. I would call it more a parallel to ID (without the logical inference of "Design must be involved") than Creationism/Evolution. ID is kind of "creation-friendly common descent", while the Third Way is "evolution-friendly common descent", where both have a healthy dose of "we don't know". Creationism/Evolution respond "yes we do". I think, Dionisio, that you will find not a lot of discussion on the Third Way until it makes assertions that go beyond "this is how biology works today". When/If they come up with their own "Origin Myth" things will change. drc466

RE: # 216 Would like to read GP's comments on this. Dionisio

Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade

During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typeI>0 switch is triggered by activation of Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS. DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.021

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High-Resolution Temporal Analysis Reveals a Functional Timeline for the Molecular Regulation of Cytokinesis

To take full advantage of fast-acting temperature-sensitive mutations, thermal control must be extremely rapid. We developed the Therminator, a device capable of shifting sample temperature in ?17 s while simultaneously imaging cell division in vivo. Applying this technology to six key regulators of cytokinesis, we found that each has a distinct temporal requirement in the Caenorhabditis elegans zygote. Specifically, myosin-II is required throughout cytokinesis until contractile ring closure. In contrast, formin-mediated actin nucleation is only required during assembly and early contractile ring constriction. Centralspindlin is required to maintain division after ring closure, although its GAP activity is only required until just prior to closure. Finally, the chromosomal passenger complex is required for cytokinesis only early in mitosis, but not during metaphase or cytokinesis. Together, our results provide a precise functional timeline for molecular regulators of cytokinesis using the Therminator, a powerful tool for ultra-rapid protein inactivation. DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.009 http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00311-6

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Control Systems of Membrane Transport at the Interface between the Endoplasmic Reticulum and the Golgi

DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.018 A fundamental property of cellular processes is to maintain homeostasis despite varying internal and external conditions. Within the membrane transport apparatus, variations in membrane fluxes from the endoplasmic reticulum (ER) to the Golgi complex are balanced by opposite fluxes from the Golgi to the ER to maintain homeostasis between the two organelles. Here we describe a molecular device that balances transport fluxes by integrating transduction cascades with the transport machinery. Specifically, ER-to-Golgi transport activates the KDEL receptor at the Golgi, which triggers a cascade that involves Gs and adenylyl cyclase and phosphodiesterase isoforms and then PKA activation and results in the phosphorylation of transport machinery proteins. This induces retrograde traffic to the ER and balances transport fluxes between the ER and Golgi. Moreover, the KDEL receptor activates CREB1 and other transcription factors that upregulate transport-related genes. Thus, a Golgi-based control system maintains transport homeostasis through both signaling and transcriptional networks. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00407-9?elsca1=etoc&elsca2=email&elsca3=1534-5807_20140811_30_3_&elsca4=Cell%20Press

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Cell fate determinants as regulators of cancer metastasis

An emerging class of genes dictating malignant behavior is cell fate regulators. In the orderly development of a given tissue, the balance between cellular differentiation and division/migration is precisely controlled by a number of lineage specific transcription factors to maintain normal tissue architecture. Deregulation of such cell fate determinants have been increasingly linked to cancer metastasis, and have been shown to play critical roles in regulating cancer stem cell activity, epithelial-mesenchymal transition (EMT), tumor invasion and metastatic colonization doi: 10.1158/1538-7445.FBCR13-IA27 http://cancerres.aacrjournals.org/content/73/19_Supplement/IA27.abstract

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microRNAs: key triggers of neuronal cell fate

Development of the central nervous system (CNS) requires a precisely coordinated series of events. During embryonic development, different intra- and extracellular signals stimulate neural stem cells to become neural progenitors, which eventually irreversibly exit from the cell cycle to begin the first stage of neurogenesis. However, before this event occurs, the self-renewal and proliferative capacities of neural stem cells and neural progenitors must be tightly regulated. Accordingly, the participation of various evolutionary conserved microRNAs is key in distinct central nervous system (CNS) developmental processes of many organisms including human, mouse, chicken, frog, and zebrafish. microRNAs specifically recognize and regulate the expression of target mRNAs by sequence complementarity within the mRNAs 3? untranslated region and importantly, ...a single microRNA can have several target mRNAs to regulate a process; ...likewise, a unique mRNA can be targeted by more than one microRNA. Thus, by regulating different target genes, microRNAs let-7, microRNA-124, and microRNA-9 have been shown to promote the differentiation of neural stem cells and neural progenitors into specific neural cell types while microRNA-134, microRNA-25 and microRNA-137 have been characterized as microRNAs that induce the proliferation of neural stem cells and neural progenitors. Here we review the mechanisms of action of these two sets of microRNAs and their functional implications during the transition from neural stem cells and neural progenitors to fully differentiated neurons. The genetic and epigenetic mechanisms that regulate the expression of these microRNAs as well as the role of the recently described natural RNA circles which act as natural microRNA sponges regulating post-transcriptional microRNA expression and function during the early stages of neurogenesis is also discussed. doi: 10.3389/fncel.2014.00175 http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00175/full#B28

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Metabolic Determinants of Stem Cell Pluripotency and Cell Fate Commitments

The metabolic needs of cells are determined by function and fate. Pluripotent cells must make the choice to either self-renew, or commit to alternative cell fates. What are the changes in metabolic programs and cell bioenergetics associated with this stem cell choice? Do cell fate decisions determine metabolic activity, or do metabolic switches trigger the commitment to alternative cell fates? How do rapidly proliferating cells signal their comprehensive needs for more ATP, reducing equivalents, and biosynthetic intermediates that provide for growth and division? Can small molecules be used to divert stem cells toward expansion of desired lineages for cell-based therapies? Speakers at this symposium presented their latest findings on stem cell metabolism vs. lineage commitment — and how this knowledge may be applied for future therapies. http://www.nyas.org/Events/Detail.aspx?cid=3ca63506-9a4b-413b-96b7-7a127c4e2813

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MicroRNAs as Neuronal Fate Determinants

Since the discovery of short, regulatory microRNAs (miRNA) 20 years ago, the understanding of their impact on gene regulation has dramatically increased. Differentiation of cells requires comprehensive changes in regulatory networks at all levels of gene expression. Posttranscriptional regulation by miRNA leads to rapid modifications in the protein level of large gene networks, and it is therefore not surprising that miRNAs have been found to influence the fate of differentiating cells. Several recent studies have shown that overexpression of a single miRNA in different cellular contexts results in forced differentiation of nerve cells. Loss of this miRNA constrains neurogenesis and promotes gliogenesis. This miRNA, miR-124, is probably the most well-documented example of a miRNA that controls nerve cell fate determination. In this review we summarize the recent findings on miR-124, potential molecular mechanisms used by miR-124 to drive neuronal differentiation, and outline future directions. doi: 10.1177/1073858413497265 http://nro.sagepub.com/content/20/3/235.abstract

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The Duration of T Cell Stimulation Is a Critical Determinant of Cell Fate and Plasticity

Variations in T cell receptor (TCR) signal strength, as indicated by differential activation of downstream signaling pathways, determine the fate of naïve T cells after encounter with antigen. Low-strength signals favor differentiation into regulatory T (Treg) cells containing the transcription factor Foxp3, whereas high-strength signals favor generation of interleukin-2–producing T helper (TH) cells. We constructed a logic circuit model of TCR signaling pathways, a major feature of which is an incoherent feed-forward loop involving both TCR-dependent activation of Foxp3 and its inhibition by mammalian target of rapamycin (mTOR), leading to the transient appearance of Foxp3+ cells under TH cell–generating conditions. Experiments confirmed this behavior and the prediction that the immunosuppressive cytokine TGF-? (transforming growth factor–?) could generate Treg cells even during continued Akt-mTOR signaling. We predicted that sustained mTOR activity could suppress FOXP3 expression upon TGF-? removal, suggesting a possible mechanism for the experimentally observed instability of Foxp3+ cells. Our model predicted, and experiments confirmed, that transient stimulation of cells with high-dose antigen generated TH, Treg, and nonactivated cells in proportions depending on the duration of TCR stimulation. Experimental analysis of cells after antigen removal identified three populations that correlated with these T cell fates. Further analysis of simulations implicated a negative feedback loop involving Foxp3, the phosphatase PTEN, and Akt-mTOR in determining fate. These results suggest that there is a critical time after TCR stimulation during which heterogeneity in the differentiating population of cells leads to increased plasticity of cell fate. DOI: 10.1126/scisignal.2004217 http://stke.sciencemag.org/content/6/300/ra97.abstract

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Follow-up to # 207 That is a simple system. How did we get it to begin with? How did it 'evolve' to more complex systems that work? Dionisio

Structure and activity investigations of the cell fate determinant, SpoIIE, from Bacillus subtitles

For many years the Gram positive bacterium Bacillus subtilis has been a model organism for prokaryotic cell and molecular biology. The asymmetric cell division which B. subtilis undergoes during sporulation is a simple system by which to study the process of cell differentiation. Sporulation is governed by a series of genetic temporal and spatial controls. Gene regulation brought about by a series of ? factors and transcriptional regulators is coupled to key morphological stages or checkpoints. ?F initiates the first step in a cascade of complex genetic control which eventually produces a resilient endospore. The activation of ?F, the first compartment-specific sigma factor, in the forespore and its regulation through interaction between three proteins; SpoIIAA, SpoIIAB and SpoIIE, is of particular interest. SpoIIE, a protein phosphatase which binds to the asymmetric division septum, is a crucial factor in the selective activation of ?F in the forespore. Of three putative domains in SpoIIE only the C-terminal PP2C phosphatase domain has been structurally characterised. The central domain, domain II, of SpoIIE has been assigned a role in interaction with the cell division machinery; however mutational studies have shown that, in addition, this domain is also responsible for the regulation of phosphatase activity. This work describes the isolation and characterisation of three new fragments of SpoIIE containing elements of the central cytoplasmic domain of SpoIIE. These include a fragment found to accurately represent the N-terminal solubility limit of domain II which shows a high degree of oligomeric character. The fragments isolated show specific phosphatase activity against SpoIIAA~P, albeit at reduced rates compared to the free phosphatase domain, which indicates an inhibitory role for SpoIIE domain II against the PP2C domain. Three ultimately unsuccessful approaches were attempted to isolate a co-complex of SpoIIE and SpoIIAA~P for structural characterisation. A tendency for domain II containing SpoIIE fragments to precipitate in the presence of Mn(2+) is also identified. An in vivo investigation into the sporulation efficiencies of amino acid substitutions in a potential regulatory interface between domains II and III of SpoIIE indicated no strong sporulation defects. http://etheses.whiterose.ac.uk/5430/

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Spatial organization within a niche as a determinant of stem-cell fate

doi:10.1038/nature12602 Stem-cell niches in mammalian tissues are often heterogeneous and compartmentalized; however, whether distinct niche locations determine different stem-cell fates remains unclear . This study provides a general model for niche-induced fate determination in adult tissues. http://www.nature.com/nature/journal/v502/n7472/full/nature12602.html

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Mitochondria: determinants of stem cell fate? doi: 10.1089/scd.2009.1806.edi. Stem cells are traditionally classified as being either embryonic stem cells (ESCs) or somatic stem cells. Such a designation has now become blurred by the advent of ostensibly pluripotent cells derived from somatic cells, referred to as induced pluripotent stem cells. Mitochondria are the membrane bound organelles that provide the majority of a cell's chemical energy via their production of adenosine triphosphate. Mitochondria are also known to be vital components in many cell processes including differentiation and apoptosis. We are still remarkably uninformed of how mitochondrial function affects stem cell behavior. Reviewed evidence suggests that mitochondrial function and integrity affect stem cell viability, proliferative and differential potential, and lifespan. Mitochondrial status therefore has profound and as yet unexamined implications for the current drive to develop induced pluripotent stem cells as a therapeutic resource. http://www.ncbi.nlm.nih.gov/m/pubmed/19563264/ Dionisio

Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo. Authors Schrode N, et al. Show all Journal Genesis. 2013 Apr;51(4):219-33. doi: 10.1002/dvg.22368. Epub 2013 Feb 25. Affiliation Abstract The preimplantation period of mouse early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast. During this period two cell fate decisions are made while cells gradually lose their totipotency. The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper. Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo. Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed. http://www.ncbi.nlm.nih.gov/m/pubmed/23349011/ Dionisio

Totipotency and lineage segregation in the human embryo. Authors De Paepe C, et al. Show all Journal Mol Hum Reprod. 2014 Jul;20(7):599-618. doi: 10.1093/molehr/gau027. Epub 2014 Apr 3. Affiliation Abstract During human preimplantation development the totipotent zygote divides and undergoes a number of changes that lead to the first lineage differentiation in the blastocyst displaying trophectoderm (TE) and inner cell mass (ICM) on Day 5. The TE is a differentiated epithelium needed for implantation and the ICM forms the embryo proper and serves as a source for pluripotent embryonic stem cells (ESCs). The blastocyst implants around Day 7. The second lineage differentiation occurs in the ICM after implantation resulting in specification of primitive endoderm and epiblast. Knowledge on human preimplantation development is limited due to ethical and legal restrictions on embryo research and scarcity of materials. Studies in the human are mainly descriptive and lack functional evidence. Most information on embryo development is obtained from animal models and ESC cultures and should be extrapolated with caution. This paper reviews totipotency and the molecular determinants and pathways involved in lineage segregation in the human embryo, as well as the role of embryonic genome activation, cell cycle features and epigenetic modifications. http://www.ncbi.nlm.nih.gov/m/pubmed/24699365/?i=6&from=/23349011/related Dionisio

Human trophectoderm cells are not yet committed. doi: 10.1093/humrep/des432. STUDY QUESTION: Are human trophectoderm (TE) cells committed or still able to develop into inner cell mass (ICM) cells? SUMMARY ANSWER: Human full blastocyst TE cells still have the capacity to develop into ICM cells expressing the pluripotency marker NANOG, thus they are not yet committed. WHAT IS KNOWN ALREADY: Human Day 5 full blastocyst TE cells express the pluripotency markers POU5F1, SOX2 and SALL4 as well as the TE markers HLA-G and KRT18 but not yet CDX2, therefore their developmental direction may not yet be definite. STUDY DESIGN, SIZE, DURATION: The potency of human blastocyst TE cells was investigated by determining their in vitro capacity to develop into a blastocyst with ICM cells expressing NANOG; TE cells were isolated either by aspiration under visual control or after labeling with fluorescent 594-wheat germ agglutinin. Further on, aspirated TE cells were also labeled with fluorescent PKH67 and repositioned in the center of the original embryo. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human preimplantation embryos were used for research after obtaining informed consent from IVF patients. The experiments were approved by the Local Ethical Committee and the 'Belgian Federal Committee on medical and scientific research on embryos in vitro'. Outer cells were isolated and reaggregated by micromanipulation. Reconstituted embryos were analyzed by immunocytochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: Isolated and reaggregated TE cells from full human blastocysts are able to develop into blastocysts with ICM cells expressing the pluripotency marker NANOG. Moreover, the majority of the isolated TE cells which were repositioned in the center of the embryo do not sort back to their original position but integrate within the ICM and start to express NANOG. LIMITATIONS, REASONS FOR CAUTION: Owing to legal and ethical restrictions, manipulated human embryos cannot be transferred into the uterus to determine their totipotent capacity. The definitive demonstration that embryos reconstructed with TE cells are a source of pluripotent cells is to obtain human embryonic stem cell 'like' line(s), which will allow full characterization of the cells. WIDER IMPLICATIONS OF THE FINDINGS: Our finding has important implications in reproductive medicine and stem cell biology because TE cells have a greater developmental potential than assumed previously. http://www.ncbi.nlm.nih.gov/m/pubmed/23257394/?i=4&from=/24699365/related Dionisio

Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns Early mammalian embryogenesis is controlled by mechanisms governing the balance between pluripotency and differentiation. The expression of early lineage-specific genes can vary significantly between species, with implications for developmental control and stem cell derivation. However, the mechanisms involved in patterning the human embryo are still unclear. We analyzed the appearance and localization of lineage-specific transcription factors in staged preimplantation human embryos from the zygote until the blastocyst. We observed that the pluripotency-associated transcription factor OCT4 was initially expressed in 8-cell embryos at 3 days post-fertilization (dpf), and restricted to the inner cell mass (ICM) in 128-256 cell blastocysts (6dpf), approximately 2 days later than the mouse. The trophectoderm (TE)-associated transcription factor CDX2 was upregulated in 5dpf blastocysts and initially coincident with OCT4, indicating a lag in CDX2 initiation in the TE lineage, relative to the mouse. Once established, the TE expressed intracellular and cell-surface proteins cytokeratin-7 (CK7) and fibroblast growth factor receptor-1 (FGFR1), which are thought to be specific to post-implantation human trophoblast progenitor cells. The primitive endoderm (PE)-associated transcription factor SOX17 was initially heterogeneously expressed in the ICM where it co-localized with a sub-set of OCT4 expressing cells at 4-5dpf. SOX17 was progressively restricted to the PE adjacent to the blastocoel cavity together with the transcription factor GATA6 by 6dpf. We observed low levels of Laminin expression in the human PE, though this basement membrane component is thought to play an important role in mouse PE cell sorting, suggesting divergence in differentiation mechanisms between species. Additionally, while stem cell lines representing the three distinct cell types that comprise a mouse blastocyst have been established, the identity of cell types that emerge during early human embryonic stem cell derivation is unclear. We observed that derivation from plating intact human blastocysts resulted predominantly in the outgrowth of TE-like cells, which impairs human embryonic stem cell derivation. Altogether, our findings provide important insight into developmental patterning of preimplantation human embryos with potential consequences for stem cell derivation. doi: 10.1016/j.ydbio.2012.12.008. http://www.ncbi.nlm.nih.gov/m/pubmed/23261930/?i=4&from=/23257394/related Dionisio

Asymmetric cell division: from A to Z Could we say from Z to A instead? from zygote to adult? Cell divisions producing two daughter cells that adopt distinct fates are defined as asymmetric. In all organisms, ranging from bacteria to mammals, in which development has been studied extensively, asymmetric cell divisions generate cell diversity. Asymmetric cell divisions can be achieved by either intrinsic or extrinsic mechanisms (Fig. 1). Intrinsic mechanisms involve the preferential segregation of cell fate determinants to one of two daughter cells during mitosis. Asymmetrically segregated factors that bind cell fate determinants and orient the mitotic spindle may also be necessary to ensure the faithful segregation of determinants into only one daughter cell. Extrinsic mechanisms involve cell–cell communication. In metazoans, a dividing’s cell’s social contex provides a wealth of positional information and opportunity for cell–cell interactions. Interactions between daughter cells or between a daughter cell and other nearby cells could specify daughter cell fate. Interaction between a progenitor cell and its environment can also influence cell polarity by directing spindle orientation and the asymmetric distribution of developmental potential to daughter cells. Recent studies have indicated that a combination of intrinsic and extrinsic mechanisms specify distinct daughter cell fates during asymmetric cell divisions. http://m.genesdev.cshlp.org/content/12/23/3625.extract Dionisio

Mechanisms regulating stem cell polarity and the specification of asymmetric divisions Hila Toledano, D. Leanne Jones,§ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037 The ability of cells to divide asymmetrically to produce two different cell types provides the cellular diversity found in every multicellular organism. Asymmetric localization of cell-cell junctions and/or intrinsic cell fate determinants and position within specific environment (“niche”) are examples of mechanisms used to specify cell polarity and direct asymmetric divisions. During development, asymmetric divisions provide the basis for establishment of the body axis and cell fate determination in a range of processes. Subsequently, asymmetric cell divisions play a critical role in maintaining adult stem cell populations, while at the same time generating an adequate number of differentiating daughter cells to maintain tissue homeostasis and repair. Loss of cell polarity, and consequently the potential for asymmetric divisions, is often linked to excessive stem cell self-renewal and tumorigenesis. Here we will discuss multiple factors and mechanisms that imbue cells with polarity to facilitate an asymmetric outcome to stem cell divisions, assuring self-renewal and maintenance of the stem cell pool. Asymmetric division is a property of stem cells that leads to the generation of two cells that can adopt different fates. One has the potential to renew stem cell identity and continue to divide in an asymmetric manner, whereas the other cell will differentiate along a specific lineage. In some cases, factors within the dividing mother cell lead to the differential segregation of cell fate determinants to give two distinct daughters upon division. In others, however, establishment of different fates is reinforced through signaling from neighboring cells. Ultimately, asymmetric divisions are regulated directly by genes that control the process of asymmetric cell division itself or determine the distinct cell fates of the two daughter cells. http://www.stembook.org/node/562 Dionisio

Cell Polarity Signaling The 2014 Gordon Research Conference on Cell Polarity Signaling is a forum for discussion at the frontiers of cell polarity research. Cell polarity is a universal biological process that is fundamental to all aspects of cell division, growth, development, and tissue morphogenesis. It is also perturbed in numerous developmental diseases, in aging, and in cancer. Cell polarity underlies the generation of diverse cell types by asymmetrically dividing stem cells, and provides the organizational structures for tissue architecture. The recognition that cell polarity, and defects in polarization, are of such broad biological importance has led to an explosion of interest in this area. Therefore, the conference will cover a broad range of topics from cell polarity in development and cancer, to neural stem cell biology, inheritance of DNA and centrosomes, ciliogenesis and tissue morphogenesis, and will be an excellent opportunity to discuss the latest developments in the field. Key questions to be discussed at the Conference will include the following: How do signaling networks spatially organize the cell into polarized structures? How are these signals used to polarize membrane traffic? Are similar signals and mechanisms used in different contexts, such as in neurons versus epithelial cells, germ cells, or yeast? Does differential inheritance of DNA strands occur in stem cells, and how important is it? How do stem cells orient their mitotic spindles and segregate cell fate determinants? How common is asymmetric cell division in stem/progenitor cells? How important is EMT and/or loss of polarity during cancer initiation and progression? How and why are RNAs polarized within cells? Is differential segregation of damaged proteins between daughter cells important in aging? Participants will include established investigators from disciplines both within and outside the cell polarity field, and participation by young investigators will be strongly emphasized. Poster presentations will take place on each day of the meeting, allowing for widespread participation of conference attendees at all career stages. Speakers will also be selected from the abstracts submitted for poster presentations, to provide opportunities for presentation of the newest findings. We envision that this GRC will facilitate discussion of cutting edge research in cell polarity and will foster collaborations that will help drive the field forward. http://www.grc.org/programs.aspx?year=2014&program=cellpolar Dionisio

Asymmetric centrosome behavior and the mechanisms of stem cell division The ability of dividing cells to produce daughters with different fates is an important developmental mechanism conserved from bacteria to fungi, plants, and metazoan animals. Asymmetric outcomes of a cell division can be specified by two general mechanisms: asymmetric segregation of intrinsic fate determinants or asymmetric placement of daughter cells into microenvironments that provide extrinsic signals that direct cells to different states. For both, spindle orientation must be coordinated with the localization of intrinsic determinants or source of extrinsic signals to achieve the proper asymmetric outcome. Recent work on spindle orientation in Drosophila melanogaster male germline stem cells and neuroblasts has brought into sharp focus the key role of differential centrosome behavior in developmentally programmed asymmetric division (for reviews see Cabernard, C., and C.Q. Doe. 2007. Curr. Biol. 17:R465–R467; Gonzalez, C. 2007. Nat. Rev. Genet. 8:462–472). These findings provide new insights and suggest intriguing new models for how cells coordinate spindle orientation with their cellular microenvironment to regulate and direct cell fate decisions within tissues. doi: 10.1083/jcb.200707083 http://m.jcb.rupress.org/content/180/2/261.abstract Dionisio

Timing germ cell development (Phys.org) —Scientists from the Friedrich Miescher Institute for Biomedical Research identify a novel mechanism in early germ cell development. They show how the chromatin modulator PRC1 coordinates the timing of sexual differentiation of germ cells during embryonic development. The study, which enhances our understanding of the mechanisms regulating stem-ness and cell fate determination Like all Royal houses in Europe prepare their heirs to the throne, the body carefully develops its germ cells specifically and early on for their sole task of propagating the lineage. As the egg and the sperm fuse to form a zygote, a new being, they look back on an extensive "training" that separated them early on from other cells in the developing embryo. During germ cell development, gene expression programs and chromatin states are prepared such that they support embryonic development after fertilization. What is more, the germ cells have to undergo an unusual type of cell division called meiosis to provide the correct set of chromosomes to the embryo. They have to reduce the two copies of each chromosome – one from the mother, one from the father – to one. It has long been a mystery what enables germ cells to undergo meiosis. Antoine Peters, senior group leader at the Friedrich Miescher Institute for Biomedical Research and Adjunct Professor at the University of Basel, and his team have now been able to identify a major regulator of this switch in cell fate. As they report in the latest issue of Nature, they could show how the chromatin modifier and transcriptional repressor PRC1 controls the development of primordial germ cells and their entry into meiosis. http://phys.org/news/2013-03-germ-cell.html Dionisio

Cell?intrinsic timing in animal development In certain instances we can witness cells controlling the sequence of their behaviors as they divide and differentiate. Striking examples occur in the nervous systems of animals where the order of differentiated cell types can be traced to internal changes in their progenitors. Elucidating the molecular mechanisms underlying such cell fate succession has been of interest for its role in generating cell type diversity and proper tissue structure. Another well?studied instance of developmental timing occurs in the larva of the nematode Caenorhabditis elegans, where the heterochronic gene pathway controls the succession of a variety of developmental events. In each case, the identification of molecules involved and the elucidation of their regulatory relationships is ongoing, but some important factors and dynamics have been revealed. In particular, certain homologs of worm heterochronic factors have been shown to work in neural development, alerting us to possible connections among these systems and the possibility of universal components of timing mechanisms. These connections also cause us to consider whether cell?intrinsic timing is more widespread, regardless of whether multiple differentiated cell types are produced in any particular order. Advanced Review Eric G. Moss, Jennifer Romer?Seibert Published Online: Jul 24 2014 DOI: 10.1002/wdev.145 http://wires.wiley.com/WileyCDA/WiresArticle/wisId-WDEV145.html Dionisio

The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea

Background: Correct specification of cell lineages and establishing angiogenic privilege within the developing cornea are essential for normal vision but the mechanisms controlling these processes are poorly understood. Results: We show that the homeodomain transcription factor PItX2 is expressed in mesenchymal cells of the developing and mature cornea and use a temporal gene knockout approach to demonstrate that PITX2 is required for corneal morphogenesis and the specification of cell fates within the surface ectoderm and mesenchymal primordia. PITX2 is also required to establish angiogenic privilege in the developing cornea. Further, the expression of Dkk2 and suppression of canonical Wnt signaling activity levels are key mechanisms by which PITX2 specifies ocular surface ectoderm as cornea. In contrast, specifying the underlying mesenchyme to corneal fates and establishing angiogenic privilege in the cornea are less sensitive to DKK2 activity. Finally, the cellular expression patterns of FOXC2, PITX1, and BARX2 in Pitx2 and Dkk2 mutants suggest that these transcription factors may be involved in specifying cell fate and establishing angiogenic privilege within the corneal mesenchyme. However, they are unlikely to play a role in specifying cell fate within the corneal ectoderm. Conclusions: Together, these data provide important insights into the mechanisms regulating cornea development. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc. DOI: 10.1002/dvdy.24165 http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24165/abstract

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maintenance of the Shugoshin Sgo1 at meiotic centromeres does not require Cdc2 activity, whereas localization of the kinase aurora does http://rsob.royalsocietypublishing.org/content/4/7/140063.abstract?sid=cb207e2a-e508-4fa7-bf96-885c4e6ce2e8 Dionisio

Polar delivery in plants; commonalities and differences to animal epithelial cells

Although plant and animal cells use a similar core mechanism to deliver proteins to the plasma membrane, their different lifestyle, body organization and specific cell structures resulted in the acquisition of regulatory mechanisms that vary in the two kingdoms. In particular, cell polarity regulators do not seem to be conserved, because genes encoding key components are absent in plant genomes. In plants, the broad knowledge on polarity derives from the study of auxin transporters, the PIN-FORMED proteins, in the model plant Arabidopsis thaliana. In animals, much information is provided from the study of polarity in epithelial cells that exhibit basolateral and luminal apical polarities, separated by tight junctions. In this review, we summarize the similarities and differences of the polarization mechanisms between plants and animals and survey the main genetic approaches that have been used to characterize new genes involved in polarity establishment in plants, including the frequently used forward and reverse genetics screens as well as a novel chemical genetics approach that is expected to overcome the limitation of classical genetics methods. doi: 10.1098/rsob.140017 Open Biol. April 2014 http://rsob.royalsocietypublishing.org/content/4/4/140017.abstract?sid=0539031c-dea3-467a-a034-91a545139fe4

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Stem cell ageing and non-random chromosome segregation http://rstb.royalsocietypublishing.org/content/366/1561/85/F1.expansion.html Dionisio

Whole-Genome Analysis of Muscle Founder Cells Implicates the Chromatin Regulator Sin3A in Muscle Identity

Skeletal muscles are formed in numerous shapes and sizes, and this diversity impacts function and disease susceptibility. To understand how muscle diversity is generated, we performed gene expression profiling of two muscle subsets from Drosophila embryos. By comparing the transcriptional profiles of these subsets, we identified a core group of founder cell-enriched genes. We screened mutants for muscle defects and identified functions for Sin3A and 10 other transcription and chromatin regulators in the Drosophila embryonic somatic musculature. Sin3A is required for the morphogenesis of a muscle subset, and Sin3A mutants display muscle loss and misattachment. Additionally, misexpression of identity gene transcription factors in Sin3A heterozygous embryos leads to direct transformations of one muscle into another, whereas overexpression of Sin3A results in the reverse transformation. Our data implicate Sin3A as a key buffer controlling muscle responsiveness to transcription factors in the formation of muscle identity, thereby generating tissue diversity. DOI: http://dx.doi.org/10.1016/j.celrep.2014.07.005

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important trigger dictates how cells change their identity and gain specialized functions.

how embryonic stem cell fate is controlled We know a lot about the complex transcriptional control circuits that maintain the naive pluripotent state under self-renewing conditions but comparatively less about how cells exit from this state in response to differentiation stimuli All of us develop into complex human beings containing millions of cells from a single cell created by fertilization of an egg To transit from this single cell state, cells must divide and eventually change their identity and gain specialized functions http://www.genengnews.com/keywordsandtools/print/4/35184/

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protein She1 appears to play a key role in chromosome- and spindle positioning during asymmetric cell division Asymmetric cell division is important in the self-renewal of stem cells and because it ensures that daughter cells have different fates and functions. http://phys.org/print271580403.html Dionisio

Function of the Mitotic Checkpoint

The mitotic checkpoint evolved to prevent cell division when chromosomes have not established connections with the chromosome segregation machinery. Many of the fundamental molecular principles that underlie the checkpoint, its spatiotemporal activation, and its timely inactivation have been uncovered. Most of these are conserved in eukaryotes, but important differences between species exist. Here we review current concepts of mitotic checkpoint activation and silencing. Guided by studies in model organisms and our phylogenomics analysis of checkpoint constituents and their functional domains and motifs, we highlight ancient and taxa-specific aspects of the core checkpoint modules in the context of mitotic checkpoint function. DOI: http://dx.doi.org/10.1016/j.devcel.2012.06.013

Dionisio

The Art of Choreographing Asymmetric Cell Division

Asymmetric cell division (ACD), a mechanism for cell-type diversification in both prokaryotes and eukaryotes, is accomplished through highly coordinated cell-fate segregation, genome partitioning, and cell division. Whereas important paradigms have arisen from the study of animal embryonic divisions, the strategies for choreographing the dynamic subprocesses are, in fact, highly varied. This review examines divergent mechanisms of ACD across different kingdoms. Examples discussed show that there is no obligatory hierarchy among the dynamic events and that asymmetry can emerge from each event, but cell polarization more often occurs as the initial instructive process for patterning ACD especially in the multicellular context. DOI: http://dx.doi.org/10.1016/j.devcel.2013.05.003

Dionisio

Long Noncoding RNA Modulates Alternative Splicing Regulators in Arabidopsis

Alternative splicing (AS) of pre-mRNA represents a major mechanism underlying increased transcriptome and proteome complexity. Here, we show that the nuclear speckle RNA-binding protein (NSR) and the AS competitor long noncoding RNA (or ASCO-lncRNA) constitute an AS regulatory module. AtNSR-GFP translational fusions are expressed in primary and lateral root (LR) meristems. Double Atnsr mutants and ASCO overexpressors exhibit an altered ability to form LRs after auxin treatment. Interestingly, auxin induces a major change in AS patterns of many genes, a response largely dependent on NSRs. RNA immunoprecipitation assays demonstrate that AtNSRs interact not only with their alternatively spliced mRNA targets but also with the ASCO-RNA in vivo. The ASCO-RNA displaces an AS target from an NSR-containing complex in vitro. Expression of ASCO-RNA in Arabidopsis affects the splicing patterns of several NSR-regulated mRNA targets. Hence, lncRNA can hijack nuclear AS regulators to modulate AS patterns during development. DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.017

Dionisio

Sizing Up Lung Stem Cells

Mammalian lungs are comprised of conducting airways and alveoli. How the distinct epithelial linings of these two zones are differentially specified and maintained is not fully understood. Two groups find critical roles for the Hippo pathway in regulation of lung progenitor cell differentiation. DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.002

Dionisio

Spatial Regionalization and Heterochrony in the Formation of Adult Pallial Neural Stem Cells

Highlights •Adult pallial stem cells derive from distinct embryonic progenitor subtypes •Lateral pallial stem cells are generated late during development •Cryptic boundaries linked with stem cell origin subdivide the pallial germinal zone •Large functional pallial areas are segregated from embryonic stages Summary Little is known on the embryonic origin and related heterogeneity of adult neural stem cells (aNSCs). We use conditional genetic tracing, activated in a global or mosaic fashion by cell type-specific promoters or focal laser uncaging, coupled with gene expression analyses and Notch invalidations, to address this issue in the zebrafish adult telencephalon. We report that the germinal zone of the adult pallium originates from two distinct subtypes of embryonic progenitors and integrates two modes of aNSC formation. Dorsomedial aNSCs derive from the amplification of actively neurogenic radial glia of the embryonic telencephalon. On the contrary, the lateral aNSC population is formed by stepwise addition at the pallial edge from a discrete neuroepithelial progenitor pool of the posterior telencephalic roof, activated at postembryonic stages and persisting lifelong. This dual origin of the pallial germinal zone allows the temporally organized building of pallial territories as a patchwork of juxtaposed compartments. DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.012

Dionisio

SAS-6 Assembly Templated by the Lumen of Cartwheel-less Centrioles Precedes Centriole Duplication

Centrioles are 9-fold symmetric structures duplicating once per cell cycle. Duplication involves self-oligomerization of the centriolar protein SAS-6, but how the 9-fold symmetry is invariantly established remains unclear. Here, we found that SAS-6 assembly can be shaped by preexisting (or mother) centrioles. During S phase, SAS-6 molecules are first recruited to the proximal lumen of the mother centriole, adopting a cartwheel-like organization through interactions with the luminal wall, rather than via their self-oligomerization activity. The removal or release of luminal SAS-6 requires Plk4 and the cartwheel protein STIL. Abolishing either the recruitment or the removal of luminal SAS-6 hinders SAS-6 (or centriole) assembly at the outside wall of mother centrioles. After duplication, the lumen of engaged mother centrioles becomes inaccessible to SAS-6, correlating with a block for reduplication. These results lead to a proposed model that centrioles may duplicate via a template-based process to preserve their geometry and copy number. DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.008

Dionisio

Mother Centrioles Do a Cartwheel to Produce Just One Daughter

evidence for a model of centriole duplication whereby the cartwheel—the starting building block in centriole biogenesis—assembles within the lumen of the mother centriole before templating the daughter centriole to ensure a single duplication event per cell cycle. DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.013

Dionisio

Axel, Glad to see your comments in this thread! Dionisio

Addendum to #177

http://emboj.embopress.org/content/early/2014/07/04/embj.201488147

Dionisio

Apparently, car dealerships now employ 'motility specialists', instead of sales people. Axel

NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane

The positioning and the elongation of the mitotic spindle must be carefully regulated. In human cells, the evolutionary conserved proteins LGN/G?i1?3 anchor the coiled?coil protein NuMA and dynein to the cell cortex during metaphase, thus ensuring proper spindle positioning. The mechanisms governing cortical localization of NuMA and dynein during anaphase remain more elusive. Here, we report that LGN/G?i1?3 are dispensable for NuMA?dependent cortical dynein enrichment during anaphase. We further establish that NuMA is excluded from the equatorial region of the cell cortex in a manner that depends on the centralspindlin components CYK4 and MKLP1. Importantly, we reveal that NuMA can directly associate with PtdInsP (PIP) and PtdInsP2 (PIP2) phosphoinositides in vitro. Furthermore, chemical or enzymatic depletion of PIP/PIP2 prevents NuMA cortical localization during mitosis, and conversely, increasing PIP2 levels augments mitotic cortical NuMA. Overall, our study uncovers a novel function for plasma membrane phospholipids in governing cortical NuMA distribution and thus the proper execution of mitosis. Sachin Kotak, Coralie Busso, Pierre Gönczy DOI: 10.15252/embj.201488147

Dionisio

Stop competing, start talking!

According to current belief, the molecular networks orchestrating cell death or exit from mitosis upon extended mitotic arrest do not interact, stubbornly executing two parallel biological programs and competing to define a stochastic decision between death and a chance for survival with uncertain destiny. However, recent findings by Diaz?Martinez et al (2014) in this issue of The EMBO Journal now call for a reassessment of the “competing network” hypothesis. Anti?mitotic drugs are essential ingredients of current anti?cancer therapy. While the molecular basis of the clinical benefit elicited by these drugs is still debated (Mitchison, 2012), cells exposed to taxanes or vinca?alkaloids in experimental settings usually undergo one of two fates after prolonged mitotic arrest: cell death, usually by apoptosis, or adaptation, that is exit from mitosis without cellular division, a process also known as mitotic slippage and a possible cause for long?term treatment failure. The “competing network” hypothesis developed by Gascoigne and Taylor suggests that two independent molecular circuits control cell death or slippage upon extended mitotic arrest (Gascoigne & Taylor, 2008). In this model, cell fate solely depends on the time needed by either program to reach a critical threshold. Gradual decline in cyclin B1 levels defines the time period to mitotic exit, since even in arrested cells, the spindle assembly checkpoint (SAC) is unable to fully restrain the activity of the APC/CCdc20 ubiquitin ligase toward cyclin B1 (Brito & Rieder, 2006). In parallel, apoptotic cell death is initiated through the integration of largely undefined signals leading to activation of the two key pro?apoptotic effectors within the Bcl?2 family, Bax and/or Bak, required for mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation (reviewed in Czabotar et al, 2013). Luca L Fava, Andreas Villunger DOI: 10.15252/embj.201489466 http://emboj.embopress.org/content/early/2014/07/25/embj.201489466

Dionisio

Regulation of dynamic polarity switching in bacteria by a Ras?like G?protein and its cognate GAP

Over the last 10 years, it has become clear that bacteria are spatially highly organized and, thus, display cell polarity (Gitai et al, 2005; Shapiro et al, 2009). Spatially organized elements of bacteria include proteins as well as the chromosome (Viollier et al, 2004). Cell polarity is a fundamental property of all cells and involves establishing and maintaining the spatial asymmetry of macromolecules (Rafelski and Marshall, 2008). An important consequence of cell polarity is that the activity of asymmetrically localized proteins is spatially confined, thus, laying the foundation for processes that require the localized activity of a protein or protein complexes (Nelson, 2003; Gitai et al, 2005). Cell polarity touches on essentially every aspect of cell function and the processes in which polarity has a decisive function are remarkably similar in eukaryotic cells and bacteria and include cell growth, cell cycle control, division, differentiation, and motility (Etienne?Manneville and Hall, 2002; Gitai et al, 2005; Shapiro et al, 2009). Major questions in understanding cell polarity are how proteins find their correct localization and how this localization may change dynamically over time The rod?shaped cells of the bacterium Myxococcus xanthus move uni?directionally and occasionally undergo reversals during which the leading/lagging polarity axis is inverted. Cellular reversals depend on pole?to?pole relocation of motility proteins that localize to the cell poles between reversals. We show that MglA is a Ras?like G?protein and acts as a nucleotide?dependent molecular switch to regulate motility and that MglB represents a novel GTPase?activating protein (GAP) family and is the cognate GAP of MglA. Between reversals, MglA/GTP is restricted to the leading and MglB to the lagging pole defining the leading/lagging polarity axis. For reversals, the Frz chemosensory system induces the relocation of MglA/GTP to the lagging pole causing an inversion of the leading/lagging polarity axis. MglA/GTP stimulates motility by establishing correct polarity of motility proteins between reversals and reversals by inducing their pole?to?pole relocation. Thus, the function of Ras?like G?proteins and their GAPs in regulating cell polarity is found not only in eukaryotes, but also conserved in bacteria. Simone Leonardy, Mandy Miertzschke, Iryna Bulyha, Eva Sperling, Alfred Wittinghofer, Lotte Søgaard?Andersen DOI: 10.1038/emboj.2010.114 http://emboj.embopress.org/content/29/14/2276#ref-45

Dionisio

Cell cycle regulation with an emphasis on chromosome replication & cell division

In all cells, accurate positioning of the cell division site is essential for generating appropriately-sized daughter cells with a correct chromosome number. In bacteria, cell division generally occurs at mid-cell and initiates with assembly of the tubulin homologue FtsZ into a circumferential ring-like structure, the Z-ring, at the incipient division site. Subsequently, FtsZ recruits the remaining components of the cell division machinery needed to carry out cytokinesis. Thus, the position of Z-ring formation dictates the cell division site. Accordingly, all known systems that regulate positioning of the division site in bacteria control Z-ring positioning. In principle, specification of the cell division site could depend on positively acting systems that precisely define the site of cell division, on negatively acting systems that inhibit cell division everywhere in a cell except at the incipient division site, or a combination of both. In other bacteria, regulators of Z-ring formation act negatively to inhibit Z-ring formation at the cell poles and over the nucleoid, leaving only mid-cell free for Z-ring formation. Our data suggest that Z-ring formation is positively regulated in M. xanthus.

Dionisio

Regulation of dynamic cell polarity in bacteria

The function of cells critically depends on the proper spatial organization of their components with proteins and other macromolecules targeted to defined subcellular locations. In eukaryotes as well as in bacteria this organization, i.e. cell polarity, forms the basis for key cellular processes, such as cell shape determination, differentiation, regulation of chromosome dynamics and cytokinesis as well as motility. Despite the immense importance of cell polarity, the mechanisms responsible for its establishment are still poorly understood. Using the rod-shaped cells of the bacterium Myxococcus xanthus we are investigating how bacteria establish and maintain cell polarity to regulate motility. I will present data demonstrating how two small Ras-like GTPases function together with the cytoskeleton in these processes.

Dionisio

Regulation of motility & cell polarity

Motility in M. xanthus depends on the polar localization of motility proteins. Some of these protein localize in a stationary manner at the poles and others (such as PilB and PilT) localize dynamically to the cell poles and switch poles during reversals. At the cellular level, these localization patterns reflect the underlying polarity of the rod-shaped M. xanthus cells with a leading and lagging cell pole. http://www.mpi-marburg.mpg.de/sogaard/regulation_of_motility_and_cell_polarity.html

Dionisio

Duh! now, can they tell us more details on how it all happened ?

Evolution of embryonic development in nematodes Jens Schulze and Einhard Schierenberg The study was conducted using 4-D microscopy and 3-D modeling of developing embryos. The pattern of cleavage, spatial arrangement and differentiation of cells diverged dramatically during the history of the phylum Nematoda without corresponding changes in the phenotype. While in all studied representatives the same distinctive developmental steps need to be taken, cell behavior leading to these is not conserved. EvoDevo 2011, 2:18 doi:10.1186/2041-9139-2-18

Dionisio

Geometrically Controlled Asymmetric Division of CD4+ T Cells Studied by Immunological Synapse Arrays

Similar to stem cells, naïve T cells undergo asymmetric division following activation. While asymmetric division of T cells has been shown to be an important mechanism for the generation of lymphocyte fate diversity during immune responses, key factors that influence whether T cells will undergo symmetric or asymmetric divisions are not completely understood. Here, we utilized immunological synapse arrays (ISAs) to begin to dissect mechanisms of asymmetric T lymphocyte division. ISAs are protein micropatterned surfaces composed of two segregated regions, activation sites and adhesion fields. Activation sites are small spots presenting activation signals such as anti-CD3 and anti-CD28, and adhesion fields are the remaining regions surrounding activation sites immobilized with interintercel adhesion molecule 1 (ICAM-1). By varying the size and the distance between the activation sites and measuring the incidence of asymmetric cell divisions, we found that the distance between activation sites is an important regulator of asymmetric division. Further analysis revealed that more symmetric divisions occurred when two nascent daughter cells stably interacted with two distinct activation sites throughout and following cytokinesis. In contrast, more asymmetric divisions occurred when only one daughter cell remained anchored on an activation site while the other daughter became motile and moved away following cytokinesis. Together, these results indicate that TCR signaling events during cytokinesis may repolarize key molecules for asymmetric partitioning, suggesting the possibility that the density of antigen presenting cells that interact with T cells as they undergo cytokinesis may be a critical factor regulating asymmetric division in T cells. Jung H-R, Song KH, Chang JT, Doh J (2014) Geometrically Controlled Asymmetric Division of CD4+ T Cells Studied by Immunological Synapse Arrays. PLoS ONE 9(3): e91926. doi:10.1371/journal.pone.0091926

Dionisio

Molecular forces are key to proper cell division

Studies revealed new details about a molecular surveillance system that helps detect and correct errors in cell division that can lead to cell death or human diseases. During the split, molecular engines pull the copies apart along microtubule tracks that take an active role in the process that includes shortening microtubules by large, flexible scaffold-like protein structures called kinetochores that assemble on every chromosome during division. For long time PEF's function as a kinetochore regulator has been underappreciated. Overall, this well orchestrated process prevents serious problems such as aneuploidy, that is, too many chromosomes in daughter cells. Aneuploidy in somatic or body cells leads to cell death and is a hallmark of most cancer cells. But in eggs or sperm, it leads to serious birth defects and miscarriages. In properly aligned division, microtubules from opposite spindle poles tug chromosome copies toward opposite poles, but they stick together with molecular glue until the proper moment. This creates tension at the kinetochores and stabilizes their interactions with microtubules. However, if attachments are bad, or syntelic, both copies attach to the same pole, leading to chromosome mis-segregation and aneuploidy if uncorrected. The main researcher said "Cells have a surveillance mechanism that allows them to wait for each for every chromosome to properly align before divvying up the chromosomes," "It's clear in our movies that the cell waits for the last kinetochores to correctly orient before moving forward." PEF = polar ejection force http://www.rdmag.com/news/2013/01/molecular-forces-are-key-proper-cell-division-0?cmpid=related_content

Dionisio

Cnn as a scaffold for centrosome maturation

Centrosomes comprise two centrioles that are surrounded by pericentriolar material (PCM). The PCM increases in size during mitosis, as centrioles recruit new PCM from the cytosol — a process known as centrosome maturation. Nature Reviews Molecular Cell Biology 15, 299 (2014) doi:10.1038/nrm3800

Dionisio

Regulating chromosome segregation

Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1). CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules. Nature Reviews Molecular Cell Biology 15, 364–365 (2014) doi:10.1038/nrm3809

Dionisio

Making the spindle checkpoint strong

Spindle checkpoint signals (generated by checkpoint proteins, including MAD1 and the RZZ (Rod–Zw10–Zwilch) complex) arrest mitosis until all kinetochores are correctly attached to spindle microtubules, whereupon checkpoint proteins are removed in a dynein-dependent manner. Nature Reviews Molecular Cell Biology 15, 430 (2014) doi:10.1038/nrm3828

Dionisio

Exploring the Function of Cell Shape and Size during Mitosis

Dividing cells almost always adopt a spherical shape. This is true of most eukaryotic cells lacking a rigid cell wall and is observed in tissue culture and single-celled organisms, as well as in cells dividing inside tissues. While the mechanisms underlying this shape change are now well described, the functional importance of the spherical mitotic cell for the success of cell division has been thus far scarcely addressed. Here we discuss how mitotic rounding contributes to spindle assembly and positioning, as well as the potential consequences of abnormal mitotic cell shape and size on chromosome segregation, tissue growth, and cancer. DOI: http://dx.doi.org/10.1016/j.devcel.2014.04.009ffdd

Dionisio

Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL

The Maf-family leucine zipper transcription factor NRL is essential for rod photoreceptor development and functional maintenance in the mammalian retina. Mutations in NRL are associated with human retinopathies, and loss of Nrl in mice leads to a cone-only retina with the complete absence of rods. Among the highly down-regulated genes in the Nrl?/? retina, we identified receptor expression enhancing protein 6 (Reep6), which encodes a member of a family of proteins involved in shaping of membrane tubules and transport of G-protein coupled receptors. Here, we demonstrate the expression of a novel Reep6 isoform (termed Reep6.1) in the retina by exon-specific Taqman assay and rapid analysis of complementary deoxyribonucleic acid (cDNA) ends (5?-RACE). The REEP6.1 protein includes 27 additional amino acids encoded by exon 5 and is specifically expressed in rod photoreceptors of developing and mature retina. Chromatin immunoprecipitation assay identified NRL binding within the Reep6 intron 1. Reporter assays in cultured cells and transfections in retinal explants mapped an intronic enhancer sequence that mediated NRL-directed Reep6.1 expression. We also demonstrate that knockdown of Reep6 in mouse and zebrafish resulted in death of retinal cells. Our studies implicate REEP6.1 as a key functional target of NRL-centered transcriptional regulatory network in rod photoreceptors. Hum. Mol. Genet. (2014) 23 (16): 4260-4271 doi:10.1093/hmg/ddu143

Dionisio

cell cycle analysis in vivo

doi: 10.1098/rsob.140063 http://rsob.royalsocietypublishing.org/content/4/7/140063.full

Dionisio

Nuclear functions of prefoldin

Prefoldin is a cochaperone, present in all eukaryotes, that cooperates with the chaperonin CCT. It is known mainly for its functional relevance in the cytoplasmic folding of actin and tubulin monomers during cytoskeleton assembly. However, both canonical and prefoldin-like subunits of this heterohexameric complex have also been found in the nucleus, and are functionally connected with nuclear processes in yeast and metazoa. Plant prefoldin has also been detected in the nucleus and physically associated with a gene regulator. In this review, we summarize the information available on the involvement of prefoldin in nuclear phenomena, place special emphasis on gene transcription, and discuss the possibility of a global coordination between gene regulation and cytoplasmic dynamics mediated by prefoldin. doi: 10.1098/rsob.140085 http://rsob.royalsocietypublishing.org/content/4/7/140085.abstract?sid=e29de81b-72fa-481e-add5-3705e50fd13a

Dionisio

Evo-devo research fresh from the oven: cleavage clock regulates features of lineage-specific differentiation

A cleavage clock regulates features of lineage-specific differentiation in the development of a basal branching metazoan, the ctenophore Mnemiopsis leidyi An important question in experimental embryology is to understand how the developmental potential responsible for the generation of distinct cell types is spatially segregated over developmental time. Classical embryological work showed that ctenophores, a group of gelatinous marine invertebrates that arose early in animal evolution, display a highly stereotyped pattern of early development and a precocious specification of blastomere fates. Here we investigate the role of autonomous cell specification and the developmental timing of two distinct ctenophore cell types (motile compound comb-plate-like cilia and light-emitting photocytes) in embryos of the lobate ctenophore, Mnemiopsis leidyi. Our work corroborates previous studies demonstrating that the cleavage program is causally involved in the spatial segregation and/or activation of factors that give rise to distinct cell types in ctenophore development. These factors are segregated independently to the appropriate lineage at the 8- and the 16-cell stages and have features of a clock, such that comb-plate-like cilia and light-emitting photoproteins appear at roughly the same developmental time in cleavage-arrested embryos as they do in untreated embryos. Nuclear division, which possibly affects DNA-cytoplasmic ratios, appears to be important in the timing of differentiation markers. Evidence suggests that the 60-cell stage, just prior to gastrulation, is the time of zygotic gene activation. Such cleavage-clock-regulated phenomena appear to be widespread amongst the Metazoa and these cellular and molecular developmental mechanisms probably evolved early in metazoan evolution. http://www.evodevojournal.com/content/5/1/4 © 2013 Fischer et al.; lísense BioMed Central Ltd. EvoDevo 2014, 5:4 doi:10.1186/2041-9139-5-4

Dionisio

Insights into the molecular mechanisms underlying diversified wing venation among insects

Insect wings are great resources for studying morphological diversities in nature as well as in fossil records. Among them, variation in wing venation is one of the most characteristic features of insect species. Venation is therefore, undeniably a key factor of species-specific functional traits of the wings; however, the mechanism underlying wing vein formation among insects largely remains unexplored. Our knowledge of the genetic basis of wing development is solely restricted to Drosophila melanogaster. A critical step in wing vein development in Drosophila is the activation of the decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signalling pathway during pupal stages. A key mechanism is the directional transport of Dpp from the longitudinal veins into the posterior crossvein by BMP-binding proteins, resulting in redistribution of Dpp that reflects wing vein patterns. Recent works on the sawfly Athalia rosae, of the order Hymenoptera, also suggested that the Dpp transport system is required to specify fore- and hindwing vein patterns. Given that Dpp redistribution via transport is likely to be a key mechanism for establishing wing vein patterns, this raises the interesting possibility that distinct wing vein patterns are generated, based on where Dpp is transported. Experimental evidence in Drosophila suggests that the direction of Dpp transport is regulated by prepatterned positional information. These observations lead to the postulation that Dpp generates diversified insect wing vein patterns through species-specific positional information of its directional transport. Extension of these observations in some winged insects will provide further insights into the mechanisms underlying diversified wing venation among insects. Published 9 July 2014 doi: 10.1098/rspb.2014.0264 Proc. R. Soc. B 22 August 2014 vol. 281 no. 1789 20140264 © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Dionisio

Biological pacemaker created by minimally invasive somatic reprogramming

Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model. Copyright © 2014, American Association for the Advancement of Science Sci Transl Med 16 July 2014: Vol. 6, Issue 245, p. 245ra94 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3008681

Reprogramming? how was the initial programming done? Dionisio

gpuccio, I look forward to reading your procedures post, but please, take your time to write it well, don't rush it. That should be a very important post for many to read and discuss. If part 1 has attracted almost 2 thousand visits and close to 500 comments, part 2 might reignite the discussion to a new level. I've been busy traveling and working on other time-consuming issues that distract my attention from the studying. Dionisio

still on #154 the devo we want to understand is the process going from zygote to adult (from Z to A or briefly Z2A). get all the devo details first - that's quite a tremendous task in and by itself, that might require some time to accomplish. once the devo is well understood, then they could move on to figure out the evo of the devo, if they still want to, because perhaps by the time they get all the pieces of the devo puzzle together in their places, they might not want to look at anything else ;-) does this sound like a plan? Dionisio

More on #154 That's what 'job security' was meant to be: a never-ending project ;-) Just to figure out the devo part it should take some time, then the evo part... Cool! Dionisio

Follow-up to 154 Wouldn't it make more sense to call it devo-evo instead? First things first. Try figuring out how the whole 'devo' thing works before trying to imagine how it came to be. Ok, it has to do with evolutionary developmental biology, that's why the name. Oh, well. Whatever. Who cares? ;-) Dionisio

Take a look at the difficult work this evo-devo scientist is trying to do ;-)

Mark Q Martindale has worked on a wide array of topics including stem cell counting, the relationship of development to adult regeneration, the evolution of identified embryonic cell lineages, egg organization and the role of the early cleavage program in the distribution of developmental potential, and body plan evolution, in a diverse set of developing systems. Current interests include the evolutionary origin of complex traits such as symmetry, mesoderm, and a functional nervous system in animal evolution and the evolution of gene regulatory networks. He was recently named as winner of the University of Hawaii's Regents’ Medal for Excellence in Research (2004) and was awarded the Alexander Kowalevsky Medal for Comparative Embryology (2010) by the St. Petersburg Society of Naturalists. Martindale was recently recruited to be the Director of the Whitney Lab in January 2013. “It is an exciting time to be an evolutionary developmental biologist and I am thrilled to be involved in promoting a trans disciplinary approach to understanding the two greatest mysteries of Life: how functional organisms arise through their own developmental process, and how this process changes over evolutionary time to give rise to novel forms.” co-Editor-in-Chief http://www.evodevojournal.com/about/edboard/userprofile/1232257793561769

Good luck, buddy ;-) Dionisio

Dionisio: I am working hard at the procedures post. I am trying to update about all this important stuff about cell differentiation and regulation, so I am afraid that I will need some more time. But it is worth the while. These things are really fascinating. I am not surprised that they are rarely cited in the neo darwinian framework. But luckily, there is a lot of experimental advanceament available. Thank you for pointing to so many key issues. You are sparing me a lot of time! :) gpuccio

signaling pathway in stem cell biology

The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), play a key role in tissue homeostasis and organ size control by regulating tissue?specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G?protein?coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer. DOI: 10.15252/embr.201438638 http://embor.embopress.org/content/15/6/642

Dionisio

pathway activity influences cell fate.

The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration. Cell. 2014 Jun 5;157(6):1324-38. doi: 10.1016/j.cell.2014.03.060. Copyright © 2014 Elsevier Inc. All rights reserved.

Dionisio

Defining the Protein–Protein Interaction Network of the Human Hippo Pathway

The Hippo pathway, which is conserved from Drosophila to mammals, has been recognized as a tumor suppressor signaling pathway governing cell proliferation and apoptosis, two key events involved in organ size control and tumorigenesis. Although several upstream regulators, the conserved kinase cascade and key downstream effectors including nuclear transcriptional factors have been defined, the global organization of this signaling pathway is not been fully understood. Thus, we conducted a proteomic analysis of human Hippo pathway, which revealed the involvement of an extensive protein–protein interaction network in this pathway. Our data suggest that 550 interactions within 343 unique protein components constitute the central protein–protein interaction landscape of human Hippo pathway. Our study provides a glimpse into the global organization of Hippo pathway, reveals previously unknown interactions within this pathway, and uncovers new potential components involved in the regulation of this pathway. Understanding these interactions will help us further dissect the Hippo signaling-pathway and extend our knowledge of organ size control. http://www.mcponline.org/content/13/1/119.abstract?sid=5b6afae5-7821-43e0-974a-54db639f3d09

lasciatemi cantare! Dionisio

#148

...but little is known about the rules that govern this process.

Rules that govern? Is that related to GP's procedures? Dionisio

A Model of Grid Cell Development through Spatial Exploration and Spike Time-Dependent Plasticity

Grid cell responses develop gradually after eye opening, but little is known about the rules that govern this process. We present a biologically plausible model for the formation of a grid cell network. An asymmetric spike time-dependent plasticity rule acts upon an initially unstructured network of spiking neurons that receive inputs encoding animal velocity and location. Neurons develop an organized recurrent architecture based on the similarity of their inputs, interacting through inhibitory interneurons. The mature network can convert velocity inputs into estimates of animal location, showing that spatially periodic responses and the capacity of path integration can arise through synaptic plasticity, acting on inputs that display neither. The model provides numerous predictions about the necessity of spatial exploration for grid cell development, network topography, the maturation of velocity tuning and neural correlations, the abrupt transition to stable patterned responses, and possible mechanisms to set grid period across grid modules. DOI: http://dx.doi.org/10.1016/j.neuron.2014.06.018

Dionisio

gpuccio, Glad to know that you can use some information posted in this thread. Dionisio

More information to enjoy

Independent Genomic Control of Neuronal Number across Retinal Cell Types The sizes of different neuronal populations within the CNS are precisely controlled, but whether neuronal number is coordinated between cell types is unknown. We examined the covariance structure of 12 different retinal cell types across 30 genetically distinct lines of mice, finding minimal covariation when comparing synaptically connected or developmentally related cell types. Variation mapped to one or more genomic loci for each cell type, but rarely were these shared, indicating minimal genetic coregulation of final number. Multiple genes, therefore, participate in the specification of the size of every population of retinal neuron, yet genetic variants work largely independent of one another during development to modulate those numbers, yielding substantial variability in the convergence ratios between pre- and postsynaptic populations. Density-dependent cellular interactions in the outer plexiform layer overcome this variability to ensure the formation of neuronal circuits that maintain constant retinal coverage and complete afferent sampling. DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.003

Dionisio

Dionisio: Thank you. I needed this! gpuccio

Regulation of asymmetric cell division For proper tissue morphogenesis, cell divisions and cell fate decisions must be tightly and coordinately regulated. One elegant way to accomplish this is to couple them with asymmetric cell divisions. Progenitor cells in the developing epidermis undergo both symmetric and asymmetric cell divisions to balance surface area growth with the generation of differentiated cell layers. Here we review the molecular machinery implicated in controlling asymmetric cell division. In addition, we discuss the ability of epidermal progenitors to choose between symmetric and asymmetric divisions and the key regulatory points that control this decision. Asymmetric cell divisions (ACDs) generate cellular diversity during the development of multi-cellular organisms from a single-celled embryo. The asymmetric division of a progenitor cell generates two daughters with non-identical cell fates, typically one daughter remains a progenitor while the other commits to a defined cell lineage through differentiation. During development and in adult stem cells, ACDs allow for the maintenance of the stem/progenitor cell pool as well as the generation of differentiated cells. While adult stem cells can also undergo symmetric divisions with subsequent differentiation, there is now compelling data that a number of tissue-specific stem/progenitor cells, including those of the neuronal, hematopoietic, muscle and epidermal lineages, undergo ACD. This work was made possible and heavily influenced by pioneering studies on ACD in D. melanogaster and C. elegans, which has been reviewed in detail elsewhere. Recent work has highlighted the advantages of studying ACD in the epidermis, with novel advances in understanding the many levels at which this process is regulated . One crucial determinant of ACD is the axis of spindle orientation and it regulation, which is the major focus of this review. Regulation of asymmetric cell division in the epidermis Samriddha Ray and Terry Lechler* Terry Lechler lechler@cellbio.duke.edu Department of Cell Biology, Duke University Medical Center, Durham, USA Cell Division 2011, 6:12 doi:10.1186/1747-1028-6-12 http://www.celldiv.com/content/6/1/12 © 2011 Ray and Lechler; licensee BioMed Central Ltd.

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Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex

CENP-A is a centromere-specific variant of histone H3 that is required for accurate chromosome segregation. The fission yeast Schizosaccharomyces pombe and mammalian Mis16 and Mis18 form a complex essential for CENP-A recruitment to centromeres. It is unclear, however, how the Mis16-Mis18 complex achieves this function. Here, we identified, by mass spectrometry, novel fission yeast centromere proteins Mis19 and Mis20 that directly interact with Mis16 and Mis18. Like Mis18, Mis19 and Mis20 are localized at the centromeres during interphase, but not in mitosis. Inactivation of Mis19 in a newly isolated temperature-sensitive mutant resulted in CENP-A delocalization and massive chromosome missegregation, whereas Mis20 was dispensable for proper chromosome segregation. Mis19 might be a bridge component for Mis16 and Mis18. We isolated extragenic suppressor mutants for temperature-sensitive mis18 and mis19 mutants and used whole-genome sequencing to determine the mutated sites. We identified two groups of loss-of-function suppressor mutations in non-sense-mediated mRNA decay factors (upf2 and ebs1), and in SWI/SNF chromatin-remodeling components (snf5, snf22 and sol1). Our results suggest that the Mis16-Mis18-Mis19-Mis20 CENP-A-recruiting complex, which is functional in the G1-S phase, may be counteracted by the SWI/SNF chromatin-remodeling complex and non-sense-mediated mRNA decay, which may prevent CENP-A deposition at the centromere. Hayashi, T., Ebe, M., Nagao, K., Kokubu, A., Sajiki, K. and Yanagida, M. (2014), Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex. Genes to Cells, 19: 541–554. doi: 10.1111/gtc.12152

Dionisio

interface between centriole and peri-centriolar material

The increase in centrosome size in mitosis was described over a century ago, and yet it is poorly understood how centrioles, which lie at the core of centrosomes, organize the pericentriolar material (PCM) in this process. Now, structured illumination microscopy reveals in Drosophila that, before clouds of PCM appear, its proteins are closely associated with interphase centrioles in two tube-like layers: an inner layer occupied by centriolar microtubules, Sas-4, Spd-2 and Polo kinase; and an outer layer comprising Pericentrin-like protein (Dplp), Asterless (Asl) and Plk4 kinase. Centrosomin (Cnn) and ?-tubulin associate with this outer tube in G2 cells and, upon mitotic entry, Polo activity is required to recruit them together with Spd-2 into PCM clouds. Cnn is required for Spd-2 to expand into the PCM during this maturation process but can itself contribute to PCM independently of Spd-2. By contrast, the centrioles of spermatocytes elongate from a pre-existing proximal unit during the G2 preceding meiosis. Sas-4 is restricted to the microtubule-associated, inner cylinder and Dplp and Cnn to the outer cylinder of this proximal part. ?-Tubulin and Asl associate with the outer cylinder and Spd-2 with the inner cylinder throughout the entire G2 centriole. Although they occupy different spatial compartments on the G2 centriole, Cnn, Spd-2 and ?-tubulin become diminished at the centriole upon entry into meiosis to become part of PCM clouds. doi: 10.1098/rsob.120104 http://rsob.royalsocietypublishing.org/content/2/8/120104.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

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Microtubule plus-ends within a mitotic cell are ‘moving platforms’ with anchoring, signalling and force-coupling roles

The microtubule polymer grows and shrinks predominantly from one of its ends called the ‘plus-end’. Plus-end regulation during interphase is well understood. However, mitotic regulation of plus-ends is only beginning to be understood in mammalian cells. During mitosis, the plus-ends are tethered to specialized microtubule capture sites. At these sites, plus-end-binding proteins are loaded and unloaded in a regulated fashion. Proper tethering of plus-ends to specialized sites is important so that the microtubule is able to translate its growth and shrinkage into pushing and pulling forces that move bulky subcellular structures. We discuss recent advances on how mitotic plus-ends are tethered to distinct subcellular sites and how plus-end-bound proteins can modulate the forces that move subcellular structures. Using end binding 1 (EB1) as a prototype plus-end-binding protein, we highlight the complex network of plus-end-binding proteins and their regulation through phosphorylation. Finally, we develop a speculative ‘moving platform’ model that illustrates the plus-end's role in distinguishing correct versus incorrect microtubule interactions. doi: 10.1098/rsob.120132 http://rsob.royalsocietypublishing.org/content/2/11/120132.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

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Exotic mitotic mechanisms

The emergence of eukaryotes around two billion years ago provided new challenges for the chromosome segregation machineries: the physical separation of multiple large and linear chromosomes from the microtubule-organizing centres by the nuclear envelope. In this review, we set out the diverse solutions that eukaryotic cells use to solve this problem, and show how stepping away from ‘mainstream’ mitosis can teach us much about the mechanisms and mechanics that can drive chromosome segregation. We discuss the evidence for a close functional and physical relationship between membranes, nuclear pores and kinetochores in generating the forces necessary for chromosome segregation during mitosis. doi: 10.1098/rsob.120140 http://rsob.royalsocietypublishing.org/content/2/12/120140.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Dual mechanisms prevent premature chromosome segregation during meiosis

In meiosis I, homologous chromosomes pair and then attach to the spindle so that the homologs can be pulled apart at anaphase I. The segregation of homologs before pairing would be catastrophic. We describe two mechanisms that prevent this. First, in early meiosis, Ipl1, the budding yeast homolog of the mammalian Aurora B kinase, triggers shedding of a kinetochore protein, preventing microtubule attachment. Second, Ipl1 localizes to the spindle pole bodies (SPBs), where it blocks spindle assembly. These processes are reversed upon expression of Ndt80. Previous studies have shown that Ndt80 is expressed when homologs have successfully partnered, and this triggers a rise in the levels of cyclin-dependent kinase (CDK). We found that CDK phosphorylates Ipl1, delocalizing it from SPBs, triggering spindle assembly. At the same time, kinetochores reassemble. Thus, dual mechanisms controlled by Ipl1 and Ntd80 coordinate chromosome and spindle behaviors to prevent the attachment of unpartnered chromosomes to the meiotic spindle. doi: 10.1101/gad.227454.113 Genes & Dev. 2013. 27: 2139-2146 © 2013 Kim et al.; Published by Cold Spring Harbor Laboratory Press

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Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle

The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules. doi: 10.1098/rsob.120185 http://rsob.royalsocietypublishing.org/content/3/3/120185.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

chromosome segregation: insights from trypanosomes

Faithful transmission of genetic material is essential for the survival of all organisms. Eukaryotic chromosome segregation is driven by the kinetochore that assembles onto centromeric DNA to capture spindle microtubules and govern the movement of chromosomes. Its molecular mechanism has been actively studied in conventional model eukaryotes, such as yeasts, worms, flies and human. However, these organisms are closely related in the evolutionary time scale and it therefore remains unclear whether all eukaryotes use a similar mechanism. The evolutionary origins of the segregation apparatus also remain enigmatic. To gain insights into these questions, it is critical to perform comparative studies. Here, we review our current understanding of the mitotic mechanism in Trypanosoma brucei, an experimentally tractable kinetoplastid parasite that branched early in eukaryotic history. No canonical kinetochore component has been identified, and the design principle of kinetochores might be fundamentally different in kinetoplastids. Furthermore, these organisms do not appear to possess a functional spindle checkpoint that monitors kinetochore–microtubule attachments. With these unique features and the long evolutionary distance from other eukaryotes, understanding the mechanism of chromosome segregation in T. brucei should reveal fundamental requirements for the eukaryotic segregation machinery, and may also provide hints about the origin and evolution of the segregation apparatus. doi: 10.1098/rsob.130023 http://rsob.royalsocietypublishing.org/content/3/5/130023.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Check this out

Left–right asymmetry: cilia stir up new surprises in the node Cilia are microtubule-based hair-like organelles that project from the surface of most eukaryotic cells. They play critical roles in cellular motility, fluid transport and a variety of signal transduction pathways. While we have a good appreciation of the mechanisms of ciliary biogenesis and the details of their structure, many of their functions demand a more lucid understanding. One such function, which remains as intriguing as the time when it was first discovered, is how beating cilia in the node drive the establishment of left–right asymmetry in the vertebrate embryo. The bone of contention has been the two schools of thought that have been put forth to explain this phenomenon. While the ‘morphogen hypothesis’ believes that ciliary motility is responsible for the transport of a morphogen preferentially to the left side, the ‘two-cilia model’ posits that the motile cilia generate a leftward-directed fluid flow that is somehow sensed by the immotile sensory cilia on the periphery of the node. Recent studies with the mouse embryo argue in favour of the latter scenario. Yet this principle may not be generally conserved in other vertebrates that use nodal flow to specify their left–right axis. Work with the teleost fish medaka raises the tantalizing possibility that motility as well as sensory functions of the nodal cilia could be residing within the same organelle. In the end, how ciliary signalling is transmitted to institute asymmetric gene expression that ultimately induces asymmetric organogenesis remains unresolved. doi: 10.1098/rsob.130052 http://rsob.royalsocietypublishing.org/content/3/5/130052.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Interesting research

Microtubule dynamics in neuronal morphogenesis Microtubules (MTs) are essential for neuronal morphogenesis in the developing brain. The MT cytoskeleton provides physical support to shape the fine structure of neuronal processes. MT-based motors play important roles in nucleokinesis, process formation and retraction. Regulation of MT stability downstream of extracellular cues is proposed to be critical for axonogenesis. Axons and dendrites exhibit different patterns of MT organization, underlying the divergent functions of these processes. Centrosomal positioning has drawn the attention of researchers because it is a major clue to understanding neuronal MT organization. In this review, we focus on how recent advances in live imaging have revealed the dynamics of MT organization and centrosome positioning during neural development. doi: 10.1098/rsob.130061 http://rsob.royalsocietypublishing.org/content/3/7/130061.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Interesting research:

Coordinating cell polarity and cell cycle progression Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression. doi: 10.1098/rsob.130083 http://rsob.royalsocietypublishing.org/content/3/8/130083.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Interesting research

A CENP-S/X complex assembles at the centromere in S and G2 phases of the human cell cycle The functional identity of centromeres arises from a set of specific nucleoprotein particle subunits of the centromeric chromatin fibre. These include CENP-A and histone H3 nucleosomes and a novel nucleosome-like complex of CENPs -T, -W, -S and -X. Fluorescence cross-correlation spectroscopy and Förster resonance energy transfer (FRET) revealed that human CENP-S and -X exist principally in complex in soluble form and retain proximity when assembled at centromeres. Conditional labelling experiments show that they both assemble de novo during S phase and G2, increasing approximately three- to fourfold in abundance at centromeres. Fluorescence recovery after photobleaching (FRAP) measurements documented steady-state exchange between soluble and assembled pools, with CENP-X exchanging approximately 10 times faster than CENP-S (t1/2 ? 10 min versus 120 min). CENP-S binding to sites of DNA damage was quite distinct, with a FRAP half-time of approximately 160 s. Fluorescent two-hybrid analysis identified CENP-T as a uniquely strong CENP-S binding protein and this association was confirmed by FRET, revealing a centromere-bound complex containing CENP-S, CENP-X and CENP-T in proximity to histone H3 but not CENP-A. We propose that deposition of the CENP-T/W/S/X particle reveals a kinetochore-specific chromatin assembly pathway that functions to switch centromeric chromatin to a mitosis-competent state after DNA replication. Centromeres shuttle between CENP-A-rich, replication-competent and H3-CENP-T/W/S/X-rich mitosis-competent compositions in the cell cycle. doi: 10.1098/rsob.130229 http://rsob.royalsocietypublishing.org/content/4/2/130229.abstract?sid=fa03888e-fc4a-4255-bffc-cb615f0ead5d

Dionisio

Interesting research

spermatozoal mRNA repertoires It is now well established that mature mammalian spermatozoa carry a population of mRNA molecules, at least some of which are transferred to the oocyte at fertilization, however, their function remains largely unclear. To shed light on the evolutionary conservation of this feature of sperm biology, we analysed highly purified populations of mature sperm from the fruitfly, Drosophila melanogaster. As with mammalian sperm, we found a consistently enriched population of mRNA molecules that are unlikely to be derived from contaminating somatic cells or immature sperm. Using tagged transcripts for three of the spermatozoal mRNAs, we demonstrate that they are transferred to the oocyte at fertilization and can be detected before, and at least until, the onset of zygotic gene expression. We find a remarkable conservation in the functional annotations associated with fly and human spermatozoal mRNAs, in particular, a highly significant enrichment for transcripts encoding ribosomal proteins (RPs). The substantial functional coherence of spermatozoal transcripts in humans and the fly opens the possibility of using the power of Drosophila genetics to address the function of this enigmatic class of molecules in sperm and in the oocyte following fertilization. doi: 10.1098/rspb.2012.0153

Dionisio

Interesting research to keep an eye on:

We are interested in the molecular mechanisms governing asymmetric stem cell divisions, with emphasis on the role of the mitotic spindle orientation in determining daughter cells’ fate. The proper execution of asymmetric divisions is crucial in generating tissue diversity during development, as well as for tissue homeostasis and regeneration in adult organisms. An increasing body of literature supports the notion that certain human cancers arise from abnormalities in adult stem cells asymmetric divisions, able to alter cell fate and leading to over-proliferation (the so called cancer stem cell hypothesis). Indeed failures in asymmetric divisions occur when pathways controlling the position of the cytokinesis plane are compromised. They cause incorrect fate specification and abnormal proliferation during mammalian neurogenesis and skin development, and correlated with cancer progression. To make a cell division asymmetric, the position of the mitotic spindle has to be tightly coordinated to the cortical polarity, so that daughter cells will be properly positioned within the tissue, inherit unequal sets of fate determinants and follow differential fates. This observation sets the stage for our studies, aimed at gaining insight into the structural and functional organization of the molecular machines responsible for spindle coupling to polarity cues during stem cells asymmetric divisions. To address this biological problem, we use a combination of high-resolution X-ray crystallography, biochemical analyses on reconstituted protein complexes and stem cell biology. Using the detailed molecular information delivered by our structural studies, we formulate precise models of how intrinsic properties of individual protein relate to the behavior of the mitotic spindle during asymmetric cell divisions, that we challenge in living cells. An emerging concept in the cancer field is that cancer stem cells may be responsible for relapse and resistance to anticancer therapies. In this view, a clear molecular description of processes underlying asymmetric cell divisions will be instrumental in identifying new stem-cell specific drug targets for therapeutic intervention. https://www.ieo.it/it/RESEARCH/Basic-research/Department-of-Experimental-Oncology11/Molecular-basis-of-asymmetric-cell-division-Unit/

Dionisio

Interesting mechanisms.

Architectural Niche Organization by LHX2 Is Linked to Hair Follicle Stem Cell Function Highlights •Ablation of LHX2 in skin impairs HF-SC maintenance, leading to baldness •LHX2 functions primarily as a transcriptional activator in hair follicle stem cells •LHX2 regulates the architectural organization of the stem cell niche •Without LHX2, the hair follicle stem cell niche transforms into a sebaceous gland Summary In adult skin, self-renewing, undifferentiated hair follicle stem cells (HF-SCs) reside within a specialized niche, where they spend prolonged times as a single layer of polarized, quiescent epithelial cells. When sufficient activating signals accumulate, HF-SCs become mobilized to fuel tissue regeneration and hair growth. Here, we show that architectural organization of the HF-SC niche by transcription factor LHX2 plays a critical role in HF-SC behavior. Using genome-wide chromatin and transcriptional profiling of HF-SCs in vivo, we show that LHX2 directly transactivates genes that orchestrate cytoskeletal dynamics and adhesion. Conditional ablation of LHX2 results in gross cellular disorganization and HF-SC polarization within the niche. LHX2 loss leads to a failure to maintain HF-SC quiescence and hair anchoring, as well as progressive transformation of the niche into a sebaceous gland. These findings suggest that niche organization underlies the requirement for LHX2 in hair follicle structure and function. DOI: http://dx.doi.org/10.1016/j.stem.2013.06.018

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Interesting, isn't it?

Immune Modulation of Stem Cells and Regeneration The immune system, best known as the first line of defense against invading pathogens, is integral to tissue development, homeostasis, and wound repair. In recent years, there has been a growing appreciation that cellular and humoral components of the immune system also contribute to regeneration of damaged tissues, including limbs, skeletal muscle, heart, and the nervous system. Here, we discuss key findings that implicate inflammatory cells and their secreted factors in tissue replacement after injury via stem cells and other reparative mechanisms. We highlight clinical conditions that are amenable to immune-mediated regeneration and suggest immune targeting strategies for tissue regeneration. DOI: http://dx.doi.org/10.1016/j.stem.2014.06.009

Dionisio

There are many complex mechanisms in the plants too. More work for the 3rd way in their OOL research.

Rice actin-binding protein RMD is a key link in the auxin–actin regulatory loop that controls cell growth The plant hormone auxin plays a central role in plant growth and development. Auxin transport and signaling depend on actin organization. Despite its functional importance, the mechanistic link between actin filaments (F-actin) and auxin intracellular signaling remains unclear. Here, we report that the actin-organizing protein Rice Morphology Determinant (RMD), a type II formin from rice (Oryza sativa), provides a key link. Mutants lacking RMD display abnormal cell growth and altered configuration of F-actin array direction. The rmd mutants also exhibit an inhibition of auxin-mediated cell elongation, decreased polar auxin transport, altered auxin distribution gradients in root tips, and suppression of plasma membrane localization of auxin transporters O. sativa PIN-FORMED 1b (OsPIN1b) and OsPIN2 in root cells. We demonstrate that RMD is required for endocytosis, exocytosis, and auxin-mediated OsPIN2 recycling to the plasma membrane. Moreover, RMD expression is directly regulated by heterodimerized O. sativa auxin response factor 23 (OsARF23) and OsARF24, providing evidence that auxin modulates the orientation of F-actin arrays through RMD. In support of this regulatory loop, osarf23 and lines with reduced expression of both OsARF23 and OsARF24 display reduced RMD expression, disrupted F-actin organization and cell growth, less sensitivity to auxin response, and altered auxin distribution and OsPIN localization. Our findings establish RMD as a crucial component of the auxin–actin self-organizing regulatory loop from the nucleus to cytoplasm that controls rice cell growth and morphogenesis. The positive feedback loop between the auxin pathway and actin cytoskeleton is essential for auxin self-organizing responsive signaling during plant development; however, its underlying mechanism remains largely unknown. Here, we showed that an actin-binding protein, rice morphology determinant (RMD), acts as a key component mediating the auxin–actin loop pathway, affecting cell growth and morphogenesis. Auxin directly promotes RMD expression via binding of Oryza sativa auxin response factor 23 (OsARF23) and OsARF24 heterodimers on the RMD promoter, triggering changes in F-actin organization. In turn, RMD-dependent F-actin arrays affect auxin intracellular signaling, including polar auxin transport, localization and recycling of auxin efflux carriers, and auxin distribution in root cells. Our work identifies RMD as a key link in the auxin–actin self-organizing regulatory loop that is required for auxin-mediated cell growth. doi: 10.1073/pnas.1401680111

Dionisio

Something else for the 3rd way to consider in their OOL research.

Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative/electrophilic stress, and Keap1 negatively regulates Nrf2. Emerging works have also suggested a role for Nrf2 as a regulator of differentiation in various cells, but the contribution of Nrf2 to the differentiation of hematopoietic stem cells (HSCs) remains elusive. Clarifying this point is important to understand Nrf2 functions in the development and/or resolution of inflammation. Here, we established two transgenic reporter mouse lines that allowed us to examine Nrf2 expression precisely in HSCs. Nrf2 was abundantly transcribed in HSCs, but its activity was maintained at low levels due to the Keap1-mediated degradation of Nrf2 protein. When we characterized Keap1-deficient mice, their bone marrow cells showed enhanced granulocyte-monocyte differentiation at the expense of erythroid and lymphoid differentiation. Importantly, Keap1-null HSCs showed lower expression of erythroid and lymphoid genes than did control HSCs, suggesting granulocyte-monocyte lineage priming in Keap1-null HSCs. This abnormal lineage commitment was restored by a concomitant deletion of Nrf2, demonstrating the Nrf2-dependency of the skewing. Analysis of Nrf2-deficient mice revealed that the physiological level of Nrf2 is sufficient to contribute to the lineage commitment. This study unequivocally shows that the Keap1-Nrf2 system regulates the cell fate determination of HSCs. DOI: 10.1111/gtc.12126 © 2014 The Authors Genes to Cells © 2014 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd

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Here's a hint for the 3rd way. Maybe this can help them to figure out the origin of all this stuff?

Evolution of the ribosome at atomic resolution The origins and evolution of the ribosome, 3–4 billion years ago, remain imprinted in the biochemistry of extant life and in the structure of the ribosome. Processes of ribosomal RNA (rRNA) expansion can be “observed” by comparing 3D rRNA structures of bacteria (small), yeast (medium), and metazoans (large). rRNA size correlates well with species complexity. Differences in ribosomes across species reveal that rRNA expansion segments have been added to rRNAs without perturbing the preexisting core. Here we show that rRNA growth occurs by a limited number of processes that include inserting a branch helix onto a preexisting trunk helix and elongation of a helix. rRNA expansions can leave distinctive atomic resolution fingerprints, which we call “insertion fingerprints.” Observation of insertion fingerprints in the ribosomal common core allows identification of probable ancestral expansion segments. Conceptually reversing these expansions allows extrapolation backward in time to generate models of primordial ribosomes. The approach presented here provides insight to the structure of pre-last universal common ancestor rRNAs and the subsequent expansions that shaped the peptidyl transferase center and the conserved core. We infer distinct phases of ribosomal evolution through which ribosomal particles evolve, acquiring coding and translocation, and extending and elaborating the exit tunnel. Ribosomes exist in every cell and are responsible for translation from mRNA to protein. The structure of the ribosomal common core is highly conserved in all living species, while the outer regions of the ribosome are variable. Ribosomal RNA of eukaryotes contains expansion segments accreted onto the surface of the core, which is nearly identical in structure to that in prokaryotic ribosomes. Comparing eukaryotic and prokaryotic ribosomes allows us to identify 3D insertion fingerprints of the expansion segments. Similar fingerprints allow us to analyze the common core and detect ancestral expansion segments within it. We construct a molecular model of ribosomal evolution starting from primordial biological systems near the dawn of life, culminating with relatively recent changes specific to metazoans. doi: 10.1073/pnas.1407205111

There are many questions to ask about this paper. Let's deal with this later. Dionisio

More stuff for the 3rd way to figure out in their ool investigation

Spatial and temporal mechanisms of cell fate determination in the developing CNS The generation of neural cell diversity in the developing central nervous system relies on mechanisms that provide spatial and temporal information to neural progenitor cells. The deployment of morphogen gradients is an important strategy to impart spatial information to the field of responding cells. In this process, cells translate different concentrations of signal into the expression of distinct sets of cell fate-determining transcription factors, which determine cell fate as progenitors leave the cell cycle and differentiate into neurons. However, the mechanisms by which time regulates cell fate determination are poorly understood. http://publications.ki.se/xmlui/handle/10616/40704?locale-attribute=en

Dionisio

how are different cell types generated at specific times and domains throughout embryonic life?

Patterning and cell fate in the inner ear: a case for Notch in the chicken embryo. The development of the inner ear provides a beautiful example of one basic problem in development, that is, to understand how different cell types are generated at specific times and domains throughout embryonic life. The functional unit of the inner ear consists of hair cells, supporting cells and neurons, all deriving from progenitor cells located in the neurosensory competent domain of the otic placode. Throughout development, the otic placode resolves into the complex inner ear labyrinth, which holds the auditory and vestibular sensory organs that are innervated in a highly specific manner. How does the early competent domain of the otic placode give rise to the diverse specialized cell types of the different sensory organs of the inner ear? We review here our current understanding on the role of Notch signaling in coupling patterning and cell fate determination during inner ear development, with a particular emphasis on contributions from the chicken embryo as a model organism. We discuss further the question of how these two processes rely on two modes of operation of the Notch signaling pathway named lateral induction and lateral inhibition. © 2012 The Authors Development, Growth & Differentiation © 2012 Japanese Society of Developmental Biologists. Dev Growth Differ. 2013 Jan;55(1):96-112. doi: 10.1111/dgd.12016. Epub 2012 Dec 17. PMID: 23252974 [PubMed - indexed for MEDLINE]

Dionisio

Lots of things must be right in order for the whole thing to be right. Very easy to mess things up. Very difficult for the whole thing to work well. How many interrelated functions can we detect in these mechanisms?

The candidate splicing factor Sfswap regulates growth and patterning of inner ear sensory organs. The Notch signaling pathway is thought to regulate multiple stages of inner ear development. Mutations in the Notch signaling pathway cause disruptions in the number and arrangement of hair cells and supporting cells in sensory regions of the ear. In this study we identify an insertional mutation in the mouse Sfswap gene, a putative splicing factor, that results in [...] vestibular and cochlear defects that are consistent with disrupted Notch signaling. Homozygous Sfswap mutants display hyperactivity and circling behavior consistent with vestibular defects, and significantly impaired hearing. The cochlea of newborn Sfswap mutant mice shows a significant reduction in outer hair cells and supporting cells and ectopic inner hair cells. This phenotype most closely resembles that seen in hypomorphic alleles of the Notch ligand Jagged1 (Jag1). We show that Jag1; Sfswap compound mutants have inner ear defects that are more severe than expected from simple additive effects of the single mutants, indicating a genetic interaction between Sfswap and Jag1. In addition, expression of genes involved in Notch signaling in the inner ear are reduced in Sfswap mutants. There is increased interest in how splicing affects inner ear development and function. Our work is one of the first studies to suggest that a putative splicing factor has specific effects on Notch signaling pathway members and inner ear development. PLoS Genet. 2014 Jan;10(1):e1004055. doi: 10.1371/journal.pgen.1004055. Epub 2014 Jan 2. PMID: 24391519 [PubMed - indexed for MEDLINE] PMCID: PMC3879212

Dionisio

More stuff for the 3rd way to figure out in their ool investigation

Notch signaling during cell fate determination in the inner ear. In the inner ear, Notch signaling has been proposed to specify the sensory regions, as well as regulate the differentiation of hair cells and supporting cell within those regions. In addition, Notch plays an important role in otic neurogenesis, by determining which cells differentiate as neurons, sensory cells and non-sensory cells. Here, I review the evidence for the complex and myriad roles Notch participates in during inner ear development. A particular challenge for those studying ear development and Notch is to decipher how activation of a single pathway can lead to different outcomes within the ear, which may include changes in the intrinsic properties of the cell, Notch modulation, and potential non-canonical pathways. Copyright © 2013 Elsevier Ltd. All rights reserved. Semin Cell Dev Biol. 2013 May;24(5):470-9. doi: 10.1016/j.semcdb.2013.04.002. Epub 2013 Apr 8. PMID: 23578865 [PubMed - indexed for MEDLINE] PMCID: PMC3725958

Dionisio

maybe the 3rd way can demonstrate how this so called 'evolutionarily conserved' mechanism originated? in the meantime, scientists will continue to investigate how this whole thing functions

The centriole is an evolutionarily conserved organelle involved in microtubule organization. Pairs of centrioles form the centrosome, which is the major microtubule-organizing center in interphase and the mitotic cells of higher animals. Centriole number is subjected to tight regulation, and aberrant centriole numbers cause genome instability and cell proliferation defects, leading to tumorigenesis and other diseases. The centriole also forms the basal body of the cilium, a microtubule-based tail-like membrane protrusion. Epithelial cells, such as those seen lining the trachea, contain many cilia on their apical surface. How are the hundreds of centrioles required for multiciliogenesis created? Zhao et al. examined multicilia formation in mouse tissues and cell lines using super-resolution three-dimensional structured illumination microscopy. Multiple centrioles were produced in ring-shaped deuterosome structures. Two related genes, Cep63 and Deup1, were important for the generation of centrioles, with Deup67 being essential for assembling the deuterosome structures required to create multiple centrioles de novo. Cep63, on the other hand, was more important for mother-centriole–based centriole duplication. Nat. Cell Biol. 15, 1434 (2013). Science 20 December 2013: Vol. 342 no. 6165 p. 1418 DOI: 10.1126/science.342.6165.1418-b Cell Biology Centriole Central Stella M. Hurtley From http://www.sciencemag.org/content/342/6165/1418.2.full

Dionisio

More stuff for the 3rd way to figure out in their ool investigation

Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes Cytoplasmic dynein is a molecular motor that transports a large variety of cargoes (e.g., organelles, mRNAs, and viruses) along microtubules over long intracellular distances. The dynactin protein complex is important for dynein activity in vivo, but its precise role has been unclear. Here, we found that purified mammalian dynein did not move processively on microtubules in vitro. However, when dynein formed a complex with dynactin and one of four different cargo-specific adapter proteins, the motor became ultra-processive, moving for distances similar to those of native cargoes in living cells. Thus, we propose that dynein is largely inactive in the cytoplasm and that a variety of adapter proteins activate processive motility by linking dynactin to dynein only when the motor is bound to its proper cargo. Science DOI: 10.1126/science.1254198

Dionisio

Quite a bit of info to chew and digest here:

Centrosomes Coordinate Cancer Invasion The centrosome is the main microtubule-organizing center in animal cells. In dividing cells, the centrosome mediates chromosome segregation and cytokinesis; in nondividing cells, the centrosome functions as a site for microtubule polymerization. Rac1 is a guanosine triphosphatase (GTPase) that is stimulated by microtubule polymerization and contributes to cytoskeletal reorganization associated with cellular motility. Centrosome amplification can be lethal to cells, yet, in many cancers, it is associated with progression, recurrence, and poor patient survival. [...] found that centrosome amplification was associated with Rac1 signaling–mediated invasive activity in breast epithelial cells. Inducible expression of pololike kinase 4 (PLK4) or addition of dihydrocytochalasin B triggered centrosome amplification (indicated by a green fluorescent protein–tagged centrin) in the non-transformed breast epithelial cell line MCF10A. MCF10A cells cultured in a three-dimensional (3D) matrix under either condition exhibited increased formation of protrusions compared with control cells or cells induced to overexpress a truncated PLK4 mutant that retained kinase activity. Live-cell imaging showed that the protrusions were dynamic structures that initiated tracts along which multiple cells migrated out of acini (grapelike clusters of cells). Although centrosome amplification is associated with aneuploidy, cilia formation, increased p53 abundance, and altered centrosome polarization, none of these, nor changes associated with the epithelial-mesenchymal transition were involved in this invasive phenotype triggered by induction of PLK4. However, the PLK4-overexpressing cells exhibited enhanced cell scattering and defective formation of adherens junctions on a micropatterned fibronectin substrate, indicating loss of epithelial cell-cell adhesion. GTP loading of Rac1 was increased in MCF10A cells with induced overexpression of PLK4 and centrosome amplification. Inhibitors of either Rac1 or one of its targets, the Arp2/3 actin polymerization complex, prevented adherens junction defects in the micropatterned substrate assay and protrusion formation from PLK4-overexpressing MCF10A acini in 3D culture. Adding paclitaxel, a microtubule-stabilizing agent, to 3D cultures of PLK4-overexpressing MCF10A cells decreased Rac1 activation, as did knockdown of CEP192, which promotes microtubule nucleation, which suggested that the increase in microtubule polymerization due to centrosome amplification may be triggering the increase in Rac1 activity. CEP192 knockdown also enabled proper adherens junction formation and prevented invasive acini formation in 3D cultures of PLK4-overexpressing MCF10A cells, without affecting cell viability or centrosome number. The findings indicate that centrosome amplification may be another mechanism that promotes the invasive progression of tumors. Sci. Signal., 10 June 2014 Vol. 7, Issue 329, p. ec156 [DOI: 10.1126/scisignal.2005581] Science Signaling, AAAS, Washington, DC 20005, USA

Dionisio

The 3rd. way may want to include this case in their pursue of the ultimate 'ool' explanation, while scientists continue to investigate how this develops and functions.

Genomic basis for the convergent evolution of electric organs Little is known about the genetic basis of convergent traits that originate repeatedly over broad taxonomic scales. The myogenic electric organ has evolved six times in fishes to produce electric fields used in communication, navigation, predation, or defense. We have examined the genomic basis of the convergent anatomical and physiological origins of these organs by assembling the genome of the electric eel (Electrophorus electricus) and sequencing electric organ and skeletal muscle transcriptomes from three lineages that have independently evolved electric organs. Our results indicate that, despite millions of years of evolution and large differences in the morphology of electric organ cells, independent lineages have leveraged similar transcription factors and developmental and cellular pathways in the evolution of electric organs. Science 27 June 2014: Vol. 344 no. 6191 pp. 1522-1525 DOI: 10.1126/science.1254432 •Report

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Lipid landscapes and pipelines in membrane homeostasis The lipid composition of cellular organelles is tailored to suit their specialized tasks. A fundamental transition in the lipid landscape divides the secretory pathway in early and late membrane territories, allowing an adaptation from biogenic to barrier functions. Defending the contrasting features of these territories against erosion by vesicular traffic poses a major logistical problem. To this end, cells evolved a network of lipid composition sensors and pipelines along which lipids are moved by non-vesicular mechanisms. We review recent insights into the molecular basis of this regulatory network and consider examples in which malfunction of its components leads to system failure and disease. Nature 510, 48–57 (05 June 2014) doi:10.1038/nature13474 Published online 04 June 2014

Evolved? How? Dionisio

Transcriptional regulation in development http://www.cell-symposia-transcriptional-regulation.com/conference-program/

Dionisio

Stem cell energetics

Growing evidence shows that cellular metabolism underlies stem cell fate, including pluripotency, differentiation and reprogramming. In addition to generating ATP, through oxidative phosphorylation, mitochondrial metabolism provides the building blocks to support biomass, such as amino acid and lipids, and is involved in cell signaling in determining stem cell fate. Altered stem cell metabolism has been implicated in aging and diseases, such as cancer, and serves as a potential target for therapeutic intervention. http://www.cell-symposia-stem-cell-energetics.com/

Dionisio

A CULLINary ride across the secretory pathway: more than just secretion Mulitmeric cullin-RING ubiquitin ligases (CRLs) represent the largest class of ubiquitin ligases in eukaryotes. However, most CRL ubiquitylation pathways remain uncharacterized. CRLs control a myriad of functions by catalyzing mono- or poly-ubiquitylation of target proteins. Recently, novel CRLs have been identified along the secretory pathway where they modify substrates involved in diverse cellular processes such as vesicle coat assembly and cell cycle progression. This review discusses our current understanding of CRL ubiquitylation within the secretory pathway, with special emphasis on the emerging role of the Golgi as a ubiquitylation platform. CRLs are also implicated in endosome function, where their specific roles are less well understood. DOI: http://dx.doi.org/10.1016/j.tcb.2014.02.001

Dionisio

Training brain networks and states Brain training refers to practices that alter the brain in a way that improves cognition, and performance in domains beyond those involved in the training. We argue that brain training includes network training through repetitive practice that exercises specific brain networks and state training, which changes the brain state in a way that influences many networks. This opinion article considers two widely used methods – working memory training (WMT) and meditation training (MT) – to demonstrate the similarities and differences between network and state training. These two forms of training involve different areas of the brain and different forms of generalization. We propose a distinction between network and state training methods to improve understanding of the most effective brain training. DOI: http://dx.doi.org/10.1016/j.tics.2014.04.002

Dionisio

"...the cellular processes involved in constructing and organizing the hippocampus remain largely unclear."

Distinct Lineage-Dependent Structural and Functional Organization of the Hippocampus The hippocampus, as part of the cerebral cortex, is essential for memory formation and spatial navigation. Although it has been extensively studied, especially as a model system for neurophysiology, the cellular processes involved in constructing and organizing the hippocampus remain largely unclear. Here, we show that clonally related excitatory neurons in the developing hippocampus are progressively organized into discrete horizontal, but not vertical, clusters in the stratum pyramidale, as revealed by both cell-type-specific retroviral labeling and mosaic analysis with double markers (MADM). Moreover, distinct from those in the neocortex, sister excitatory neurons in the cornu ammonis 1 region of the hippocampus rarely develop electrical or chemical synapses with each other. Instead, they preferentially receive common synaptic input from nearby fast-spiking (FS), but not non-FS, interneurons and exhibit synchronous synaptic activity. These results suggest that shared inhibitory input may specify horizontally clustered sister excitatory neurons as functional units in the hippocampus. DOI: http://dx.doi.org/10.1016/j.cell.2014.03.067

Dionisio

Wow! Just noticed I have posted over 100 consecutive comments in this thread without anyone else adding other comments. Perhaps this thread is too boring, or my comments made it unattractive? Hmmm... BTW, most of the posts after #9 are articles I'm reading for my project on cell fate determination mechanisms. A few are just refreshing reports. I thought other readers would find them interesting too. Dionisio

Yes, No, Maybe? Remember this old song?

You say yes, I say no You say stop and I say go go go, oh no You say goodbye and I say hello

Well, here's a newer version ;-)

Two back-to-back studies in the journal Science last year said the answer is yes, but a study just published in Cell Reports by researchers at the Icahn School of Medicine at Mount Sinai found the opposite.

Here's a link to the entire article:

Mammals Defend Against Viruses Differently than Invertebrates Biologists have long wondered if mammals share the elegant system used by insects, bacteria and other invertebrates to defend against viral infection. Two back-to-back studies in the journal Science last year said the answer is yes, but a study just published in Cell Reports by researchers at the Icahn School of Medicine at Mount Sinai found the opposite. In the Mount Sinai study, the results found that the defense system used by invertebrates—RNA interferences or RNAi—is not used by mammals as some had argued. RNAi are small molecules that attach to molecular scissors used by invertebrates to cut up invading viruses. Mammals use a form of RNAi to fine-tune the expression of hundreds of genes that coordinate development in the womb, says the study’s senior author, Benjamin tenOever, PhD, Fishberg Professor in the Department of Medicine and Department of Microbiology at the Icahn School of Medicine at Mount Sinai. But it has never been clear that adult mammals use RNAi the same way that plants and insects do, he says. “Mammals have cell machinery that looks capable of producing RNAi to fight virus, but we believe it only helps to produce different small RNA products called microRNAs, which are not antiviral,” Dr. tenOever says. http://www.biosciencetechnology.com/news/2014/06/mammals-defend-against-viruses-differently-invertebrates?et_cid=4012990&et_rid=653535995&location=top

Dionisio

Do we know these brain mechanisms well enough to describe them accurately?

Study shows puzzle games can improve mental flexibility A recent study by Nanyang Technological University (NTU) scientists showed that adults who played the physics-based puzzle video game Cut the Rope regularly, for as little as an hour a day, had improved executive functions. The executive functions in your brain are important for making decisions in everyday life when you have to deal with sudden changes in your environment—better known as thinking on your feet. An example would be when the traffic light turns amber and a driver has to decide in an instant if he will be able to brake in time or if it is safer to travel across the junction/intersection. http://www.rdmag.com/news/2014/06/study-shows-puzzle-games-can-improve-mental-flexibility?et_cid=4012582&et_rid=653535995&type=cta

Dionisio

Protein Found that Controls Centriole and Centrosome Copy Number Science paper also describes Orc1’s mechanism of action. Researchers at Cold Spring Harbor Laboratory have discovered the protein that controls the copying of the centrosome in human cells and prevents it from being re-duplicated. The molecule, called ORC1, is among the six proteins that comprise the origin recognition complex (ORC), an assembly that attaches to particular sequences within all DNA in the cell and prepares it for duplication. http://www.genengnews.com/keywordsandtools/print/4/7607/

Dionisio

“Living Drug” Stem Cells to Fight Cancer, Blindness, HIV—and Infertility? Led by PBS’s Charlie Rose, top US stem cell experts this month hailed new clinic-bound techniques designed to persuade “aspects of the body to cure itself,” as New York Stem Cell Foundation head Susan Solomon put it. The main technique hailed involves making stem cells from adult cells, then forging those into armies of robust, proliferating, specialized cells that may let people essentially cure their own blindness; kill their own tumors; and, as Cornell Center for Reproductive Medicine chief Zev Rosenwaks noted, “obliterate” their own infertility. http://www.biosciencetechnology.com/blogs/2014/06/%E2%80%9Cliving-drug%E2%80%9D-stem-cells-fight-cancer-blindness-hiv%E2%80%94and-infertility?et_cid=4012990&et_rid=653535995&type=cta

Dionisio

Distinct phosphatases antagonize the p53 response in different phases of the cell cycle The basic machinery that detects DNA damage is the same throughout the cell cycle. Here, we show, in contrast, that reversal of DNA damage responses (DDRs) and recovery are fundamentally different in G1 and G2 phases of the cell cycle. We find that distinct phosphatases are required to counteract the checkpoint response in G1 vs. G2. Whereas WT p53-induced phosphatase 1 (Wip1) promotes recovery in G2-arrested cells by antagonizing p53, it is dispensable for recovery from a G1 arrest. Instead, we identify phosphoprotein phosphatase 4 catalytic subunit (PP4) to be specifically required for cell cycle restart after DNA damage in G1. PP4 dephosphorylates Krüppel-associated box domain-associated protein 1-S473 to repress p53-dependent transcriptional activation of p21 when the DDR is silenced. Taken together, our results show that PP4 and Wip1 are differentially required to counteract the p53-dependent cell cycle arrest in G1 and G2, by antagonizing early or late p53-mediated responses, respectively. Cell cycle checkpoints coordinate repair of DNA damage with progression through the cell cycle to prevent propagation of DNA mutations and tumor formation. Here, we show that two phosphatases, phosphoprotein phosphatase 4 catalytic subunit (PP4) and WT p53-induced phosphatase 1 (Wip1), are required to promote cell cycle reentry after DNA damage. PP4 is essential for cell cycle reentry in G1, whereas Wip1 is required for reentry in G2, but both act to revert the p53 response. These findings help us understand how overexpression of PP4 and Wip1, frequently observed in human cancers, may translate to a poor response to genotoxic therapies. doi: 10.1073/pnas.1322021111

Dionisio

Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin Aging is associated with the accumulation of several types of damage: in particular, damage to the proteome. Recent work points to a conserved replicative rejuvenation mechanism that works by preventing the inheritance of damaged and misfolded proteins by specific cells during division. Asymmetric inheritance of misfolded and aggregated proteins has been shown in bacteria and yeast, but relatively little evidence exists for a similar mechanism in mammalian cells. Here, we demonstrate, using long-term 4D imaging, that the vimentin intermediate filament establishes mitotic polarity in mammalian cell lines and mediates the asymmetric partitioning of damaged proteins. We show that mammalian JUNQ inclusion bodies containing soluble misfolded proteins are inherited asymmetrically, similarly to JUNQ quality-control inclusions observed in yeast. Mammalian IPOD-like inclusion bodies, meanwhile, are not always inherited by the same cell as the JUNQ. Our study suggests that the mammalian cytoskeleton and intermediate filaments provide the physical scaffold for asymmetric inheritance of dynamic quality-control JUNQ inclusions. Mammalian IPOD inclusions containing amyloidogenic proteins are not partitioned as effectively during mitosis as their counterparts in yeast. These findings provide a valuable mechanistic basis for studying the process of asymmetric inheritance in mammalian cells, including cells potentially undergoing polar divisions, such as differentiating stem cells and cancer cells. We show, for the first time to our knowledge, that vimentin intermediate filaments establish mitotic polarity in dividing mammalian cell lines. By confining damaged, misfolded, and aggregated proteins in JUNQ inclusion bodies, vimentin mediates their asymmetric partitioning during division. We also, to our knowledge, provide the first direct evidence of active proteasomal degradation in dynamic JUNQ inclusion bodies. This work sheds light on an important rejuvenation mechanism in mammalian cells and provides new biological insight into the role of inclusion bodies in regulating aggregation, toxicity, and aging. doi: 10.1073/pnas.1324035111

Dionisio

Centrosomes are autocatalytic droplets of pericentriolar material organized by centrioles How cells position their proteins is still an open question. Here, we propose a physical description of centrosomes, which are membraneless organelles involved in cell division. In our model, centrosome material occurs in a soluble form and a form that tends to form droplets by phase separation. We find that an autocatalytic chemical transition between these forms quantitatively accounts for our experimental data. Importantly, a catalytic activity of the centrioles, which are located inside centrosomes, can control centrosome nucleation and suppress Ostwald ripening to allow for two equal-sized centrosomes to coexist in the cell. Consequently, our example shows how the combination of chemical reactions and phase separation can be used to control the formation of liquid-like compartments in cells. Centrosomes are highly dynamic, spherical organelles without a membrane. Their physical nature and their assembly are not understood. Using the concept of phase separation, we propose a theoretical description of centrosomes as liquid droplets. In our model, centrosome material occurs in a form soluble in the cytosol and a form that tends to undergo phase separation from the cytosol. We show that an autocatalytic chemical transition between these forms accounts for the temporal evolution observed in experiments. Interestingly, the nucleation of centrosomes can be controlled by an enzymatic activity of the centrioles, which are present at the core of all centrosomes. This nonequilibrium feature also allows for multiple stable centrosomes, a situation that is unstable in equilibrium phase separation. Our theory explains the growth dynamics of centrosomes for all cell sizes down to the eight-cell stage of the Caenorhabditis elegans embryo, and it also accounts for data acquired in experiments with aberrant numbers of centrosomes and altered cell volumes. Furthermore, the model can describe unequal centrosome sizes observed in cells with perturbed centrioles. We also propose an interpretation of the molecular details of the involved proteins in the case of C. elegans. Our example suggests a general picture of the organization of membraneless organelles. doi: 10.1073/pnas.1404855111

Dionisio

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors. doi: 10.1073/pnas.1321330111

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Maybe these juicy materials will be available before the end of this year? Call for Papers for a Special Issue on Organogenesis Call for Papers for a Special Issue on Organogenesis Guest Editor: Paul Trainor, Stowers Institute Submission Deadline: August 31, 2014 You are encouraged to submit: • Research articles exploring mechanisms of organogenesis • Techniques articles describing new techniques of broad impact • Disease Connections articles describing novel models/approaches for understanding the developmental basis of disease • Regeneration/Stem Cell Biology articles describing methods or mechanisms in development/regeneration of any organ system • Reviews articles or Critical Commentaries All articles will undergo a thorough peer review to determine their merits for publication. All special issues and reviews published in Developmental Dynamics are open access immediately upon publication, allowing your work to be disseminated widely throughout the scientific community. Submit manuscripts online at: http://mc.manuscriptcentral.com/dvdy-wiley Author Guidelines can be found under 'for Contributors' on the left side of the page at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-0177 Please contact the editorial office (mailto:DVDY@anatomy.org) for additional information and to let us know that you plan to submit a manuscript. Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Function of the Mitotic Checkpoint The mitotic checkpoint evolved to prevent cell division when chromosomes have not established connections with the chromosome segregation machinery. Many of the fundamental molecular principles that underlie the checkpoint, its spatiotemporal activation, and its timely inactivation have been uncovered. Most of these are conserved in eukaryotes, but important differences between species exist. Here we review current concepts of mitotic checkpoint activation and silencing. Guided by studies in model organisms and our phylogenomics analysis of checkpoint constituents and their functional domains and motifs, we highlight ancient and taxa-specific aspects of the core checkpoint modules in the context of mitotic checkpoint function. DOI: http://dx.doi.org/10.1016/j.devcel.2012.06.013

Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

The Art of Choreographing Asymmetric Cell Division Asymmetric cell division (ACD), a mechanism for cell-type diversification in both prokaryotes and eukaryotes, is accomplished through highly coordinated cell-fate segregation, genome partitioning, and cell division. Whereas important paradigms have arisen from the study of animal embryonic divisions, the strategies for choreographing the dynamic subprocesses are, in fact, highly varied. This review examines divergent mechanisms of ACD across different kingdoms. Examples discussed show that there is no obligatory hierarchy among the dynamic events and that asymmetry can emerge from each event, but cell polarization more often occurs as the initial instructive process for patterning ACD especially in the multicellular context. © 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.devcel.2013.05.003

Dionisio

Kinetochores accelerate centrosome separation to ensure faithful chromosome segregation. At the onset of mitosis, cells need to break down their nuclear envelope, form a bipolar spindle and attach the chromosomes to microtubules via kinetochores. Previous studies have shown that spindle bipolarization can occur either before or after nuclear envelope breakdown. In the latter case, early kinetochore-microtubule attachments generate pushing forces that accelerate centrosome separation. However, until now, the physiological relevance of this prometaphase kinetochore pushing force was unknown. We investigated the depletion phenotype of the kinetochore protein CENP-L, which we find to be essential for the stability of kinetochore microtubules, for a homogenous poleward microtubule flux rate and for the kinetochore pushing force. Loss of this force in prometaphase not only delays centrosome separation by 5-6 minutes, it also causes massive chromosome alignment and segregation defects due to the formation of syntelic and merotelic kinetochore-microtubule attachments. By contrast, CENP-L depletion has no impact on mitotic progression in cells that have already separated their centrosomes at nuclear envelope breakdown. We propose that the kinetochore pushing force is an essential safety mechanism that favors amphitelic attachments by ensuring that spindle bipolarization occurs before the formation of the majority of kinetochore-microtubule attachments. Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, 8093 Zürich, Switzerland. Journal of Cell Science (Impact Factor: 5.88). 03/2012; 125(Pt 4):906-18. DOI:10.1242/jcs.091967 Source: PubMed

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Limitations of the Sequencing Technologies: Whole-genome sequencing, whole-exome sequencing—they sound comprehensive, don’t they? But so-called whole-genome sequencing doesn’t cover 100% of the genome, any more than whole-exome sequencing covers 100% of the exome. Because of the way the target DNA sequences are gathered and assembled, not all of the DNA can be sequenced. Sequencing may not pick up longer variations or repetitions of sequences, or long deletions that are responsible for some genetic disorders. Rather, it is best at detecting single-nucleotide variants, or alterations in sequences of no more than 8–10 base pairs. Exome sequencing may not provide a diagnosis. On average, about 25% of such tests identify a gene variant that causes disease; most tests come up empty. Because of the technology’s gaps, however, a negative result doesn’t necessarily rule out a genetic cause for the disease. http://www.genengnews.com/keywordsandtools/print/4/35259/

Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Stem cell differentiation as a many-body problem A molecular understanding of stem cell differentiation requires the study of gene regulatory network dynamics that includes the statistics of synthesizing transcription factors, their degradation, and their binding to the DNA. Brute force simulation for complex large realistic networks can be computationally challenging. Stem cell differentiation has been viewed as coming from transitions between attractors on an epigenetic landscape that governs the dynamics of a regulatory network involving many genes. doi: 10.1073/pnas.1408561111

Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Organelle asymmetry for proper fitness, function, and fate. Dorothy A Lerit,Jeremy T Smyth,Nasser M Rusan •Chromosome Research •Published in: Volume:21 Issue 3: 2013 May 01 •Abstract • During cellular division, centrosomes are tasked with building the bipolar mitotic spindle, which partitions the cellular contents into two daughter cells. While every cell will receive an equal complement of chromosomes, not every organelle is symmetrically passaged to the two progeny in many cell types. In this review, we highlight the conservation of nonrandom centrosome segregation in asymmetrically dividing stem cells, and we discuss how the asymmetric function of centrosomes could mediate nonrandom segregation of organelles and mRNA. We propose that such a mechanism is critical for insuring proper cell fitness, function, and fate. From http://www.genengnews.com/search/pubget/organelle-asymmetry-for-proper-fitness-function-and-fate/23681659/?kwrd=centrosome segregation#gsaccess

Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells. Dorothy A Lerit,Nasser M Rusan •Journal of Cell Biology •Published in: Volume:202 Issue 7: 2013 September 30 •Abstract • Centrosomes determine the mitotic axis of asymmetrically dividing stem cells. Several studies have shown that the centrosomes of the Drosophila melanogaster central brain neural stem cells are themselves asymmetric, organizing varying levels of pericentriolar material and microtubules. This asymmetry produces one active and one inactive centrosome during interphase. We identify pericentrin-like protein (PLP) as a negative regulator of centrosome maturation and activity. We show that PLP is enriched on the inactive interphase centrosome, where it blocks recruitment of the master regulator of centrosome maturation, Polo kinase. Furthermore, we find that ectopic Centrobin expression influenced PLP levels on the basal centrosome, suggesting it may normally function to regulate PLP. Finally, we conclude that, although asymmetric centrosome maturation is not required for asymmetric cell division, it is required for proper centrosome segregation to the two daughter cells. From http://www.genengnews.com/search/pubget/plp-inhibits-the-activity-of-interphase-centrosomes-to-ensure-their-proper-segregation-in-stem-cells/24081489/?kwrd=centrosome segregation#gsaccess

Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Nucleoporin Nup62 maintains centrosome homeostasis. Chieko Hashizume,Akane Moyori,Akiko Kobayashi,Nana Yamakoshi,Aoi Endo,Richard W Wong •Cell Cycle •Published in: Volume:12 Issue 24: 2013 December 15 •Abstract • Centrosomes are comprised of 2 orthogonally arranged centrioles surrounded by the pericentriolar material (PCM), which serves as the main microtubule organizing center of the animal cell. More importantly, centrosomes also control spindle polarity and orientation during mitosis. Recently, we and other investigators discovered that several nucleoporins play critical roles during cell division. Here, we show that nucleoporin Nup62 plays a novel role in centrosome integrity. Knockdown of Nup62 induced mitotic arrest in G 2/M phases and mitotic cell death. Depletion of Nup62 using RNA interference results in defective centrosome segregation and centriole maturation during the G 2 phase. Moreover, Nup62 depletion in human cells leads to the appearance of multinucleated cells and induces the formation of multipolar centrosomes, centriole synthesis defects, dramatic spindle orientation defects, and centrosome component rearrangements that impair cell bi-polarity. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. From http://www.genengnews.com/search/pubget/nucleoporin-nup62-maintains-centrosome-homeostasis/24107630/?kwrd=centrosome segregation#gsaccess

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Human & Chimp DNA Similarities http://www.reasons.org/rtb-101/humanchimpdnasimilarities

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Hypernaturalism and the Origin of Life For nearly six decades the scientific community has labored to explain the origin of life via chemical evolution. Researchers have identified chemical routes that generate the key building blocks of life—amino acids, nucleobases, sugars, and fatty acids—from simple chemical compounds. They've demonstrated how these compounds can assemble into complex, information-rich biopolymers and aggregate into proto-cellular entities. They've used in vitro evolution to evolve RNA molecules with a wide range of functional capabilities. If nothing else, the origin-of-life research community has confirmed the existence of the physicochemical processes and mechanisms needed to get life started. Small wonder many people believe the mystery is close to being solved. More on this at http://www.reasons.org/articles/hypernaturalism-and-the-origin-of-life

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Hypernaturalism?

Unwarranted researcher involvement consistently characterizes the prebiotic simulation studies carried out over the last 60 years. Even though these experiments are designed to validate a naturalistic explanation for life’s origin, they end up demonstrating the necessity of intelligent agency in creating life from inanimate matter. Yet, many in the scientific community continue to resist any suggestion that life’s origin stems from supernatural work. As a means to build a bridge with these skeptics, we apply the concept of hypernaturalism as a means to address the concerns of the scientific community Read more here http://www.reasons.org/articles/how-did-god-create-the-first-life-on-earth

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Looking back at the last 80 comments, the 3rd. way might want to consider explaining how all the currently known mechanisms ended up working together in biological systems in the manner, timing and sequence they appear to do. Basically, the whole enchilada. Any drink with it? ;-) Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Genome-Preserving, Cancer-Preventing Enzyme Pathway Found In processes such as cell division, enzymatic events succeed each other like so many dominoes. If, for whatever reason, a domino were to go missing, the consequences could be catastrophic. In the case of one newly discovered enzyme pathway, the dominoes must fall just so—otherwise a parent cell may divide into daughter cells that receive too many or too few chromosomes. And if that happens, the result can be cancer. The string of dominoes that falls during cell division includes enzymes responsible for DNA damage detection and repair. One such enzyme, Cdc14, has been linked to DNA damage repair in humans, but exactly how the enzyme helps preserve the genome and which proteins it regulates in this process remained obscure—at least until researchers at Purdue University took a closer look. GEN News Highlights : Apr 24, 2014 read more on this at http://www.genengnews.com/keywordsandtools/print/4/34678/

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

Cell Division Proteins Pay Their Own Way, Energetically At certain gatherings, it is understood that each person will pick up their share of the tab, or some portion of it, at least. Now it appears that the idea of paying one’s own way isn’t just for lunch meetings and the like. It even reaches down to the subcellular scale, where the occasion is cell division, the partiers are subunits of a key protein complex, and the exchange of currency is represented by phosphorylation. To be more precise, the occasion is the G2 phase of the cell cycle, during which cell division pauses after DNA replication to check for genetic damage. Once any damage has been repaired, the cell can move into mitosis and begin dividing. The subcellular partiers are the proteins of the cyclin B1/Cdk1 complex, which has long been known to play a key role in cell division. This complex, it now appears, also boosts mitochondrial activity to help power the process. GEN News Highlights Read more on this at http://www.genengnews.com/gen-news-highlights/cell-division-proteins-pay-their-own-way-energetically/81249764/

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

When a cell divides into two new cells, a mitotic spindle forms. Microtubules of protein fan out from each end of the cell, capture chromosomes, and draw them apart into what will become the two new cells. Precise coordination of this process is crucial for cells to divide properly, and for avoiding birth and developmental defects. Cancer cells divide continuously, so this process repeats itself much more often in cancer cells than in normal cells. GEN News Highlights : Apr 9, 2014 http://www.genengnews.com/keywordsandtools/print/4/34520/

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.

GEN News Highlights : Jun 13, 2014 Trigger Discovered to Decode the Genome Researchers from the University of Manchester say they have identified an important trigger that dictates how cells change their identity and gain specialized functions. The believe their study (“Otx2 and Oct4 Drive Early Enhancer Activation during Embryonic Stem Cell Transition from Naive Pluripotency”), published in Cell Reports, has brought them a step closer to being able to decode the genome. The scientists have found out how embryonic stem cell fate is controlled, which will lead to future research into how cells can be artificially manipulated. Lead author Andrew Sharrocks, Ph.D., professor in molecular biology, said: “Understanding how to manipulate cells is crucial in the field of regenerative medicine, which aims to repair or replace damaged or diseased human cells or tissues to restore normal function.” During the research the team focused on an enhancer, which controls the conversion of DNA from genes into proteins. Different enhancers are active in different cell types, allowing the production of distinct gene products and hence a range of alternative cell types. In the current study, the team have determined how these enhancers become active. http://www.genengnews.com/keywordsandtools/print/4/35184/

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Forces Generated by Cell Intercalation Tow Epidermal Sheets in Mammalian Tissue Morphogenetic Highlights •Embryonic eyelid closure is established as a model of collective cell movements in mice •Cells within a differentiating epidermis become motile likely through Wnt signaling •Localized cell intercalation generates a region of active shear at the eyelid front •Laser ablation and genetic loss of function suggest a towing mechanism of closure Summary While gastrulation movements offer mechanistic paradigms for how collective cellular movements shape developing embryos, far less is known about coordinated cellular movements that occur later in development. Studying eyelid closure, we explore a case where an epithelium locally reshapes, expands, and moves over another epithelium. Live imaging, gene targeting, and cell-cycle inhibitors reveal that closure does not require overlying periderm, proliferation, or supracellular actin cable assembly. Laser ablation and quantitative analyses of tissue deformations further distinguish the mechanism from wound repair and dorsal closure. Rather, cell intercalations parallel to the tissue front locally compress it perpendicularly, pulling the surrounding epidermis along the closure axis. Functional analyses in vivo show that the mechanism requires localized myosin-IIA- and ?5?1 integrin/fibronectin-mediated migration and E-cadherin downregulation likely stimulated by Wnt signaling. These studies uncover a mode of epithelial closure in which forces generated by cell intercalation are leveraged to tow the surrounding tissue. DOI: http://dx.doi.org/10.1016/j.devcel.2014.02.011

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Mitotic Spindle Asymmetry: A Wnt/PCP-Regulated Mechanism Generating Asymmetrical Division in Cortical Precursors Highlights •Spindle-size asymmetry (SSA) is linked to asymmetric division in the neocortex •The daughter cell inheriting the larger spindle gives rise to a neuron •SSA is under the control of the Wnt/PCP pathway and P-ERM signaling •In vivo increase in SSA leads to a loss of late-born neurons Summary The regulation of asymmetric cell division (ACD) during corticogenesis is incompletely understood. We document that spindle-size asymmetry (SSA) between the two poles occurs during corticogenesis and parallels ACD. SSA appears at metaphase and is maintained throughout division, and we show it is necessary for proper neurogenesis. Imaging of spindle behavior and division outcome reveals that neurons preferentially arise from the larger-spindle pole. Mechanistically, SSA magnitude is controlled by Wnt7a and Vangl2, both members of the Wnt/planar cell polarity (PCP)-signaling pathway, and relayed to the cell cortex by P-ERM proteins. In vivo, Vangl2 and P-ERM downregulation promotes early cell-cycle exit and prevents the proper generation of late-born neurons. Thus, SSA is a core component of ACD that is conserved in invertebrates and vertebrates and plays a key role in the tight spatiotemporal control of self-renewal and differentiation during mammalian corticogenesis. DOI: http://dx.doi.org/10.1016/j.celrep.2013.12.026

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Measuring Microtubule Polarity in Spindles with Second-Harmonic Generation The spatial organization of microtubule polarity, and the interplay between microtubule polarity and protein localization, is thought to be crucial for spindle assembly, anaphase, and cytokinesis, but these phenomena remain poorly understood, in part due to the difficulty of measuring microtubule polarity in spindles. We develop and implement a method to nonperturbatively and quantitatively measure microtubule polarity throughout spindles using a combination of second-harmonic generation and two-photon fluorescence. We validate this method using computer simulations and by comparison to structural data on spindles obtained from electron tomography and laser ablation. This method should provide a powerful tool for studying spindle organization and function, and may be applicable for investigating microtubule polarity in other systems. DOI: http://dx.doi.org/10.1016/j.bpj.2014.03.009

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Genome-wide Analysis Reveals Novel and Discrete Functions for Tubulin Carboxy-Terminal Tails Highlights •?- and ?-tubulin CTTs promote unique, nonessential functions in yeast •?-tubulin CTT promotes microtubule dynamics •?-tubulin CTT supports kinesin-5 activity •Genetic interactions suggest novel roles for tubulin CTTs Summary Background Microtubules (MTs) support diverse transport and force generation processes in cells. Both ?- and ?-tubulin proteins possess carboxy-terminal tail regions (CTTs) that are negatively charged, intrinsically disordered, and project from the MT surface where they interact with motors and other proteins. Although CTTs are presumed to play important roles in MT networks, these roles have not been determined in vivo. Results We examined the function of CTTs in vivo by using a systematic collection of mutants in budding yeast. We find that CTTs are not essential; however, loss of either ?- or ?-CTT sensitizes cells to MT-destabilizing drugs. ?-CTT, but not ?-CTT, regulates MT dynamics by increasing frequencies of catastrophe and rescue events. In addition, ?-CTT is critical for the assembly of the mitotic spindle and its elongation during anaphase. We use genome-wide genetic interaction screens to identify roles for ?- and ?-CTTs, including a specific role for ?-CTT in supporting kinesin-5/Cin8. Our genetic screens also identified novel interactions with pathways not related to canonical MT functions. Conclusions We conclude that ?- and ?-CTTs play important and largely discrete roles in MT networks. ?-CTT promotes MT dynamics. ?-CTT also regulates force generation in the mitotic spindle by supporting kinesin-5/Cin8 and dampening dynein. Our genetic screens identify links between ?- and ?-CTT and additional cellular pathways and suggest novel functions. DOI: http://dx.doi.org/10.1016/j.cub.2014.03.078

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This very interesting Webinar on lncRNAs just finished this afternoon. Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Probing nuclear pore complex architecture with proximity-dependent biotinylation Proximity-dependent biotinylation (BioID) is a readily accessible method for identifying protein associations that occur in living cells. Fusion of a promiscuous biotin ligase to a bait protein for expression in live cells enables covalent biotin labeling, and thus identification, of proteins proximate to the bait. Here we used BioID to probe the organization of the nuclear pore complex, a large structure that regulates molecular transport between the nucleus and cytoplasm. These studies enhance our understanding of major subcomplexes within the nuclear pore complex and demonstrate the utility of BioID for studying the organization of large protein assemblies. Additionally, we have measured the labeling radius of BioID, thus enabling the rational application of this method and more meaningful data interpretation. Proximity-dependent biotin identification (BioID) is a method for identifying protein associations that occur in vivo. By fusing a promiscuous biotin ligase to a protein of interest expressed in living cells, BioID permits the labeling of proximate proteins during a defined labeling period. In this study we used BioID to study the human nuclear pore complex (NPC), one of the largest macromolecular assemblies in eukaryotes. Anchored within the nuclear envelope, NPCs mediate the nucleocytoplasmic trafficking of numerous cellular components. We applied BioID to constituents of the Nup107–160 complex and the Nup93 complex, two conserved NPC subcomplexes. A strikingly different set of NPC constituents was detected depending on the position of these BioID-fusion proteins within the NPC. By applying BioID to several constituents located throughout the extremely stable Nup107–160 subcomplex, we refined our understanding of this highly conserved subcomplex, in part by demonstrating a direct interaction of Nup43 with Nup85. Furthermore, by using the extremely stable Nup107–160 structure as a molecular ruler, we defined the practical labeling radius of BioID. These studies further our understanding of human NPC organization and demonstrate that BioID is a valuable tool for exploring the constituency and organization of large protein assemblies in living cells. doi: 10.1073/pnas.1406459111

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Bacterial scaffold directs pole-specific centromere segregation Bacteria use molecular partitioning systems based on the ATPase ParA to segregate chromosome centromeres before cell division, but how these machines target centromeres to specific locations is unclear. This study shows that, in Caulobacter crescentus, a multimeric complex composed of the PopZ protein directs the ParA machine to transfer centromeres to the cell pole. Spent ParA subunits released from the mitotic apparatus during segregation are recruited throughout a 3D PopZ matrix at the pole. ParA recruitment and sequestration by PopZ stimulates the cell-pole proximal recycling of ParA into a nucleoid-bound complex to ensure pole-specific centromere transfer. PopZ therefore utilizes a 3D scaffolding strategy to create a subcellular microdomain that directly regulates the function of the bacterial centromere segregation machine. Bacteria use partitioning systems based on the ParA ATPase to actively mobilize and spatially organize molecular cargoes throughout the cytoplasm. The bacterium Caulobacter crescentus uses a ParA-based partitioning system to segregate newly replicated chromosomal centromeres to opposite cell poles. Here we demonstrate that the Caulobacter PopZ scaffold creates an organizing center at the cell pole that actively regulates polar centromere transport by the ParA partition system. As segregation proceeds, the ParB-bound centromere complex is moved by progressively disassembling ParA from a nucleoid-bound structure. Using superresolution microscopy, we show that released ParA is recruited directly to binding sites within a 3D ultrastructure composed of PopZ at the cell pole, whereas the ParB-centromere complex remains at the periphery of the PopZ structure. PopZ recruitment of ParA stimulates ParA to assemble on the nucleoid near the PopZ-proximal cell pole. We identify mutations in PopZ that allow scaffold assembly but specifically abrogate interactions with ParA and demonstrate that PopZ/ParA interactions are required for proper chromosome segregation in vivo. We propose that during segregation PopZ sequesters free ParA and induces target-proximal regeneration of ParA DNA binding activity to enforce processive and pole-directed centromere segregation, preventing segregation reversals. PopZ therefore functions as a polar hub complex at the cell pole to directly regulate the directionality and destination of transfer of the mitotic segregation machine. doi: 10.1073/pnas.1405188111

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin We show, for the first time to our knowledge, that vimentin intermediate filaments establish mitotic polarity in dividing mammalian cell lines. By confining damaged, misfolded, and aggregated proteins in JUNQ inclusion bodies, vimentin mediates their asymmetric partitioning during division. We also, to our knowledge, provide the first direct evidence of active proteasomal degradation in dynamic JUNQ inclusion bodies. This work sheds light on an important rejuvenation mechanism in mammalian cells and provides new biological insight into the role of inclusion bodies in regulating aggregation, toxicity, and aging. Aging is associated with the accumulation of several types of damage: in particular, damage to the proteome. Recent work points to a conserved replicative rejuvenation mechanism that works by preventing the inheritance of damaged and misfolded proteins by specific cells during division. Asymmetric inheritance of misfolded and aggregated proteins has been shown in bacteria and yeast, but relatively little evidence exists for a similar mechanism in mammalian cells. Here, we demonstrate, using long-term 4D imaging, that the vimentin intermediate filament establishes mitotic polarity in mammalian cell lines and mediates the asymmetric partitioning of damaged proteins. We show that mammalian JUNQ inclusion bodies containing soluble misfolded proteins are inherited asymmetrically, similarly to JUNQ quality-control inclusions observed in yeast. Mammalian IPOD-like inclusion bodies, meanwhile, are not always inherited by the same cell as the JUNQ. Our study suggests that the mammalian cytoskeleton and intermediate filaments provide the physical scaffold for asymmetric inheritance of dynamic quality-control JUNQ inclusions. Mammalian IPOD inclusions containing amyloidogenic proteins are not partitioned as effectively during mitosis as their counterparts in yeast. These findings provide a valuable mechanistic basis for studying the process of asymmetric inheritance in mammalian cells, including cells potentially undergoing polar divisions, such as differentiating stem cells and cancer cells. doi: 10.1073/pnas.1324035111 Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved April 28, 2014 (received for review December 24, 2013)

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The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Like a Grandfather Clock: The Splicesome's Intricate Dance of Parts http://www.evolutionnews.org/2014/06/like_a_grandfat086791.html

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New research discoveries, old assumptions trashed, basic concepts revised,... what else is new? This is science.

It’s broadly assumed that [...], but researchers at [...] have discovered that... The findings, published in the June 17 online Early Edition of PNAS, suggest some basic biology may need revising,... http://www.biosciencetechnology.com/news/2014/06/getting-rid-old-mitochondria?et_cid=4000663&et_rid=653535995&location=top

Stay tuned, more to come ;-) Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

The basal position of nuclei is one pre-requisite for asymmetric cell divisions DOI: 10.1016/j.ydbio.2014.05.009 • In 8-cell embryo most of the nuclei move from apical to basal positions. • The nuclear movement depends on microtubules and kinesins. • Only blastomeres with basally located nuclei can divide asymmetrically. • Blastomeres with apically located nuclei divide only symmetrically. • Position of the nucleus is regulated by interdependence of Cdx2 and cell polarity The early mouse embryo undertakes two types of cell division: symmetric that gives rise to the trophectoderm and then placenta or asymmetric that gives rise to inner cells that generate the embryo proper. Although cell division orientation is important, the mechanism regulating it has remained unclear. Here, we identify the relationship between the plane of cell division and the position of the nucleus and go towards identifying the mechanism behind it. We first find that as the 8-cell embryo progresses through the cell cycle, the nuclei of most – but not all – cells move from apical to more basal positions, in a microtubule- and kinesin-dependent manner. We then find that all asymmetric divisions happen when nuclei are located basally and, in contrast, all cells, in which nuclei remain apical, divide symmetrically. To understand the potential mechanism behind this, we determine the effects of modulating expression of Cdx2, a transcription factor key for trophectoderm formation and cell polarity. We find that increased expression of Cdx2 leads to an increase in a number of apical nuclei, whereas down-regulation of Cdx2 leads to more nuclei moving basally, which explains a previously identified relationship between Cdx2 and cell division orientation. Finally, we show that down-regulation of aPKC, involved in cell polarity, decreases the number of apical nuclei and doubles the number of asymmetric divisions. These results suggest a model in which the mutual interdependence of Cdx2 and cell polarity affects the cytoskeleton-dependent positioning of nuclei and, in consequence, the plane of cell division in the early mouse embryo.

Now, wonder how is this in the human embryo? Looking for that information around. Would prefer to look at the exact process in human development. If you find it, please post the link here. Thanks. Dionisio

The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.

Epigenetic Links Discovered in Cell-fate Decisions of Adult Stem Cells The ability to control whether certain stem cells ultimately become bone cells holds great promise for regenerative medicine and potential therapies aimed at treating metabolic bone diseases. Scientists have discovered two key epigenetic regulating genes that govern the cell-fate determination of human bone marrow stem cells. "However, while we know certain genes must be turned on in order for the cells to become bone-forming cells, as opposed to fat cells, we have only a few clues as to how those genes are switched on." - the leading scientist said. http://www.biosciencetechnology.com/news/2012/07/epigenetic-links-discovered-cell-fate-decisions-adult-stem-cells?cmpid=related_content

This report -published a couple of years ago- shows that science research is moving ahead very fast these days. Probably today more information is available on this subject, than it was known when this report was published. We look forward with much anticipation to reading more reports on this subject in the coming days. These seem like exciting times to be in science or at least to look at what's going on in serious science. Dionisio

the mechanisms referred in previous #67 could be broken down into minimum steps, so that no important questions are left unanswered when trying to explain the origin of those mechanisms. Many questions come to mind when one reads that paper. Dionisio

The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.

Drosophila Lipid Droplets Buffer the H2Av Supply to Protect Early Embryonic Development •In Drosophila embryos, lipid droplets can sequester newly synthesized H2Av •This sequestration protects embryos against H2Av overexpression •Lack of sequestration results in an abnormal H2Av/H2A ratio in the nucleus and DNA damage Assembly of DNA into chromatin requires a delicate balancing act, as both dearth and excess of histones severely disrupt chromatin function [1–3]. In particular, cells need to carefully control histone stoichiometry: if different types of histones are incorporated into chromatin in an imbalanced manner, it can lead to altered gene expression, mitotic errors, and death [4–6]. Both the balance between individual core histones and the balance between core histones and histone variants are critical [5, 7]. Here, we find that in early Drosophila embryos, histone balance in the nuclei is regulated by lipid droplets, cytoplasmic fat-storage organelles [8]. Lipid droplets were previously known to function in long-term histone storage: newly laid embryos contain large amounts of excess histones generated during oogenesis [9], and the maternal supplies of core histone H2A and the histone variant H2Av are anchored to lipid droplets via the novel protein Jabba [3]. We find that in these embryos, synthesis of new H2A and H2Av is imbalanced, and that newly produced H2Av can be recruited to lipid droplets. When droplet sequestration is disrupted by mutating Jabba, embryos display an elevated H2Av/H2A ratio in nuclei as well as mitotic defects, reduced viability, and hypersensitivity to H2Av overexpression. We propose that in Drosophila embryos, lipid droplets serve as a histone buffer, not only storing maternal histones to support the early cell cycles but also transiently sequestering H2Av produced in excess and thus ensuring proper histone balance in the nucleus. DOI: http://dx.doi.org/10.1016/j.cub.2014.05.022

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The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.

Coordinating cell polarity with cell division in space and time Decisions of when and where to divide are crucial for cell survival and fate, and for tissue organization and homeostasis. The temporal coordination of mitotic events during cell division is essential to ensure that each daughter cell receives one copy of the genome. The spatial coordination of these events is also crucial because the cytokinetic furrow must be aligned with the axis of chromosome segregation and, in asymmetrically dividing cells, the polarity axis. Several recent papers describe how cell shape and polarity are coordinated with cell division in single cells and tissues and begin to unravel the underlying molecular mechanisms, revealing common principles and molecular players. Here, we discuss how cells regulate the spatial and temporal coordination of cell polarity with cell division. DOI: http://dx.doi.org/10.1016/j.tcb.2011.08.006

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The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.

Amorphous no more: subdiffraction view of the pericentriolar material architecture •The PCM is not amorphous, but has a defined molecular architecture. •The PCM comprises proteins organized as molecular fibers and matrices. •During centrosome maturation the PCM proximal layer acts as a scaffold for PCM expansion. •3D volume alignment and averaging determines protein position within few nm error. •Super-resolution microscopy with quantitative image analysis reveals organelle architecture. The centrosome influences the shape, orientation and activity of the microtubule cytoskeleton. The pericentriolar material (PCM), determines this functionality by providing a dynamic platform for nucleating microtubules and acts as a nexus for molecular signaling. Although great strides have been made in understanding PCM activity, its diffraction-limited size and amorphous appearance on electron microscopy (EM) have limited analysis of its high-order organization. Here, we outline current knowledge of PCM architecture and assembly, emphasizing recent super-resolution imaging studies that revealed the PCM has a layered structure made of fibers and matrices conserved from flies to humans. Notably, these studies debunk the long-standing view of an amorphous PCM and provide a paradigm to dissect the supramolecular organization of organelles in cells. DOI: http://dx.doi.org/10.1016/j.tcb.2013.10.001

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The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.

Immune synapse: conductor of orchestrated organelle movement •The IS beats the drum for orchestrated organelle motion. •The centrosome polarizes to the IS and organizes a dynamic microtubular network. •Microtubule-dependent vesicular traffic at the IS regulates T cell activation. •Mitochondrial network polarization at the IS fine-tunes T cell activation. To ensure proper cell function, intracellular organelles are not randomly distributed within the cell, but polarized and highly constrained by the cytoskeleton and associated adaptor proteins. This relationship between distribution and function was originally found in neurons and epithelial cells; however, recent evidence suggests that it is a general phenomenon occurring in many highly specialized cells including T lymphocytes. Recent studies reveal that the orchestrated redistribution of organelles is dependent on antigen-specific activation of and immune synapse (IS) formation by T cells. This review highlights the functional implications of organelle polarization in early T cell activation and examines recent findings on how the IS sets the rhythm of organelle motion and the spread of the activation signal to the nucleus. DOI: http://dx.doi.org/10.1016/j.tcb.2013.09.005

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The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.

Knowing when to cut and run: mechanisms that control cytokinetic abscission •Spatiotemporal coordination of the abscission machinery is required for completion of cytokinesis. •CEP55 and MITD1 play key roles in the temporal regulation of the abscission machinery. •NoCut prevents DNA damage by delaying abscission in the context of lagging chromosomes. Abscission, the final step of cytokinesis, mediates the severing of the membrane tether, or midbody, that connects two daughter cells. It is now recognized that abscission is a complex process requiring tight spatiotemporal regulation of its machinery to ensure equal chromosome segregation and cytoplasm content distribution between daughter cells. Failure to coordinate these events results in genetic damage. Here, we review recent evidence suggesting that proper abscission timing is coordinated by cytoskeletal rearrangements and recruitment of regulators of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery such as CEP55 and MIT-domain-containing protein 1 (MITD1) to the abscission site. Additionally, we discuss the surveillance mechanism known as the Aurora B-mediated abscission checkpoint (NoCut), which prevents genetic damage by ensuring proper abscission delay when chromatin is trapped at the midbody. Department of Infectious Diseases, King's College London School of Medicine, London SE1 9RT, UK DOI: http://dx.doi.org/10.1016/j.tcb.2013.04.006

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The 3rd. Way might like some statements in this paper, because they refer to potential ways some mechanisms evolved. However, how solid are these arguments? What evidences are they based on? Let's itemize the vague descriptions.

Coiled-Coil Proteins Facilitated the Functional Expansion of the Centrosomes Repurposing existing proteins for new cellular functions is recognized as a main mechanism of evolutionary innovation, but its role in organelle evolution is unclear. Here, we explore the mechanisms that led to the evolution of the centrosome, an ancestral eukaryotic organelle that expanded its functional repertoire through the course of evolution. We developed a refined sequence alignment technique that is more sensitive to coiled coil proteins, which are abundant in the centrosome. For proteins with high coiled-coil content, our algorithm identified 17% more reciprocal best hits than BLAST. Analyzing 108 eukaryotic genomes, we traced the evolutionary history of centrosome proteins. In order to assess how these proteins formed the centrosome and adopted new functions, we computationally emulated evolution by iteratively removing the most recently evolved proteins from the centrosomal protein interaction network. Coiled-coil proteins that first appeared in the animal–fungi ancestor act as scaffolds and recruit ancestral eukaryotic proteins such as kinases and phosphatases to the centrosome. This process created a signaling hub that is crucial for multicellular development. Our results demonstrate how ancient proteins can be co-opted to different cellular localizations, thereby becoming involved in novel functions.[?] The centrosome helps cells to divide, and is important for the development of animals. It has its evolutionary origins in the basal body, which was present in the last common ancestor of all eukaryotes. Here, we study how the evolution of novel proteins helped the formation of the centrosome. Coiled-coil proteins are important for the function of the centrosome. But, they have repeating patterns that can confuse existing methods for finding related proteins. We refined these methods by adjusting for the special properties of the coiled-coil regions. This enabled us to find more distant relatives of centrosomal proteins. We then tested how novel proteins affect the protein interaction network of the centrosome. We did this by removing the most novel proteins step by step. At each stage, we observed how the remaining proteins are connected to the centriole, the core of the centrosome. We found that coiled-coil proteins that first occurred in the ancestor of fungi and animals help to recruit older proteins. By being recruited to the centrosome, these older proteins acquired new functions. We thus now have a clearer picture of how the centrosome became such an important part of animal cells. PLoS Comput Biol. Jun 2014; 10(6): e1003657. Published online Jun 5, 2014. doi: 10.1371/journal.pcbi.1003657

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Can the 3rd. way explain the origin of these mechanisms, while scientists try to understand how they work?

Expression and Function Analysis of Mitotic Checkpoint Genes Identifies TTK as a Potential Therapeutic Target for Human Hepatocellular Carcinoma The mitotic spindle checkpoint (SAC) genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC) therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA) in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8%) of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma. PLoS One. 2014; 9(6): e97739. Published online Jun 6, 2014. doi: 10.1371/journal.pone.0097739

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Research tips

Every laboratory with a fluorescence microscope should consider counting molecules Protein numbers in cells determine rates of biological processes, influence the architecture of cellular structures, reveal the stoichiometries of protein complexes, guide in vitro biochemical reconstitutions, and provide parameter values for mathematical modeling. doi: 10.1091/mbc.E13-05-0249 Mol. Biol. Cell May 15, 2014 vol. 25 no. 10 1545-1548

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Can the 3rd. way explain the origin of these mechanisms, while scientists keep trying to understand how they work and what they do?

Cdk1 Promotes Cytokinesis in Fission Yeast through Activation of the Septation Initiation Network late mitotic events are coordinated with cytokinesis by the septation initiation network (SIN), an essential spindle pole body (SPB)-associated kinase cascade, which controls the formation, maintenance and constriction of the cytokinetic ring. It is not fully understood how SIN initiation is temporally regulated, but it depends on the activation of the GTPase Spg1 that is inhibited during interphase by the essential bipartite GAP, Byr4-Cdc16. Cells are particularly sensitive to the modulation of Byr4, which undergoes cell cycle-dependent phosphorylation presumed to regulate its function. Polo-like kinase, which promotes SIN activation, is partially responsible for Byr4 phosphorylation. Here, we show that Byr4 is also controlled by Cdk1-mediated phosphorylation. A Cdk1 non-phosphorylatable Byr4 phosphomutant displays severe cell division defects including the formation of elongated, multinucleate cells, failure to maintain the cytokinetic ring and compromised SPB association of the SIN kinase Cdc7. Our analyses reveal that Cdk1-mediated phosphoregulation of Byr4 facilitates complete removal of Byr4 from metaphase SPBs in concert with Plo1, revealing an unexpected role for Cdk1 in promoting cytokinesis through activation of the SIN pathway. Published online before print June 11, 2014, doi: 10.1091/mbc.E14-04-0936 Mol. Biol. Cell June 11, 2014 mbc.E14-04-0936

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Maybe the 3rd way can investigate the origin of this, while scientists keep trying to understand it.

Cytoplasmic carboxypeptidase 5 regulates tubulin glutamylation and zebrafish cilia formation and function Glutamylation is a functionally important tubulin posttranslational modification enriched on stable microtubules of neuronal axons, mitotic spindles, centrioles, and cilia. In vertebrates, balanced activities of tubulin glutamyl ligase and cytoplasmic carboxypeptidase deglutamylase enzymes maintain organelle- and cell type–specific tubulin glutamylation patterns. Tubulin glutamylation in cilia is regulated via restricted subcellular localization or expression of tubulin glutamyl ligases (ttlls) and nonenzymatic proteins, including the zebrafish TPR repeat protein Fleer/Ift70. Here we analyze the expression patterns of ccp deglutamylase genes during zebrafish development and the effects of ccp gene knockdown on cilia formation, morphology, and tubulin glutamylation. The deglutamylases ccp2, ccp5, and ccp6 are expressed in ciliated cells, whereas ccp1 expression is restricted to the nervous system. Only ccp5 knockdown increases cilia tubulin glutamylation, induces ciliopathy phenotypes, including axis curvature, hydrocephalus, and pronephric cysts, and disrupts multicilia motility, suggesting that Ccp5 is the principal tubulin deglutamylase that maintains functional levels of cilia tubulin glutamylation. The ability of ccp5 knockdown to restore cilia tubulin glutamylation in fleer/ift70 mutants and rescue pronephric multicilia formation in both fleer- and ift88-deficient zebrafish indicates that tubulin glutamylation is a key driver of ciliogenesis. doi: 10.1091/mbc.E13-01-0033 Mol. Biol. Cell June 15, 2014 vol. 25 no. 12 1836-1844

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The 3rd way may try to investigate the origin of this, while scientists try to understand it better.

The Decapentaplegic (Dpp) signaling pathway is used in many developmental and homeostatic contexts, each time resulting in cellular responses particular to that biological niche. The flexibility of Dpp signaling is clearly evident in epithelial cells of the Drosophila wing imaginal disc. During larval stages of development, Dpp functions as a morphogen, patterning the wing developmental field and stimulating tissue growth. A short time later, however, as wing-epithelial cells exit the cell cycle and begin to differentiate, Dpp is a critical determinant of vein-cell fate. It is likely that the Dpp signaling pathway regulates different sets of target genes at these two developmental time points. To identify mechanisms that temporally control the transcriptional output of Dpp signaling in this system, we have taken a gene expression profiling approach. We identified genes affected by Dpp signaling at late larval or early pupal developmental time points, thereby identifying patterning- and differentiation-specific downstream targets, respectively. Conclusions: Analysis of target genes and transcription factor binding sites associated with these groups of genes revealed potential mechanisms by which target-gene specificity of the Dpp signaling pathway is temporally regulated. In addition, this approach revealed novel mechanisms by which Dpp affects the cellular differentiation of wing-veins. Developmental Dynamics 243:818–832, 2014. © 2014 Wiley Periodicals, Inc. Temporal regulation of Dpp signaling output in the Drosophila wing David D. O'Keefe1, Sean Thomas2, Bruce A. Edgar3 and Laura Buttitta4,* Article first published online: 21 MAR 2014 DOI: 10.1002/dvdy.24122 © 2014 Wiley Periodicals, Inc.

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The 3rd. way could try to explain the origin of this, while scientists try to understand it.

Poly(ADP-ribose): An organizer of cellular architecture Distinct properties of poly(ADP-ribose)—including its structural diversity, nucleation potential, and low complexity, polyvalent, highly charged nature—could contribute to organizing cellular architectures. Emergent data indicate that poly(ADP-ribose) aids in the formation of nonmembranous structures, such as DNA repair foci, spindle poles, and RNA granules. Informatics analyses reported here show that RNA granule proteins enriched for low complexity regions, which aid self-assembly, are preferentially modified by poly(ADP-ribose), indicating how poly(ADP-ribose) could direct cellular organization. Published June 9, 2014 // JCB vol. 205 no. 5 613-619 The Rockefeller University Press, doi: 10.1083/jcb.201402114 © 2014 Leung

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The 3rd. Way could try to explain the origin of this, while scientists try to understand it.

Nucleosome assembly is required for nuclear pore complex assembly in zygotes Packaging of DNA into nucleosomes not only helps to store genetic information but also creates diverse means for regulating DNA-templated processes. Attempts to reveal additional functions of the nucleosome have been unsuccessful, owing to cell lethality caused by nucleosome deletion. Taking advantage of the mammalian fertilization process, in which sperm DNA assembles into nucleosomes de novo, we generated nucleosome-depleted (ND) paternal pronuclei by depleting maternal histone H3.3 or its chaperone HIRA in mouse zygotes. We found that the ND pronucleus forms a nuclear envelope devoid of nuclear pore complexes (NPCs). Loss of NPCs is accompanied by defective localization of ELYS, a nucleoporin essential for NPC assembly, to the nuclear rim. Interestingly, tethering ELYS to the nuclear rim of the ND nucleus rescues NPC assembly. Our study thus demonstrates that nucleosome assembly is a prerequisite for NPC assembly during paternal pronuclear formation. Nature Structural & Molecular Biology (2014) doi:10.1038/nsmb.2839 Published online 08 June 2014

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#58 error correction:

The 3rd. Way may went want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effect they have.

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The 3rd. Way may went to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effect they have.

A Regulatory Transcriptional Loop Controls Proliferation and Differentiation in Drosophila Neural Stem Cells Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis. PLoS One. 2014; 9(5): e97034. Published online May 7, 2014. doi: 10.1371/journal.pone.0097034 PMCID: PMC4013126

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Important elaborate mechanisms still poorly understood

Mitotic spindle multipolarity without centrosome amplification Nature Cell Biology 16, 386–394 (2014) doi:10.1038/ncb2958 Published online 02 May 2014 Mitotic spindle bipolarity is essential for faithful segregation of chromosomes during cell division. Multipolar spindles are often seen in human cancers and are usually associated with supernumerary centrosomes that result from centrosome overduplication or cytokinesis failure. A less-understood path to multipolar spindle formation may arise due to loss of spindle pole integrity in response to spindle and/or chromosomal forces. Here we discuss the different routes leading to multipolar spindle formation, focusing on spindle multipolarity without centrosome amplification. We also present the distinct and common features between these pathways and discuss their therapeutic implications.

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Not a very recent document (4 years old), but still valid.

Asymmetric cell division: recent developments and their implications for tumour biology The ability of cells to divide asymmetrically is essential for generating diverse cell types during development. The past 10 years have seen tremendous progress in our understanding of this important biological process. We have learned that localized phosphorylation events are responsible for the asymmetric segregation of cell fate determinants in mitosis, and that centrosomes and microtubules play important roles. The relevance of asymmetric cell division for stem cell biology has added a new dimension, and exciting connections between asymmetric cell division and tumorigenesis have begun to emerge. The development of multicellular organisms involves the specification of diverse cell types from a single fertilized egg. To generate this diversity, some cells can undergo an asymmetric cell division, during which they segregate protein or RNA determinants into one of the two daughter cells, thereby determining distinct cell fates. Juergen A. Knoblich Nat Rev Mol Cell Biol. Author manuscript; available in PMC Mar 4, 2014. Published in final edited form as: Nat Rev Mol Cell Biol. Dec 2010; 11(12): 849–860. doi: 10.1038/nrm3010 PMCID: PMC3941022 EMSID: EMS52311

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Interesting mechanisms.

Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs Nature Communications 4, Article number: 2338 doi:10.1038/ncomms3338 Published 04 September 2013 Mammalian HELQ is a 3?–5? DNA helicase with strand displacement activity. Here we show that HELQ participates in a pathway of resistance to DNA interstrand crosslinks (ICLs). Genetic disruption of HELQ in human cells enhances cellular sensitivity and chromosome radial formation by the ICL-inducing agent mitomycin C (MMC). A significant fraction of MMC sensitivity is independent of the Fanconi anaemia pathway. Sister chromatid exchange frequency and sensitivity to UV radiation or topoisomerase inhibitors is unaltered. Proteomic analysis reveals that HELQ is associated with the RAD51 paralogs RAD51B/C/D and XRCC2, and with the DNA damage-responsive kinase ATR. After treatment with MMC, reduced phosphorylation of the ATR substrate CHK1 occurs in HELQ-knockout cells, and accumulation of G2/M cells is reduced. The results indicate that HELQ operates in an arm of DNA repair and signalling in response to ICL. Further, the association with RAD51 paralogs suggests HELQ as a candidate ovarian cancer gene.

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The 3rd. way will have a lot of explaining to do on this 2-year old paper alone. Some of the issues relate to the highlighted text. The questions associated with the highlighted text are implicitly obvious. Scientists have a lot of research work ahead, to understand how the mechanisms function and their effects. Many outstanding questions to answer. Puzzle missing parts to find.

Mutat Res. 2012 Oct-Dec; 751(2):158-246. doi: 10.1016/j.mrrev.2012.06.002. Epub 2012 Jun 26. Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Thompson LH. The faithful maintenance of chromosome continuity in human cells during DNA replication and repair is critical for preventing the conversion of normal diploid cells to an oncogenic state. The evolution of higher eukaryotic cells endowed them with a large genetic investment in the molecular machinery that ensures chromosome stability. In mammalian and other vertebrate cells, the elimination of double-strand breaks with minimal nucleotide sequence change involves the spatiotemporal orchestration of a seemingly endless number of proteins ranging in their action from the nucleotide level to nucleosome organization and chromosome architecture. DNA DSBs trigger a myriad of post-translational modifications that alter catalytic activities and the specificity of protein interactions: phosphorylation, acetylation, methylation, ubiquitylation, and SUMOylation, followed by the reversal of these changes as repair is completed. "Superfluous" protein recruitment to damage sites, functional redundancy, and alternative pathways ensure that DSB repair is extremely efficient, both quantitatively and qualitatively. This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR). The exponential growth of molecular studies, heavily driven by RNA knockdown technology, now reveals an outline of how many key protein players in genome stability and cancer biology perform their interwoven tasks, e.g. ATM, ATR, DNA-PK, Chk1, Chk2, PARP1/2/3, 53BP1, BRCA1, BRCA2, BLM, RAD51, and the MRE11-RAD50-NBS1 complex. Thus, the nature of the intricate coordination of repair processes with cell cycle progression is becoming apparent. This review also links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships. Copyright © 2012 Elsevier B.V. All rights reserved. PMID: 22743550 [PubMed - indexed for MEDLINE]

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Protein choreography? How are they put together for different functional situations?

Correlated motions are a fundamental property of ?-sheets Nature Communications 5, Article number: 4070 doi:10.1038/ncomms5070 Published 11 June 2014 Correlated motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. The mechanisms that underlie these processes remain largely unknown due mainly to limitations in their direct detection. Here, based on a detailed analysis of protein structures deposited in the protein data bank, as well as on state-of-the art molecular simulations, we provide general evidence for the transfer of structural information by correlated backbone motions, mediated by hydrogen bonds, across ?-sheets. We also show that the observed local and long-range correlated motions are mediated by the collective motions of ?-sheets and investigate their role in large-scale conformational changes. Correlated motions represent a fundamental property of ?-sheets that contributes to protein function.

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protein choreography ? This is not about the physical and chemical properties of the individual proteins, not even about the physical or chemical properties that allow the interactions between proteins, because those properties are the same in all choreographies. The question is mainly about their specific coordinated arrangements in space and time, which are different for separate choreographies, so that all things work together to produce the observed specific effects. What steps would it take to put together each of those choreographies? As analogy, the same ballet dancers can appear in different scenes, and also in different ballet choreographies. The same orchestra, with the same musicians playing on the same instruments, and directed by the same conductor, can produce totally different ballet choreographies.

The team of scientists have discovered how the motions of various parts of proteins, although physically far apart, are correlated. “The same thing happens to proteins as happens to the choreography of ballet dancers, where the movements of the participants are interconnected in spite of being physically apart. If the first one lifts an arm, the last one lifts an arm too,” described the researcher. http://www.dddmag.com/news/2014/06/scientists’-findings-may-revolutionize-drug-discovery?et_cid=3992150&et_rid=653535995&type=cta

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Can the 3rd. way explain the origin of all these mechanisms, while scientists keep trying to understand what they do and how they function?

Cyclin B2 and p53 control proper timing of centrosome separation Nature Cell Biology 16, 538–549 (2014) doi:10.1038/ncb2952 Published online 28 April 2014 Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B-type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A-mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers.

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The 3rd. way may want to explain the origin of this, while scientists try to understand it well:

The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival NEK2 is a serine/threonine kinase that promotes centrosome splitting and ensures correct chromosome segregation during the G2/M phase of the cell cycle, through phosphorylation of specific substrates. Aberrant expression and activity of NEK2 in cancer cells lead to dysregulation of the centrosome cycle and aneuploidy. Thus, a tight regulation of NEK2 function is needed during cell cycle progression. In this study, we found that NEK2 localizes in the nucleus of cancer cells derived from several tissues. In particular, NEK2 co-localizes in splicing speckles with SRSF1 and SRSF2. Moreover, NEK2 interacts with several splicing factors and phosphorylates some of them, including the oncogenic SRSF1 protein. Overexpression of NEK2 induces phosphorylation of endogenous SR proteins and affects the splicing activity of SRSF1 toward reporter minigenes and endogenous targets, independently of SRPK1. Conversely, knockdown of NEK2, like that of SRSF1, induces expression of pro-apoptotic variants from SRSF1-target genes and sensitizes cells to apoptosis. Our results identify NEK2 as a novel splicing factor kinase and suggest that part of its oncogenic activity may be ascribed to its ability to modulate alternative splicing, a key step in gene expression regulation that is frequently altered in cancer cells. http://nar.oxfordjournals.org/content/early/2013/12/24/nar.gkt1307.full

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Hey, they're getting close, almost there. Just a few more things and bingo! they'll have all the missing pieces in the biological puzzle. Then finally, the 3rd. way will have it very easy to explain how this all started. But let's take it easy, no rush, 'poco a poco'. In the meantime, let the scientists continue their research.

Neural Correlates of Feedback Processing in Toddlers External feedback provides essential information for successful learning. Feedback is especially important for learning in early childhood, as toddlers strongly rely on external signals to determine the consequences of their actions. In adults, many electrophysiological studies have elucidated feedback processes using a neural marker called the feedback-related negativity (FRN). The neural generator of the FRN is assumed to be the ACC, located in medial frontal cortex. As frontal brain regions are the latest to mature during brain development, it is unclear when in early childhood a functional feedback system develops. Is feedback differentiated on a neural level in toddlers and in how far is neural feedback processing related to children's behavioral adjustment? In an EEG experiment, we addressed these questions by measuring the brain activity and behavioral performance of 2.5-year-old toddlers while they played a feedback-guided game on a touchscreen. Electrophysiological results show differential brain activity for feedback with a more negative deflection for incorrect than correct outcomes, resembling the adult FRN. This provides the first neural evidence for feedback processing in toddlers. Notably, FRN amplitudes were predictive of adaptive behavior: the stronger the differential brain activity for feedback, the better the toddlers' adaptive performance during the game. Thus, already in early childhood toddlers' feedback-guided performance directly relates to the functionality of their neural feedback processing. Implications for early feedback-based learning as well as structural and functional brain development are discussed. Journal of Cognitive Neuroscience July 2014, Vol. 26, No. 7, Pages 1519-1527 Posted Online May 29, 2014. (doi:10.1162/jocn_a_00560) © 2014 Massachusetts Institute of Technology

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Another simple neuroscience case. Maybe the 3rd. way can explain the origin of this, while scientists continue to research the mechanisms behind the functionality of all this stuff?

Medial-lateral Organization of the Orbitofrontal Cortex Emerging evidence suggests that specific cognitive functions localize to different subregions of OFC, but the nature of these functional distinctions remains unclear. One prominent theory, derived from human neuroimaging, proposes that different stimulus valences are processed in separate orbital regions, with medial and lateral OFC processing positive and negative stimuli, respectively. Thus far, neurophysiology data have not supported this theory. We attempted to reconcile these accounts by recording neural activity from the full medial-lateral extent of the orbital surface in monkeys receiving rewards and punishments via gain or loss of secondary reinforcement. We found no convincing evidence for valence selectivity in any orbital region. Instead, we report differences between neurons in central OFC and those on the inferior-lateral orbital convexity, in that they encoded different sources of value information provided by the behavioral task. Neurons in inferior convexity encoded the value of external stimuli, whereas those in OFC encoded value information derived from the structure of the behavioral task. We interpret these results in light of recent theories of OFC function and propose that these distinctions, not valence selectivity, may shed light on a fundamental organizing principle for value processing in orbital cortex. Journal of Cognitive Neuroscience July 2014, Vol. 26, No. 7, Pages 1347-1362 Posted Online May 29, 2014. (doi:10.1162/jocn_a_00573) © 2014 Massachusetts Institute of Technology

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The 3rd. Way shouldn't run out of work, even if all they will do is try to explain the origin of the biological systems, while the scientists try to understand better how those systems function. Here's an easy one to start from:

Different Neural Networks Are Involved in Audiovisual Speech Perception Depending on the Context How are we able to easily and accurately recognize speech sounds despite the lack of acoustic invariance? One proposed solution is the existence of a neural representation of speech syllable perception that transcends its sensory properties. In the present fMRI study, we used two different audiovisual speech contexts both intended to identify brain areas whose levels of activation would be conditioned by the speech percept independent from its sensory source information. We exploited McGurk audiovisual fusion to obtain short oddball sequences of syllables that were either (a) acoustically different but perceived as similar or (b) acoustically identical but perceived as different. We reasoned that, if there is a single network of brain areas representing abstract speech perception, this network would show a reduction of activity when presented with syllables that are acoustically different but perceived as similar and an increase in activity when presented with syllables that are acoustically similar but perceived as distinct. Consistent with the long-standing idea that speech production areas may be involved in speech perception, we found that frontal areas were part of the neural network that showed reduced activity for sequences of perceptually similar syllables. Another network was revealed, however, when focusing on areas that exhibited increased activity for perceptually different but acoustically identical syllables. This alternative network included auditory areas but no left frontal activations. In addition, our findings point to the importance of subcortical structures much less often considered when addressing issues pertaining to perceptual representations. Journal of Cognitive Neuroscience July 2014, Vol. 26, No. 7, Pages 1572-1586 Posted Online May 29, 2014. (doi:10.1162/jocn_a_00565) © 2014 Massachusetts Institute of Technology

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To the 3rd. way: where did these mechanisms come from? How? To the researchers: how do these mechanisms work?

gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size Nature Communications 5, Article number: 3885 doi:10.1038/ncomms4885 Published 30 May 2014 Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly.

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While scientists try to understand this mystery, the 3rd. Way could try to explain the origin of the mysterious mechanisms.

Where Have All the Mitochondria Gone? It’s common knowledge that all organisms inherit their mitochondria—the cell’s “power plants”—from their mothers. But what happens to all the father’s mitochondria? Surprisingly, how—and why—paternal mitochondria are prevented from getting passed on to their offspring after fertilization is still shrouded in mystery; the only thing that’s certain is that there must be a compelling reason, seeing as this phenomenon has been conserved throughout evolution. Now, Dr. Eli Arama and a team in the Weizmann Institute’s Molecular Genetics Department have discovered special cellular vesicles that originate in the female fruit flies’ egg and which actively seek out and destroy the father’s mitochondria upon fertilization. http://www.biosciencetechnology.com/videos/2014/05/where-have-all-mitochondria-gone

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While scientists try to understand these complex mechanisms, the 3rd. way folks could try to explain the origin of those mechanisms.

Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing Hongqing Liang, Nature Communications 5, Article number: 4048 doi:10.1038/ncomms5048 Published 04 June 2014 The G2 checkpoint monitors DNA damage, preventing mitotic entry until the damage can be resolved. The mechanisms controlling checkpoint recovery are unclear. Here, we identify non-genetic heterogeneity in the fidelity and timing of damage-induced G2 checkpoint enforcement in individual cells from the same population. Single-cell fluorescence imaging reveals that individual damaged cells experience varying durations of G2 arrest, and recover with varying levels of remaining checkpoint signal or DNA damage. A gating mechanism dependent on polo-like kinase-1 (PLK1) activity underlies this heterogeneity. PLK1 activity continually accumulates from initial levels in G2-arrested cells, at a rate inversely correlated to checkpoint activation, until it reaches a threshold allowing mitotic entry regardless of remaining checkpoint signal or DNA damage. Thus, homeostatic control of PLK1 by the dynamic opposition between checkpoint signalling and pro-mitotic activities heterogeneously enforces the G2 checkpoint in each individual cell, with implications for cancer pathogenesis and therapy.

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recent email to The 3rd. Way:

Sent: ?Thu, ?Jun? ?5?, ?2014 at ?5?:?53? ?AM To: mail@thethirdwayofevolution.com Subject: FYI- Your 3rd. Way is a discussion topic in the UD blog. Hello! Your initiative seems very interesting. FYI- Your 3rd. Way is a discussion topic in this blog: https://uncommondescent.com/evolution/a-third-way-of-evolution/#comment-502812 I want to share with you several comments I have posted in that particular discussion thread. However, the thread about your new blog does not seem like attracting as much attention (visitors) as other topics in the same blog. The majority of the comments in that thread have been mine. At this point I'm more interested in learning how certain biological systems work, not how they originated. But it's interesting to look at the origin discussion from the side, at least from time to time. Kind regards.

My enormous science-related ignorance compels me to respect the members of The Third Way and recognize their tremendous scientific knowledge and academic experience. Seriously would like to read their opinions within the ongoing 'origin' debate. However, I'm more interested in learning about the way certain biological systems function in their current state, not how they originated. I strongly believe science should focus in on trying to understand very well how biological systems work, so better medical treatments and preventive programs can be developed and implemented soon. Can the 'origin' discussion produce comparable benefits? Fortunately, most scientists are busy working on interesting research projects that should discover more details about the wonderful biological systems. Dionisio

Can the 3rd. Way explain the origin of the 'right' route(s) to bipolarity and the rest of these mechanisms? In the meantime, scientists could work on trying to understand how they work and what could mess them up.

Mitotic spindle multipolarity without centrosome amplification Nature Cell Biology 16, 386–394 (2014) doi:10.1038/ncb2958 Published online 02 May 2014 Mitotic spindle bipolarity is essential for faithful segregation of chromosomes during cell division. Multipolar spindles are often seen in human cancers and are usually associated with supernumerary centrosomes that result from centrosome over-duplication or cytokinesis failure. A less-understood path to multipolar spindle formation may arise due to loss of spindle pole integrity in response to spindle and/or chromosomal forces. Here we discuss the different routes leading to multipolar spindle formation, focusing on spindle multipolarity without centrosome amplification. We also present the distinct and common features between these pathways and discuss their therapeutic implications.

Dionisio

Can the 3rd. Way figure out how to explain the origin of these mechanisms, while scientists try to understand their effect and how they work?

Cargo recognition and trafficking in selective autophagy Nature Cell Biology 16, 495–501 (2014) doi:10.1038/ncb2979 Published online 30 May 2014 Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways.

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Can the 3rd. Way explain the origin of these mechanisms? In the meantime, scientists can work hard on trying to understand how these mechanisms work.

The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification Nature Cell Biology 16, 516–528 (2014) doi:10.1038/ncb2965 Published online 25 May 2014 The precise relationship of embryonic stem cells (ESCs) to cells in the mouse embryo remains controversial. We present transcriptional and functional data to identify the embryonic counterpart of ESCs. Marker profiling shows that ESCs are distinct from early inner cell mass (ICM) and closely resemble pre-implantation epiblast. A characteristic feature of mouse ESCs is propagation without ERK signalling. Single-cell culture reveals that cell-autonomous capacity to thrive when the ERK pathway is inhibited arises late during blastocyst development and is lost after implantation. The frequency of deriving clonal ESC lines suggests that all E4.5 epiblast cells can become ESCs. We further show that ICM cells from early blastocysts can progress to ERK independence if provided with a specific laminin substrate. These findings suggest that formation of the epiblast coincides with competence for ERK-independent self-renewal in vitro and consequent propagation as ESC lines.

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The 3rd. Way may try to explain the origin of this, while scientists try to understand how this works. The latter is what may help for medical advance, hence research should focus in on that area.

A centrosomal route for cancer genome instability Nature Cell Biology 16, 504–506 (2014) doi:10.1038/ncb2978 Published online 30 May 2014 Despite the widespread occurrence of aneuploidy in cancer cells, the molecular causes for chromosomal instability are not well established. Cyclin B2 is now shown to control a pathway — involving the centrosomal kinases aurora A and Plk1 and the tumour suppressor p53 — the alteration of which causes defective centrosome separation, aneuploidy and tumour development.

Dionisio

The 3rd. Way may try to explain the origin of this, while scientists try to understand how this works. Is the latter by far more important for medical advance? Is the former just to fuel the ongoing philosophical debates?

Somatic Guidance for the Oocyte DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.006 The capacity of oocytes to support embryo development and a healthy pregnancy is dependent on complex and poorly understood interactions with the somatic cells that enclose it during its development.

Dionisio

Can the 3rd. way explain the origin of this, while scientists try to understand how it works?

Synergy between Multiple Microtubule-Generating Pathways Confers Robustness to Centrosome-Driven Mitotic Spindle Formation DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.001 •Chromosome-driven MT generation exists in embryos and is dependent on D-HURP •Centrosome disruption results in cytoplasmic aMTOCs, driving spindle formation •Augmin generates MTs from centrosomal, chromatin, and aMTOC MTs indiscriminately •Reducing one pathway synergistically increases MT growth of the remaining pathways The mitotic spindle is defined by its organized, bipolar mass of microtubules, which drive chromosome alignment and segregation. Although different cells have been shown to use different molecular pathways to generate the microtubules required for spindle formation, how these pathways are coordinated within a single cell is poorly understood. We have tested the limits within which the Drosophila embryonic spindle forms, disrupting the inherent temporal control that overlays mitotic microtubule generation, interfering with the molecular mechanism that generates new microtubules from preexisting ones, and disrupting the spatial relationship between microtubule nucleation and the usually dominant centrosome. Our work uncovers the possible routes to spindle formation in embryos and establishes the central role of Augmin in all microtubule-generating pathways. It also demonstrates that the contributions of each pathway to spindle formation are integrated, highlighting the remarkable flexibility with which cells can respond to perturbations that limit their capacity to generate microtubules.

Dionisio

Can the 3rd. way explain the origin of this, while scientists try to understand how it works? Piece of cake, isn't it?

APCCdc20 Suppresses Apoptosis through Targeting Bim for Ubiquitination and Destruction DOI: http://dx.doi.org/10.1016/j.devcel.2014.04.022 •Bim expression is repressed during M phase of cell cycle, when Cdc20 is most active •Cdc20 promotes Bim ubiquitination and destruction in a D-box-dependent manner •Hyperactivation of Cdc20 by paclitaxel confers chemoresistance via Bim destruction •Cdc20 knockdown sensitizes cancer cells to chemoradiation via Bim accumulation Anaphase-promoting complex Cdc20 (APCCdc20) plays pivotal roles in governing mitotic progression. By suppressing APCCdc20, antimitotic agents activate the spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APCCdc20 target, such that depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in a small interfering RNA screen that, upon knockdown, sensitizes otherwise resistant cancer cells to chemoradiation in a Bim-dependent manner. Consistently, human adult T cell leukemia cells that acquire elevated APCCdc20 activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APCCdc20 in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.

Dionisio

Can the 3rd. way explain the origin of this?

Developmental Regulation of Microtubule Dynamics DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.007 •MT dynamics can be followed throughout differentiation in situ •MT dynamics are regulated stepwise over the course of differentiation •Distinct MAPs are required for tissue biogenesis and tissue function •Selective MT dynamics are required in proliferative versus differentiated cells Microtubules (MTs) are cytoskeletal polymers that undergo dynamic instability, the stochastic transition between growth and shrinkage phases. MT dynamics are required for diverse cellular processes and, while intrinsic to tubulin, are highly regulated. However, little is known about how MT dynamics facilitate or are regulated by tissue biogenesis and differentiation. We imaged MT dynamics in a smooth muscle-like lineage in intact developing Caenorhabditis elegans. All aspects of MT dynamics change significantly as stem-like precursors exit mitosis and, secondarily, as they differentiate. We found that suppression, but not enhancement, of dynamics perturbs differentiated muscle function in vivo. Distinct ensembles of MT-associated proteins are specifically required for tissue biogenesis versus tissue function. A CLASP family MT stabilizer and the depolymerizing kinesin MCAK are differentially required for MT dynamics in the precursor or differentiated cells, respectively. All of these multidimensional phenotypic comparisons were facilitated by a data display method called the diamond graph.

Dionisio

Can the 3rd. Way explain the origin of this, while scientists try to understand how this actually works?

A Microtubule-Associated Zinc Finger Protein, BuGZ, Regulates Mitotic Chromosome Alignment by Ensuring Bub3 Stability and Kinetochore Targeting DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.013 •BuGZ regulates kinetochore-microtubule interaction via Bub3 •BuGZ and Bub3 form a complex of equal stoichiometry •BuGZ uses its GLEBS motif to bind and stabilize Bub3 •The microtubule-binding domain of BuGZ facilitates Bub3 loading onto kinetochores Equal chromosome segregation requires proper assembly of many proteins, including Bub3, onto kinetochores to promote kinetochore-microtubule interactions. By screening for mitotic regulators in the spindle envelope and matrix (Spemix), we identify a conserved Bub3 interacting and GLE-2-binding sequence (GLEBS) containing ZNF207 (BuGZ) that associates with spindle microtubules and regulates chromosome alignment. Using its conserved GLEBS, BuGZ directly binds and stabilizes Bub3. BuGZ also uses its microtubule-binding domain to enhance the loading of Bub3 to kinetochores that have assumed initial interactions with microtubules in prometaphase. This enhanced Bub3 loading is required for proper chromosome alignment and metaphase to anaphase progression. Interestingly, we show that microtubules are required for the highest kinetochore loading of Bub3, BubR1, and CENP-E during prometaphase. These findings suggest that BuGZ not only serves as a molecular chaperone for Bub3 but also enhances its loading onto kinetochores during prometaphase in a microtubule-dependent manner to promote chromosome alignment.

Dionisio

Can the third way explain the origin of this?

BuGZ Is Required for Bub3 Stability, Bub1 Kinetochore Function, and Chromosome Alignment DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.014 •BuGZ is a kinetochore protein that binds to and stabilizes Bub3 •BuGZ localizes to the kinetochore and binds to Bub3 through a conserved GLEBS domain •BuGZ depletion in transformed cells results in severe chromosome alignment defects •Inhibiting Bub3’s GLEBS domain interactions may be a therapeutic strategy for GBM Summary During mitosis, the spindle assembly checkpoint (SAC) monitors the attachment of kinetochores (KTs) to the plus ends of spindle microtubules (MTs) and prevents anaphase onset until chromosomes are aligned and KTs are under proper tension. Here, we identify a SAC component, BuGZ/ZNF207, from an RNAi viability screen in human glioblastoma multiforme (GBM) brain tumor stem cells. BuGZ binds to and stabilizes Bub3 during interphase and mitosis through a highly conserved GLE2p-binding sequence (GLEBS) domain. Inhibition of BuGZ results in loss of both Bub3 and its binding partner Bub1 from KTs, reduction of Bub1-dependent phosphorylation of centromeric histone H2A, attenuation of KT-based Aurora B kinase activity, and lethal chromosome congression defects in cancer cells. Phylogenetic analysis indicates that BuGZ orthologs are highly conserved among eukaryotes, but are conspicuously absent from budding and fission yeasts. These findings suggest that BuGZ has evolved to facilitate Bub3 activity and chromosome congression in higher eukaryotes.

Dionisio

Can the 3rd. way explain the origin of this?

A Protective Chaperone for the Kinetochore Adaptor Bub3 Zhejian Ji, Hongtao Yu DOI: http://dx.doi.org/10.1016/j.devcel.2014.01.024 two complementary studies by Jiang et al. (2014) and Toledo et al. (2014) identify BuGZ as an interacting protein of the kinetochore adaptor Bub3 and show that it promotes the stabilization and kinetochore loading of Bub3, chromosome alignment, and mitotic progression.

Dionisio

Can the 3rd. Way explain the origin of this? [although science is busy trying to understand just how this works]

Rab11 Endosomes Contribute to Mitotic Spindle Organization and Orientation Heidi Hehnly, Stephen Doxsey DOI: http://dx.doi.org/10.1016/j.devcel.2014.01.014 Highlights •Endosomes are not rendered inactive during mitosis as previously envisioned •Endosomes are MT-nucleating, MT-anchoring, and spindle pole material carriers •Rab11 regulates mitotic progression and spindle symmetry •Rab11 activity regulates astral microtubule organization Summary During interphase, Rab11-GTPase-containing endosomes recycle endocytic cargo. However, little is known about Rab11 endosomes in mitosis. Here, we show that Rab11 localizes to the mitotic spindle and regulates dynein-dependent endosome localization at poles. We found that mitotic recycling endosomes bind ?-TuRC components and associate with tubulin in vitro. Rab11 depletion or dominant-negative Rab11 expression disrupts astral microtubules, delays mitosis, and redistributes spindle pole proteins. Reciprocally, constitutively active Rab11 increases astral microtubules, restores ?-tubulin spindle pole localization, and generates robust spindles. This suggests a role for Rab11 activity in spindle pole maturation during mitosis. Rab11 depletion causes misorientation of the mitotic spindle and the plane of cell division. These findings suggest a molecular mechanism for the organization of astral microtubules and the mitotic spindle through Rab11-dependent control of spindle pole assembly and function. We propose that Rab11 and its associated endosomes contribute to these processes through retrograde transport to poles by dynein.

Dionisio

Can the 3rd. Way explain the origin of this?

Spindlegate: The Biological Consequences of Disrupting Traffic Megan M. Gnazzo, Ahna R. Skop DOI: http://dx.doi.org/10.1016/j.devcel.2014.02.014 The function of membrane trafficking during mitosis has become the focus of increasing interest. In this issue of Developmental Cell, Hehnly and Doxsey (2014) provide new insight into the role that endosomes play during spindle assembly.

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Can the 3rd. way folks explain the origin of this?

Asymmetric Friction of Nonmotor MAPs Can Lead to Their Directional Motion in Active Microtubule Networks Scott Forth, Kuo-Chiang Hsia, Yuta Shimamoto, Tarun M. Kapoor DOI: http://dx.doi.org/10.1016/j.cell.2014.02.018 Highlights •Motion along microtubules of non-motor proteins generates friction •Magnitudes of frictional force differ for three proteins needed for cell division •Frictional forces can be anisotropic with respect to filament polarity •Asymmetric friction can lead to motion of proteins in active microtubule networks Summary Diverse cellular processes require microtubules to be organized into distinct structures, such as asters or bundles. Within these dynamic motifs, microtubule-associated proteins (MAPs) are frequently under load, but how force modulates these proteins’ function is poorly understood. Here, we combine optical trapping with TIRF-based microscopy to measure the force dependence of microtubule interaction for three nonmotor MAPs (NuMA, PRC1, and EB1) required for cell division. We find that frictional forces increase nonlinearly with MAP velocity across microtubules and depend on filament polarity, with NuMA’s friction being lower when moving toward minus ends, EB1’s lower toward plus ends, and PRC1's exhibiting no directional preference. Mathematical models predict, and experiments confirm, that MAPs with asymmetric friction can move directionally within actively moving microtubule pairs they crosslink. Our findings reveal how non-motor MAPs can generate frictional resistance in dynamic cytoskeletal networks via micromechanical adaptations whose anisotropy may be optimized for MAP localization and function within cellular structures.

Dionisio

Maybe the 'third way' group can figure out the origin of this?

Friction on MAP Determines Its Traveling Direction on Microtubules Sadanori Watanabe, Gohta Goshima DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.022 Microtubule networks generate various forces, and the forces are applied to microtubule-associated proteins (MAPs). Forth et al. (2014) show in a recent issue of Cell that asymmetric frictional force between MAPs and microtubules leads to directional movement of MAPs along microtubules, providing insight into the mechanism of microtubule network self-organization.

Dionisio

Another task for the 3rd way: find the origin of this:

Exploring the Function of Cell Shape and Size during Mitosis Clotilde Cadart 3, Ewa Zlotek-Zlotkiewicz 3, Maël Le Berre, Matthieu Piel, Helen K. Matthews 3Co-first author DOI: http://dx.doi.org/10.1016/j.devcel.2014.04.009 Dividing cells almost always adopt a spherical shape. This is true of most eukaryotic cells lacking a rigid cell wall and is observed in tissue culture and single-celled organisms, as well as in cells dividing inside tissues. While the mechanisms underlying this shape change are now well described, the functional importance of the spherical mitotic cell for the success of cell division has been thus far scarcely addressed. Here we discuss how mitotic rounding contributes to spindle assembly and positioning, as well as the potential consequences of abnormal mitotic cell shape and size on chromosome segregation, tissue growth, and cancer.

Dionisio

Another question for The Third Way: where did this come from?

Genome Stress Response in Early Development William F. Marzluff, Robert J. Duronio DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.010 Cells with irreparable genomic damage pose a problem for development and must be eliminated to prevent disease. Reporting in this issue of Developmental Cell, Iampietro et al. (2014) describe a mechanism in Drosophila that removes damaged nuclei from syncytial blastoderm embryos via DNA damage checkpoint kinase-mediated retention of specific mRNAs within the nucleus.

Dionisio

More questions for the 3rd. Way folks about origin: how did all this start?

Cell fate can be controlled through asymmetric division and segregation of protein determinants, but the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein-binding protein Lis1 is critically required for hematopoietic stem cell function and leukemogenesis. Conditional deletion of Lis1 (also known as Pafah1b1) in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, real-time imaging revealed that loss of Lis1 caused defects in spindle positioning and inheritance of cell fate determinants, triggering accelerated differentiation. Finally, deletion of Lis1 blocked the propagation of myeloid leukemia and led to a marked improvement in survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. From http://www.nature.com/ng/journal/v46/n3/full/ng.2889.html

Dionisio

What's the origin of these mechanisms?

Structural basis for the inhibition of Polo-like kinase 1 Nature Structural & Molecular Biology 20, 1047–1053 (2013) doi:10.1038/nsmb.2623 Received 13 December 2012 Accepted 30 May 2013 Published online 28 July 2013 Polo-like kinase 1 (PLK1) is a master regulator of mitosis and is considered a potential drug target for cancer therapy. PLK1 is characterized by an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD). The KD and PBD are mutually inhibited, but the molecular mechanisms of the autoinhibition remain unclear. Here we report the 2.3-Å crystal structure of the complex of the Danio rerio KD and PBD together with a PBD-binding motif of Drosophila melanogaster microtubule-associated protein 205 (Map205PBM). The structure reveals that the PBD binds and rigidifies the hinge region of the KD in a distinct conformation from that of the phosphopeptide-bound PBD. This structure provides a framework for understanding the autoinhibitory mechanisms of PLK1 and also sheds light on the activation mechanisms of PLK1 by phosphorylation or phosphopeptide binding. http://www.nature.com/nsmb/journal/v20/n9/full/nsmb.2623.html

Dionisio

The 3rd. Way could work on the origin of this:

Published September 30, 2013 // JCB vol. 202 no. 7 1013-1022 The Rockefeller University Press, doi: 10.1083/jcb.201303141 Copyright © 2013 Report PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells Dorothy A. Lerit and Nasser M. Rusan Centrosomes determine the mitotic axis of asymmetrically dividing stem cells. Several studies have shown that the centrosomes of the Drosophila melanogaster central brain neural stem cells are themselves asymmetric, organizing varying levels of pericentriolar material and microtubules. This asymmetry produces one active and one inactive centrosome during interphase. We identify pericentrin-like protein (PLP) as a negative regulator of centrosome maturation and activity. We show that PLP is enriched on the inactive interphase centrosome, where it blocks recruitment of the master regulator of centrosome maturation, Polo kinase. Furthermore, we find that ectopic Centrobin expression influenced PLP levels on the basal centrosome, suggesting it may normally function to regulate PLP. Finally, we conclude that, although asymmetric centrosome maturation is not required for asymmetric cell division, it is required for proper centrosome segregation to the two daughter cells. http://jcb.rupress.org/content/202/7/1013.long

Dionisio

The 3rd. Way should figure out the origin of this:

the centromeric protein CENP-I cooperates with the Aurora B kinase to control the kinetochore localization of spindle checkpoint proteins. Mad1 and the RZZ complex are critical components of the spindle assembly checkpoint that prevent anaphase onset by binding to kinetochores that aren’t attached to the mitotic spindle correctly. Once spindle microtubules are properly attached, the motor protein dynein strips Mad1 and the RZZ complex away from kinetochores and allows mitosis to proceed. Aurora B helps recruit RZZ and Mad1 to kinetochores in early mitosis, but cells treated with Aurora B inhibitors and the microtubule-depolymerizing drug nocodazole can still activate the spindle checkpoint as long as they express a group of centromeric proteins that includes CENP-I. How CENP-I supports checkpoint activation is unknown, however. Matson and Stukenberg found that CENP-I stabilized RZZ and Mad1’s interaction with kinetochores, limiting their dissociation and preventing dynein from stripping them away prematurely. Thus, when Aurora B activity is lowered by inhibitors, CENP-I helps retain enough RZZ and Mad1 at unattached kinetochores to activate the spindle checkpoint. On the other hand, Aurora B promoted RZZ and Mad1’s association with kinetochores. The kinase’s activity was enhanced by so-called PreK-fibers, microtubule bundles nucleated by the kinetochores themselves. In prometaphase cells lacking the stabilizing influence of CENP-I, checkpoint proteins only accumulated at kinetochores with PreK-fibers and high levels of Aurora B activity. Under normal circumstances, however, Aurora B and CENP-I combine to regulate checkpoint signaling at individual kinetochores according to their microtubule attachment status. Matson, D.R., P.T. Stukenberg . 2014. J. Cell Biol. doi:10.1083/jcb.201307137 http://jcb.rupress.org/content/205/4/430.3

Piece of cake, isn't it? The 3rd. Way folks can figure this out right away ;-) Dionisio

The 3rd. Way should describe how this originated:

The mitotic checkpoint is an important mechanism that prevents aneuploidy by restraining the activity of the anaphase-promoting complex (APC). The deubiquitinase USP44 was identified as a key regulator of APC activation; however, the physiological importance of USP44 and its impact on cancer biology are unknown. From http://www.jci.org/articles/view/63084

Dionisio

The 3rd. Way folks should try hard to heed the rules for valid research:

Oops! stimulus-triggered acquisition of pluripotency (STAP) lead author agrees to retract the work in full. From http://www.the-scientist.com//?articles.view/articleNo/40132/title/Final-Straw-for-STAP-/

Shoddy pseudo-science should not be permitted. Dionisio

The 3rd. Way should figure out the origin of this too:

Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within. Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explained Chay Kuo, an assistant professor of cell biology, neurobiology and pediatrics. From http://www.biosciencetechnology.com/news/2014/06/brain-may-be-able-repair-itself-within?et_cid=3974854&et_rid=653535995&type=cta

Piece of cake, isn't it? Dionisio

The 3rd. Way has to figure out the origin of this, while serious science tries to understand how this works:

During mitosis and meiosis, the spindle assembly checkpoint acts to maintain genome stability by delaying cell division until accurate chromosome segregation can be guaranteed. Accuracy requires that chromosomes become correctly attached to the microtubule spindle apparatus via their kinetochores. When not correctly attached to the spindle, kinetochores activate the spindle assembly checkpoint network, which in turn blocks cell cycle progression. Once all kinetochores become stably attached to the spindle, the checkpoint is inactivated, which alleviates the cell cycle block and thus allows chromosome segregation and cell division to proceed. Here we review recent progress in our understanding of how the checkpoint signal is generated, how it blocks cell cycle progression and how it is extinguished. From http://www.ncbi.nlm.nih.gov/pubmed/23174302

Dionisio

The 3td. Way should find the origin of this:

With the goal of creating two genetically identical daughter cells, cell division culminates in the equal segregation of sister chromatids. This phase of cell division is monitored by a cell cycle checkpoint known as the spindle assembly checkpoint (SAC). The SAC actively prevents chromosome segregation while one or more chromosomes, or more accurately kinetochores, remain unattached to the mitotic spindle. Such unattached kinetochores recruit SAC proteins to assemble a diffusible anaphase inhibitor. Kinetochores stop production of this inhibitor once microtubules (MTs) of the mitotic spindle are bound, but productive attachment of all kinetochores is required to satisfy the SAC, initiate anaphase, and exit from mitosis. Although mechanisms of kinetochore signaling and SAC inhibitor assembly and function have received the bulk of attention in the past two decades, recent work has focused on the principles of SAC silencing. Here, we review the mechanisms that silence SAC signaling at the kinetochore, and in particular, how attachment to spindle MTs and biorientation on the mitotic spindle may turn off inhibitor generation. Future challenges in this area are highlighted towards the goal of building a comprehensive molecular model of this process. From http://www.ncbi.nlm.nih.gov/pubmed/22782189

Piece of cake, isn't it? ;-) Dionisio

Is the second way associated with the scandalous extrapolation of the adaptability mechanisms observed in the Galapagos finch population in the mid 19th century? Dionisio

The First Way doesn't have to figure out the origin of anything, because it is written in their ancient book: Genesis 1:1 And was also written by the people of The Way* in their book: John 1:1-4 (*) The Way is related to The First Way and The Only Way. Dionisio

First science should figure out how all these complex things work, before worrying about how they came to be. The 3rd. Way can work on the latter part.

In eukaryotes, chromosome segregation during cell division is facilitated by the kinetochore, a multiprotein structure that is assembled on centromeric DNA. The kinetochore attaches chromosomes to spindle microtubules, modulates the stability of these attachments and relays the microtubule-binding status to the spindle assembly checkpoint (SAC), a cell cycle surveillance pathway that delays chromosome segregation in response to unattached kinetochores. Recent studies are shaping current thinking on how each of these kinetochore-centred processes is achieved, and how their integration ensures faithful chromosome segregation, focusing on the essential roles of kinase-phosphatase signalling and the microtubule-binding KMN protein network. From http://www.ncbi.nlm.nih.gov/pubmed/23258294

"Recent studies are shaping current thinking on how... and how..." The Energizer bunny ad comes to mind, doesn't it? Dionisio

Since the first and second ways can't figure out the origin of all that complicated stuff, maybe the third way will do it? If not, then someone will come up with a fourth way. Or a fifth, sixth, seventh way? With the data avalanche flooding bioinformatics centers, and more data coming out of research labs at an increasing rate, they should have plenty of information to figure it out. Or could this all be part of the unending revelation of the ultimate reality? Dionisio

The 3rd. Way should be able to figure out the origin of this:

Specialised chromatin in which canonical histone H3 is replaced by CENP-A, an H3 related protein, is a signature of active centromeres and provides the foundation for kinetochore assembly. The location of centromeres is not fixed since centromeres can be inactivated and new centromeres can arise at novel locations independently of specific DNA sequence elements. Therefore, the establishment and maintenance of CENP-A chromatin and kinetochores provide an exquisite example of genuine epigenetic regulation. The composition of CENP-A nucleosomes is contentious but several studies suggest that, like regular H3 particles, they are octamers. Recent analyses have provided insight into how CENP-A is recognised and propagated, identified roles for post-translational modifications and dissected how CENP-A recruits other centromere proteins to mediate kinetochore assembly. From http://www.ncbi.nlm.nih.gov/pubmed/24529245

Dionisio

The 3rd. Way should figure out the origin of this: http://jcb.rupress.org/content/205/4/430.3 Dionisio

The 3rd. Way should be able to explain the origin of this:

Postnatal and adult subventricular zone (SVZ) neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular and niche-driven cues. Although behavioral experiments and disease states have suggested possibilities for higher level inputs, it is unknown whether neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We identified a previously unknown population of choline acetyltransferase (ChAT)+ neurons residing in the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts and released acetylcholine locally in an activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo indicated that they were necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with fibroblast growth factor receptor activation to increase neuroblast production. These results reveal an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control and suggest possibilities for modulating neuroregenerative capacities in health and disease. From http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3734.html

Dionisio

The 3rd. Way should be able to explain the origin of this: http://www.biosciencetechnology.com/news/2014/06/brain-may-be-able-repair-itself-within?et_cid=3974854&et_rid=653535995&type=cta Dionisio

Moose Dr, you made the point i was thinking about... I read about James Shapiro's natural genetic engineering (NGE) (and the third way idea by the way) about a year ago (here's that article, by the way - http://new.bostonreview.net/BR22.1/shapiro.html ). Indeed how is the existence of such an ability as NGE explained? It's not simply a program contained somewhere in DNA or elsewhere, it possesses properties of intelligence! It can act purposefully, it can create new functional information... Is it the new hero who can turn frogs into princesses? And how did that amazing NGE come about? Will the answer be "by chance"? Lesia

The notable thing here is that pro evolution researchers are admitting their is important problems with evolution. Surely creationisms influence is having a effect. they say there is a third way but thats not a hypothesis yet. in fact the bible simply is fine still and dArwin s is coming unglued in modern times. yes there are other mechanisms in biology not yet discovered as God did all creation on week one. yEt biology has done great things since. People looks being case in point. these people are okay to frustrate evolution but still they are not sharp enough to see YEC/ID are the ones actually on the right trail. i'm not sending money. Robert Byers

What an intriguing concept. I presume that the "third way" is that somehow simple life "evolved" the ability to strategically edit their own DNA. Of course they did so before the development of the Eukaryota. No problem. Perfectly reasonable. Moose Dr

Or they could consider IDvolution.org - God “breathed” the super language of DNA into the “kinds” in the creative act. This accounts for the diversity of life we see. The core makeup shared by all living things have the necessary complex information built in that facilitates rapid and responsive adaptation of features and variation while being able to preserve the “kind” that they began as. Life has been created with the creativity built in ready to respond to triggering events. Since it has been demonstrated that all living organisms on Earth have the same core, it is virtually certain that living organisms have been thought of AT ONCE by the One and the same Creator endowed with the super language we know as DNA that switched on the formation of the various kinds, the cattle, the swimming creatures, the flying creatures, etc.. in a pristine harmonious state and superb adaptability and responsiveness to their environment for the purpose of populating the earth that became subject to the ravages of corruption by the sin of one man (deleterious mutations). IDvolution considers the latest science and is consistent with the continuous teaching of the Church. buffalo

Here is another one: http://www.macroevolution.net/ Or is that just evo-devo? Jehu

Nagel's hypothesis largely rests upon his HOPE that their is no Designer. He has explicitly admitted that he does not want there to be a god. OldArmy94

IOW, let's invent a compatibilist evolutionary narrative because we need to steal some concepts otherwise unavailable to materialist/physicalist/naturalist ideology. William J Murray

There is no third way to explain evolution, and I doubt (though I am of course just speculating) any of these scientists really believe they are going to find a reasonable scientific explanation apart from Darwinism or design: we are not talking about explaining earthquakes, for goodness sakes, we are talking about explaining hearts, lungs, brains and human consciousness! They just realize that Darwinism is nonsense are honest enough to admit it, but can't accept design as a scientific theory (or in some cases perhaps, just don't want to admit it publically---again I am speculating, based on personal conversations with other scientists and mathematicians). So I think the third "way" is not really a third way to explain evolution, it is a third way to talk about it: admit you don't understand evolution, but don't accept design. And yes, we should certainly welcome these people, admitting that you don't know something when you really don't know is a refreshing new "way" to talk about evolution. Granville Sewell