Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. The classical cell cycle regulatory pRb/E2f pathway has emerged as an important effector of fate decisions in a number of cell types, including in the brain. The cell cycle machinery is a pivotal regulator of brain development and function by influencing key cell fate decisions, typically via E2f transcription factor activity. E2f transcription factors are poised as widespread regulators of cell fate-associated genes in NPCs, establishing a pervasive direct role for the cell cycle machinery in fate determination, and E2f3 is associated with specialized, tissue-specific differentiation programs. This finding underscores the importance of identifying factor-specific targets in an unbiased manner to fully appreciate the genetic mechanisms driving biological phenomena. [...] in cells that are actively making stem cell fate decisions, pRb/E2f factors can direct these decisions independently from cell cycle regulation [...] through direct regulation of networks of cell fate-associated genes. We unexpectedly* identified Ctcf as a potential regulatory co-factor for E2f3 at differentiation genes in NPCs. More functional analyses are required to determine if this association is unique to NPCs or is more widespread, and to clarify how Ctcf–E2f interactions impact transcription. We were also surprised** to observe that E2f3 binds target sites in a highly tissue-specific manner in NPCs compared with MBs. It will be important for future studies to examine E2f3a&b binding patterns in other tissue and cell types to reveal the extent by which E2f3 may function as a determinant of tissue-specific differentiation programs***.
Tissue-specific targeting of cell fate regulatory genes by E2f factors. Julian LM1, Liu Y2, Pakenham CA1, Dugal-Tessier D1, Ruzhynsky V1, Bae S3, Tsai SY3, Leone G3, Slack RS1, Blais A2. Cell Death Differ.;23(4):565-75. doi: 10.1038/cdd.2015.36. http://www.nature.com/cdd/journal/v23/n4/full/cdd201536a.html

(*) unexpectedly? (**) surprised? (***) differentiation programs? 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.Dionisio_{April 4, 2016
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Paired box (Pax) genes encode for transcription factors that are considered key players in organogenesis and embryonic development. The importance of alternative splicing as a mechanism for divergent evolution* is established. [...] a mechanism through which alternative splicing contributes to the increase of complexity at the level of protein function. [...] the exact junction sequence between exon 2 and intron 2 is not known [...] [...] an important re-arrangement of coding and non-coding sequences in the region of paired domain took place during evolution*. Introns are required for alternative splicing and alternative splicing increases the size of the proteome, thus increasing the level of complexity in higher eukaryotes. Moreover, introns have been found to harbor many conserved non-coding elements, necessary for gene regulation. [...] at this stage, it is not easy to conclude as to the regulation of these isoforms. Nonetheless there is an indication of a temporal regulation [...], which requires further investigation.
Pax2/5/8 and Pax6 alternative splicing events in basal chordates and vertebrates: a focus on paired box domain Peter Fabian, Iryna Kozmikova, Zbynek Kozmik and Chrysoula N. Pantzartzi* Front. Genet., http://dx.doi.org/10.3389/fgene.2015.00228 http://journal.frontiersin.org/article/10.3389/fgene.2015.00228/full

(*) [how? what determined the sequence of cut&paste steps? what triggered it? what stopped it?] 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.Dionisio_{April 4, 2016
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While advances over the past few years have greatly expanded our view of the functional importance of transcriptional regulation by E2Fs and PPs, the mechanistic understanding of their role in stem cell fate regulation is in its infancy. We need a better understanding of which stem cell populations rely on E2F/PP activity when making key cell fate decisions, as well as which epigenetic co-factors contribute to gene class and cell type-specific gene expression. [...] it will be important [...] to understand the full extent of E2F/PP function in stem cell fate control. [...] will shed important mechanistic insight on the epigenetic role of E2Fs/PPs in cell fate decision making. An important question for future investigations, which is currently largely unaddressed, is how E2Fs and PPs may regulate cell fate genes in post-mitotic cells. Gaining a clearer understanding of the mechanisms underlying epigenetic cell fate regulation by E2Fs/PPs by addressing these key questions will have important implications in the contexts of tumorigenesis and disease, development, tissue homeostasis, and regeneration.
Transcriptional control of stem cell fate by E2Fs and pocket proteins Lisa M. Julian1,* and Alexandre Blais2,3,* Front Genet. 6: 161. doi: 10.3389/fgene.2015.00161 http://journal.frontiersin.org/article/10.3389/fgene.2015.00161/full

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The CRISPR–Cas9 system holds the potential to revolutionize developmental biology by making it possible to probe with exquisite control the interplay between genome activity and developmental events such as cell proliferation, differentiation, and morphogenesis.
A CRISPR view of development Melissa M. Harrison1, Brian V. Jenkins2, Kate M. O’Connor-Giles3,4 and Jill Wildonger2 10.1101/gad.248252.114 Genes & Dev. 28: 1859-1872 http://genesdev.cshlp.org/content/28/17/1859.full

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Coordination of differentiation and cell cycle progression represents an essential process for embryonic development and adult tissue homeostasis. These mechanisms ultimately determine the quantities of specific cell types that are generated. Despite their importance, the precise molecular interplays between cell cycle machinery and master regulators of cell fate choice remain to be fully uncovered. [...] cell cycle regulators can orchestrate cell fate decisions by organising transcriptional networks in human stem cells. [...] E2F factors could orchestrate stem cell and progenitor differentiation in a diversity of tissues, underlining that cell cycle control of cell fate choice could be a common mechanism between a diversity of progenitors. [...] the basic mechanisms uncovered by these studies could also be relevant for adult stem cells and represent an important step toward understanding the balance between differentiation and self-renewal during organ development and repair
Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D Siim Pauklin,1 Pedro Madrigal,1,2 Alessandro Bertero,1 and Ludovic Vallier1, Genes Dev.; 30(4): 421–433. doi: 10.1101/gad.271452.115 http://genesdev.cshlp.org/content/30/4/421.full

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Gastrulation is a critical milestone of early embryogenesis in mammals when the primary germ layers are formed and the multipotent embryonic cells are allocated to the progenitors of tissue lineages within the germ layers. Morphogenesis of the germ layers during gastrulation entails a complex mechanism that regulates the proliferation, movement, and patterning of cell populations, and the choreography of switches in genetic and signaling activity that may drive lineage specification and tissue modeling in the embryo. [...] the molecular controls in time and space that underpin the exit of cells from the multipotent state, the specification of lineage-restricted progenitors and the regionalization of cell fates pertaining to the establishment of the body plan are not fully known. A holistic knowledge of the activity of the genome specifically at gastrulation is essential for gleaning a better understanding of the molecular mechanism for lineage specification and embryonic patterning.
Spatial Transcriptome for the Molecular Annotation of Lineage Fates and Cell Identity in Mid-gastrula Mouse Embryo Guangdun Peng, Shengbao Sue, Jun Chen, Weiyang Chen, Chang Liu, Fang Yu, Ran Wang, Shirui Chen, Na Sun, Guizhong Cui, Lu Song, Patrick P.L. Tam, Jing-Dong J. Han, Naihe Jingo DOI: http://dx.doi.org/10.1016/j.devcel.2016.02.020 Developmental Cell Volume 36, Issue 6, p681–697 http://www.cell.com/developmental-cell/fulltext/S1534-5807(16)30075-2

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Modifications of the ground-state developmental programme are orchestrated by different combinations of MADS-domain transcription factors encoded by floral organ identity genes. [...] much less is known about cell type-specific target genes. [...] the interaction between organ identity genes and general regulators of organ development may produce the overall structure of floral organs on which organ-specific cell types and structures are added or suppressed by interaction with more specialized gene expression programmes. One important next step will be to test how floral organ identity genes modify organ morphology through changes in the temporal or spatial expression patterns of general regulators of shoot development. In the years to come, these approaches may finally give a full understanding of exactly how shoot organs can be ‘metamorphosed’ [...]
Control of patterning, growth, and differentiation by floral organ identity genes Robert Sablowski J. Exp. Bot. (2015) doi: 10.1093/jxb/eru514 http://jxb.oxfordjournals.org/content/early/2015/01/20/jxb.eru514.full

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Floral morphogenesis is the result of the interaction of an elaborate network of factors [...] Amongst the vast variety in flower shapes and colours in nature, most are composed of the same basic four organs arranged in concentric rings or whorls: sepals, petals, stamens and carpels. Of those, only the two internal organs produce gametes – male gametes in pollen produced in stamens, and female gametes within carpels. Once fertilization occurs, carpel tissues develop into the fruit containing the seeds. Future studies will no doubt go on to further test the relationships among these genes in multiple mutant combinations to reveal the effects of this additional redundancy [...]
Duplicate MADS genes with split roles Valérie Hecht J. Exp. Bot. (2016) 67 (6): 1609-1611. doi: 10.1093/jxb/erw086 http://jxb.oxfordjournals.org/content/67/6/1609.full

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The genetic code letters, codons, are in all life forms translated to protein building blocks, amino acids, on ribosomes with the help of tRNAs. [...] the quality of the ensembles of proteins in cells is determined by “error hot spots” in code translation, where amino acid substitutions are frequent. It is conceivable that G:C/C:G base pairs in the first codon position confer stacking free energies that favor U:G mismatched rather than matched base pairs in the second codon position. The question of why middle-position U:G mismatches have much smaller d values when associated with tRNA Glu UUC tRNAUUCGlu and tRNA His GUG tRNAGUGHis than with tRNA Tyr GUA tRNAGUATyr , tRNA Asp GUC tRNAGUCAsp and, in particular, tRNA Lys UUU tRNAUUULys (Table S1), will, however, remain unanswered. This may suggest a general decoding pattern such that the base pair in the first codon position greatly affects the level of discrimination against third codon position mismatches. This hypothesis, which may be a determinant of codon use patterns, will need further testing against larger datasets of translational d values. [...] precious little is known about the stacking interactions in codon–anticodon helices on the ribosome. Understanding the physical chemistry of the tRNA-dependent d-value variations will provide keys to the evolutionary constraints that have led to the present-day design of the tRNAs that translate the genetic code. It is likely that this variation pattern will be extended as our knowledge of cognate codon reading increases. Knowledge of the complete cognate codon reading pattern will be particularly important [...] We are optimistic that the present dataset and its future extensions will serve as an inspiration and testing ground for theoretical approaches to explain the accuracy of codon reading and its idiosyncratic variation with tRNA type and codon context. We do hope that the linear trade-off lines for efficiency and accuracy of genetic code translation will further our understanding of its determinants in the living cell.
Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome Jingji Zhang, Ka-Weng Ieong, Magnus Johansson, and Måns Ehrenberg PNAS, vol. 112 no. 31, 9602–9607, doi: 10.1073/pnas.1506823112 http://www.pnas.org/content/112/31/9602.full

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The circadian clock, an internal timekeeping system, is implicated in the regulation of metabolism and physiology [...] [...] molecular mechanisms and key regulators are mostly unknown.
Transcriptional Control of Antioxidant Defense by the Circadian Clock Sonal A. Patel, Nikkhil S. Velingkaar, and Roman V. Kondratov Antioxid Redox Signal. ; 20(18): 2997–3006. doi: 10.1089/ars.2013.5671 http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5671

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Posttranscriptional modifications at the wobble position of transfer RNAs play a substantial role in deciphering the degenerate genetic code on the ribosome. Modifications of RNA are carried out by complex cellular pathways, which involve countless protein enzymes and catalytic RNA–protein complexes, which primarily target tRNAs and, to a lesser extent, ribosomal RNA and mRNAs. [...] proper understanding of most often subtle fine-tuning effects of tRNA modifications on the codon–anticodon pairing geometries would require advanced experimental system consisting of full-length ligands and complete ribosome. From the observation we can derive both a wider spatial tolerance of the wobble base-pair environment than expected before and, on the other hand, a certain degree of strictness imposed on the base pair, forcing it into the conformation unusual for a relaxed duplex. [...] discrimination between tRNAs is primarily founded on spatial fit rather than on the number of hydrogen bonds between the ‘closed’ decoding centre and the codon–anticodon duplex.
Novel base-pairing interactions at the tRNA wobble position crucial for accurate reading of the genetic code Alexey Rozov, Natalia Demeshkina,Iskander Khusainov, Eric Westhof, Marat Yusupov & Gulnara Yusupova Nature Communications Volume:7,Article number:10457 DOI:doi:10.1038/ncomms10457 http://www.nature.com/ncomms/2016/160121/ncomms10457/full/ncomms10457.html

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Cellular health and growth requires protein synthesis to be both efficient to ensure sufficient production, and accurate to avoid producing defective or unstable proteins. Less is known about the effect of modification on near-cognate decoding and some of that has been controversial. [...] the distinct changes in accuracy reflect an essential difference between the pairs of tRNAs. To understand how modification interferes with near-cognate decoding by these tRNAs structural studies of modified and unmodified tRNAs will be required. A clear understanding of the effect of Q on tRNA Tyr QUA tRNA QUATyr will require solution of the structure of the tRNA bound to A site cognate and near-cognate codons. [...] the effect of anticodon loop modifications depends on their structural context.
Effects of tRNA modification on translational accuracy depend on intrinsic codon–anticodon strength Nandini Manickam, Kartikeya Joshi, Monika J. Bhatt, and Philip J. Firebaugh Nucl. Acids Res. 44 (4): 1871-1881. doi: 10.1093/nar/gkv1506 http://nar.oxfordjournals.org/content/44/4/1871.full

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Nucleotide modifications in the anticodons of transfer RNAs (tRNA) play a central role in translation efficiency, fidelity, and regulation of translation, but, for most of these modifications, the details of their function remain unknown. [...] it remains unclear whether inosine is widely used in eukaryotes to restrict or expand the pairing capacity of A34 containing codons. The reason why stretches of TAPS amino acids are enriched in ADAT-dependent codons remains to be determined.
Distribution of ADAT-Dependent Codons in the Human Transcriptome Àlbert Rafels-Ybern,1 Camille Stephan-Otto Attolini,1 and Lluís Ribas de Pouplana Int. J. Mol. Sci., 16(8), 17303-17314; doi:10.3390/ijms160817303 http://www.mdpi.com/1422-0067/16/8/17303/htm

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The C–U interactions are puzzling because of the close distance between the O2 atoms: 2.9–3.0 Å. C and U, in their classical forms, have carbonyl O atoms in position 2 and their close proximity would give rise to substantial repulsive interactions between them unless a hydrogen atom is present in between. [...] there is a controversy as to whether CUG-BP1 is hyperphosphorylated in the presence of CCUG repeats, so it remains to be determined if PKC is activated by CCUG.
Watson-Crick-like pairs in CCUG repeats: evidence for tautomeric shifts or protonation Wojciech Rypniewski, Katarzyna Banaszak, Tadeusz Kuli?ski and Agnieszka Kiliszek doi: 10.1261/rna.052399.115 RNA 2016. 22: 22-31 http://rnajournal.cshlp.org/content/22/1/22

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The circadian clock is a cellular timekeeping mechanism that helps organisms from bacteria to humans to organize their behaviour and physiology around the solar cycle. Circadian rhythms are ubiquitous biological rhythms with a period of about 24 h that are generated by single-cell molecular clocks. These cellular timing systems orchestrate a multitude of metabolic processes as uncovered by several global surveys of rhythmic transcripts , proteins and metabolites. [...] circadian redox oscillations may originate from a cell-autonomous biochemical oscillator. [...] it is likely that the distinction between circadian and redox pathways will become more and more difficult to define. A recurring theme in chronobiology is the interplay between circadian and metabolic cycles. [...] rhythmic respiration controlled by the clock is likely to feed back onto transcriptional rhythms through redox mechanisms. Understanding further how redox and circadian cycles are coupled together will be of great importance for understanding the basic mechanisms of timekeeping and their integration into cellular physiology. [...] it is plausible that the architecture of the circadian system is based on several layers, including overt circadian rhythms, transcriptional oscillations and redox oscillations [...]
Interplay between cellular redox oscillations and circadian clocks G. Rey and A. B. Reddy* DOI: 10.1111/dom.12519 Diabetes, Obesity and Metabolism Supplement: The Islet and Metabolism Keep Time. Proceedings of the 16th Servier-IGIS Symposium, St Jean Cap Ferrat, France, 9–12 April 2015 Volume 17, Issue Supplement S1, pages 55–64 http://onlinelibrary.wiley.com/doi/10.1111/dom.12519/full

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Peroxiredoxins (Prxs) are a very large and highly conserved family of peroxidases that reduce peroxides, with a conserved cysteine residue, designated the “peroxidatic” Cys (CP) serving as the site of oxidation by peroxides [...] As in all biology, acronyms are overwhelming in Prx literature. Prx acts on muiltiple steps of MAPK signaling pathways in various organisms. The oscillation in 2-Cys Prx–SO2H abundance appears to be a cellular clock output driven by an underlying rhythm in oxidative metabolism. [...] the in vivo relevance of chaperone function is yet to be established.
Overview on Peroxiredoxin Sue Goo Rhee* Mol. Cells 2016; 39(1): 1~5 http://dx.doi.org/10.14348/molcells.2016.2368 http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2016.2368

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Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. Intracellular redox state determines the direction of redox reactions that occur in the cell, and is determined by the balance of pro-oxidants compared with antioxidants. [...] there is good evidence for cellular redox state being circadian regulated. [...] it is premature to conclude there is an important role for redox signalling in the mammalian cellular clock. [...] need to understand the molecular underpinnings of PRX-SO2/3 oscillations – what is the timing mechanism that drives them? Inducible expression/repression models would be of great utility here. [...] there exists great potential for cross fertilisation between research into redox signalling and circadian rhythms. [...] it is of prime importance to establish explicitly whether crosstalk occurs bidirectionally and its mechanism(s), [...] [...] investigating whether the cell interprets a redox signal differently, depending upon the (biological) time of day.
Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal Marrit Putker*, and John Stuart O’Neill* Mol. Cells 2016; 39(1): 6~19 http://dx.doi.org/10.14348/molcells.2016.2323 http://www.molcells.org/journal/view.html?doi=10.14348/molcells.2016.2323

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The mammalian suprachiasmatic nucleus (SCN) drives daily rhythmic behavior and physiology, yet a detailed understanding of its coordinated transcriptional programmes is lacking. The daily cycles of life in mammals are driven by a small region of the brain called the suprachiasmatic nucleus (or SCN). The SCN receives signals from sunlight and other environmental factors to help coordinate most aspects of daily biological activity and behaviour. To work correctly, it is essential that the SCN switches certain genes on and off at exactly the right time. However, many questions remain over the identity of these genes and how their levels of activity change during a 24-hour period. More work is required to determine how the timing or relative level of gene expression mediates these light-induced behavioural changes. [...] oscillations in the SCN transcriptome play an important role in gating the differential responses to light, a fundamental circadian process. The complex relationship between photic and non-photic cues and their relative roles in phase adjustment must also be considered [...] The novel and canonical Cry1 isoforms are expressed in antiphase, as confirmed by qPCR from LCM SCN samples [...], indicating an unanticipated mode of temporal regulation in the SCN for this core clock gene. [...] this first temporal analysis of the SCN using RNA-sequencing reveals the presence of a twin-peaking transcriptional module with a suspected function in circadian control, and identifies thousands of novel transcripts, including a novel Cry1 isoform, which may play important roles in SCN function.
Temporal transcriptomics suggest that twin-peaking genes reset the clock William G Pembroke, Arran Babbs, Kay E Davies,* Chris P Ponting,* and Peter L Oliver* DOI: http://dx.doi.org/10.7554/eLife.10518.001 eLife. 2015; 4: e10518. doi: 10.7554/eLife.10518 http://elifesciences.org/content/4/e10518v2

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[...] the comparison between mpfa and opfa indicated that the translation of PFA in B. amyloliquefaciens was complicated and required further study.
A new strategy to express the extracellular ?-amylase from Pyrococcus furiosus in Bacillus amyloliquefaciens Ping Wang1 n1, Peili Wang1 n1, Jian Tian1, Xiaoxia Yu1, Meihui Chang1, Xiaoyu Chu1 & Ningfeng Wu Scientific Reports 6, Article number: 22229 (2016) doi:10.1038/srep22229 http://www.nature.com/articles/srep22229

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Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms.
Synthetic biology to access and expand nature's chemical diversity Michael J. Smanski,1, 2, Hui Zhou,2, Jan Claesen,3, Ben Shen,4, Michael A. Fischbach3, & Christopher A. Voigt Nature Reviews Microbiology Volume:14, Pages:135–149 (2016)DOI:doi:10.1038/nrmicro.2015.24 http://www.nature.com/nrmicro/journal/v14/n3/full/nrmicro.2015.24.html

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Knowledge of protein 3D structures has significantly accelerated scientific discovery in many research areas, including protein biological function, drug screening and design, and human health and disease. It remains a significant challenge for structural genomics consortiums to crystalize and solve the 3D structures of proteins that possess important biological functions, but are difficult to crystalize. To promote further investigation, the Crysalis design mode integrates several bioinformatics tools to annotate predicted secondary structure elements, residue solvent accessibility, disordered regions, transmembrane regions, functional domains, and conserved sites. [...] may accelerate experimental studies and help to determine the crystal structures of biologically important proteins.
Crysalis: an integrated server for computational analysis and design of protein crystallization Huilin Wang1, Liubin Feng1, Ziding Zhang2, Geoffrey I. Webb3, Donghai Lin1 & Jiangning Song Scientific Reports 6, Article number: 21383 (2016) doi:10.1038/srep21383 http://www.nature.com/articles/srep21383

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[...] the major contribution of Wnt signalling is in induction of the later endodermal marker Sox17 and consolidation of the endoderm gene regulatory network. [...] it may be of interest to explore how the molecular pathways uncovered in this study operate in human cancers. [...] does dysregulation of TCF7L1/FOXA2 lead to loss of differentiated features, [...] ?
Convergence of cMyc and ?-catenin on Tcf7l1 enables endoderm specification Gillian Morrison1,†,*, Roberta Scognamiglio2,3, Andreas Trumpp2,3 and Austin Smith DOI: 10.15252/embj.201592116 The EMBO Journal Volume 35, Issue 3, pages 356–368 http://onlinelibrary.wiley.com/doi/10.15252/embj.201592116/full

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.Dionisio_{March 11, 2016
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It would be of interest in the future to perform live-time imaging studies to track the fate of various TBX3 states to their progeny in pre- and postimplantation embryonic stages. Further studies need to clarify the precise role of TBX3 for germ cell development, particularly in light of the intimate connection between DPPA3/STELLA and TBX3 [...] [...] the intimate connection between TBX3 and DPPA3 remains and needs to be explored in detail in future studies. Our observations of an enriched DNA-methylation signature only in TBX3-null and not in the TBX3-low cells indicate additional epigenetic mechanisms that may be implicated and warrant further investigation [...]
A Dynamic Role of TBX3 in the Pluripotency Circuitry Ronan Russell,1,7 Marcus Ilg,1,7 Qiong Lin,2,7 Guangming Wu,3,7 André Lechel,1 Wendy Bergmann,1 Tim Eiseler,1 Leonhard Linta,4 Pavan Kumar P.,5 Moritz Klingenstein,4 Kenjiro Adachi,3 Meike Hohwieler,1 Olena Sakk,6 Stefanie Raab,4 Anne Moon,5 Martin Zenke,2 Thomas Seufferlein,1 Hans R. Schöler,3 Anett Illing,1,8 Stefan Liebau,4,8 and Alexander Kleger1 DOI: http://dx.doi.org/10.1016/j.stemcr.2015.11.003 http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(15)00339-2

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.Dionisio_{March 11, 2016
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Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. [...] limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. It will be important to define stromal sources of VEGFC. [...] it will be important to define the direct effect of stress on lymphatic vasculature function [...] Further studies using strategies such as cell-specific knockout will be required to assess the effect of ?-adrenergic signalling on these various cell populations and determine their respective contributions to remodelling of lymphatic vasculature. [...] the capacity of anaesthetic sympathectomy to limit tumour cell dissemination or perioperative inflammation is still unclear [...]
Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination Caroline P. Le,1, Cameron J. Nowell,1, Corina Kim-Fuchs,1, 2, Edoardo Botteri,3, Jonathan G. Hiller,4, Hilmy Ismail,4, Matthew A. Pimentel,1, Ming G. Chai,1, Tara Karnezis,5, 6, Nicole Rotmensz,3, Giuseppe Renne,7, Sara Gandini,3, Colin W. Pouton,8, Davide Ferrari,9, Andreas Möller,10, Steven A. Stacker5, 6, & Erica K. Sloan Nature CommunicationsVolume:7,Article number:10634DOI:doi:10.1038/ncomms10634 http://www.nature.com/ncomms/2016/160301/ncomms10634/full/ncomms10634.html

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.Dionisio_{March 11, 2016
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A major endeavor in synthetic biology is to program functions of cells and cell populations in a predictable manner [...] When engineering a circuit, the host cell is typically considered a static “chassis”, or a reactor for the biochemical reactions associated with the circuit function. Depending on environmental conditions, including stress, nutrient, and temperature, many bacteria can form spatial structures consisting of cell aggregates, [...] that allow them to achieve functions beyond the capability of individual cells or homogenous cell populations. [...] this property represents a novel design strategy to engineer sophisticated functions in engineered cell populations. Drawing inspiration from natural systems, we sought to develop a platform technology [...] [...] an essential property of multicellular bacterial structures in nature [...] —a combination of spatial arrangement and dynamic environment sensing.
Coupling spatial segregation with synthetic circuits to control bacterial survival Shuqiang Huang, Anna Jisu Lee, Ryan Tsoi, Feilun Wu, Ying Zhang, Kam W Leong, Lingchong You DOI 10.15252/msb.20156567 Molecular Systems Biology (2016) 12: 859 http://msb.embopress.org/content/12/2/859

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.Dionisio_{March 11, 2016
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"...enormous scientific, engineering and institutional challenges remain."
Advances in sequencing technology have triggered a tsunami of genomic data, and these are joined by waves of information from other '-omics' studies, clinical trials and patient records. Analysis of this big data is launching the era of precision medicine — but enormous scientific, engineering and institutional challenges remain. Big data in biomedicine http://www.nature.com/nature/outlook/big-data/?WT.mc_id=BAN_NA_1511_BIGDATA
Complex complexity. Work in progress... stay tuned.Dionisio_{February 28, 2016
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ER molecular chaperones and folding enzymes are multidomain proteins that are designed to support nascent proteins entering ER lumen to achieve their native conformation, mediate post-translational modification, prevent misfolded protein aggregation, and facilitate exit from the ER. Here, we illustrate the multifunctional nature of many ER associated molecular chaperones and folding enzymes and unique functional overlap of these proteins all designed to support the many functions of the ER membrane. The ER is at the heart of many, if not all cellular processes. As mentioned, the ER is the site of protein folding, post-translational modifications, and QC of secretory and transmembrane proteins, maintaining Ca2+ for signaling, and is involved in ER stress and protein degradation. To help the ER perform these vast and diverse functions, resident ER chaperones work in both in concert to achieve both their general and specialized functions.
The many functions of the endoplasmic reticulum chaperones and folding enzymes Laura Halperin†, Joanna Jung† and Marek Michalak* DOI: 10.1002/iub.1272 IUBMB Life Volume 66, Issue 5, pages 318–326 http://onlinelibrary.wiley.com/doi/10.1002/iub.1272/full

Did anybody say 'designed'? [Emphasis mine]Dionisio_{February 27, 2016
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Oscillatory responses are ubiquitous in regulatory networks of living organisms, a fact that has led to extensive efforts to study and replicate the circuits involved. However, to date, design principles that underlie the robustness of natural oscillators are not completely known. In biomolecular regulatory networks, oscillatory systems control many vital functions, including circadian rhythms [...], glycolysis [...], DNA damage response [...], among others [...] [...] the requirements for robust oscillations in biomolecular networks are yet to be identi?ed. [...] biomolecular regulatory networks often operate under uncertain conditions and considerable levels of biomolecular noise [...] Robustness, the ability of a system to maintain functionality under perturbations, is therefore of paramount importance in any biomolecular regulatory network. [...] there is not yet a thorough and comprehensive set of guidelines for engineering robust oscillators.
Design principles for robust oscillatory behavior Sebastian M. Castillo-Hair, Elizabeth R. Villota, Alberto M. Coronado doi:10.?1007/?s11693-015-9178-6 Systems and Synthetic Biology Volume 9, Issue 3, pp 125-133 http://link.springer.com/article/10.1007/s11693-015-9178-6?no-access=true http://link.springer.com/content/esm/art:10.1007/s11693-015-9178-6/file/MediaObjects/11693_2015_9178_MOESM1_ESM.pdf http://link.springer.com/content/pdf/10.1007%2Fs11693-015-9178-6.pdf http://www.ncbi.nlm.nih.gov/pubmed/26279706

Did anybody say 'design'? :)Dionisio_{February 26, 2016
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The cellular–molecular mechanism for regulating circadian rhythms is located primarily in the suprachiasmatic nuclei (SCN) of the hypothalamus in mammals. The major ‘clock’ genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. The suprachiasmatic nuclei (SCN) of the hypothalamus regulates most circadian rhythms. Melatonin provides a feedback signal to the suprachiasmatic nuclei. Feedback loops control clock genes. A major unanswered question is how melatonin stimulates transcription of the SCN molecular clock genes. Clearly, additional clarification related to the effects of melatonin on feedback of PER/CRY and REV-ERB? on Bmal1 transcription is needed. [...] the circadian interaction of melatonin and the proteasome in the SCN and PT has yet to be fully characterized. Peripheral tissues also contain the classical molecular timing molecules. How does melatonin influence clock genes: translation or transcription? [...] rhythms in the SCN ‘clock’ regulate to some degree rhythms in peripheral tissues. These considerations raise a number of questions concerning the role of melatonin in proteasome-regulated transcription of clock genes.
Melatonin feedback on clock genes: a theory involving the proteasome Jerry Vriend1,* and Russel J. Reiter2 DOI: 10.1111/jpi.12189 Journal of Pineal Research Volume 58, Issue 1, pages 1–11, http://onlinelibrary.wiley.com/doi/10.1111/jpi.12189/full

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.Dionisio_{February 23, 2016
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The beneficial effects of melatonin (N-acetyl-5-methoxytryptamine) on human health are well known and are frequently associated with the attenuation of oxidative damage [1-9]. The protective effects of melatonin against the deleterious effects caused by oxidative stress (OS) are well documented [10-18]. One of the most appealing properties of melatonin, which distinguishes it from most antioxidants, is that its metabolites also have the ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS). The continuous protection exerted by melatonin and its metabolites, referred as the free radical scavenging cascade [19-21], makes melatonin highly effective, even at low concentrations, in protecting organisms from OS [...] [...] melatonin and its metabolite AMK constitute an efficient team of scavengers capable of deactivating a wide variety of ROS, under different conditions.
On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK Annia Galano1,*, Dun Xian Tan2 and Russel J. Reiter2 DOI: 10.1111/jpi.12010 Journal of Pineal Research Volume 54, Issue 3, pages 245–257, http://onlinelibrary.wiley.com/doi/10.1111/jpi.12010/full

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.Dionisio_{February 23, 2016
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