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A third way of evolution?

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That’s the new buzz here:

The vast majority of people believe that there are only two alternative ways to explain the origins of biological diversity. One way is Creationism that depends upon supernatural intervention by a divine Creator. The other way is Neo-Darwinism, which has elevated Natural Selection into a unique creative force that solves all the difficult evolutionary problems. Both views are inconsistent with significant bodies of empirical evidence and have evolved into hard-line ideologies. There is a need for a more open “third way” of discussing evolutionary change based on empirical observations.

Supporters include Shapiro, Noble, Koonin, Neuman, Jablonka—non-Darwin lobby researchers into  evolution. Interested in understanding nature, not getting a judge to agree to enshrine their beliefs in a tax-funded, union-infested school system.

Sounds interesting. Stuff to get started.

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1,283 Responses to A third way of evolution?

  1. 1
    Granville Sewell

    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.

  2. IOW, let’s invent a compatibilist evolutionary narrative because we need to steal some concepts otherwise unavailable to materialist/physicalist/naturalist ideology.

  3. 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.

  4. Here is another one:

    http://www.macroevolution.net/

    Or is that just evo-devo?

  5. 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.

  6. 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.

  7. 7

    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.

  8. 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”?

  9. The 3rd. Way should be able to explain the origin of this:

    http://www.biosciencetechnolog.....8;type=cta

  10. 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/jo......3734.html

  11. The 3rd. Way should figure out the origin of this:

    http://jcb.rupress.org/content/205/4/430.3

  12. 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

  13. 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?

  14. 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?

  15. 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.

  16. Is the second way associated with the scandalous extrapolation of the adaptability mechanisms observed in the Galapagos finch population in the mid 19th century?

  17. 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? 😉

  18. 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

  19. 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.biosciencetechnolog.....8;type=cta

    Piece of cake, isn’t it?

  20. 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//.....for-STAP-/

    Shoddy pseudo-science should not be permitted.

  21. 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

  22. 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 😉

  23. 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

  24. 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/jou......2623.html

  25. 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/journ......2889.html

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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:

    http://www.uncommondescent.com.....ent-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.

  44. 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.

  45. 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.biosciencetechnolog.....ndria-gone

  46. 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.

  47. 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

  48. 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

  49. 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

  50. 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/.....t1307.full

  51. 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.

  52. 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/201.....8;type=cta

  53. 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.

  54. 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]

  55. 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.

  56. 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

  57. 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.

  58. 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

  59. #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.

  60. 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

  61. 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

  62. 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.

  63. 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

  64. 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

  65. 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

  66. 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

  67. 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

  68. 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

  69. 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

  70. 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

  71. 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

  72. 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

  73. 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.

  74. 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.biosciencetechnolog.....ed_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.

  75. 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.

  76. 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.biosciencetechnolog.....cation=top

    Stay tuned, more to come 😉

  77. 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/2.....86791.html

  78. 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)

  79. 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

  80. 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

  81. 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

  82. 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

  83. 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

  84. 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

  85. 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/keyw.....t/4/35184/

  86. 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/keyw.....t/4/34520/

  87. 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-...../81249764/

  88. 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/keyw.....t/4/34678/

  89. 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? 😉

  90. 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/article.....e-on-earth

  91. 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/article.....in-of-life

  92. Human & Chimp DNA Similarities

    http://www.reasons.org/rtb-101.....milarities

  93. 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/sear.....centrosome segregation#gsaccess

  94. 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/sear.....centrosome segregation#gsaccess

  95. 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/sear.....centrosome segregation#gsaccess

  96. 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

  97. 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/keyw.....t/4/35259/

  98. 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

  99. 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

  100. 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

  101. 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.....)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.

  102. 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

  103. 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

  104. 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

  105. 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

  106. “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.biosciencetechnolog.....8;type=cta

  107. 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/keyw.....nt/4/7607/

  108. 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.....8;type=cta

  109. 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.biosciencetechnolog.....cation=top

  110. 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.

  111. “…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

  112. 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

  113. 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

  114. 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/

  115. Transcriptional regulation in development

    http://www.cell-symposia-trans.....e-program/

  116. 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?

  117. 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

  118. 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

  119. 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

  120. 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/cont.....418.2.full

  121. 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

  122. 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

  123. 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]

  124. 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/xmlu.....tribute=en

  125. 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.

  126. 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

  127. 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

  128. 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

  129. 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

  130. 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/

  131. 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

  132. 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.royalsocietypublis.....615f0ead5d

  133. 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.royalsocietypublis.....615f0ead5d

  134. 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.royalsocietypublis.....615f0ead5d

  135. 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.royalsocietypublis.....615f0ead5d

  136. 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.royalsocietypublis.....615f0ead5d

  137. 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.royalsocietypublis.....615f0ead5d

  138. 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

  139. 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.royalsocietypublis.....615f0ead5d

  140. 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.royalsocietypublis.....615f0ead5d

  141. 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.royalsocietypublis.....615f0ead5d

  142. 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

  143. 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.

  144. Dionisio:

    Thank you. I needed this!

  145. 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

  146. gpuccio,

    Glad to know that you can use some information posted in this thread.

  147. 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

  148. #148

    …but little is known about the rules that govern this process.

    Rules that govern?

    Is that related to GP’s procedures?

  149. 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/conte.....db639f3d09

    lasciatemi cantare!

  150. 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.

  151. 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

  152. 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! 🙂

  153. 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/.....7793561769

    Good luck, buddy 😉

  154. 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? 😉

  155. 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!

  156. 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?

  157. 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.

  158. 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?

  159. 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.

  160. 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

  161. 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.royalsocietypublis.....05e50fd13a

  162. cell cycle analysis in vivo

    doi: 10.1098/rsob.140063

    http://rsob.royalsocietypublis.....40063.full

  163. 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

  164. 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

  165. 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

  166. 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

  167. 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

  168. 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.....ed_content

  169. 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

  170. 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

  171. 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/.....arity.html

  172. 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.

  173. 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.

  174. 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/con.....276#ref-45

  175. 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/con......201489466

  176. 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

  177. Apparently, car dealerships now employ ‘motility specialists’, instead of sales people.

  178. Axel,
    Glad to see your comments in this thread!

  179. 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

  180. 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

  181. 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

  182. 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

  183. 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

  184. 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

  185. 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

  186. 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

  187. 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/keyw.....t/4/35184/

  188. 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

  189. Stem cell ageing and non-random chromosome segregation

    http://rstb.royalsocietypublis.....nsion.html

  190. 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.royalsocietypublis.....a545139fe4

  191. maintenance of the Shugoshin Sgo1 at meiotic centromeres does not require Cdc2 activity, whereas localization of the kinase aurora does

    http://rsob.royalsocietypublis.....5c4e6ce2e8

  192. 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.....5/abstract

  193. 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/WileyCD.....EV145.html

  194. 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

  195. 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/conte.....1.abstract

  196. 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.as.....=cellpolar

  197. 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

  198. 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/co.....25.extract

  199. 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/.....94/related

  200. 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/.....65/related

  201. 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/.....11/related

  202. 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/

  203. 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/

  204. 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/j.....12602.html

  205. 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/

  206. 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?

  207. 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/con.....7.abstract

  208. 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

  209. 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/Det.....127c4e2813

  210. 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.....5/full#B28

  211. 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......7.abstract

  212. 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/developmen.....ll%20Press

  213. 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/developmen.....14)00311-6

  214. 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

  215. RE: # 216

    Would like to read GP’s comments on this.

  216. 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.

  217. drc466
    I think I understood your explanation and see your point. Thank you for the comments.

  218. 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.royalsocietypublis.....0fac0be6ef

    7

  219. 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.royalsocietypublis.....bc6e9ab40b

  220. 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.....6/abstract

  221. 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.....9/abstract

  222. 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.....4/abstract

  223. 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.....2/abstract

  224. 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.....6/abstract

  225. 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.....0/abstract

  226. 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.....0/abstract

  227. 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.....12592/full

  228. 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

  229. 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.

  230. 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

  231. 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.

  232. 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

  233. 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

  234. 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-.....ll%20Press

  235. 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.

  236. 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.....ame-forces

  237. 239

    #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.

  238. Silver Asiatic @ 239

    Excellent detailed review of that article!
    Thank you for the insightful comments!

  239. 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/11.....1aa0472954

  240. 243

    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.

  241. A whole conference dedicated mainly to protein folding issues, including chaperones.

    https://secure.faseb.org/FASEB/meetings/summrconf/Programs/11617.pdf

  242. Molecular high-speed origami: Researchers elucidate important mechanism of protein folding

    http://phys.org/news/2014-05-m.....rtant.html

  243. A better understanding of cell to cell communication
    http://phys.org/news/2014-08-cell.html#nRlv

  244. 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-c.....lions.html

  245. 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.

  246. 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/d.....208-092442

  247. 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

  248. 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

  249. 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/con......201489670

  250. 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.....5.abstract

  251. 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.c.....ommitments

  252. 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/con.....1.abstract

  253. 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/.....e_decision

  254. 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

  255. 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

  256. 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/cel.....14)00065-8

  257. 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/cel.....14)00069-5

  258. 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/cel.....14)00062-2

  259. 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

  260. 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.

  261. regulated expression of certain genes during differentiation of some cell types ?

    […]

  262. 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.

  263. 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

  264. 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.

  265. 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.

  266. 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/con......201338114

  267. 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/1906.....ysfunction

  268. 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/2.....75151.html

  269. 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.ne.....89039.html

  270. 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

  271. 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/pu.....checkpoint

  272. 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

  273. 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/

  274. 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.o.....20123.html

  275. 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

  276. 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

  277. 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

  278. 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

  279. 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

  280. 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

  281. Need for multi-scale systems to identify spindle orientation regulators

    doi: 10.3389/fphys.2014.00278

    http://www.ncbi.nlm.nih.gov/pm.....MC4110440/

    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/co.....-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).

  282. 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

  283. 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

  284. Dionisio #286,
    What controls the Hox genes? And what controls the controllers of Hox genes? And …

  285. Dionisio, are they looking for the master-controller? What would that look like? Is such a thing even conceivable?

  286. 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…

  287. 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?

  288. 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]

  289. 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! 🙂

  290. 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?

  291. 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! 😉

  292. 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.

  293. #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.

  294. 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-...../81250296/

  295. Nucleic Acid Rain?

  296. Mung

    Nucleic Acid Rain?

    Did you mean “amino acid” clouds?

    http://ghr.nlm.nih.gov/handboo.....rk/protein

  297. 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/.....fault.aspx

  298. 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.c.....hp?id=1080

  299. 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

  300. #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.

    🙂

  301. 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.royalsocietypublis.....1.abstract

  302. 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!

  303. #306 follow-up

    Sorry, forgot to add the link

    http://app.aaas-science.org/e/.....9275a23527

  304. #303 correction

    Sorry, forgot to include the link

    http://www.jointbscbbs.org/

  305. 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//.....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.

  306. #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_.....062314.php

  307. 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/Co.....fault.aspx

  308. 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

  309. 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

  310. 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

  311. 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

  312. 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

  313. 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

  314. 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

  315. 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

  316. 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

  317. 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

  318. 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

  319. 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/con.....6979c5409e

  320. 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/con.....6979c5409e

  321. 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/con.....4d441b9017

  322. 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/con.....4d441b9017

  323. 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/con.....2e6bfedd87

  324. 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.

  325. 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.

  326. 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.

  327. 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.biosciencetechnolog.....cation=top

  328. 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.biosciencetechnolog.....8;type=cta

  329. 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.....cation=top

  330. 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/.....7f990bb80b

  331. epigenome reorganization during early embryogenesis

    Briefings in Functional Genomics (2014)
    13 (3): 246-253.
    doi: 10.1093/bfgp/elu007

    http://bfg.oxfordjournals.org/.....7f990bb80b

    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.

  332. 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/.....7f990bb80b

  333. Epigenetic regulation of the genome

    Briefings in Functional Genomics (2014)
    13 (3): 203-216.
    doi: 10.1093/bfgp/elt047

    http://bfg.oxfordjournals.org/.....7f990bb80b

  334. 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/.....7f990bb80b

  335. 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/.....0a4e37cccc

  336. 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/.....0a4e37cccc

  337. 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/.....0a4e37cccc

    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.

  338. Chromosome and Kinetochore in Mitosis video

    https://www.youtube.com/embed/0JpOJ4F4984?rel=0

  339. 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/ea.....122cab965b

  340. 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/11.....122cab965b

  341. 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/11......html?etoc

  342. 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/11......html?etoc

  343. 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.

  344. 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/.....0998e03ceb

  345. 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/.....cfe19c039c

  346. 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/.....73957d97ea

  347. 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/.....73957d97ea

  348. 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/.....5/294.full

  349. 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/.....72d5abe451

  350. 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/.....72d5abe451

  351. 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.....00368/full

  352. 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.....1/abstract

  353. 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.physiol.....t/46/9/309

  354. 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.....6/abstract

  355. 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/

  356. 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/

  357. lymphatic cell fate specification pathways

    doi: 10.1242/dev.105031

    http://www.ncbi.nlm.nih.gov/pubmed/24523456

  358. 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.....00049/full

  359. 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/El.....01148.html

  360. 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......2014-1084

  361. 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

  362. 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

  363. 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

  364. Diverse patterns of genomic targeting by transcriptional regulators

    doi: 10.1101/gr.168807.113.

    http://www.ncbi.nlm.nih.gov/pubmed/24985916

  365. 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

  366. 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

  367. 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/ency.....ation.html

  368. (In)sights Into Pluripotency, Cell Fate Specification, and Tissue Formation

    http://www.mskcc.org/events/sk.....-formation

  369. 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/201.....eed-signal

  370. 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/s.....9608616125

  371. 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.

  372. 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?

  373. 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/El.....00786.html

  374. 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/jour.....n3643.html

  375. 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/jour.....n3751.html

  376. 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/jour.....n3579.html

  377. 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/jour.....n3628.html

  378. 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.....9/abstract

  379. 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.....0/abstract

  380. 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/s.....2713004205

  381. 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/artic.....014-0184-2

  382. #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!

  383. 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/s.....8207000512

  384. 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/re.....121550.htm

  385. 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/re.....121450.htm

  386. 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/jo......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/re.....091553.htm

  387. 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/jour.....b2984.html

  388. 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

  389. 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/jour.....b3029.html

  390. 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/jour.....b2965.html

  391. 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/jour.....b2958.html

  392. 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/jour.....b2941.html

  393. 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/jour.....b3019.html

  394. 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/jour.....b2996.html

  395. 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/jour.....b2938.html

  396. 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/jour.....b2920.html

  397. 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

  398. 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/20.....rist-code/

  399. 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/2.....s3964.html

  400. 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/jour.....m3133.html

  401. 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/2.....s5795.html

  402. 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/jour.....m3494.html

  403. 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/El.....06237.html

  404. 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.o.....6.abstract

  405. 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/.....541ef81a34

  406. 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.....02de12ee3e

  407. 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

  408. I love this thread Dio. Thank You.

  409. 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? 😉

  410. 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/2.....s5951.html

  411. The human centromere/kinetochore complex

    http://www.fli-leibniz.de/grou....._hk_en.php

  412. Interaction of the mitotic checkpoint complex (MCC) with the anaphase promoting complex/cyclosome (APC/C)

    http://www.fli-leibniz.de/grou.....ion_en.php

  413. The dynamic kinetochore-microtubule interface

    http://jcs.biologists.org/cont......large.jpg

  414. 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/.....centromere

  415. 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/.....nd-lncrnas

  416. 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/jour.....4a_F1.html

  417. 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/cont......large.jpg

  418. 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/.....f7063022fb

  419. 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/.....f7063022fb

  420. 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

  421. 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/co.....8.abstract

  422. 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/cont.....6cc7782dcf

  423. 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-t.....-cell.html

  424. 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-c.....-cell.html

  425. 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-f.....ghtly.html

  426. 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-c.....urate.html

  427. 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-m.....osome.html

  428. 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/cel.....ll%20Press

  429. 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/cel.....all%3Dtrue

  430. 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/cel.....ll%20Press

  431. 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/con.....ab2fc7bad6

  432. 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/jour.....m3828.html

  433. 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.

  434. #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.
    🙂

  435. 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/conte.....abstract-1

  436. 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/conte.....3AWaS.dpuf

  437. #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.

  438. Garbage In = Garbage Out? Complex Biological Sample Preparation for Omics Studies

    http://www.genengnews.com/webi.....udies/232/

  439. 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/re.....101958.htm

  440. 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

  441. 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.....b69b5d83c0

  442. 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.....b69b5d83c0

  443. 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.....b69b5d83c0

  444. 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.....b69b5d83c0

  445. 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.....285c19d79e

  446. What drugs are you on Dio?
    I want some of that.

  447. 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.....285c19d79e

  448. #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]

    🙂

  449. 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?

  450. 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.

  451. 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!

  452. 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.

  453. So you refuse to honestly answer the question as to if you are on drugs? Now I’m really starting to get suspicious!

  454. #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:

    http://www.uncommondescent.com.....ical-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.

  455. #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.

    http://www.uncommondescent.com.....ent-494560

    Would that comment give us an idea about a possible answer to your question? 🙂

  456. 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/searc.....l-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.

  457. 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

  458. 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.

  459. #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:

    http://www.uncommondescent.com.....ent-517080

  460. 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

  461. 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/jour.....m2784.html

  462. 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/s.....2113000748

  463. 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/conte.....7.abstract

  464. 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

  465. 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/ea......html?etoc

  466. 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/ea......html?etoc

  467. #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. 🙂

  468. Any news from The Third Way front yet? Any progress there? 😉

  469. 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…

  470. 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

  471. BA77

    RE: your questions posted on #454, #456 and #458.

    Any hope you’ll get a reply from our interlocutor?

    🙂

  472. 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.

  473. 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. 🙂

  474. 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.....eruola.htm

  475. 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

  476. 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

  477. Challenging bioinformatics, imaging, computational biology issues

    http://www.ncbi.nlm.nih.gov/pubmed/24672759

  478. 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

  479. 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

  480. 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//.....onnection/

  481. 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-.....ll%20Press

  482. 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

  483. 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?

  484. 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/.....581de47e66

  485. 488 addendum

    Here’s the link to the referred article:

    http://emboj.embopress.org/con......201387637

  486. 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/go.....scher.html

  487. 488 addendum 2

    Here’s a separate source to the same article where the controversial term is used:

    http://onlinelibrary.wiley.com.....87637/full

  488. 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/.....7b980de051

  489. 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.....9/abstract

  490. 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/jou......2886.html

    http://www.nature.com/nsmb/jou......2886.html

  491. 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/jou......2876.html

  492. 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.....4/abstract

  493. 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/cel.....13)00191-8

  494. 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/cel.....14)00103-2

  495. 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/cont.....8.abstract

  496. 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.....jcb.2071if

  497. 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

  498. 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/jour.....m3888.html

  499. 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/jour.....m3857.html

  500. 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/jour.....m3853.html

  501. 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/jour.....m3828.html

  502. 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/jour.....m3819.html

  503. 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/jour.....m3809.html

  504. 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/jour.....m3786.html

  505. 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/jour.....m3777.html

  506. 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/jour.....m3768.html

  507. 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.or.....ingid=1274

  508. 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/journ.....0-844.html

  509. 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.

  510. 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

  511. 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......neSets.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

  512. 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

  513. 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/jour.....m3772.html

  514. 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/jour.....m3756.html

  515. 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/jour.....m3759.html

  516. 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/jour.....m3733.html

  517. 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/.....c0b2f241c9

  518. 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/.....6ef6ee92ef

  519. 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/.....3b7a48f096

  520. 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/.....3b7a48f096

  521. 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/regi.....9491135649

  522. 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/bio.....14)00150-9