Mystery at the heart of life

_{Denyse O'Leary

December 21, 2014

Cell biology, Intelligent Design, News}

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

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

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

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

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Comments

gpuccio @ 77
“Doesn’t this seem like a never-ending story?” It does, indeed! The problem is: we learn layer after layer of complexity in the regulation cascade, but we never get to the decisions. How are the decisions made? What determines the different decisions? After all, different cells make different decisions, which activate different, unending layers of “differentiation” (yes, the word indeed comes from “different”, although we often forget it). Where do those different decisions come into existence? What codes for them? And for the strict connection between the decisions and the following multiple, endless layers of regulation? And why are there so many layers of regulation, parallel or sequential, and interconnected? The reasonable answer to that seems to be: to allow for more decisions, in the course of action: checkpoints, alternatives, meta-regulations, and so on. How does the neo darwinist paradigm help in understanding all that? Again, at least this answer is easy: it does not help at all.
Would anyone else like to comment on this? You may want to let all your interlocutors know that their comments are most welcome this time. :)Dionisio_{January 7, 2015
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Easy-peasy! Random chance and Co.Axel_{January 7, 2015
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Dionisio: Just a quick read of the abstract of the last paper you linked will be enough to give a taste of what we are discussing here:
Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation (pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1–SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1–SNF2H–mediated relaxation for DSB repair. ACF1–SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1–mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1–SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair.
And this is only part of a repair mechanism!gpuccio_{January 7, 2015
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Dionisio: "Doesn’t this seem like a never-ending story?" It does, indeed! The problem is: we learn layer after layer of complexity in the regulation cascade, but we never get to the decisions. How are the decisions made? What determines the different decisions? After all, different cells make different decisions, which activate different, unending layers of "differentiation" (yes, the word indeed comes from "different", although we often forget it). Where do those different decisions come into existence? What codes for them? And for the strict connection between the decisions and the following multiple, endless layers of regulation? And why are there so many layers of regulation, parallel or sequential, and interconnected? The reasonable answer to that seems to be: to allow for more decisions, in the course of action: checkpoints, alternatives, meta-regulations, and so on. How does the neo darwinist paradigm help in understanding all that? Again, at least this answer is easy: it does not help at all.gpuccio_{January 7, 2015
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Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair doi: 10.1083/jcb.201405077 however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. http://jcb.rupress.org/content/207/6/717.abstract?sid=eed2af90-bd06-4d55-b0c5-8e45dcec0140Dionisio_{January 7, 2015
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Actin is good at long division doi: 10.1083/jcb.2081iti2 F-actin helps mitochondria divide by polymerizing on the organelles, Li et al. show. The GTPase Drp1 forms spirals around mitochondria to cut the organelles in two. Studies suggest that actin also has a role in mitochondrial division and recruitment of Drp1. The mechanisms, however, remain unclear. Mitochondria are abnormally long in both types of cells, suggesting that Drp1 accumulation and F-actin polymerization are necessary for mitochondrial fission. But how actin polymerization helps Drp1 cleave mitochondria remains unknown. http://jcb.rupress.org/content/208/1/2.2.full
Can't wait to see the revelation of the unknown part. :)Dionisio_{January 7, 2015
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Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission doi: 10.1083/jcb.201404050 In addition to established membrane remodeling roles in various cellular locations, actin has recently emerged as a participant in mitochondrial fission. However, the underlying mechanisms of its participation remain largely unknown. http://jcb.rupress.org/content/208/1/109.abstract?sid=eed2af90-bd06-4d55-b0c5-8e45dcec0140
Can't wait to see the revelation of the unknown part. :)Dionisio_{January 7, 2015
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Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction doi: 10.1083/jcb.201409108 The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. http://jcb.rupress.org/content/208/1/23.abstract?sid=eed2af90-bd06-4d55-b0c5-8e45dcec0140Dionisio_{January 7, 2015
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#71 addendum
Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamina doi: 10.1083/jcb.201405110 Nuclear organization has been implicated in regulating gene activity. Recently, large developmentally regulated regions of the genome dynamically associated with the nuclear lamina have been identified. However, little is known about how these lamina-associated domains (LADs) are directed to the nuclear lamina. http://jcb.rupress.org/content/208/1/33.abstract?sid=eed2af90-bd06-4d55-b0c5-8e45dcec0140
Dionisio_{January 7, 2015
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When DNA gets sent to time-out
For a skin cell to do its job, it must turn on a completely different set of genes than a liver cell—and keep genes it doesn’t need switched off. One way of turning off large groups of genes at once is to send them to “time-out” at the edge of the nucleus, where they are kept quiet. New research from Johns Hopkins sheds light on how DNA gets sent to the nucleus’ far edge, a process critical to controlling genes and determining cell fate. “Now we have a lot of interesting questions to answer about how different types of cells use this mechanism to regulate different sets of genes.”
http://www.rdmag.com/news/2015/01/when-dna-gets-sent-time-out?et_cid=4350426&et_rid=653535995&location=top “Now we have a lot of interesting questions to answer about how different types of cells use this mechanism to regulate different sets of genes.”? A new discovery, which may or may not have answered outstanding questions, has raised "a lot of interesting questions"! Doesn't this seem like a never-ending story? :)Dionisio_{January 7, 2015
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Establishing neural crest identity: a gene regulatory recipe doi: 10.1242/dev.105445 Neural crest development is thought to be controlled by a suite of transcriptional and epigenetic inputs arranged hierarchically in a gene regulatory network. http://dev.biologists.org/content/142/2/242Dionisio_{January 6, 2015
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STEM CELLS AND REGENERATION Postnatal subventricular zone progenitors switch their fate to generate neurons with distinct synaptic input patterns doi: 10.1242/dev.110767 It is unknown to what extent the distinct synaptic input patterns are already determined in SVZ progenitors and/or by the brain circuit into which neurons integrate. http://dev.biologists.org/content/142/2/303.abstract?etocDionisio_{January 6, 2015
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CENP-W Plays a Role in Maintaining Bipolar Spindle Structure http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198083/ Kinetochore-microtubule stability governs the metaphase requirement for Eg5 Although it is known that Kif15, a second mitotic kinesin, enforces spindle bipolarity in the absence of Eg5, how Kif15 functions in this capacity and/or whether other biochemical or physical properties of the spindle promote its bipolarity have been poorly studied. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072578/ The spindle and kinetochore-associated (Ska) complex enhances binding of the anaphase-promoting complex/cyclosome (APC/C) to chromosomes and promotes mitotic exit. http://www.ncbi.nlm.nih.gov/pubmed/24403607 Molecular Characterization of an Intact p53 Pathway Subtype http://www.ncbi.nlm.nih.gov/pubmed/25460179Dionisio_{January 6, 2015
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Sensors at Centrosomes Reveal Determinants of Local Separase Activity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191886/Dionisio_{January 6, 2015
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Targeting the Cell's 'Biological Clock' in Promising New Cancer Therapy Cell biologists at UT Southwestern Medical Center have targeted telomeres with a small molecule called 6-thiodG that takes advantage of the cell’s “biological clock” to kill cancer cells and shrink tumor growth. http://www.biosciencetechnology.com/news/2015/01/targeting-cells-biological-clock-promising-new-cancer-therapy?et_cid=4349013&et_rid=653535995&location=topDionisio_{January 5, 2015
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#64 follow-up / important reminder: https://www.youtube.com/embed/Ug75diEyiA0Dionisio_{January 5, 2015
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Fed up with so many boring references to research papers posted here lately? Wanna try something lighter, more entertaining? Considering that apparently the fiction genre has been more popular in literature history, here's an amusing story, which I think was referred to in another post in this site in the last quarter of last year. (if this doesn't make you laugh, perhaps nothing else will):
An inside-out origin for the eukaryotic cell doi:10.1186/s12915-014-0076-2 Although the origin of the eukaryotic cell has long been recognized as the single most profound change in cellular organization during the evolution of life on earth, this transition remains poorly understood. Models have always assumed that the nucleus and endomembrane system evolved within the cytoplasm of a prokaryotic cell.
You may read more on this here: http://www.biomedcentral.com/1741-7007/12/76 Enjoy it! :)Dionisio_{January 5, 2015
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Membranes Organize Cellular Complexity http://learn.genetics.utah.edu/content/cells/membranes/Dionisio_{January 4, 2015
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A two-step mechanism for epigenetic specification of centromere identity and function doi:10.1038/ncb2805 The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively. http://www.nature.com/ncb/journal/v15/n9/full/ncb2805.htmlDionisio_{January 4, 2015
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DNA methylation changes during cell differentiation overall perspective on the connections between DNA methylation and other epigenetic marks and the interplay with transcription factors http://www.abcam.com/events/dna-methylation-changes-during-cell-differentiation-free-webinarDionisio_{January 4, 2015
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Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces doi:10.1038/ncb3060 Accurate chromosome segregation during cell division in metazoans relies on proper chromosome congression at the equator. Chromosome congression is achieved after bi-orientation to both spindle poles shortly after nuclear envelope breakdown, or by the coordinated action of motor proteins that slide misaligned chromosomes along pre-existing spindle microtubules1. These proteins include the minus-end-directed kinetochore motor dynein2, 3, 4, 5, and the plus-end-directed motors ?CENP-E at kinetochores6, 7 and chromokinesins on chromosome arms8, 9, 10, 11. However, how these opposite and spatially distinct activities are coordinated to drive chromosome congression remains unknown. Here we used RNAi, chemical inhibition, kinetochore tracking and laser microsurgery to uncover the functional hierarchy between kinetochore and arm-associated motors, exclusively required for congression of peripheral polar chromosomes in human cells. We show that dynein poleward force counteracts chromokinesins to prevent stabilization of immature/incorrect end-on kinetochore–microtubule attachments and random ejection of polar chromosomes. At the poles, ?CENP-E becomes dominant over dynein and chromokinesins to bias chromosome ejection towards the equator. Thus, dynein and ?CENP-E at kinetochores drive congression of peripheral polar chromosomes by preventing arm-ejection forces mediated by chromokinesins from working in the wrong direction. http://www.nature.com/ncb/journal/v16/n12/full/ncb3060.htmlDionisio_{January 4, 2015
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#58 Quest Interesting observation. Thanks.Dionisio_{January 4, 2015
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These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.
What about the cell membrane...? Will DNA, RNA and proteins work together without it even if they are present and "active' at the same time...? Or... will the cell continue to live and function if one of the components is removed from the living and active cell...? The answer is obvious to all logically thinking people... except the blind followers of Darwin... They believe that the obvious can somehow be omitted... ignored... so that their blind beliefs can be kept alive... but only in their blinded minds due to their hardened hearts...Quest_{January 1, 2015
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Genomic Determinants of Gene Regulation by 1,25-Dihydroxyvitamin D3 during Osteoblast-lineage Cell Differentiation*? doi: 10.1074/jbc.M114.578104 The biological effects of 1?,25-dihydroxyvitamin D3 (1,25 (OH)2D3) on osteoblast differentiation and function differ significantly depending upon the cellular state of maturation. Continued novel regulation by 1,25(OH)2D3, however, suggested that factors in addition to the VDR might also be involved. We conclude that each of these mechanisms may contribute to the diverse actions of 1,25(OH)2D3 on differentiating osteoblasts. http://www.jbc.org/content/289/28/19539.abstractDionisio_{January 1, 2015
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O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells* doi: 10.1074/mcp.M114.040691 Runx2 is the master switch controlling osteoblast differentiation and formation of the mineralized skeleton. The post-translational modification of Runx2 by phosphorylation, ubiquitinylation, and acetylation modulates its activity, stability, and interactions with transcriptional co-regulators and chromatin remodeling proteins downstream of osteogenic signals. Altogether, these findings link O-GlcNAc cycling to the Runx2-dependent regulation of the early ALP marker under osteoblast differentiation conditions. http://www.mcponline.org/content/13/12/3381.abstractDionisio_{January 1, 2015
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Inhibition of FOXO1/3 Promotes Vascular Calcification doi: 10.1161/ATVBAHA.114.304786 ...the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification. http://atvb.ahajournals.org/content/35/1/175.abstractDionisio_{January 1, 2015
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Translational Regulation of the Post-Translational Circadian Mechanism •DOI: 10.1371/journal.pgen.1004628 http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1004628Dionisio_{December 31, 2014
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Spatial regulation of the spindle assembly checkpoint and anaphase-promoting complex DOI: 10.1111/mmi.12871 The spindle assembly checkpoint (SAC) plays a critical role in preventing mitotic errors by inhibiting anaphase until all kinetochores are correctly attached to spindle microtubules. In spite of the economic and medical importance of filamentous fungi, relatively little is known about the behavior of SAC proteins in these organisms. In our efforts to understand the role of ?-tubulin in cell cycle regulation, we have created functional fluorescent protein fusions of four SAC proteins in Aspergillus nidulans, the homologs of Mad2, Mps1, Bub1/BubR1 and Bub3. Time-lapse imaging reveals that SAC proteins are in distinct compartments of the cell until early mitosis when they co-localize at the spindle pole body. SAC activity is, thus, spatially regulated in A.?nidulans. Likewise, Cdc20, an activator of the anaphase-promoting complex/cyclosome, is excluded from interphase nuclei, but enters nuclei at mitotic onset and accumulates to a higher level in mitotic nuclei than in the surrounding nucleoplasm before leaving in anaphase/telophase. The activity of this critical cell cycle regulatory complex is likely regulated by the location of Cdc20. Finally, the ?-tubulin mutation mipAD159 causes a nuclear-specific failure of nuclear localization of Mps1 and Bub1/R1 but not of Cdc20, Bub3 or Mad2. http://onlinelibrary.wiley.com/doi/10.1111/mmi.12871/abstractDionisio_{December 31, 2014
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Erk Signaling Suppresses Embryonic Stem Cell Self-Renewal to Specify Endoderm DOI: http://dx.doi.org/10.1016/j.celrep.2014.11.032 Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages. To dissect the role of Erk in both ESC self-renewal and lineage specification, we explored the requirements for this pathway in various in vitro differentiation settings. A combination of pharmacological inhibition of Erk signaling and genetic loss of function reveal a role for Erk signaling in endodermal, but not neural differentiation. Neural differentiation occurs normally despite a complete block to Erk phosphorylation. In support of this, Erk activation in ESCs derepresses primitive endoderm (PrE) gene expression as a consequence of inhibiting the pluripotent/epiblast network. The early response to Erk activation correlates with functional PrE priming, whereas sustained Erk activity results in PrE differentiation. Taken together, our results suggest that Erk signaling suppresses pluripotent gene expression to enable endodermal differentiation. http://www.cell.com/cell-reports/abstract/S2211-1247(14)00998-XDionisio_{December 30, 2014
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In Vivo Single-Cell Detection of Metabolic Oscillations in Stem Cells DOI: http://dx.doi.org/10.1016/j.celrep.2014.12.007 Through the use of bulk measurements in metabolic organs, the circadian clock was shown to play roles in organismal energy homeostasis. However, the relationship between metabolic and circadian oscillations has not been studied in vivo at a single-cell level. Also, it is unknown whether the circadian clock controls metabolism in stem cells. We used a sensitive, noninvasive method to detect metabolic oscillations and circadian phase within epidermal stem cells in live mice at the single-cell level. We observe a higher NADH/NAD+ ratio, reflecting an increased glycolysis/oxidative phosphorylation ratio during the night compared to the day. Furthermore, we demonstrate that single-cell metabolic heterogeneity within the basal cell layer correlates with the circadian clock and that diurnal fluctuations in NADH/NAD+ ratio are Bmal1 dependent. Our data show that, in proliferating stem cells, the circadian clock coordinates activities of oxidative phosphorylation and glycolysis with DNA synthesis, perhaps as a protective mechanism against genotoxicity. http://www.cell.com/cell-reports/abstract/S2211-1247(14)01018-3Dionisio_{December 30, 2014
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