Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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

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

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

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

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Regulation of cell fate determination in plants Front. Plant Sci., DOI: http://dx.doi.org/10.3389/fpls.2014.00368 Building a multicellular organism, like a plant, from a single cell requires the coordinated formation of different cell types in a spatiotemporal arrangement. How different cell types arise in appropriate places and at appropriate times is one of the most intensively investigated questions in modern plant biology. [...] scientists have begun to discover some of the answers, including the importance of transcriptional regulatory networks, intrinsic signals such as plant hormones, and extrinsic signals such as environmental stimuli. The specification of distinct cell types in plants is accomplished largely via the establishment of different gene expression, primarily, transcription factor gene expression. [...] recent studies have revealed [...] transcription factors are likely to be master regulators of specification [...] [...] the roles of these regulatory genes that are involved in epidermal cell fate specification [...] [...] possible mechanisms that limit the expression and/or activity [...] [...] regulated through a combination of endogenous developmental programs and external signals [...] The expression of component genes of the transcriptional activator complex is regulated by other transcription factors [...] [...] controlled by both an intrinsic genetic regulatory network and environmental stimuli [...] [...] cells are differentiated in a spatiotemporally organized manner [...] Recent studies revealed that xylem cell fate determination is controlled by functional interactions among these key regulators Post-translational modifications of proteins are often important for regulation of their functions. http://journal.frontiersin.org/article/10.3389/fpls.2014.00368/full
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Regulation of epidermal cell fate in Arabidopsis roots: the importance of multiple feedback loops Front. Plant Sci., DOI: http://dx.doi.org/10.3389/fpls.2014.00047 The specification of distinct cell types in multicellular organisms is accomplished via establishment of differential gene expression. A major question is the nature of the mechanisms that establish this differential expression in time and space. Recent findings show surprising complexity in the number and the types of regulatory interactions between the multiple transcription factor genes/proteins influencing root epidermis cell fate. Genetic and molecular studies over the past 20 years have now provided a fairly clear picture of the transcriptional regulators responsible for establishing this differential cell-type gene expression. What has been surprising is the large number of regulatory mechanisms and interactions by these transcription factors in the process of root epidermal cell specification. Unexpectedly, the transcription of these one-repeat Mybs was found to occur predominately in the N cells, [...] What is unusual about the lateral inhibition used here is its direct nature; the molecule produced by the inhibiting cell is used as both the signal and the inhibitor of the recipient cell. This was an unexpected finding, since [...] The observed preferential accumulation of CPC (and presumably TRY and ETC1) in the H cells is believed to be necessary for robust pattern formation, though the mechanism responsible for causing these mobile factors to accumulate in H cells has long been a mystery. A possible explanation has recently been provided by the finding that [...] Interestingly, the preferential SCM action in the H cells is likely due to differential accumulation of SCM. It is proposed that this mechanism helps to “lock in” the cell fate decision, [...] [...] there may be an intermediate set of histone-regulated genes responsible for this level of control. Thoughts on the Complexity of the Network In this minireview, we have highlighted the multitude of regulatory mechanisms that are employed to control the relative abundance of the critical transcription factors in epidermal cell specification. Considering these many components and interactions, it is appropriate to wonder why this system has evolved such complexity to control a seemingly simple case of cell fate specification. One possible explanation is that the complex regulatory interactions reflect a requirement for robustness; to ensure that once a cell fate decision is made, that this decision is fully adopted and is not allowed to be altered at any step. Another possibility for the existence of multiple regulatory mechanisms may be that they provide opportunities for the modification/adjustment of the cell fate decision at many points in the process, perhaps enabling it to respond to the many known internal and external factors that influence root hair development. Future studies on the control of root epidermal cell fate in Arabidopsis and other species will likely yield additional insight into the importance of the many components and interactions in this complex regulatory network. http://journal.frontiersin.org/article/10.3389/fpls.2014.00047/full
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Why Is Nuclear Organization Dynamic, Hierarchical and Intricate? Implications for Gene Regulation, Cellular Differentiation and Disease doi:10.1016/j.jmb.2014.12.015 http://www.sciencedirect.com/science/article/pii/S0022283614006512
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Early divergence of central and peripheral neural retina precursors during vertebrate eye development DOI: 10.1002/dvdy.24218 Developmental Dynamics Volume 244, Issue 3, pages 266–276 Little information is available regarding lineage relationships between mature optic cup tissues and the mechanisms that couple fate commitment to eye morphogenesis. Refinement of our understanding of eye development and how it underlies domain-specific eye diseases and developmental disorders requires amalgamation of knowledge mined with such complimentary tools. http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24218/full
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A complex choreography of cell movements shapes the vertebrate eye doi: 10.1242/dev.071407 Development 139, 359-372. the underlying choreography is conserved among vertebrates. Further work is required to determine the extent to which non-epithelial cell behaviors drive subsequent steps of OCM. It will be interesting to integrate the data and determine whether regional behaviors, including subdomain boundaries, persist from neural plate stages through OC formation. The answers might be informative as to the signals regulating specific cell movements. A surprising aspect of OV elongation is the concurrent movement... Our results suggest that these tissue layers are moving in concert at earlier stages, raising the intriguing possibility that coordinated movement enables... Not every cell was tracked, so domain boundaries are somewhat imprecise Surprisingly, this domain is subdivided into discrete regions Combining gene expression data with our fate maps might suggest the signaling events involved in patterning the OV. How do we reconcile similar morphogenetic movements with fate map differences? http://dev.biologists.org/content/139/2/359.full
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Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein DOI: http://dx.doi.org/10.7554/eLife.05216 eLife 2015;4:e05216 This cannot be explained by the classical view of eye development. Strikingly, and in contrast to the former model, [...] almost the entire bi-layered optic vesicle gives rise to the neural retina. This new perspective on optic cup formation raises the question of how the elongated oval optic vesicle is transformed into the hemispheric optic cup. Our data support a scenario in which the entire optic vesicle is initially composed of stem cells that at the lens-facing side respond to a signal to take a progenitor fate. We propose a tight coupling of morphogenesis with cell determination by inductive signals derived from the surface ectoderm to explain the successive spreading of retinal differentiation from the center to the periphery We demonstrated that cell motility and thus tissue fluidity are a prerequisite for neuroretinal flow. These characteristics are likely maintained through signaling, raising the question of which system might be involved. forces established outside the neuroretina are likely to drive the flow. One tissue potentially involved is the mono-layered-forming RPE. We speculate that this tissue contributes to the flow by changing its shape from a columnar to a flat epithelium, massively enlarging its surface. This remains an interesting point, in particular given that epithelial flow is maintained even if cell proliferation is inhibited in both neuroretina and RPE. http://elifesciences.org/content/4/e05216
A few newly raised questions?Dionisio_{May 28, 2015
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Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease Nature Medicine 21, 467–475 (2015) doi:10.1038/nm.3842 During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.??) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues. http://www.nature.com/nm/journal/v21/n5/full/nm.3842.html
It seems like these researchers have found an important piece of information for the effective treatment of a very painful condition that affects particularly older people. Keep an eye on this PEPITEM stuff. Now, this seems like a good illustration for serious research. Let's encourage the younger generations to consider pursuing science (particularly biology and biomedical) careers.Dionisio_{May 27, 2015
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Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates Nature Genetics (2015) doi:10.1038/ng.3306 Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. We uncover a new reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germ line by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings show that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3306.html
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Discovering centromere proteins: from cold white hands to the A, B, C of CENPs Nature Reviews Molecular Cell Biology (2015) doi:10.1038/nrm4001 The kinetochore is a complex molecular machine that directs chromosome segregation during mitosis. It is one of the most elaborate subcellular protein structures in eukaryotes, comprising more than 100 different proteins. Inner kinetochore proteins associate with specialized centromeric chromatin containing the histone H3 variant centromere protein A (CENP-A) in place of H3. Outer kinetochore proteins bind to microtubules and signal to delay anaphase onset when microtubules are absent. Since the first kinetochore proteins were discovered and cloned 30 years ago using autoimmune sera from patients with scleroderma-spectrum disease, much has been learnt about the composition, functions and regulation of this remarkable structure. http://www.nature.com/nrm/journal/vaop/ncurrent/full/nrm4001.html
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DNA replication origin activation in space and time Nature Reviews Molecular Cell Biology 16, 360–374 (2015) doi:10.1038/nrm4002 DNA replication begins* with the assembly of pre-replication complexes (pre-RCs) at thousands of DNA replication origins during the G1 phase of the cell cycle. At the G1–S-phase transition, pre-RCs are converted into pre-initiation complexes, in which the replicative helicase is activated, leading to DNA unwinding and initiation of DNA synthesis. However, only a subset of origins are activated during any S phase. Recent insights into the mechanisms underlying this choice reveal how flexibility in origin usage and temporal activation are linked to chromosome structure and organization, cell growth and differentiation, and replication stress. http://www.nature.com/nrm/journal/v16/n6/full/nrm4002.html
(*) what does determine the timing for that beginning?Dionisio_{May 26, 2015
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Integrated ?-catenin, BMP, PTEN, and Notch signalling patterns the nephron DOI: http://dx.doi.org/10.7554/eLife.04000 eLife 2015;4:e04000 The different segments of the nephron and glomerulus in the kidney balance the processes of water homeostasis, solute recovery, blood filtration, and metabolite excretion. Little is known about nephron patterning during embryogenesis. Our data therefore identifies a molecular network for nephron patterning. A major outstanding question in kidney development has been to understand how the nephrons are patterned. While cell proliferation and apoptosis are likely to be essential in other aspects of nephrogenesis, our data exclude a direct role in the initial patterning mechanism. With the current data, it is difficult to identify key downstream targets and that way describe the next level of mechanism of this process, as many targets are also widely used as segmentation markers. Since proliferation was not affected by either increasing or decreasing ?-catenin signalling, the changes in tubular morphology and length must have been caused by another mechanism. [duh!] The tubules appeared thinner, suggesting cellular rearrangements as a likely cause. Whether this indicates redundancy or an ability to overcome increased ?-catenin levels through ureteric bud-derived signals remains to be determined. It will be important to explore precisely how PI3K and BMP/pSMAD signalling regulate the Wnt/?-catenin pathway, in the nephron and elsewhere. This should be the subject of future studies. The mechanism of the rescue needs to be further studied, particularly in light of that the expression of known Notch target genes was not rescued by the ?-catenin inhibitor Further, biochemical analysis of ?-catenin function will be needed to elucidate this mechanism. At present we do not know which Wnt (assuming it is a Wnt) it is that drives the gradient or how ?-catenin activity is antagonised in the proximal cells. Again, extensive further analysis of the Wnt9b model is required to demonstrate involvement in the processes we describe here. A second question is how a single source of Wnt could establish a ?-catenin signalling gradient within a morphologically convoluted tissue. Whilst additional Wnt and other knockout studies, either conventional or conditional, might provide new clues to extend our data into a yet more complete genetic pathway, the rate of nephron formation makes this a particularly challenging process. At present we do not know of any Cre driver that would be able to do this, so this might be a long-term goal. http://elifesciences.org/content/4/e04000
An outstanding question answered, a few newer questions pop up. What else is new? Work in progress... stay tuned. I dislike the unknown. Every new discovery sheds more light on the elaborate molecular and cellular choreographies orchestrated within the biological systems. I don't like the knowledge gaps. That's why I look forward with much anticipation to reading future research papers. Unending Revelation of the Ultimate Reality. :) Sing hallelujah!Dionisio_{May 26, 2015
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Precise control of miR-125b levels is required to create a regeneration-permissive environment after spinal cord injury doi: 10.1242/dmm.014837 Dis. Model. Mech. vol. 7 no. 6 601-611 Most spinal cord injuries lead to permanent paralysis in mammals. By contrast, the remarkable regenerative abilities of salamanders enable full functional recovery even from complete spinal cord transections. The molecular differences underlying this evolutionary divergence between mammals and amphibians are poorly understood. * It is unknown what regulates the miR response after injury, and regulation might occur at many different levels because the response of cells to injury is extremely complex.* In the future, it will be essential to test whether multiple treatments with miRNA alone increase the functional recovery, or whether combinations of modulators of miRNAs are more effective. http://dmm.biologists.org/content/7/6/601.full
(*) understatement? Work in progress... stay tuned.Dionisio_{May 26, 2015
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microRNA control of cell-cell signaling during development and disease PMCID: PMC2697031 NIHMSID: NIHMS111406 MicroRNAs (miRNAs) are critical post-transcriptional regulators that may collectively control a majority of animal genes. With thousands of miRNAs identified, a pressing challenge is now to understand their specific biological activities. Many predicted miRNA target interactions only subtly alter gene activity. It has consequently not been trivial to deduce how miRNAs are relevant to phenotype, and by extension, relevant to disease. We note that the major signal transduction cascades that control animal development are highly dose-sensitive and frequently altered in human disorders. On this basis, we hypothesize that developmental cell signaling pathways represent prime candidates for mediating some of the major phenotypic consequences of miRNA deregulation, especially under gain-of-function conditions. This perspective reviews the evidence for miRNA targeting of the major signaling pathways, and discusses its implications for how aberrant miRNA activity might underlie human disease and cancer. miRNAs are integrated into vast regulatory networks that impinge upon a broad spectrum of biological events. While we are decades from a complete understanding of the endogenous functions of miRNAs, we now have tools with which to rapidly assess the potential contributions of miRNAs to discrete biological events. We believe that directed investigation, using activity based screening of cell signaling pathways, will yield many additional examples of functionally relevant regulatory relationships. Their elucidation will define endogenous functions and, perhaps more critically, provide insight into the roles of miRNAs in human disease. http://europepmc.org/articles/PMC2697031
This was several years ago... let's find out where are things now... stay tuned.Dionisio_{May 26, 2015
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microRNA regulation of Wnt signaling pathways in development and disease doi:10.1016/j.cellsig.2015.03.018 Wnt signaling pathways and microRNAs (miRNAs) are critical regulators of development. Wnt signaling pathways regulate a plethora of cellular processes during embryonic development and maintain homeostasis of adult tissues. A majority of Wnt signaling components are regulated by miRNAs which are small noncoding RNAs that are expressed in both animals and plants. This review discusses components of the Wnt signaling pathways that are regulated by miRNAs in the context of development and diseases. A fundamental understanding of miRNA functions in Wnt signaling transduction pathways may yield new insight into crosstalks of regulatory mechanisms essential for development and disease pathophysiology leading to novel therapeutics. http://www.sciencedirect.com/science/article/pii/S0898656815001175
Work in progress... stay tuned.Dionisio_{May 26, 2015
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A bioinformatics expert system linking functional data to anatomical outcomes in limb regeneration Regeneration. 1(2): 37–56. doi: 10.1002/reg2.13 Amphibians and molting arthropods have the remarkable8 capacity to regenerate amputated limbs, as described by an extensive literature of experimental cuts, amputations, grafts, and molecular techniques. Despite a rich history of experimental effort, no comprehensive mechanistic model exists that can account for the pattern regulation observed in these experiments. While bioinformatics algorithms have revolutionized the study of signaling pathways, no such tools have heretofore been available to assist scientists in formulating testable models of large-scale morphogenesis that match published data in the limb regeneration field. Major barriers to preventing an algorithmic approach are the lack of formal descriptions for experimental regenerative information and a repository to centralize storage and mining of functional data on limb regeneration. Establishing a new bioinformatics of shape would significantly accelerate the discovery of key insights into the mechanisms that implement complex regeneration. Here, we describe a novel mathematical ontology for limb regeneration to unambiguously encode phenotype, manipulation, and experiment data. Based on this formalism, we present the first centralized formal database of published limb regeneration experiments together with a user-friendly expert system tool to facilitate its access and mining. These resources are freely available for the community and will assist both human biologists and artificial intelligence systems to discover testable, mechanistic models of limb regeneration. http://onlinelibrary.wiley.com/doi/10.1002/reg2.13/full
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Notum Is Required for Neural and Head Induction via Wnt Deacylation, Oxidation, and Inactivation DOI: http://dx.doi.org/10.1016/j.devcel.2015.02.014 Secreted Wnt morphogens are essential for embryogenesis and homeostasis and require a lipid/palmitoleoylate modification for receptor binding and activity. Notum is a secreted Wnt antagonist that belongs to the ?/? hydrolase superfamily, but its mechanism of action and roles in vertebrate embryogenesis are not fully understood. Notum is a prerequisite for the “default” neural fate and that distinct mechanisms of Wnt inactivation by the Tiki protease in the Organizer and the Notum deacylase in presumptive neuroectoderm orchestrate vertebrate brain development. http://www.cell.com/developmental-cell/abstract/S1534-5807%2815%2900132-X
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STEM CELLS AND REGENERATION teashirt is required for head-versus-tail regeneration polarity in planarians doi: 10.1242/dev.119685 Development 142, 1062-1072. Regeneration requires that the identities of new cells are properly specified to replace missing tissues. The Wnt signaling pathway serves a central role in specifying posterior cell fates during planarian regeneration. These findings identify teashirt as a transcriptional target of Wnt signaling required for Wnt-mediated specification of posterior blastemas. http://dev.biologists.org/content/142/6/1062.abstract
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Sulf1 has ligand-dependent effects on canonical* and non-canonical Wnt signaling doi: 10.1242/?jcs.164467 2015 J Cell Sci 128, 1408-1421. Wnt signalling plays essential roles during embryonic development There are many molecular mechanisms that ensure tight regulation of Wnt activity. not all data are consistent with Sulf1 enhancing Wnt signaling the effects of Sulf1 are ligand specific and reflect the diverse molecular mechanisms regulated by HSPGs, such as the establishment of signalling complexes and the formation of morphogen gradients. the effects of Sulf1 on distinct Wnt ligands are different depending on cellular context. Confirmation of this hypothesis will require depletion of maternal mRNAs such as shown previously (Tao et al., 2005), or other genetic approaches. Any biological effect of Sulf1 needs be considered in light of all signalling pathways that require HSPGs A better understanding of the molecular and cellular mechanisms underlying Sulf activity will inform and advance these [medical?] efforts. Here's an apparent "oops" moment (oh, well, things happen):
These data show that in contrast to the accepted model, in this assay, Sulf1 inhibits rather than enhances canonical Wnt signaling.
(*) Here's something related to the comments @450:
A thorough review of Wnt signalling has been published recently (Hoppler and Moon, 2014). Wnt proteins have been classified as either being canonical or non-canonical ligands (Du et al., 1995), but this distinction is questionable because both Wnt5a and Wnt11b (the classic non-canonical Wnts) can activate canonical Wnt signalling (Mikels and Nusse, 2006; Tao et al., 2005) in the presence of the necessary receptors and pathway specific co-receptors (Yamamoto et al., 2008a).
http://jcs.biologists.org/content/128/7/1408.full
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Noncanonical* Wnt5a enhances Wnt/?-catenin signaling during osteoblastogenesis Scientific Reports 4, Article number: 4493 doi:10.1038/srep04493 Wnt signaling plays critical roles in the development, growth, and homeostasis of various organs including the skeletal system. The binding of Wnt to receptor complexes activates ?-catenin-dependent canonical and ?-catenin-independent noncanonical signaling pathways. Wnt regulates bone formation through ?-catenin-dependent canonical and -independent noncanonical signaling pathways. However, the cooperation that exists between the two signaling pathways during osteoblastogenesis remains to be elucidated. Wnt5a-induced noncanonical signaling cooperates with Wnt/?-catenin signaling to achieve proper bone formation. Wnt5a regulates osteoblastogenesis and adipogenesis through the up-regulation of Wnt/?-catenin signaling. [...] the regulation of Lrp5 and Lrp6 expression in osteoblasts has not been fully elucidated. both canonical and noncanonical Wnt signalings are required for proper bone formation. However, there is little information about how these two signaling pathways might cooperate with each other during osteoblastogenesis. Further studies are needed to clarify how Wnt5a enhances Lrp6 expression and enhances BMP2 signaling during osteoblast differentiation.
(*) see comments @450Dionisio_{May 25, 2015
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RNA Cytidine Acetyltransferase of Small-Subunit Ribosomal RNA: Identification of Acetylation Sites and the Responsible Acetyltransferase in Fission Yeast, Schizosaccharomyces pombe DOI: 10.1371/journal.pone.0112156 Taoka M, Ishikawa D, Nobe Y, Ishikawa H, Yamauchi Y, Terukina G, et al. (2014) [...] the acetylation sites and the acetyltransferase responsible for the acetylation have not been identified. For more than three decades, [...] identification of the exact acetylation site has remained elusive, and little is known about its physiological significance in ribosome biogenesis and function or the presumptive acetyltransferase responsible for the modification. we were able to identify the positions of AcCs along the sequence of the SSU rRNA of the fission yeast, Schizosaccharomyces pombe, and we also determined the enzyme responsible for this modification. Based on our data, it appears that cytidine acetylation has a regulatory role in ribosome assembly, particularly in the process of SSU formation from a precursor rRNA. Determination of Acetylcytidine Positions of SSU rRNA [...] the results clearly showed that the fission yeast SSU rRNA has two AcCs at positions 1297 and 1815. The N-acetyltransferase Encoded by Nat10 Is Responsible for the Cytidine Acetylation of Eukaryotic SSU rRNA Lack of SSU rRNA Acetylation Affects Ribosome Assembly cytidine acetylation of SSU rRNA may have a role in the maturation of precursor rRNAs and the ability to generate SSU complexes during ribosome assembly. We report the sites of acetylation in the fission yeast SSU rRNA and the corresponding N-acetyltransferase responsible for this acetylation. [...] the cytidine acetylation appears to be essential for normal ribosome assembly via the SSU rRNA formation. [...] we speculate that Nat10p and TmcA have similar catalytic mechanisms; however, this requires experimental evidence. [...] the human Nat10 ortholog is thought to play a role in regulating cytokinesis, mitotic chromosome decondensation, and telomerase expression,[...] [...] the N-acetyltransferase encoded by Nat10 participates in a variety of biological processes owing to its broad range of target substrates, including rRNA reported here and subsets of proteins such as histones. [...] further studies are needed to elucidate the Nat10 N-acetyltransferase function. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112156
Just over 4 months ago we had a related discussion here: https://uncommondescent.com/news/proteins-are-defying-textbooks/#comment-541472 Work in progress:
[...] the cytidine acetylation appears to be essential for normal ribosome assembly via the SSU rRNA formation. [is it sufficient?] [...] we speculate that Nat10p and TmcA have similar catalytic mechanisms; however, this requires experimental evidence. [...] the human Nat10 ortholog is thought to play a role in regulating cytokinesis, mitotic chromosome decondensation, and telomerase expression,[...] [which role? how does it play it?] [...] the N-acetyltransferase encoded by Nat10 participates in a variety of biological processes [ how? which processes? where is all that described in?] [...] further studies are needed to elucidate the Nat10 N-acetyltransferase function.
Dionisio_{May 25, 2015
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#449 follow up...
What is the difference between canonical and non-canonical signalling pathway? Could anyone please tell me the difference between canonical and non-canonical signalling pathway. Shishir K Gupta Universität Heidelberg James R Woodgett · Mount Sinai Hospital, Toronto The terminology of canonical vs non-canonical has become less meaningful. In the classical example of the Wnt pathway, canonical refers to the pathway components that lead to stabilization of beta-catenin in response to certain Wnt ligands. Any other biological outcomes of Wnt signaling are termed non-canonical. But this is an historic accident due to the pioneering work in Drosophila genetics that initially detailed the genes associated with wingless signaling. Different Wnt ligands and Frizzled receptors can engage various signaling responses including G protein coupled receptors, calcium signals, etc. I am also not sure one can call a given response typical versus atypical - it all depends on the precise stimuli and cell type. We know that cellular context, crosstalk and multiple outputs have rendered the idea of linear pathways to the garbage bin and so its probably better to think of programs of responses than pathways. Best not to think "canonically" as a scientist! Khalid Matrougui · Eastern Virginia Medical School I agree with James. We should not talk on canonical vs. non-canonical, which does not make sense in term of signaling Vsevolod V Gurevich · Vanderbilt University Basically, what is called canonical is largely in the eye of the beholder. As a rule, the pathway discovered first is called canonical in every field. In GPCR field signaling via G proteins is called canonical, whereas G protein-independent signaling via arrestins is called non-canonical. Recently, the signaling by GPCRs from the cell surface was called canonical, as opposed to signaling by internalized GPCRs via the same G proteins, which was called non-canonical. Can't agree with James R. Woodgett more: there is no such thing as a pathway, cells use complex signaling networks (the interactions between branches are often called "cross-talk" by those who prefer to think in terms of linear pathways). Anil Shanker · Meharry Medical College School of Medicine / Vanderbilt-Ingram Cancer Center Very rightly said....Multidirectional cooperativity is the norm of signaling networks rather than oversimplistic canonical or non-canonical linear pathways... http://www.researchgate.net/post/What_is_the_difference_between_canonical_and_non-canonical_signalling_pathway
Is the 'canonical' terminology in biology getting outdated so fast lately? :)Dionisio_{May 24, 2015
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Primary cilia modulate balance of canonical and non-canonical Wnt signaling responses in the injured kidney Shoji Saito, Björn Tampe, Gerhard A Müller and Michael Zeisberg* Fibrogenesis & Tissue Repair 2015, 8:6 doi:10.1186/s13069-015-0024-y While kidney injury is associated with re-expression of numerous Wnt ligands and receptors, molecular mechanisms which underlie regulation of distinct Wnt signaling pathways and ensuing biological consequences remain incompletely understood. [...] in the context of renal injury, primary cilia act as molecular switches between canonical and non-canonical Wnt signaling activity, possibly determining between regenerative and pro-fibrotic effects of Wnt re-expression in the injured kidney With regard to conflicting interpretations of the sum effect of Wnt signaling on kidney fate, it may be also important to note that loss of cilia appears to be model specific... Similarly, impact of genetic background remains unclear... [...] one may speculate that loss of cilia in injured tubular epithelial cells contributes to... [...] it is attractive to speculate that... [...] qualitative analysis of stunted cilia in the UUO model may provide important insights into the role of cilia in modulation of Wnt signaling [...] We are aware that our study focuses entirely on the impact of cilia and Wnt signaling in tubular epithelial cells. If such mechanism is relevant for other cell types such as fibroblasts remains to be seen. http://www.fibrogenesis.com/content/8/1/6
Dionisio_{May 24, 2015
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Coordination of kidney organogenesis by Wnt signaling Journal of the International Pediatric Nephrology Association 10.1007/s00467-013-2733-z The signal-transduction mechanisms of the Wnts in kidney ontogeny have not been resolved, but studies characterizing the downstream signaling pathways are emerging. The nephron stem cell pool marked by sine oculis-related homeobox 2 (Six2) maintains the putative self-renewal potential of these cells and prevents their premature epithelization, but how is still poorly understood. some discrepancies exist between reporter line studies. Such complex architecture with defined tube length and diameter requires oriented cell division and coordinated cell motility. In addition to mutual organization, well-controlled differentiation of the nephron epithelium into highly specialized cell types is critical for kidney function. Even though the essential role of the Wnt ligands in kidney organogenesis is well demonstrated, we have very limited knowledge of their receptors. This evidence suggests Wn7b and Wnt4 are utilized as coordinating signals in developing kidney medulla. The key role of Wnt signaling in nephron induction and differentiation is well established, but the later morphogenic events that involve the PCP pathway need to be revealed in more detail. We expect to find more direct links between the renal Wnt signaling pathway and genetic diseases, which may lead to the identification of new signal transduction components and mechanisms. There are Wnt ligands, such as Wnt2b, Wnt5a, and Wnt6, that are expressed in the embryonic kidney but of which the role remains open. http://link.springer.com/article/10.1007/s00467-013-2733-z/fulltext.html
Dionisio_{May 23, 2015
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As @428 & @446, here's another interesting R2TP-related paper that answers some outstanding questions and raises new ones:
Nop17 is a key R2TP factor for the assembly and maturation of box C/D snoRNP complex Marcela B Prieto, Raphaela C Georg, Fernando A Gonzales-Zubiate, Juliana S Luz and Carla C Oliveira* BMC Molecular Biology 2015, 16:7 doi:10.1186/s12867-015-0037-5 The molecular function of Nop17, however, has not yet been described. we propose a model for the assembly of box C/D snoRNP, according to which R2TP complex is important for reducing the affinity of Nop58 for snoRNA, and for the binding of the other snoRNP subunits. snoRNP complexes are conserved from archaea to eukaryotes, although in the latter they are more complex Despite the studies on the interactions between the R2TP complex and Hsp90, and the determination of the structure of the complex, the molecular function of Nop17 remains elusive. Based on the data presented here, we propose a model for the role of R2TP in snoRNP assembly. It remains to be determined whether the serine 444 is phosphorylated, and whether its phosphorylated state changes upon snoRNP assembly. These results indicate a key role played by Nop17 in snoRNP assembly, and suggest a stepwise process that requires molecular rearrangements of the proteins for the binding of all subunits and formation of the mature snoRNP. http://www.biomedcentral.com/1471-2199/16/7
Dionisio_{May 23, 2015
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Phosphorylation-Dependent PIH1D1 Interactions Define Substrate Specificity of the R2TP Cochaperone Complex Zuzana Ho?ejší, Lasse Stach, Thomas G. Flower, Dhira Joshi, Helen Flynn, J. Mark Skehel, Nicola J. O’Reilly, Roksana W. Ogrodowicz, Stephen J. Smerdon, Simon J. Boulton DOI: http://dx.doi.org/10.1016/j.celrep.2014.03.013 March 20, 2014 http://www.cell.com/cell-reports/fulltext/S2211-1247(14)00191-0
Perhaps this is somehow related to the newer paper referenced @428?
Substrate recognition and function of the R2TP complex in response to cellular stress Front. Genet., 25 February 2015 http://dx.doi.org/10.3389/fgene.2015.00069 Patrick von Morgen, Zuzana Ho?ejší1,* and Libor Macurek* http://journal.frontiersin.org/article/10.3389/fgene.2015.00069/full
Some important keywords are shared: "Substrate", "R2TP Complex". Also one author is shared by both papers.Dionisio_{May 23, 2015
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Regulation of Cilium Length and Intraflagellar Transport by the RCK-Kinases ICK and MOK in Renal Epithelial Cells •DOI: 10.1371/journal.pone.0108470 Primary cilia are important sensory organelles. They exist in a wide variety of lengths, which could reflect different cell-specific functions. How cilium length is regulated is unclear, but it probably involves intraflagellar transport (IFT), which transports protein complexes along the ciliary axoneme. both ICK and MOK modulate cilium length and add to the complexity required to achieve the variety in lengths and morphologies of cilia that are probably necessary for different cell-specific functions. Further research is necessary to gain more insight in the signal transduction pathways that regulate cilium length as well as the role of IFT in achieving these differences in cilium length. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108470
Dionisio_{May 20, 2015
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New Insights into an Old Organelle: Meeting Report on Biology of Cilia and Flagella DOI: 10.1111/tra.12166 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd A major unresolved issue in cilia biology is an understanding of how the ciliary length is regulated it remains unclear whether soluble proteins enter the cilium through an active (such as in nuclear transport) or passive process. Newly discovered and tantalizing roles of cilia as secretors of signaling vesicles and potential positioning devices on migrating cells, as well as their largely mysterious roles in neurons and other cells embedded deep in tissues and organs will no doubt continue to fascinate researchers. Given the rapid advances in the field, we look forward to more revelations at another exciting meeting on this topic 19 July 2015 to 24 July 2015 in Snowmass, CO, which will be organized by Maureen Barr, Iain Drummond and Jagesh Shah. http://onlinelibrary.wiley.com/doi/10.1111/tra.12166/full http://onlinelibrary.wiley.com/doi/10.1111/tra.12166/epdf
Really cool! © 2015 DTZ-TWBG-URURDionisio_{May 20, 2015
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The more we know, the more we have to discover: an exciting future for understanding cilia and ciliopathies Cilia 2015, 4:5 doi:10.1186/s13630-015-0014-0 Since cilia and flagella are complex organelles composed of hundreds of proteins assembled in a very structured manner, the mechanisms underlying their construction have fascinated scientists over years. Deciphering this process could be the key in the understanding of the ciliary diversity and the aetiology of ciliopathies. http://www.ciliajournal.com/content/4/1/5
Dionisio_{May 20, 2015
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Here's a repeat:
Centrosomes back in the limelight DOI: 10.1098/rstb.2013.0452 Cell polarity and its transmission to daughter cells through division in somatic lineages, or from the male gamete to the zygote through fertilization in most animal species, come across as a broad unifying theme that encompasses the numerous functions in which the centrosome can be involved. [...] one cannot hope to get at a comprehensive understanding of centrosome function in diverse systems without a comparative analysis of the cellular economy resulting from the survival strategy* of each organism. This is what makes the study of centrosomes both important and attractive. We trust that this Theme Issue will both provide a snapshot of the progress to date and fuel advances for the years to come. Hopefully, the next collective coverage will have answers for many of the questions that are open in 2014 and undoubtedly come up with new ones! http://rstb.royalsocietypublishing.org/content/369/1650/20130452
(*) survival strategy say what? As much deeper research is done and newer discoveries are made, the big picture of the elaborate cellular and molecular choreographies orchestrated within the biological systems look amazingly interesting. That’s why I look forward, with much anticipation, to reading future research papers shedding more light on all these information-processing interwoven complexities.Dionisio_{May 20, 2015
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Cartwheel assembly DOI: 10.1098/rstb.2013.0458 The cartwheel is a subcentriolar structure consisting of a central hub and nine radially arranged spokes, located at the proximal end of the centriole. Significant progress has since been made in understanding its fine structure and assembly mechanism. many important questions have been left unresolved. First, how is the rotational symmetry of the cartwheel restricted to ninefold? Second, how are cartwheel spokes properly arranged in radial symmetry? Third, how do the SAS-6 rings form a stack? The molecular identity of the factors and their function must await further studies An obvious question regarding the centriole structure is why it has the ninefold symmetry, or, in other words, why this symmetry is so highly conserved among divergent organisms. Is it conserved because it is necessary for ciliary movement? Even the latest knowledge about the molecular mechanism for ciliary/flagellar motility cannot provide reasonable explanations for this question. To explore the meaning of ninefold symmetry in the centriole/axoneme, we need to change the microtubule number and examine the effects. Development of such an experimental system is only possible by engineering the cartwheel structure. Understanding the molecular mechanism for the cartwheel assembly will allow us to approach this fundamental question in biology http://rstb.royalsocietypublishing.org/content/369/1650/20130458
Excellent!Dionisio_{May 20, 2015
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