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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Regulatory models: networks, motifs, modules, sequence drivers and predictive models doi:10.1038/nature14312 Integrative analyses of reference epigenomes reveal context-specific regulatory motifs, factors, modules, pathways and networks http://www.nature.com/nature/2015/180215/full/nature14312.html
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Annotation of the non-coding genome doi:10.1038/nature14309 Reference epigenomes enable comprehensive annotations of dynamic non-coding regulatory and transcribed elements across hundreds of human cell types and tissues http://www.nature.com/nature/2015/180215/full/nature14309.html
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Integrative analysis of 111 reference human epigenomes doi:10.1038/nature14248 The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. http://www.nature.com/nature/journal/v518/n7539/full/nature14248.html
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The formation of the zygote The zygote, the first cell of a new organism with an individual genome (2n4C) is created by the alignment of the maternal chromosomes together with the paternal ones on a common spindle apparatus. http://www.embryology.ch/anglais/dbefruchtung/zygote03.html From Wikipedia: A zygote [...] is the initial cell formed when two gamete cells are joined by means of sexual reproduction. Zygotes are usually produced by a fertilization event between two haploid cells—an ovum (female gamete) and a sperm cell (male gamete)—which combine to form the single diploid cell. http://en.wikipedia.org/wiki/Zygote
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The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells DOI: http://dx.doi.org/10.1016/j.stem.2014.12.004 Stem cells undergo a shift in metabolic substrate utilization during specification and/or differentiation, a process that has been termed metabolic reprogramming. Here, we report that during the transition from quiescence to proliferation, skeletal muscle stem cells experience a metabolic switch from fatty acid oxidation to glycolysis. This reprogramming of cellular metabolism decreases intracellular NAD+ levels and the activity of the histone deacetylase SIRT1, leading to elevated H4K16 acetylation and activation of muscle gene transcription. Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in SCs. Moreover, mice with muscle-specific inactivation of the SIRT1 deacetylase domain display reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes. Overall, these findings reveal how metabolic cues can be mechanistically translated into epigenetic modifications that regulate skeletal muscle stem cell biology. http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00562-1
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Self-Restrained B Cells Arise following Membrane IgE Expression DOI: http://dx.doi.org/10.1016/j.celrep.2015.01.023 Among immunoglobulins (Igs), IgE can powerfully contribute to antimicrobial immunity and severe allergy despite its low abundance. IgE protein and gene structure resemble other Ig classes, making it unclear what constrains its production to thousand-fold lower levels. Whether class-switched B cell receptors (BCRs) differentially control B cell fate is debated, and study of the membrane (m)IgE class is hampered by its elusive in vivo expression. Here, we demonstrate a self-controlled mIgE+ B cell stage. Primary or transfected mIgE+ cells relocate the BCRs into spontaneously internalized lipid rafts, lose mobility to chemokines, and change morphology. We suggest that combined proapoptotic mechanisms possibly involving Hax1 prevent mIgE+ memory lymphocyte accumulation. By uncoupling in vivo IgE switching from cytokine and antigen stimuli, we show that these features are independent from B cell stimulation and instead result from mIgE expression per se. Consequently, few cells survive IgE class switching, which might ensure minimal long-term IgE memory upon differentiation into plasma cells. http://www.cell.com/cell-reports/abstract/S2211-1247(15)00048-0
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Simulating the Entropic Collapse of Coarse-Grained Chromosomes DOI: http://dx.doi.org/10.1016/j.bpj.2014.12.032 Depletion forces play a role in the compaction and decompaction of chromosomal material in simple cells, but it has remained debatable whether they are sufficient to account for chromosomal collapse. We present coarse-grained molecular dynamics simulations, which reveal that depletion-induced attraction is sufficient to cause the collapse of a flexible chain of large structural monomers immersed in a bath of smaller depletants. These simulations use an explicit coarse-grained computational model that treats both the supercoiled DNA structural monomers and the smaller protein crowding agents as combinatorial, truncated Lennard-Jones spheres. By presenting a simple theoretical model, we quantitatively cast the action of depletants on supercoiled bacterial DNA as an effective solvent quality. The rapid collapse of the simulated flexible chromosome at the predicted volume fraction of depletants is a continuous phase transition. Additional physical effects to such simple chromosome models, such as enthalpic interactions between structural monomers or chain rigidity, are required if the collapse is to be a first-order phase transition. http://www.cell.com/biophysj/abstract/S0006-3495(14)04809-7
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Structural Damage in the C. elegans Epidermis Causes Release of STA-2 and Induction of an Innate Immune Response DOI: http://dx.doi.org/10.1016/j.immuni.2015.01.014 The epidermis constantly encounters invasions that disrupt its architecture, yet whether the epidermal immune system utilizes damaged structures as danger signals to activate self-defense is unclear. Here, we used a C. elegans epidermis model in which skin-penetrating infection or injury activates immune defense and antimicrobial peptide (AMP) production. By systemically disrupting each architectural component, we found that only disturbance of the apical hemidesmosomes triggered an immune response and robust AMP expression. The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. This machinery enabled the epidermis to bypass certain signaling amplification and directly trigger AMP production when subjected to extensive architectural damage. Together, our findings uncover an evolutionarily conserved mechanism for the epithelial barriers to detect danger and activate immune defense. http://www.cell.com/immunity/abstract/S1074-7613(15)00040-0
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Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies DOI: http://dx.doi.org/10.1016/j.cell.2015.01.027 Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope. http://www.cell.com/abstract/S0092-8674(15)00070-7
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Regulation of T Cell Motility In Vitro and In Vivo by LPA and LPA2 •DOI: 10.1371/journal.pone.0101655 Lysophosphatidic acid (LPA) and the LPA-generating enzyme autotaxin (ATX) have been implicated in lymphocyte trafficking and the regulation of lymphocyte entry into lymph nodes. High local concentrations of LPA are thought to be present in lymph node high endothelial venules, suggesting a direct influence of LPA on cell migration. However, little is known about the mechanism of action of LPA, and more work is needed to define the expression and function of the six known G protein-coupled receptors (LPA 1–6) in T cells. Taken together, these data highlight a previously unsuspected and non-redundant role for LPA2 in intranodal T cell motility, and suggest that specific functions of LPA may be manipulated by targeting T cell LPA receptors. Although LPA2 appears to regulate T cell dynamics within lymph nodes at early stages after adoptive transfer, the fact that we recovered similar numbers of lpa2?/? and wild-type CD4+ T cells 42 hours after adoptive transfer (Figure 6) indicates that this receptor does not control steady-state T cell recirculation over time. We cannot exclude the possibility that deficiency of LPA2 compromises T cell localization or migratory behavior within lymph nodes at later stages after adoptive transfer, even if bulk recirculation patterns are unaffected. Future studies will be needed to determine if other LPA receptors compensate for the lack of lpa2 over time, or if T cells were simply able to catch up over time independent of the influence of other receptors. What are the consequences of delayed migration of naïve CD4+ T cells within lymph nodes? The answer to this question will require further study, but the kinetics of T cell entry into secondary lymphoid organs could affect the quality or intensity of the effector response. Our discovery of a non-redundant role for LPA2 in T cell migration is important, since naïve CD4+ T cells express multiple LPA receptors. Future studies using gene-targeted mice and specific receptor inhibitors will help to dissect the individual roles of each LPA receptor on CD4+ T cell immune responses. There is likely cross-talk between the different LPA receptors in a cell-type specific manner, as well as interactions with other G-protein coupled receptors that regulate T cell migration [68]. Our results add to the growing body of literature documenting an important role for LPA in the immune system, and suggest that future studies of LPA generation and action in vivo will enhance our understanding of initiation of immune responses. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101655
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#279 addendum Trip6 protein localizes to focal adhesion sites and along actin stress fibers. [why?] [how?] Recruitment of this protein to the plasma membrane occurs in a lysophosphatidic acid (LPA)-dependent manner and it regulates LPA-induced cell migration. http://www.ncbi.nlm.nih.gov/gene/7205Dionisio_{February 15, 2015
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Trip6 Promotes Dendritic Morphogenesis through Dephosphorylated GRIP1-Dependent Myosin VI and F-Actin Organization doi: 10.1523/JNEUROSCI.2125-14.2015 Thyroid receptor-interacting protein 6 (Trip6), a multifunctional protein belonging to the zyxin family of LIM proteins, is involved in various physiological and pathological processes, including cell migration and tumorigenesis. However, the role of Trip6 in neurons remains unknown. Here, we show that Trip6 is expressed [why? how?] in mouse hippocampal neurons and promotes dendritic morphogenesis. Through interaction with the glutamate receptor-interacting protein 1 (GRIP1) and myosin VI, Trip6 is crucial for the total dendritic length and the number of primary dendrites in cultured hippocampal neurons. Trip6 depletion reduces F-actin content and impairs dendritic morphology, and this phenocopies GRIP1 or myosin VI knockdown. Furthermore, phosphorylation of GRIP1956T by AKT1 inhibits the interaction between GRIP1 and myosin VI, but facilitates GRIP1 binding to 14-3-3 protein, which is required for regulating F-actin organization and dendritic morphogenesis. Thus, the Trip6–GRIP1–myosin VI interaction and its regulation on F-actin network play a significant role in dendritic morphogenesis. http://www.jneurosci.org/content/35/6/2559.short
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Actin depolymerisation and crosslinking join forces with myosin II to contract actin coats on fused secretory vehicles doi: 10.1242/?jcs.165571 In many secretory cells actin and myosin are specifically recruited to the surface of secretory granules following their fusion with the plasma membrane. Actomyosin-dependent compression of fused granules is essential to promote active extrusion of cargo. Yet, little is known about molecular mechanisms regulating actin coat formation and contraction. Here we provide a detailed kinetic analysis of the molecules regulating actin coat contraction on fused lamellar bodies (LBs) in primary alveolar type II cells. We demonstrate that Rock1 and myosin light chain kinase (MLCK) translocate to fused LBs and activate myosin II on actin coats. Yet, myosin II activity is not sufficient for efficient actin coat contraction. In addition, cofilin-1 and ?-actinin translocate to actin coats. Rock1-dependent, regulated actin depolymerisation by cofilin-1 in cooperation with actin crosslinking by ?-actinin is essential for complete coat contraction. In summary, our data suggest a complementary role for regulated actin depolymerisation/crosslinking and myosin II activity to contract actin coats and drive secretion. http://jcs.biologists.org/content/early/2015/01/29/jcs.165571.short?rss=1
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Cdk1-dependent mitotic enrichment of cortical myosin II promotes cell rounding against confinement doi:10.1038/ncb3098 Actomyosin-dependent mitotic rounding occurs in both cell culture and tissue, where it is involved in cell positioning and epithelial organization. How actomyosin is regulated to mediate mitotic rounding is not well understood. Here we characterize the mechanics of single mitotic cells while imaging actomyosin recruitment to the cell cortex. At mitotic onset, the assembly of a uniform ?DIAPH1-dependent F-actin cortex coincides with initial rounding. Thereafter, cortical enrichment of F-actin remains stable while myosin II progressively accumulates at the cortex, and the amount of myosin at the cortex correlates with intracellular pressure. Whereas F-actin provides only short-term (<10 s) resistance to mechanical deformation, myosin sustains intracellular pressure for a longer duration (>60 s). Our data suggest that progressive accumulation of myosin II to the mitotic cell cortex probably requires the ?Cdk1 activation of both ?p21-activated kinases, which inhibit myosin recruitment, and of Rho kinase, which stimulates myosin recruitment to the cortex. http://www.nature.com/ncb/journal/v17/n2/full/ncb3098.html
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Myosin II controls cellular branching morphogenesis and migration in three dimensions by minimizing cell-surface curvature doi:10.1038/ncb3092 In many cases, cell function is intimately linked to cell shape control. We used endothelial cell branching morphogenesis as a model to understand the role of myosin II in shape control of invasive cells migrating in 3D collagen gels. We applied principles of differential geometry and mathematical morphology to 3D image sets to parameterize cell branch structure and local cell-surface curvature. We find that Rho/ROCK-stimulated myosin II contractility minimizes cell-scale branching by recognizing and minimizing local cell-surface curvature. Using microfabrication to constrain cell shape identifies a positive feedback mechanism in which low curvature stabilizes myosin II cortical association, where it acts to maintain minimal curvature. The feedback between regulation of myosin II by curvature and control of curvature by myosin II drives cycles of localized cortical myosin II assembly and disassembly. These cycles in turn mediate alternating phases of directionally biased branch initiation and retraction to guide 3D cell migration. http://www.nature.com/ncb/journal/v17/n2/full/ncb3092.html
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Solving the centriole disengagement puzzle doi:10.1038/ncb3087 The microcephaly protein, Cep215, contributes to the engagement of duplicated centrioles in interphase. Now two distinct pools of Cep215 at centrosomes are identified, one bound to Cep68 and the other to pericentrin. Plk1-mediated degradation of Cep68 and separase-mediated cleavage of pericentrin release both pools of Cep215, thereby promoting centriole disengagement. http://www.nature.com/ncb/journal/v17/n1/full/ncb3087.html
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The dendritic cell cytoskeleton promotes T cell adhesion and activation by constraining ICAM-1 mobility doi: 10.1083/jcb.201406120 Integrity of the dendritic cell (DC) actin cytoskeleton is essential for T cell priming, but the underlying mechanisms are poorly understood. We show that the DC F-actin network regulates the lateral mobility of intracellular cell adhesion molecule 1 (ICAM-1), but not MHCII. ICAM-1 mobility and clustering are regulated by maturation-induced changes in the expression and activation of moesin and ?-actinin-1, which associate with actin filaments and the ICAM-1 cytoplasmic domain. Constrained ICAM-1 mobility is important for DC function, as DCs expressing a high-mobility ICAM-1 mutant lacking the cytoplasmic domain exhibit diminished antigen-dependent conjugate formation and T cell priming. These defects are associated with inefficient induction of leukocyte functional antigen 1 (LFA-1) affinity maturation, which is consistent with a model in which constrained ICAM-1 mobility opposes forces on LFA-1 exerted by the T cell cytoskeleton, whereas ICAM-1 clustering enhances valency and further promotes ligand-dependent LFA-1 activation. Our results reveal an important new mechanism through which the DC cytoskeleton regulates receptor activation at the immunological synapse. http://jcb.rupress.org/content/early/2015/02/03/jcb.201406120.abstract
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Actin works both sides of the immunological synapse doi: 10.1083/jcb.2084if The cytoskeleton of both T cells and antigen-presenting cells promotes mechanical signaling during T cell activation. Antigen-presenting cells (APCs) activate T cells by forming a specialized contact site called the immunological synapse (IS). The T cell receptor (TCR) and its downstream signaling molecules cluster in the center of the IS, surrounded by a ring of integrin molecules such as LFA-1, which lower the threshold for T cell priming by both tightly adhering to ligands on the surface of the APC and by activating downstream signaling pathways of their own. The next questions, says Burkhardt, are how the adhesion and signaling activities of active LFA-1 promote T cell priming, and how mechanical forces at the IS affect T cell functions in vivo. http://jcb.rupress.org/content/early/2015/02/03/jcb.2084if.full
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F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse doi: 10.1083/jcb.201406121 Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse. http://jcb.rupress.org/content/early/2015/02/03/jcb.201406121.short?rss=1
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A unique chromatin complex occupies young ?-satellite arrays of human centromeres DOI: 10.1126/sciadv.1400234 The intractability of homogeneous ?-satellite arrays has impeded understanding of human centromeres. Artificial centromeres are produced from higher-order repeats (HORs) present at centromere edges, although the exact sequences and chromatin conformations of centromere cores remain unknown. We use high-resolution chromatin immunoprecipitation (ChIP) of centromere components followed by clustering of sequence data as an unbiased approach to identify functional centromere sequences. We find that specific dimeric ?-satellite units shared by multiple individuals dominate functional human centromeres. We identify two recently homogenized ?-satellite dimers that are occupied by precisely positioned CENP-A (cenH3) nucleosomes with two ~100–base pair (bp) DNA wraps in tandem separated by a CENP-B/CENP-C–containing linker, whereas pericentromeric HORs show diffuse positioning. Precise positioning is largely maintained, whereas abundance decreases exponentially with divergence, which suggests that young ?-satellite dimers with paired ~100-bp particles mediate evolution of functional human centromeres. Our unbiased strategy for identifying functional centromeric sequences should be generally applicable to tandem repeat arrays that dominate the centromeres of most eukaryotes. http://advances.sciencemag.org/content/1/1/e1400234
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Structural basis for RNA replication by the hepatitis C virus polymerase DOI: 10.1126/science.1259210 Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A ? loop and a C-terminal membrane–anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3? terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site. http://www.sciencemag.org/content/347/6223/771.abstract?sid=768e7f85-3cab-4180-8de4-5c2e5917defa
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William J Murray: You are perfectly right. Observing intelligent people who force their cognitive "creativity" to defend what is utterly indefensible is an experience at the same time funny and sad. Unable to explain the origin of one single functional protein, they happily accept the dogma that complex and irreducible systems implying that coordinated and controlled interactions of hundreds of proteins and structures certainly originated by the same mythical mechanism which exists only in their imagination and faithgpuccio_{February 14, 2015
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The real marvel on display is the capacity of Darwinists to stare at the unveiling of the most sophisticated software/engineering/technology ever witnessed, beyond what has ever been imagined, and resolutely insist that it all occurred completely undirected by any intelligence whatsoever. Religious zealotry is blinding Darwinists to the mounting evidence before their eyes.William J Murray_{February 14, 2015
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Bacterial armor holds clues for self-assembling nanostructures http://www.rdmag.com/news/2015/02/bacterial-armor-holds-clues-self-assembling-nanostructures?et_cid=4414308&et_rid=653535995&location=topDionisio_{February 14, 2015
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#265 addendum
Architecture of the nuclear pore complex coat DOI: 10.1126/science.aaa4136 The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. Despite half a century of structural characterization, the architecture of the NPC remains unknown. Here, we present the crystal structure of a reconstituted ~400 kDa coat nucleoporin complex (CNC) from S. cerevisiae at a 7.4-Å resolution. The crystal structure revealed a curved Y-shaped architecture and the molecular details of the coat nucleoporin interactions forming the central “triskelion” of the Y. A structural comparison of the yeast CNC with an electron microscopy reconstruction of its human counterpart suggested the evolutionary conservation of the elucidated architecture. Moreover, 32 copies of the CNC crystal structure docked readily into a cryoelectron tomographic reconstruction of the fully-assembled human NPC, thereby accounting for ~16 MDa of its mass. https://www.sciencemag.org/content/early/2015/02/11/science.aaa4136.abstract
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Shedding light on structure of key cellular “gatekeeper” Facing a challenge akin to solving a 1,000-piece jigsaw puzzle while blindfolded—and without touching the pieces—many structural biochemists thought it would be impossible to determine the atomic structure of a massive cellular machine called the nuclear pore complex (NPC), which is vital for cell survival. But after 10 years of attacking the problem, a team led by André Hoelz, assistant professor of chemistry, recently solved almost a third of the puzzle. "This is an incredibly important structure to study," he says, "but because it is so large and complex, people thought it was crazy to work on it. But 10 years ago, we hypothesized that we could solve the atomic structure with a divide-and-conquer approach—basically breaking the task into manageable parts—and we've shown that for a major section of the NPC, this actually worked." Still, he adds, "My dream actually goes much farther. I don't really want to have a static image of the pore. What I really would like—and this is where people look at me with a bit of a smile on their face, like they're laughing a little bit—is to get an image of how the pore is moving, how the machine actually works. The pore is not a static hole, it can open up like the iris of a camera to let something through that's much bigger. How does it do it?" To understand that machine in motion, he adds, "you don't just need one snapshot, you need multiple snapshots. But once you have one, you can infer the other ones much quicker, so that's the ultimate goal. That's the dream." http://www.rdmag.com/news/2015/02/shedding-light-structure-key-cellular-gatekeeper?et_cid=4414308&et_rid=653535995&type=headline
Can't wait to see their dream become real. It should be fascinating to understand how that complex machinery functions.Dionisio_{February 14, 2015
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#263 addendum
Dr. Emily Baker conducted the research in the laboratory of Prof. Dek Woolfson. She explains: “The amide bonds can be thought of as tiny bar magnets. When an a-helix is formed these all line up. For almost 40 years it was thought that the smaller bar magnets, which are known as dipoles, add up to give one large effective magnet, called the helix macrodipole.” As Prof. Woolfson puts it: “We are not saying that the helix macrodipole doesn't exist, it is just that it is very weak and its influence is far less than previously thought. Indeed, it is trumped by the local effects that we studied. In short, we do not need to use the macrodipole concept anymore to explain the vast majority of phenomena that have been attributed to it in the past, including in textbooks.” http://www.rdmag.com/news/2015/02/scientists-shed-light-controversial-theory-protein-structure?et_cid=4414308&et_rid=653535995&type=headline
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Local and macroscopic electrostatic interactions in single ?-helices doi:10.1038/nchembio.1739 The noncovalent forces that stabilize protein structures are not fully understood. One way to address this is to study equilibria between unfolded states and ?-helices in peptides. Electrostatic forces—which include interactions between side chains, the backbone and side chains, and side chains and the helix macrodipole—are believed to contribute to these equilibria. Here we probe these interactions experimentally using designed peptides. We find that both terminal backbone–side chain and certain side chain–side chain interactions (which include both local effects between proximal charges and interatomic contacts) contribute much more to helix stability than side chain–helix macrodipole electrostatics, which are believed to operate at larger distances. This has implications for current descriptions of helix stability, the understanding of protein folding and the refinement of force fields for biomolecular modeling and simulations. In addition, this study sheds light on the stability of rod-like structures formed by single ?-helices, which are common in natural proteins such as non-muscle myosins. http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.1739.html
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Measuring Extracellular Vesicle Stability: A New Frontier in Analytical Technology The study of extracellular vesicles is an area that has recently become the subject of intense interest. These vesicles are apparently ubiquitous in prokaryotic and eukaryotic organisms and it is believed they have a wide role to play in many physiological and pathological processes. They are typically described either as exosomes, which are produced from the cell endosome, or microvesicles, produced by cell membrane budding. Despite increased academic and commercial interest, much of the understanding of their cellular origin, structure, functions and size is still the subject of debate, as are the preferred methods of isolation and characterization. http://www.biosciencetechnology.com/articles/2015/02/measuring-extracellular-vesicle-stability-new-frontier-analytical-technology?et_cid=4413211&et_rid=653535995&location=topDionisio_{February 14, 2015
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An Integrated View of Cellular Systems By integrating information from the genome, transcriptome, proteome, and metabolome, dynamic interactions can be examined to decipher complex biological networks. This systems approach involves the integration of high-throughput technology and multiple interdisciplinary areas or fields, including molecular biology, cell biology, genomics, proteomics, metabolomics, and bioinformatics. http://www.the-scientist.com//?articles.view/articleNo/41998/title/An-Integrated-View-of-Cellular-Systems/Dionisio_{February 14, 2015
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