2,684 research outputs found

    Strong Purifying Selection at Synonymous Sites in D. melanogaster

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    Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in D. melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated

    Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus).

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    Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model

    Ascertaining the Core Collapse Supernova Mechanism: An Emerging Picture?

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    Here we present the results from two sets of simulations, in two and three spatial dimensions. In two dimensions, the simulations include multifrequency flux-limited diffusion neutrino transport in the "ray-by-ray-plus" approximation, two-dimensional self gravity in the Newtonian limit, and nuclear burning through a 14-isotope alpha network. The three-dimensional simulations are model simulations constructed to reflect the post stellar core bounce conditions during neutrino shock reheating at the onset of explosion. They are hydrodynamics-only models that focus on critical aspects of the shock stability and dynamics and their impact on the supernova mechanism and explosion. In two dimensions, we obtain explosions (although in one case weak) for two progenitors (11 and 15 Solar mass models). Moreover, in both cases the explosion is initiated when the inner edge of the oxygen layer accretes through the shock. Thus, the shock is not revived while in the iron core, as previously discussed in the literature. The three-dimensional studies of the development of the stationary accretion shock instability (SASI) demonstrate the fundamentally new dynamics allowed when simulations are performed in three spatial dimensions. The predominant l=1 SASI mode gives way to a stable m=1 mode, which in turn has significant ramifications for the distribution of angular momentum in the region between the shock and proto-neutron star and, ultimately, for the spin of the remnant neutron star. Moreover, the three-dimensional simulations make clear, given the increased number of degrees of freedom, that two-dimensional models are severely limited by artificially imposed symmetries.Comment: 9 pages, 3 figure

    Alteration of Availability of Heavy Metals to Aquatic Microflora by Complexation with Organics Associated with Oil Shale Development

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    Leachates from both raw (unretorted) and Paraho retorted oil shale show the ability to bind copper, and perhaps cadmium, strongly enough to mitigate the inhibitory effects of these metals on the growth of the test algal

    A Solvable Sequence Evolution Model and Genomic Correlations

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    We study a minimal model for genome evolution whose elementary processes are single site mutation, duplication and deletion of sequence regions and insertion of random segments. These processes are found to generate long-range correlations in the composition of letters as long as the sequence length is growing, i.e., the combined rates of duplications and insertions are higher than the deletion rate. For constant sequence length, on the other hand, all initial correlations decay exponentially. These results are obtained analytically and by simulations. They are compared with the long-range correlations observed in genomic DNA, and the implications for genome evolution are discussed.Comment: 4 pages, 4 figure

    Examining Military Population And Trauma Type As Moderators Of Treatment Outcome For First-Line Psychotherapies For PTSD: A Meta-Analysis

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    There is conflicting evidence as to whether military populations (i.e., veteran and active-duty military service members) demonstrate a poorer response to psychotherapy for posttraumatic stress disorder (PTSD) compared to civilians. Existing research may be complicated by the fact that treatment outcomes differences could be due to the type of trauma exposure (e.g., combat) or population differences (e.g., military culture). This meta-analysis evaluated PTSD treatment outcomes as a function of trauma type (combat v. assault v. mixed) and population (military v. civilian). Unlike previous meta-analyses, we focused exclusively on manualized, first-line psychotherapies for PTSD as defined by expert treatment guidelines. Treatment outcomes were large across trauma types and population; yet differences were observed between trauma and population subgroups. Military populations demonstrated poorer treatment outcomes compared to civilians. The combat and assault trauma subgroups had worse treatment outcomes compared to the mixed trauma subgroup, but differences were not observed between assault and combat subgroups. Higher attrition rates predicted poorer treatment outcomes, but did not vary between military populations and civilians. Overall, manualized, first-line psychotherapies for PTSD should continue to be used for civilians and military populations with various trauma types. However, greater emphasis should be placed on enhancing PTSD psychotherapies for military populations and on treatment retention across populations based on findings from this meta-analysis
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