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Computing phenotypic similarity has been shown to be useful in identification of new disease genes and for rare disease diagnostic support. Genotype–phenotype data from orthologous genes in model organisms can compensate for lack of human data to greatly increase genome coverage. Work over the past decade has demonstrated the power of cross-species phenotype comparisons, and several cross-species phenotype ontologies have been developed for this purpose. The relative contribution of different model organisms to computational identification of disease-associated genes is not yet fully explored. We use methods based on phenotype ontologies to semantically relate phenotypes resulting from loss-of-function mutations in different model organisms to disease-associated phenotypes in humans. Semantic machine learning methods are used to measure how much different model organisms contribute to the identification of known human gene–disease associations. We find that mouse genotype-phenotype data is the most important dataset in the identification of human disease genes by semantic similarity and machine learning over phenotype ontologies. Data from other model organisms does not improve identification over that obtained by using the mouse alone, and therefore does not contribute significantly to this task. Our work has implications for the future development of integrated phenotype ontologies, as well as for the use of model organism phenotypes in human genetic variant interpretation., King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) under Award No.URF/1/3790-01-01, URF/1/4355-01-01, and FCC/1/1976-34-01.

In this paper, I appeal to the notion of practical identity in order to defend the possibility of synchronic duties to the self—that is, self-directed duties focused on one’s present self as opposed to one’s future self. While many dismiss the idea of self-directed duties, I show that a person may be morally required to act in ways that advance her present interests and autonomy by virtue of her occupying multiple practical identities at a single moment.

Background Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations. Objectives We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool. Methods As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability. Results Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95). Conclusions We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.

The International Energy Agency Technology Collaboration Programme for Ocean Energy Systems (OES) initiated the OES Wave Energy Conversion Modelling Task, which focused on the verification and validation of numerical models for simulating wave energy converters (WECs). The long-term goal is to assess the accuracy of and establish confidence in the use of numerical models used in design as well as power performance assessment of WECs. To establish this confidence, the authors used different existing computational modelling tools to simulate given tasks to identify uncertainties related to simulation methodologies: (i) linear potential flow methods; (ii) weakly nonlinear Froude–Krylov methods; and (iii) fully nonlinear methods (fully nonlinear potential flow and Navier–Stokes models). This article summarizes the code-to-code task and code-to-experiment task that have been performed so far in this project, with a focus on investigating the impact of different levels of nonlinearities in the numerical models. Two different WECs were studied and simulated. The first was a heaving semi-submerged sphere, where free-decay tests and both regular and irregular wave cases were investigated in a code-to-code comparison. The second case was a heaving float corresponding to a physical model tested in a wave tank. We considered radiation, diffraction, and regular wave cases and compared quantities, such as the WEC motion, power output and hydrodynamic loading. The Danish partners acknowledge the support from the Danish Energy Agency through project 374 64017-05197. The Swedish partners were supported by the Swedish Energy Agency under Grants P44423-1 and 375 P44432-1. J.V.R. and G.G. acknowledge the support by Science Foundation Ireland under Grant 13/IA/1886. This research was made possible by support from U.S. the Department of Energy’s EERE Water Power Technologies Office. Sandia National Laboratories is a multi-mission laboratory managed and operated by National Technology and Engineering Solutions of Sandia, LLC., a wholly owned subsidiary of Honeywell International, Inc., for the U.S. Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525. This work was authored (in part) by the National Renewable Energy Laboratory, operated by Alliance for Sustainable Energy, LLC, for the U.S. Department of Energy (DOE) under Contract No. DE-AC36-08GO28308. Funding was provided by the U.S. Department of Energy Office of Energy Efficiency and Renewable Energy Wind Energy Technologies Office. The views expressed in this article do not necessarily represent the views of the DOE or the U.S. Government. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledge that the U.S. Government retains a non-exclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this work, or allow others to do so, for U.S. Government purposes.

Deficiency of lysosomal acid β-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, α-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and 4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P

Deficiency of lysosomal acid β-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, α-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and 4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P

Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.

Biodiversity informatics plays a central enabling role in the research community's efforts to address scientific\ud conservation and sustainability issues. Great strides have been made in the past decade establishing a framework\ud for sharing data, where taxonomy and systematics has been perceived as the most prominent discipline involved.\ud To some extent this is inevitable, given the use of species names as the pivot around which information is\ud organised. To address the urgent questions around conservation, land-use, environmental change, sustainability,\ud food security and ecosystem services that are facing Governments worldwide, we need to understand how the\ud ecosystem works. So, we need a systems approach to understanding biodiversity that moves significantly beyond\ud taxonomy and species observations. Such an approach needs to look at the whole system to address species\ud interactions, both with their environment and with other species.\ud It is clear that some barriers to progress are sociological, basically persuading people to use the technological\ud solutions that are already available. This is best addressed by developing more effective systems that deliver\ud immediate benefit to the user, hiding the majority of the technology behind simple user interfaces. An\ud infrastructure should be a space in which activities take place and, as such, should be effectively invisible.\ud This community consultation paper positions the role of biodiversity informatics, for the next decade, presenting\ud the actions needed to link the various biodiversity infrastructures invisibly and to facilitate understanding that can\ud support both business and policy-makers. The community considers the goal in biodiversity informatics to be full\ud integration of the biodiversity research community, including citizens’ science, through a commonly-shared,\ud sustainable e-infrastructure across all sub-disciplines that reliably serves science and society alike.

In a multicentre study, 824 patients with operable rectal cancer were randomized to receive surgery alone, surgery plus a single fraction of 500 rad (5 Gy) and surgery plus 2000 rad (20 Gy) in 10 equal daily, i.e. multiple, fractions. The ratio of abdominoperineal excision to anterior restorative operations was 3:1. There was no evidence of an increased morbidity or mortality following irradiation. The multiple fraction 2000 rad group had tumours which were significantly smaller than those of the other groups. There was also a reduction in the Dukes' C cases in the multiple fraction group. Neither the tumour size nor the lymph node status was altered in the single fraction group.

Until 1930 it was generally true that aspiring middle western painters, when they were really ambitious, moved on to the East. When the depression broke, however, the situation changed abruptly. On the one hand the procession to New York halted; on the other a number of other painters who had already jumped the gun, finding themselves now suddenly destitute, returned to their homes. Out of this reunion a new generation formed, and it is the question now to ascertain what, during the past seven years, it has done.Even so recently as a year ago it would have been easier to find an answer. For then the subject still seemed on the ascendant. The movement inspired originally (or at least immediately) by the Mexicans, and fostered by such homecomers as Grant Wood, to paint what was familiarly around one, was then still flowering into record after record of red barns and tall windmills and lush haystacks, which constituted almost exclusively the “American scene.” It was on to this bandwagon that young men like J...