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Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.  相似文献   
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A sparingly-soluble ammonium argentothiosulphate bromide salt (called B-salt) has been prepared by the addition of excess silver bromide to an ammonium thiosulphate solution over the concentration range 0·5 M to 2·5 M. Its nearest “simple” empirical formula is (NH4)4(AgS2O3)3Br. Chemical and physical properties of the salt are described. B-salt is formed in the practical fixing bath and in the photographic emulsion. The fixation of a bromo-iodide emulsion yields a B-salt containing a small quantity of iodide.  相似文献   
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We report a low-cost piezoresistive nanocomposite based organic micro electro mechanical system (MEMS) strain sensor that has been combined to an organic field effect transistor (OFET) with the objective of amplifying the sensitivity of the sensor. When the MEMS cantilever is strained by a mechanical deflection, the resulting variation of resistivity influences the gate voltage (VGS) of the OFET and, hence, changes the drain current (IDS) of the transistor. The present combination allows an enhancement of sensitivity to strain by a factor 3.7, compared to the direct detection of resistance changes of the nanocomposite. As a consequence, a low limit of detection of 24 ppm has been estimated in terms of strain transduction efficiency. Furthermore, the organic microsystem exhibits a short response time and operates reversibly with an excellent robustness.  相似文献   
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Direct steam generation in parabolic trough or linear Fresnel collectors represents one interesting technological option for concentrating solar electricity production. Today's state of the art characterized by the first commercial plants in operation is a result of more than 20 years of intensive research on this topic. This article provides a review on the key results from research that includes physical effects like heat transfer and pressure drop in horizontal boiler tubes, plant layout considerations, and thermal storage options. An overview on test and demonstration facilities as well as on commercial plants is given, leading to an outlook on the next generation of direct steam generation systems.  相似文献   
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While increasing evidence suggests an association between physical infrastructure in neighborhoods and health outcomes, relatively little research examines how neighborhoods change physically over time and how these physical improvements are spatially distributed across populations. This paper describes the change over 25 years (1985–2010) in bicycle lanes, off-road trails, bus transit service and parks, and spatial clusters of changes in these domains relative to neighborhood sociodemographics in four US cities that are diverse in terms of geography, size, and population. Across all four cities we identified increases in bicycle lanes, off-road trails, and bus transit service, with spatial clustering in these changes that related to neighborhood sociodemographics. Overall, we found evidence of positive changes in physical infrastructure commonly identified as supportive of physical activity. However, the patterning of infrastructure change by sociodemographic change encourages attention to the equity in infrastructure improvements across neighborhoods.  相似文献   
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