A key challenge of modern biology is to uncover the functional role of the protein entities that compose cellular proteomes. To this end, the availability of reliable three-dimensional atomic models of proteins is often crucial. This protocol presents a community-wide web-based method using RaptorX (http://raptorx.uchicago.edu/) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling. RaptorX distinguishes itself from other servers by the quality of the alignment between a target sequence and one or multiple distantly related template proteins (especially those with sparse sequence profiles) and by a novel nonlinear scoring function and a probabilistic-consistency algorithm. Consequently, RaptorX delivers high-quality structural models for many targets with only remote templates. At present, it takes RaptorX ~35 min to finish processing a sequence of 200 amino acids. Since its official release in August 2011, RaptorX has processed ~6,000 sequences submitted by ~1,600 users from around the world.
Despite intense interest in expanding chemical space, libraries of hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here, we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds otherwise unavailable. The library was docked against AmpC β-lactamase and the D 4 dopamine receptor. From the top-ranking molecules, 44 and 549 were synthesized and tested, respectively. This revealed an unprecedented phenolate inhibitor of AmpC, which was optimized to 77 nM, the most potent non-covalent AmpC inhibitor known. Crystal structures of this and other new AmpC inhibitors confirmed the docking predictions. Against D 4 , hit rates fell monotonically with docking score, and a hit-rate vs. score curve predicted 453,000 D 4 ligands in the library. Of 81 new chemotypes discovered, 30 were sub-micromolar, including a 180 pM sub-type selective agonist.
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Prepared by the LSST Science Collaborations, with contributions from the LSST Project. PrefaceMajor advances in our understanding of the Universe over the history of astronomy have often arisen from dramatic improvements in our ability to observe the sky to greater depth, in previously unexplored wavebands, with higher precision, or with improved spatial, spectral, or temporal resolution. Aided by rapid progress in information technology, current sky surveys are again changing the way we view and study the Universe, and the next-generation instruments, and the surveys that will be made with them, will maintain this revolutionary progress. Substantial progress in the important scientific problems of the next decade (determining the nature of dark energy and dark matter, studying the evolution of galaxies and the structure of our own Milky Way, opening up the time domain to discover faint variable objects, and mapping both the inner and outer Solar System) all require wide-field repeated deep imaging of the sky in optical bands.The wide-fast-deep science requirement leads to a single wide-field telescope and camera which can repeatedly survey the sky with deep short exposures. The Large Synoptic Survey Telescope (LSST), a dedicated telecope with an effective aperture of 6.7 meters and a field of view of 9.6 deg 2 , will make major contributions to all these scientific areas and more. It will carry out a survey of 20,000 deg 2 of the sky in six broad photometric bands, imaging each region of sky roughly 2000 times (1000 pairs of back-to-back 15-sec exposures) over a ten-year survey lifetime.The LSST project will deliver fully calibrated survey data to the United States scientific community and the public with no proprietary period. Near real-time alerts for transients will also be provided worldwide. A goal is worldwide participation in all data products. The survey will enable comprehensive exploration of the Solar System beyond the Kuiper Belt, new understanding of the structure of our Galaxy and that of the Local Group, and vast opportunities in cosmology and galaxy evolution using data for billions of distant galaxies. Since many of these science programs will involve the use of the world's largest non-proprietary database, a key goal is maximizing the usability of the data. Experience with previous surveys is that often their most exciting scientific results were unanticipated at the time that the survey was designed; we fully expect this to be the case for the LSST as well.The purpose of this Science Book is to examine and document in detail science goals, opportunities, and capabilities that will be provided by the LSST. The book addresses key questions that will be confronted by the LSST survey, and it poses new questions to be addressed by future study. It contains previously available material (including a number of White Papers submitted to the ASTRO2010 Decadal Survey) as well as new results from a year-long campaign of study and evaluation. This book does not attempt to be complete; there are many ...
Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H 2 O 2 into hydroxyl radical (•OH), but endogenous H 2 O 2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H 2 O 2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H 2 O 2 . The CP nanodots were prepared through coordination of H 2 O 2 to Cu 2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu 2+ and H 2 O 2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.
The host tissue microenvironment influences malignant cell proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34 + (HPC-enriched) cells. CD34 + cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34 + cell migration into malignant niches, normalized CD34 + cell numbers, and restored CD34 + cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in the setting of malignancy.
Ion channels on the mitochondrial inner membrane influence cell function in specific ways that can be detrimental or beneficial to cell survival. At least one type of potassium (K+) channel, the mitochondrial adenosine triphosphate-sensitive K+ channel (mitoKATP), is an important effector of protection against necrotic and apoptotic cell injury after ischemia. Here another channel with properties similar to the surface membrane calcium-activated K+ channel was found on the mitochondrial inner membrane (mitoKCa) of guinea pig ventricular cells. MitoKCa significantly contributed to mitochondrial K+ uptake of the myocyte, and an opener of mitoKCa protected hearts against infarction.
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