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SARS-CoV-2 identified through crystallographic screening and computational docking

Science Advances 2021年第16期7卷

作者： Schuller, Marion Correy, Galen J. Gahbauer, Stefan Fearon, Daren Wu, Taiasean Díaz, Roberto Efraín Young, Iris D. Martins, Luan Carvalho Smith, Dominique H. Schulze-Gahmen, Ursula Owens, Tristan W. Deshpande, Ishan Merz, Gregory E. Thwin, Aye C. Biel, Justin T. Peters, Jessica K. Moritz, Michelle Herrera, Nadia Kratochvil, Huong T. Aimon, Anthony Bennett, James M. Neto, Jose Brandao Cohen, Aina E. Dias, Alexandre Douangamath, Alice Dunnett, Louise Fedorov, Oleg Ferla, Matteo P. Fuchs, Martin R. Gorrie-Stone, Tyler J. Holton, James M. Johnson, Michael G. Krojer, Tobias Meigs, George Powell, Ailsa J. Rack, Johannes Gregor Matthias Rangel, Victor L. Russi, Silvia Skyner, Rachael E. Smith, Clyde A. Soares, Alexei S. Wierman, Jennifer L. Zhu, Kang O Brien, Peter Jura, Natalia Ashworth, Alan Irwin, John J. Thompson, Michael C. Gestwicki, Jason E. Von Delft, Frank Shoichet, Brian K. Fraser, James S. Ahel, Ivan Sir William Dunn School of Pathology University of Oxford South Parks Road OxfordOX1 3RE United Kingdom Department of Bioengineering and Therapeutic Sciences University of California San Francisco San FranciscoCA94158 United States Department of Pharmaceutical Chemistry University of California San Francisco San FranciscoCA94158 United States Diamond Light Source Ltd. Harwell Science and Innovation Campus DidcotOX11 0DE United Kingdom Institute for Neurodegenerative Disease University of California San Francisco San FranciscoCA94158 United States Chemistry and Chemical Biology Graduate Program University of California San Francisco San FranciscoCA94158 United States Tetrad Graduate Program University of California San Francisco San FranciscoCA94158 United States Coronavirus Research Group Structural Biology Consortium University of California San Francisco San FranciscoCA94158 United States Biochemistry Department Institute for Biological Sciences Federal University of Minas Gerais Belo Horizonte Brazil Helen Diller Family Comprehensive Cancer University of California San Francisco San FranciscoCA94158 United States Centre for Medicines Discovery University of Oxford South Parks Road HeadingtonOX3 7DQ United Kingdom Stanford Synchrotron Radiation Lightsource Slac National Accelerator Center Menlo ParkCA94025 United States Wellcome Centre for Human Genetics University of Oxford Old Road Campus OxfordOX3 7BN United Kingdom National Synchrotron Light Source Ii Brookhaven National Laboratory UptonNY11973 United States Department of Biochemistry and Biophysics University of California San Francisco San FranciscoCA94158 United States Department of Molecular Biophysics and Integrated Bioimaging Lawrence Berkeley National Laboratory BerkeleyCA94720 United States ChemPartner Corporation South San FranciscoCA94080 United States Structural Genomics Consortium University of Oxford Old Road Campus HeadingtonOX3 7DQ United Kingdom School of

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors. © 2021 American Association for the Advancement of Science. All rights reserved.

关键词： Coronavirus

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From mechanism to medicine: The progress and potential of epigenetics in osteoarthritis

Osteoarthritis and Cartilage Open

引用

Osteoarthritis and Cartilage Open 2025年第3期7卷 100621-100621页

作者： Roberts, Jack B. Rockel, Jason S. Mulders, Rick Capellini, Terence D. Appleton, C. Thomas Phanstiel, Douglas H. Lories, Rik Geurts, Jeroen Ali, Shabana Amanda Bhutani, Nidhi Stone, Laura Cruz-Almeida, Yenisel Jurisica, Igor Boer, Cindy G. Ramos, Yolande F.M. Rice, Sarah J. Kapoor, Mohit Biosciences Institute Newcastle University Newcastle upon Tyne United Kingdom Division of Orthopedics Osteoarthritis Research Program Schroeder Arthritis Institute University Health Network and Krembil Research Institute University Health Network Toronto ON Canada Department of Medical Biophysics and Computer Science University of Toronto Toronto ON Canada Department of Biomedical Data Sciences Section Molecular Epidemiology Leiden University Medical Center Leiden Netherlands Department of Human Evolutionary Biology Harvard University Cambridge MA United States Bone and Joint Institute and Department of Medicine Schulich School of Medicine and Dentistry Western University London Canada Curriculum in Bioinformatics and Computational Biology University of North Carolina Chapel Hill NC United States Laboratory of Tissue Homeostasis and Disease Skeletal Biology and Engineering Research Centre Department of Development and Regeneration KU Leuven Leuven Belgium Division of Rheumatology University Hospitals Leuven Leuven Belgium Rheumatology Department of Musculoskeletal Medicine Lausanne University Hospital and University of Lausanne (CHUV-UNIL) Lausanne Switzerland Bone and Joint Center Henry Ford Health + Michigan State University Health Sciences Detroit MI United States Department of Orthopaedic Surgery Stanford School of Medicine Stanford CA United States Department of Anesthesiology School of Medicine University of Minnesota Minneapolis MN United States Pain Research and Intervention Center of Excellence (PRICE) at the University of Florida Gainesville FL United States Department of Internal Medicine Genomics Medicine Center Erasmus MC University Medical Center Rotterdam Netherlands Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada Department of Surgery University of Toronto Toronto ON Canada

Objective: Osteoarthritis (OA) is a chronic, degenerative disease of the articular joints. The disease presents an enormous clinical and economic burden globally, due in part to the lack of disease modifying therapies. For over a decade, OA researchers have been working to determine epigenetic mechanisms underlying the disease to better understand pathology, identify biomarkers of progression, and pinpoint novel targets for therapeutic intervention. Design: This article presents a summary of the 3rd International Workshop on the Epigenetics of Osteoarthritis held in Toronto, Ontario, Canada, in September 2024. The purpose of this meeting was to gather the international community to discuss the status of OA epigenetic research and share expertise on innovative techniques for future. Results: Since the two previous meetings, there has been increasing adoption of advanced single-cell and spatial sequencing technologies and bioinfomatic analyses. Furthermore, investigations of multiple joint tissues has highlighted the shifting paradigm from OA as a cartilage centric disease to the consideration of all joint tissues. Conclusions: The workshop provided a unique opportunity for early-career researchers to expand their network, and for all participants to discuss new or improved approaches to advance the field, including international consortia and data sharing. The highlights and outcomes from this OA epigenetics workshop are described in this report. © 2025 The Authors

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structural insights into binding specificity, efficacy and bias of a β2AR partial agonist (vol 14, pg 1059, 2018)

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NATURE CHEMICAL biology 2019年第2期15卷 205-205页

作者： Masureel, Matthieu Zou, Yaozhong Picard, Louis-Philippe van der Westhuizen, Emma Mahoney, Jacob P. Rodrigues, Joao P. G. L. M. Mildorf, Thomas J. Dror, Ron O. Shaw, David E. Bouvier, Michel Pardon, Els Steyaert, Jan Sunahara, Roger K. Weis, William I. Zhang, Cheng Kobilka, Brian K. Department of Molecular and Cellular Physiology Stanford University School of Medicine Stanford USA Geneus Technologies Ltd Chengdu People’s Republic of China Department of Biochemistry Institute for Research in Immunology and Cancer Université de Montreal Montreal Québec Canada Monash Institute for Pharmaceutical Sciences Monash University Victoria Australia Department of Pharmacology University of Michigan Ann Arbor USA Department of Computer Science Stanford University Stanford USA Department of Structural Biology Stanford University Stanford USA D. E. Shaw Research New York USA Dropbox New York USA Department of Computer Science and Institute for Computational and Mathematical Engineering Stanford University Stanford USA Department of Biochemistry and Molecular Biophysics Columbia University New York USA Structural Biology Brussels Vrije Universiteit Brussel Brussels Belgium Structural Biology Research Center VIB Brussels Belgium Department of Pharmacology University of California San Diego School of Medicine La Jolla USA Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh USA

In the version of this paper originally published, the structure for epinephrine shown in Figure 1a was redrawn with an extra carbon. The structure has been replaced in the HTML and PDF versions of the article. The or... 详细信息

关键词： Statistical Biases bias(electronics) Bias Specificity partial agonist

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Going Deeper in Cryo Electron Tomography with Neural Networks

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Microscopy and Microanalysis 2017年第S1期23卷 814-815页

作者： Muyuan Chen Wei Dai Stella Y. Sun Michael F. Schmid Wah Chiu Steven J. Ludtke Graduate Program in Structural and Computational Biology and Molecular Biophysics Baylor College of Medicine Houston TX Verna Marrs and McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX

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Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer's disease

npj metabolic health and disease

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npj metabolic health and disease 2024年第1期2卷 15页

作者： Annalise Schweickart Richa Batra Bryan J Neth Cameron Martino Liat Shenhav Anru R Zhang Pixu Shi Naama Karu Kevin Huynh Peter J Meikle Leyla Schimmel Amanda Hazel Dilmore Kaj Blennow Henrik Zetterberg Colette Blach Pieter C Dorrestein Rob Knight Suzanne Craft Rima Kaddurah-Daouk Jan Krumsiek Tri-Institutional Program in Computational Biology & Medicine Weill Cornell Medicine New York NY USA. Department of Physiology and Biophysics Weill Cornell Medicine Institute for Computational Biomedicine Englander Institute for Precision Medicine New York NY USA. Department of Neurology Mayo Clinic Rochester MN USA. Department of Pediatrics University of California San Diego La Jolla CA USA. Department of Microbiology New York University Grossman School of Medicine New York NY USA. Department of Biostatistics and Bioinformatics Duke University Durham NC USA. Tasmanian Independent Metabolomics and Analytical Chemistry Solutions (TIMACS) Hobart TAS Australia. Baker Heart and Diabetes Institute 75 Commercial Road Melbourne VIC Australia. Baker Department of Cardiovascular Research Translation and Implementation La Trobe University Bundoora VIC Australia. Department of Psychiatry and Behavioral Sciences Duke University Durham NC USA. Department of Psychiatry and Neurochemistry University of Gothenburg Gothenburg Sweden. Duke Molecular Physiology Institute Duke University Durham NC USA. Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego La Jolla CA USA. Departments of Pediatrics Computer Science and Engineering Bioengineering University of California San Diego La Jolla CA USA. Department of Gerontology and Geriatric Medicine Wake Forest University School of Medicine Winston Salem NC USA. Duke Institute of Brain Sciences Duke University Durham NC USA. Department of Medicine Duke University Durham NC USA.

Alzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

关键词： Diseases Metabolomics

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TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells (vol 50, pg 83, 2017)

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NATURE GENETICS 2018年第5期50卷 764-764页

作者： Verma, Nipun Pan, Heng Dore, Louis C. Shukla, Abhijit Li, Qing V. Pelham-Webb, Bobbie Teijeiro, Virginia Gonzalez, Federico Krivtsov, Andrei Chang, Chan-Jung Papapetrou, Eirini P. He, Chuan Elemento, Olivier Huangfu, Danwei Developmental Biology Program Sloan Kettering Institute New York NY USA Weill Graduate School of Medical Sciences at Cornell University/The Rockefeller University/Sloan Kettering Institute Tri-Institutional MD-PhD Program New York NY USA Department of Physiology and Biophysics Englander Institute for Precision Medicine Institute for Computational Biomedicine Weill Cornell Medical College New York NY USA Weill Cornell Graduate School of Medical Sciences Weill Cornell Medical College New York NY USA Department of Chemistry Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics Howard Hughes Medical Institute University of Chicago Chicago IL USA Louis V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY USA Cancer Biology and Genetics Program Sloan Kettering Institute New York NY USA Department of Oncological Sciences and Black Family Stem Cell Institute Icahn School of Medicine at Mount Sinai New York NY USA

TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish owing to challenges in distinguishing global versus locus-specific effects. Here we show that TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) exhibit prominent bivalent promoter hypermethylation without an overall corresponding decrease in gene expression in the undifferentiated state. Focusing on the bivalent PAX6 locus, we find that increased DNMT3B binding is associated with promoter hypermethylation, which precipitates a neural differentiation defect and failure of PAX6 induction during differentiation. dCas9-mediated locus-specific demethylation and global inactivation of DNMT3B in TKO hESCs partially reverses the hypermethylation at the PAX6 promoter and improves differentiation to neuroectoderm. Taking these findings together with further genome-wide methylation and TET1 and DNMT3B ChIP-seq analyses, we conclude that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation.

关键词： Epigenetics Stem cells

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Structuring stress for active materials control

arXiv

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arXiv 2019年

作者： Zhang, Rui Redford, Steven A. Ruijgrok, Paul V. Kumar, Nitin Mozaffari, Ali Zemsky, Sasha Dinner, Aaron R. Vitelli, Vincenzo Bryant, Zev Gardel, Margaret L. de Pablo, Juan J. Pritzker School of Molecular Engineering University of Chicago ChicagoIL60637 United States The graduate program in Biophysical Sciences University of Chicago ChicagoIL60637 United States James Franck Institute University of Chicago ChicagoIL60637 United States Department of Bioengineering Stanford University StanfordCA94305 United States Program in Biophysics Stanford University StanfordCA94305 United States Department of Chemistry University of Chicago ChicagoIL60637 United States Department of Physics University of Chicago ChicagoIL60637 United States Department of Structural Biology Stanford University Medical Center StanfordCA94305 United States Center for Molecular Engineering Argonne National Laboratory LemontIL60439 United States

Active materials are capable of converting free energy into mechanical work to produce autonomous motion, and exhibit striking collective dynamics that biology relies on for essential functions. Controlling those dynamics and transport in synthetic systems has been particularly challenging. Here, we introduce the concept of spatially structured activity as a means to control and manipulate transport in active nematic liquid crystals consisting of actin filaments and light-sensitive myosin motors. Simulations and experiments are used to demonstrate that topological defects can be generated at will, and then constrained to move along specified trajectories, by inducing local stresses in an otherwise passive material. These results provide a foundation for design of autonomous and reconfigurable microfluidic systems where transport is controlled by modulating activity with light. Copyright © 2019, The Authors. All rights reserved.

关键词： Nematic liquid crystals

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Analyses of protein cores reveal fundamental differences between solution and crystal structures

arXiv

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arXiv 2019年

作者： Mei, Zhe Treado, John D. Grigas, Alex T. Levine, Zachary A. Regan, Lynne O'Hern, Corey S. Integrated Graduate Program in Physical & Engineering Biology Yale University New HavenCT06520 United States Department of Chemistry Yale University New HavenCT06520 United States Department of Mechanical Engineering & Materials Science Yale University New HavenCT06520 United States Graduate Program in Computational Biology & Bioinformatics Yale University New HavenCT06520 United States Department of Pathology Yale University New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Center for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

There have been several studies suggesting that protein structures solved by NMR spectroscopy and x-ray crystallography show significant differences. To understand the origin of these differences, we assembled a database of high-quality protein structures solved by both methods. We also find significant differences between NMR and crystal structures|in the root-mean-square deviations of the Cα atomic positions, identities of core amino acids, backbone and sidechain dihedral angles, and packing fraction of core residues. In contrast to prior studies, we identify the physical basis for these differences by modelling protein cores as jammed packings of amino-acid-shaped particles. We find that we can tune the jammed packing fraction by varying the degree of thermalization used to generate the packings. For an athermal protocol, we find that the average jammed packing fraction is identical to that observed in the cores of protein structures solved by x-ray crystallography. In contrast, highly thermalized packing-generation protocols yield jammed packing fractions that are even higher than those observed in NMR structures. These results indicate that thermalized systems can pack more densely than athermal systems, which suggests a physical basis for the structural differences between protein structures solved by NMR and x-ray crystallography. Copyright © 2019, The Authors. All rights reserved.

关键词： X ray crystallography

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Precision and accuracy of single-molecule FRET measurements-a multi-laboratory benchmark study (vol 15, pg 984, 2018)

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NATURE METHODS 2018年第11期15卷 984-984页

作者： Hellenkamp, Bjorn Schmid, Sonja Doroshenko, Olga Opanasyuk, Oleg Kuhnemuth, Ralf Adariani, Soheila Rezaei Ambrose, Benjamin Aznauryan, Mikayel Barth, Anders Birkedal, Victoria Bowen, Mark E. Chen, Hongtao Cordes, Thorben Eilert, Tobias Fijen, Carel Gebhardt, Christian Gotz, Markus Gouridis, Giorgos Gratton, Enrico Ha, Taekjip Hao, Pengyu Hanke, Christian A. Hartmann, Andreas Hendrix, Jelle Hildebrandt, Lasse L. Hirschfeld, Verena Hohlbein, Johannes Hua, Boyang Hubner, Christian G. Kallis, Eleni Kapanidis, Achillefs N. Kim, Jae-Yeol Krainer, Georg Lamb, Don C. Lee, Nam Ki Lemke, Edward A. Levesque, Brie Levitus, Marcia McCann, James J. Naredi-Rainer, Nikolaus Nettels, Daniel Thuy Ngo Qiu, Ruoyi Robb, Nicole C. Rocker, Carlheinz Sanabria, Hugo Schlierf, Michael Schroder, Tim Schuler, Benjamin Seidel, Henning Streit, Lisa Thurn, Johann Tinnefeld, Philip Tyagi, Swati Vandenberk, Niels Vera, Andres Manuel Weninger, Keith R. Wunsch, Bettina Yanez-Orozco, Inna S. Michaelis, Jens Seidel, Claus A. M. Craggs, Timothy D. Hugel, Thorsten Institute of Physical Chemistry University of Freiburg Freiburg im Breisgau Germany Engineering and Applied Sciences Columbia University New York NY USA Department of Bionanoscience Kavli Institute of Nanoscience Delft Delft University of Technology Delft the Netherlands Molecular Physical Chemistry Heinrich-Heine-Universität Düsseldorf Düsseldorf Germany Department of Physics and Astronomy Clemson University Clemson SC USA Department of Chemistry University of Sheffield Sheffield UK Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry Aarhus University Aarhus Denmark Physical Chemistry Department of Chemistry Nanosystems Initiative Munich (NIM) Center for Integrated Protein Science Munich (CiPSM) and Center for Nanoscience (CeNS) Ludwig-Maximilians-Universität München Munich Germany Department of Physiology & Biophysics Stony Brook University Stony Brook NY USA Department of Biomedical Engineering University of California Irvine Irvine CA USA Molecular Microscopy Research Group Zernike Institute for Advanced Materials University of Groningen Groningen the Netherlands Physical and Synthetic Biology Faculty of Biology Ludwig-Maximilians-Universität München Planegg-Martinsried Germany Institute for Biophysics Ulm University Ulm Germany Laboratory of Biophysics Wageningen University & Research Wageningen the Netherlands Department of Biomedical Engineering John Hopkins University Baltimore MD USA Department of Physics North Carolina State University Raleigh NC USA B CUBE—Center for Molecular Bioengineering TU Dresden Dresden Germany Laboratory for Photochemistry and Spectroscopy Department of Chemistry University of Leuven Leuven Belgium Dynamic Bioimaging Lab Advanced Optical Microscopy Center and Biomedical Research Institute Hasselt University Hasselt Belgium Institute of Physics University of Lübeck Lübeck Germany Microspectroscopy Research Facility Wageningen Wageningen University & Research Wageningen the Netherla

Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods.

关键词： Biophysical methods DNA Fluorescence resonance energy transfer Single-molecule biophysics Structure determination

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Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs

arXiv

引用

arXiv 2018年

作者： Bepler, Tristan Morin, Andrew Brasch, Julia Shapiro, Lawrence Noble, Alex J. Berger, Bonnie Computational and Systems Biology MIT CambridgeMA United States Computer Science and Artificial Intelligence Laboratory MIT CambridgeMA United States Department of Mathematics MIT CambridgeMA United States Department of Biochemistry and Molecular Biophysics Mortimer B. Zuckerman Mind Brain Behavior Institute Columbia University NY United States National Resource for Automated Molecular Microscopy Simons Electron Microscopy Center New York Structural Biology Center NY United States

Cryo-electron microscopy (cryoEM) is an increasingly popular method for protein structure determination. However, identifying a sufficient number of particles for analysis (often >100,000) can take months of manual effort. Current computational approaches are limited by high false positive rates and require significant ad-hoc post-processing, especially for unusually shaped particles. To address this shortcoming, we develop Topaz, an efficient and accurate particle picking pipeline using neural networks trained with few labeled particles by newly leveraging the remaining unlabeled particles through the framework of positive-unlabeled (PU) learning. Remarkably, despite using minimal labeled particles, Topaz allows us to improve reconstruction resolution by up to 0.15 Å over published particles on three public cryoEM datasets without any post-processing. Furthermore, we show that our novel generalized-expectation criteria approach to PU learning outperforms existing general PU learning approaches when applied to particle detection, especially for challenging datasets of non-globular proteins. We expect Topaz to be an essential component of cryoEM analysis. Copyright © 2018, The Authors. All rights reserved.

关键词： Topaz

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