AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

<scp>ReSurveyEurope</scp>: A database of resurveyed vegetation plots in Europe

AbstractAimsWe introduce ReSurveyEurope — a new data source of resurveyed vegetation plots in Europe, compiled by a collaborative network of vegetation scientists. We describe the scope of this initiative, provide an overview of currently available data, governance, data contribution rules, and accessibility. In addition, we outline further steps, including potential research questions.ResultsReSurveyEurope includes resurveyed vegetation plots from all habitats. Version 1.0 of ReSurveyEurope contains 283,135 observations (i.e., individual surveys of each plot) from 79,190 plots sampled in 449 independent resurvey projects. Of these, 62,139 (78%) are permanent plots, that is, marked in situ, or located with GPS, which allow for high spatial accuracy in resurvey. The remaining 17,051 (22%) plots are from studies in which plots from the initial survey could not be exactly relocated. Four data sets, which together account for 28,470 (36%) plots, provide only presence/absence information on plant species, while the remaining 50,720 (64%) plots contain abundance information (e.g., percentage cover or cover–abundance classes such as variants of the Braun‐Blanquet scale). The oldest plots were sampled in 1911 in the Swiss Alps, while most plots were sampled between 1950 and 2020.ConclusionsReSurveyEurope is a new resource to address a wide range of research questions on fine‐scale changes in European vegetation. The initiative is devoted to an inclusive and transparent governance and data usage approach, based on slightly adapted rules of the well‐established European Vegetation Archive (EVA). ReSurveyEurope data are ready for use, and proposals for analyses of the data set can be submitted at any time to the coordinators. Still, further data contributions are highly welcome.</jats:sec

The persistent shadow of the supermassive black hole of M 87

In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3−3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30° relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5 × 109 M⊙. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet

First Sagittarius A* Event Horizon Telescope Results. VIII. Physical Interpretation of the Polarized Ring

In a companion paper, we present the first spatially resolved polarized image of Sagittarius A* on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%–28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87*, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A* (equivalent to ≈46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow

Trimeric Hemibastadin Congener from the Marine Sponge <i>Ianthella basta</i>

The first naturally occurring trimeric hemibastadin congener, sesquibastadin 1 (<b>1</b>), and the previously reported bastadins 3, 6, 7, 11, and 16 (<b>2</b>–<b>6</b>) were isolated from the marine sponge <i>Ianthella basta</i>, collected in Indonesia. The structure of <b>1</b> was elucidated on the basis of 1D and 2D NMR measurements and by HRMS. Among all the isolated compounds, the linear sesquibastadin 1 (<b>1</b>) and bastadin 3 (<b>2</b>) showed the strongest inhibition rates for at least 22 protein kinases (IC₅₀ = 0.1–6.5 μM), while the macrocyclic bastadins (<b>3</b>–<b>6</b>) demonstrated a strong cytotoxic potential against the murine lymphoma cell line L5178Y (IC₅₀ = 1.5–5.3 μM)

Key Structure–Property Relationships in CO₂ Capture by Supported Alkanolamines

Heterogeneous interfaces exhibit remarkable material properties resulting from their structural motifs, the judicious placement of functional chemical groups, etc. It has been a long-standing challenge to manipulate and design interface structures at the atomic level to achieve new functionalities. Here, we demonstrate that by modifying the length of the backbone in alkanolamines one can control the packing density of organic monolayers adsorbed on rutile TiO₂ and the interaction strength between their amine functional group and the substrate. As a result, we observed strikingly different activities in CO₂ capture by the amine functional group of different alkanolamines on TiO₂(110). Synchrotron photoelectron spectroscopy at near-ambient CO₂ pressures showed that adsorbed 2-amino-1-ethanol (monoethanolamine, MEA) is inactive, whereas the amine group in 3-amino-1-propanol (3AP)/TiO₂(110) readily reacts with and captures CO₂. Our results suggest that the geometry of the interface plays a decisive role in the reactivity of adsorbed functionalized organic molecules, such as solid-supported alkanolamines for CO₂ capture

Synthesis, Characterization, and Nanoencapsulation of Tetrathiatriarylmethyl and Tetrachlorotriarylmethyl (Trityl) Radical DerivativesA Study To Advance Their Applicability as in Vivo EPR Oxygen Sensors

Tissue oxygenation plays an important role in the pathophysiology of various diseases and is often a marker of prognosis and therapeutic response. EPR (ESR) is a suitable noninvasive oximetry technique. However, to reliably deploy soluble EPR probes as oxygen sensors in complex biological systems, there is still a need to investigate and improve their specificity, sensitivity, and stability. We reproducibly synthesized various derivatives of tetrathiatriarylmethyl and tetrachlorotriarylmethyl (trityl) radicals. Hydrophilic radicals were investigated in aqueous solution mimicking physiological conditions by, e.g., variation of viscosity and ionic strength. Their specificity was satisfactory, but the oxygen sensitivity was low. To enhance the capability of trityl radicals as oxygen sensors, encapsulation into oily core nanocapsules was performed. Thus, different lipophilic triesters were prepared and characterized in oily solution employing oils typically used in drug formulations, i.e., middle-chain triglycerides and isopropyl myristate. Our screening identified the deuterated ethyl ester of D-TAM (radical <b>13</b>) to be suitable. It had an extremely narrow single EPR line under anoxic conditions and excellent oxygen sensitivity. After encapsulation, it retained its oxygen responsiveness and was protected against reduction by ascorbic acid. These biocompatible and highly sensitive nanosensors offer great potential for future EPR oximetry applications in preclinical research

Synthesis of Hydroxyapatite Substrates: Bridging the Gap between Model Surfaces and Enamel

Hydroxyapatite substrates are common biomaterials, yet samples of natural teeth do not meet the demands for well-defined, highly reproducible properties. Pellets of hydroxyapatite were produced via the field assisted sintering technology (FAST) as well as via pressureless sintering (PLS). The applied synthesis routes provide samples of very high density (95%–99% of the crystallographic density) and of very low surface roughness (lower than 1 nm when averaged per 1 μm²). The chemical composition of the raw material (commercial HAP powder) as well as the crystalline structure is maintained by the sintering processes. These specimens can therefore be considered as promising model surfaces for studies on the interactions of biomaterial with surfaces of biological relevance, as demonstrated for the adsorption of BSA proteins

Acute kidney disease beyond day 7 after major surgery: a secondary analysis of the EPIS-AKI trial

Purpose: Acute kidney disease (AKD) is a significant health care burden worldwide. However, little is known about this complication after major surgery. Methods: We conducted an international prospective, observational, multi-center study among patients undergoing major surgery. The primary study endpoint was the incidence of AKD (defined as new onset of estimated glomerular filtration rate (eCFR) &lt; 60&nbsp;ml/min/1.73&nbsp;m2 present on day 7 or later) among survivors. Secondary endpoints included the relationship between early postoperative acute kidney injury (AKI) (within 72&nbsp;h after major surgery) and subsequent AKD, the identification of risk factors for AKD, and the rate of chronic kidney disease (CKD) progression in patients with pre-existing CKD. Results: We studied 9510 patients without pre-existing CKD. Of these, 940 (9.9%) developed AKD after 7&nbsp;days of whom 34.1% experiencing an episode of early postoperative-AKI. Rates of AKD after 7&nbsp;days significantly increased with the severity (19.1% Kidney Disease Improving Global Outcomes [KDIGO] 1, 24.5% KDIGO2, 34.3% KDIGO3; P &lt; 0.001) and duration (15.5% transient vs 38.3% persistent AKI; P &lt; 0.001) of early postoperative-AKI. Independent risk factors for AKD included early postoperative-AKI, exposure to perioperative nephrotoxic agents, and postoperative pneumonia. Early postoperative-AKI carried an independent odds ratio for AKD of 2.64 (95% confidence interval [CI] 2.21-3.15). Of 663 patients with pre-existing CKD, 42 (6.3%) had worsening CKD at day 90. In patients with CKD and an episode of early AKI, CKD progression occurred in 11.6%. Conclusion: One in ten major surgery patients developed AKD beyond 7&nbsp;days after surgery, in most cases without an episode of early postoperative-AKI. However, early postoperative-AKI severity and duration were associated with an increased rate of AKD and early postoperative-AKI was strongly associated with AKD independent of all other potential risk factors

Search for supersymmetry in hadronic final states with missing transverse energy using the variables αT and b-quark multiplicity in pp collisions at √s = 8 TeV

Submitted by Vitor Silverio Rodrigues ([email protected]) on 2014-05-27T11:30:34Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:48:49Z : No. of bitstreams: 1 2-s2.0-84883824987.pdf: 1540579 bytes, checksum: be6bbff5192436d9fcdbc367ffd1650e (MD5) Made available in DSpace on 2014-05-27T11:30:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-09-01 An inclusive search for supersymmetric processes that produce final states with jets and missing transverse energy is performed in pp collisions at a centre-of-mass energy of 8 TeV. The data sample corresponds to an integrated luminosity of 11.7 fb-1 collected by the CMS experiment at the LHC. In this search, a dimensionless kinematic variable, αT, is used to discriminate between events with genuine and misreconstructed missing transverse energy. The search is based on an examination of the number of reconstructed jets per event, the scalar sum of transverse energies of these jets, and the number of these jets identified as originating from bottom quarks. No significant excess of events over the standard model expectation is found. Exclusion limits are set in the parameter space of simplified models, with a special emphasis on both compressed-spectrum scenarios and direct or gluino-induced production of third-generation squarks. For the case of gluino-mediated squark production, gluino masses up to 950-1125 GeV are excluded depending on the assumed model. For the direct pair-production of squarks, masses up to 450 GeV are excluded for a single light first- or second-generation squark, increasing to 600 GeV for bottom squarks. © 2013 CERN for the benefit of the CMS collaboration. CERN, Geneva Yerevan Physics Institute, Yerevan Institut für Hochenergiephysik der OeAW, Wien National Centre for Particle and High Energy Physics, Minsk Universiteit Antwerpen, Antwerpen Vrije Universiteit Brussel, Brussel Université Libre de Bruxelles, Bruxelles Ghent University, Ghent Université Catholique de Louvain, Louvain-la-Neuve Université de Mons, Mons Centro Brasileiro de Pesquisas Fisicas, Rio de Janeiro Universidade do Estado do Rio de Janeiro, Rio de Janeiro Universidade Estadual Paulista, São Paulo Universidade Federal do ABC, São Paulo Institute for Nuclear Research and Nuclear Energy, Sofia University of Sofia, Sofia Institute of High Energy Physics, Beijing State Key Laboratory of Nuclear Physics and Technology Peking University, Beijing Universidad de Los Andes, Bogota Technical University of Split, Split University of Split, Split Institute Rudjer Boskovic, Zagreb University of Cyprus, Nicosia Charles University, Prague Academy of Scientific Research and Technology of the Arab Republic of Egypt Egyptian Network of High Energy Physics, Cairo National Institute of Chemical Physics and Biophysics, Tallinn Department of Physics University of Helsinki, Helsinki Helsinki Institute of Physics, Helsinki Lappeenranta University of Technology, Lappeenranta DSM/IRFU CEA/Saclay, Gif-sur-Yvette Laboratoire Leprince-Ringuet, Ecole Polytechnique IN2P3-CNRS, Palaiseau Institut Pluridisciplinaire Hubert Curien, Universite de Strasbourg, Universite de Haute Alsace Mulh CNRS/IN2P3, Strasbourg CNRS-IN2P3, Institut de Physique Nucléaire de Lyon Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne Institute of High Energy Physics and Informatization Tbilisi State University, Tbilisi I. Physikalisches Institut RWTH Aachen University, Aachen III. Physikalisches Institut A RWTH Aachen University, Aachen III. Physikalisches Institut B RWTH Aachen University, Aachen Deutsches Elektronen-Synchrotron, Hamburg University of Hamburg, Hamburg Institut für Experimentelle Kernphysik, Karlsruhe Institute of Nuclear and Particle Physics (INPP) NCSR Demokritos, Aghia Paraskevi University of Athens, Athens University of Ioánnina, Ioánnina KFKI Research Institute for Particle and Nuclear Physics, Budapest Institute of Nuclear Research ATOMKI, Debrecen University of Debrecen, Debrecen Panjab University, Chandigarh University of Delhi, Delhi Saha Institute of Nuclear Physics, Kolkata Bhabha Atomic Research Centre, Mumbai Tata Institute of Fundamental Research - EHEP, Mumbai Tata Institute of Fundamental Research - HECR, Mumbai Institute for Research in Fundamental Sciences (IPM), Tehran INFN Sezione di Bari, Bari Università di Bari, Bari Politecnico di Bari, Bari INFN Sezione di Bologna, Bologna Università di Bologna, Bologna INFN Sezione di Catania, Catania Università di Catania, Catania INFN Sezione di Firenze, Firenze Università di Firenze, Firenze INFN Laboratori Nazionali di Frascati, Frascati INFN Sezione di Genova, Genova Università di Genova, Genova INFN Sezione di Milano-Bicocca, Milano Università di Milano-Bicocca, Milano INFN Sezione di Napoli, Napoli Università di Napoli 'Federico II', Napoli Università della Basilicata (Potenza), Napoli Università G. Marconi (Roma), Napoli INFN Sezione di Padova, Padova Università di Padova, Padova Università di Trento (Trento), Padova INFN Sezione di Pavia, Pavia Università di Pavia, Pavia INFN Sezione di Perugia, Perugia Università di Perugia, Perugia INFN Sezione di Pisa, Pisa Università di Pisa, Pisa Scuola Normale Superiore di Pisa, Pisa INFN Sezione di Roma, Roma Università di Roma, Roma INFN Sezione di Torino, Torino Università di Torino, Torino Università del Piemonte Orientale (Novara), Torino INFN Sezione di Trieste, Trieste Università di Trieste, Trieste Kangwon National University, Chunchon Kyungpook National University, Daegu Institute for Universe and Elementary Particles Chonnam National University, Kwangju Korea University, Seoul University of Seoul, Seoul Sungkyunkwan University, Suwon Vilnius University, Vilnius Centro de Investigacion y de Estudios Avanzados del IPN, Mexico City Universidad Iberoamericana, Mexico City Benemerita Universidad Autonoma de Puebla, Puebla Universidad Autónoma de San Luis Potosí, San Luis Potosí University of Auckland, Auckland University of Canterbury, Christchurch National Centre for Physics Quaid-I-Azam University, Islamabad National Centre for Nuclear Research, Swierk Institute of Experimental Physics, Faculty of Physics University of Warsaw, Warsaw Laboratório de Instrumentação e Física Experimental de Partículas, Lisboa Joint Institute for Nuclear Research, Dubna Petersburg Nuclear Physics Institute, Gatchina (St. Petersburg) Institute for Nuclear Research, Moscow Institute for Theoretical and Experimental Physics, Moscow P.N. Lebedev Physical Institute, Moscow Skobeltsyn Institute of Nuclear Physics Lomonosov Moscow State University, Moscow State Research Center of Russian Federation Institute for High Energy Physics, Protvino Faculty of Physics and Vinca Institute of Nuclear Sciences University of Belgrade, Belgrade Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Madrid Universidad Autónoma de Madrid, Madrid Universidad de Oviedo, Oviedo Instituto de Física de Cantabria (IFCA) CSIC-Universidad de Cantabria, Santander European Organization for Nuclear Research CERN, Geneva Paul Scherrer Institut, Villigen Institute for Particle Physics ETH Zurich, Zurich Universität Zürich, Zurich National Central University, Chung-Li National Taiwan University (NTU), Taipei Chulalongkorn University, Bangkok Cukurova University, Adana Physics Department Middle East Technical University, Ankara Bogazici University, Istanbul Istanbul Technical University, Istanbul National Scientific Center Kharkov Institute of Physics and Technology, Kharkov University of Bristol, Bristol Rutherford Appleton Laboratory, Didcot Imperial College, London Brunel University, Uxbridge Baylor University, Waco The University of Alabama, Tuscaloosa Boston University, Boston Brown University, Providence University of California, Davis, Davis University of California, Los Angeles University of California, Riverside, Riverside University of California, San Diego, La Jolla University of California, Santa Barbara, Santa Barbara California Institute of Technology, Pasadena Carnegie Mellon University, Pittsburgh University of Colorado at Boulder, Boulder Cornell University, Ithaca Fairfield University, Fairfield Fermi National Accelerator Laboratory, Batavia University of Florida, Gainesville Florida International University, Miami Florida State University, Tallahassee Florida Institute of Technology, Melbourne University of Illinois at Chicago (UIC), Chicago The University of Iowa, Iowa City Johns Hopkins University, Baltimore The University of Kansas, Lawrence Kansas State University, Manhattan Lawrence Livermore National Laboratory, Livermore University of Maryland, College Park Massachusetts Institute of Technology, Cambridge University of Minnesota, Minneapolis University of Mississippi, Oxford University of Nebraska-Lincoln, Lincoln State University of New York at Buffalo, Buffalo Northeastern University, Boston Northwestern University, Evanston University of Notre Dame, Notre Dame The Ohio State University, Columbus Princeton University, Princeton University of Puerto Rico, Mayaguez Purdue University, West Lafayette Purdue University Calumet, Hammond Rice University, Houston University of Rochester, Rochester The Rockefeller University, New York Rutgers The State University of New Jersey, Piscataway University of Tennessee, Knoxville Texas A and M University, College Station Texas Tech University, Lubbock Vanderbilt University, Nashville University of Virginia, Charlottesville Wayne State University, Detroit University of Wisconsin, Madison Universidade Estadual Paulista, São Paul