Shedding light on dark chemical matter: the discovery of a SARS-CoV-2 Mpro main protease inhibitor through Intensive virtual screening and in vitro evaluation

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 µM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.Peer ReviewedPostprint (published version

Efecto del manejo a brotes in vitro de Xanthosoma sagittifolium (L.) Schott y Colocasia esculenta (L.) Schott durante la fase de multiplicación

To solve the limited in vitro multiplication coefficients in taro (Xanthosoma and Colocasia) several strategies are used. This work was carried out with the aim of to determine the effect of the in vitro management of shoots of both species of taro that allows to increase the multiplication coefficient in order to develop a simple method of in vitro propagation of this crop. Four cultivars of Xanthosoma ('Mexico 1', 'Mexico 8', 'Yellow Special', 'Selection INIVIT') and the cultivar 'Cameroon 14' of C. esculenta were used in the multiplication phase. The treatments included variants of decapitation and cut of the shoots. After 25 days of culture, the number of shoots per explant was quantified and the fresh mass was determined. The best results were achieved with treatments 6 (Decapitated 75% of the shoot and cut in the apical bud) and 7 (Decapitated 75% of the shoot, longitudinal cut and bevel of the apical bud) in all cultivars. The multiplication coefficients in both treatments varied from 3.00 to 6.98 depending on the cultivar. It is possible to increase the multiplication coefficient using other forms of cutting of the explants different from the traditional ones used (Beheaded 50% of the shoot and bevel cut).Keywords: cocoyam, decapitated, in vitro handlings, in vitro shoot, multiplication, taroPara resolver los limitados coeficientes de multiplicación in vitro en malanga (Xanthosoma y Colocasia)se emplean varias estrategias. Este trabajo fue realizado con el objetivo de determinar el efecto del manejo a los brotes in vitro de ambas especies de malanga que permita incrementar el coeficiente de multiplicación con el fin de desarrollar un método sencillo de propagación in vitro de este cultivo. Se emplearon cuatro cultivares de Xanthosoma (‘México 1’, ‘México 8’, ‘Amarilla Especial’, ‘Selección INIVIT’) y el cultivar ‘Camerún 14’ de C. esculenta en la fase de multiplicación.Los tratamientos incluyeron variantes de decapitado y corte de los brotes. A los 25 días de cultivo se cuantificó el número de brotes por explante y se determinó la masa fresca. Los mejores resultados se alcanzaron con los tratamientos 6 (Decapitado 75% del brote y corte en la yema apical) y 7 (Decapitado 75% del brote, corte longitudinal y a bisel de la yema apical) en todos los cultivares. Los coeficientes de multiplicación en ambos tratamientos variaron desde 3.00 hasta 6.98 en dependencia del cultivar.Es posible aumentar el coeficiente de multiplicación utilizando otras formas de corte de los explantes diferentes a las tradicionales empleadas (Decapitado 50% del brote y corte a bisel).Palabras clave: brote in vitro, decapitado, malangas, manejo in vitro, multiplicació

Supporting information Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

PDF file contains: Tables S1-S6 and Figures S1-S5Peer reviewe

A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine

A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine

DVINO: A RISC-V vector processor implemented in 65nm technology

This paper describes the design, verification, implementation and fabrication of the Drac Vector IN-Order (DVINO) processor, a RISC-V vector processor capable of booting Linux jointly developed by BSC, CIC-IPN, IMB-CNM (CSIC), and UPC. The DVINO processor includes an internally developed two-lane vector processor unit as well as a Phase Locked Loop (PLL) and an Analog-to-Digital Converter (ADC). The paper summarizes the design from architectural as well as logic synthesis and physical design in CMOS 65nm technology.The DRAC project is co-financed by the European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014-2020 with a grant of 50% of total eligible cost. The authors are part of RedRISCV which promotes activities around open hardware. The Lagarto Project is supported by the Research and Graduate Secretary (SIP) of the Instituto Politecnico Nacional (IPN) from Mexico, and by the CONACyT scholarship for Center for Research in Computing (CIC-IPN).Peer ReviewedArticle signat per 43 autors/es: Guillem Cabo∗, Gerard Candón∗, Xavier Carril∗, Max Doblas∗, Marc Domínguez∗, Alberto González∗, Cesar Hernández†, Víctor Jiménez∗, Vatistas Kostalampros∗, Rubén Langarita∗, Neiel Leyva†, Guillem López-Paradís∗, Jonnatan Mendoza∗, Francesco Minervini∗, Julian Pavón∗, Cristobal Ramírez∗, Narcís Rodas∗, Enrico Reggiani∗, Mario Rodríguez∗, Carlos Rojas∗, Abraham Ruiz∗, Víctor Soria∗, Alejandro Suanes‡, Iván Vargas∗, Roger Figueras∗, Pau Fontova∗, Joan Marimon∗, Víctor Montabes∗, Adrián Cristal∗, Carles Hernández∗, Ricardo Martínez‡, Miquel Moretó∗§, Francesc Moll∗§, Oscar Palomar∗§, Marco A. Ramírez†, Antonio Rubio§, Jordi Sacristán‡, Francesc Serra-Graells‡, Nehir Sonmez∗, Lluís Terés‡, Osman Unsal∗, Mateo Valero∗§, Luís Villa† // ∗Barcelona Supercomputing Center (BSC), Barcelona, Spain. Email: [email protected]; †Centro de Investigación en Computación, Instituto Politécnico Nacional (CIC-IPN), Mexico City, Mexico; ‡ Institut de Microelectronica de Barcelona, IMB-CNM (CSIC), Spain. Email: [email protected]; §Universitat Politecnica de Catalunya (UPC), Barcelona, Spain. Email: [email protected] (author's final draft

Measurements of the suppression and correlations of dijets in Xe+Xe collisions at Formula Presented TeV

Measurements of the suppression and correlations of dijets is performed using 3 µ b − 1 of Xe+Xe data at s N N = 5.44 TeV collected with the ATLAS detector at the CERN Large Hadron Collider. Dijets with jets reconstructed using the R = 0.4 anti- k t algorithm are measured differentially in jet p T over the range of 32 to 398 GeV and the centrality of the collisions. Significant dijet momentum imbalance is found in the most central Xe+Xe collisions, which decreases in more peripheral collisions. Results from the measurement of per-pair normalized and absolutely normalized dijet p T balance are compared with previous Pb + Pb measurements at s N N = 5.02 TeV. The differences between the dijet suppression in Xe+Xe and Pb + Pb are further quantified by the ratio of pair nuclear-modification factors. The results are found to be consistent with those measured in Pb + Pb data when compared in classes of the same event activity and when taking into account the difference between the center-of-mass energies of the initial parton scattering process in Xe+Xe and Pb + Pb collisions. These results should provide input for a better understanding of the role of energy density, system size, path length, and fluctuations in the parton energy loss

Search for supersymmetry in final states with missing transverse momentum and three or more b-jets in 139 fb-1 of proton–proton collisions at √s=13 TeV with the ATLAS detector

A search for supersymmetry involving the pair production of gluinos decaying via off-shell third-generation squarks into the lightest neutralino (χ~10) is reported. It exploits LHC proton–proton collision data at a centre-of-mass energy s=13 TeV with an integrated luminosity of 139 fb collected with the ATLAS detector from 2015 to 2018. The search uses events containing large missing transverse momentum, up to one electron or muon, and several energetic jets, at least three of which must be identified as containing b-hadrons. Both a simple kinematic event selection and an event selection based upon a deep neural-network are used. No significant excess above the predicted background is found. In simplified models involving the pair production of gluinos that decay via off-shell top (bottom) squarks, gluino masses less than 2.44 TeV (2.35 TeV) are excluded at 95% CL for a massless χ~10. Limits are also set on the gluino mass in models with variable branching ratios for gluino decays to bb¯χ~10,tt¯χ~10 and tb¯χ~1-/t¯bχ~1+

Measurements of W+W- production in decay topologies inspired by searches for electroweak supersymmetry

This paper presents a measurement of fiducial and differential cross-sections for WW production in proton–proton collisions at s=13 TeV with the ATLAS experiment at the Large Hadron Collider using a dataset corresponding to an integrated luminosity of 139 fb . Events with exactly one electron, one muon and no hadronic jets are studied. The fiducial region in which the measurements are performed is inspired by searches for the electroweak production of supersymmetric charginos decaying to two-lepton final states. The selected events have moderate values of missing transverse momentum and the ‘stransverse mass’ variable m , which is widely used in searches for supersymmetry at the LHC. The ranges of these variables are chosen so that the acceptance is enhanced for direct WW production and suppressed for production via top quarks, which is treated as a background. The fiducial cross-section and particle-level differential cross-sections for six variables are measured and compared with two theoretical SM predictions from perturbative QCD calculations