8 research outputs found

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Measurement of the lifetime of the Bc+B_c^+ meson using the Bc+J/ψπ+B_c^+\rightarrow J/\psi\pi^+ decay mode

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    The difference in total widths between the Bc+B_c^+ and B+B^+ mesons is measured using 3.0fb1^{-1} of data collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton-proton collisions at the LHC. Through the study of the time evolution of Bc+J/ψπ+B_c^+ \rightarrow J/\psi \pi^+ and B+J/ψK+B^+\rightarrow J/\psi K^+ decays, the width difference is measured to be ΔΓΓBc+ΓB+=4.46±0.14±0.07mm1c, \Delta\Gamma \equiv \Gamma_{B_c^+} - \Gamma_{B^+} = 4.46 \pm 0.14 \pm 0.07mm^{-1}c, where the first uncertainty is statistical and the second systematic. The known lifetime of the B+B^+ meson is used to convert this to a precise measurement of the Bc+B_c^+ lifetime, τBc+=513.4±11.0±5.7fs,\tau_{B_c^+} = 513.4 \pm 11.0 \pm 5.7fs, where the first uncertainty is statistical and the second systematic.Comment: 19 pagers, 3 figure

    The Physics of the B Factories

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    The BaBar detector: Upgrades, operation and performance

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    Contains fulltext : 121729.pdf (preprint version ) (Open Access

    The locus of Action of CGRPergic Monoclonal Antibodies Against Migraine: Peripheral Over Central Mechanisms

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    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Observation of CP violation in the B0 meson system

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    We present an updated measurement of time-dependent CP-violating asymmetries in neutral B decays with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. This result uses an additional sample of Upsilon(4S) decays collected in 2001, bringing the data available to 32 million B-anti-B pairs. We select events in which one neutral B meson is fully reconstructed in a final state containing charmonium and the flavor of the other neutral B meson is determined from its decay products. The amplitude of the CP-violating asymmetry, which in the Standard Model is proportional to sin2beta, is derived from the decay time distributions in such events. The result sin2beta = 0.59 +/- 0.14 (stat) +/- 0.05 (syst) establishes CP violation in the B^0 meson system. We also determine |lambda| = 0.93 +/- 0.09 {stat} +/- 0.03 {syst}, consistent with no direct CP violation.Comment: 8 pages, 2 figures, submitted to Physical Review Letter
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