37 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

    A SYSTEMATIC STUDY OF 2s2 2pk - 2s2pk+l - 2pk+2 TRANSITIONS IN MULTIPLY-CHARGED Cl IONS.

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    Nous avons fait une étude systematique des durées de vie des niveaux bas de Cl avec de 3 à 9 electrons. La technique faisceau-lame a été utilisée pour la mesure. Les forces d'oscillateurs pour les transitions Δn=0 du type 2s22pk - 2s2pk+1 - 2pk+2 sont déduites des résultats.A systematic study has been made of the radiative lifetimes of the lowlying levels of Cl ions with from 3 to 9 bound electrons. The beam-foil time of flight method was used to make the measurements and f values for allowed Δn=0 transitions of the type 2s2 2pk - 2s2pk+1 - 2pk+2 are derived from the lifetime results

    A Pathway and Genetic Factors Contributing to Elevated Gene Expression Noise in Stationary Phase

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    Previous studies have identified factors associated with transcription and translation efficiency, such as promoter strength and mRNA sequences, that can affect stochasticity in gene expression. Here we present evidence for a pathway and associated genetic factors (namely, the ribosome modulation factor RMF and ppGpp) in Escherichia coli that contribute to heightened levels of gene expression noise during stationary phase. Endogenous cellular mechanisms that globally affect gene expression noise, such as those identified in this study, could provide phenotypic diversity under adverse conditions such as stationary phase
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