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

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

Análise comparativa de fragmentos identificáveis de forrageiras, pela técnica micro-histológica Comparative analysis of identifiable fragments of forages, by the microhistological technique

Objetivou-se, com este trabalho, verificar, pela técnica micro-histológica, diferenças entre espécies forrageiras quanto ao percentual de fragmentos identificáveis, em função do processo digestivo e da época do ano. Lâminas foliares frescas recém-expandidas, correspondentes à última e à penúltima posição no perfilho, das espécies Melinis minutiflora Pal. de Beauv (capim-gordura), Hyparrhenia rufa (Nees) Stapf. (capim-jaraguá), Brachiaria decumbens Stapf. (capim-braquiária), Imperata brasiliensis Trin. (capim-sapé), de Medicago sativa L. (alfafa) e de Schinus terebenthifolius Raddi (aroeira), amostradas nos períodos chuvoso e seco, foram digeridas in vitro e preparadas de acordo com a técnica micro-histológica. Observou-se que as espécies apresentaram diferenças marcantes na porcentagem de fragmentos identificáveis e que a digestão alterou estas porcentagens em torno de 10 %; que o período de amos&shy;tragem não influenciou a porcentagem de fragmentos identificáveis para a maioria das espécies; que a presença de pigmentos e a adesão da epiderme às células dos tecidos internos da folha prejudicaram a identificação dos fragmentos; e que a digestão melhorou a visualização dos fragmentos dos capins sapé e jaraguá e da aroeira, mas prejudicou a do capim-braquiária e, principalmente, a da alfafa.<br>The objetive of this study was to verify differences among forages species in relation to the percentage of identifiable fragment as affected by the digestion process and season. Fresh last expanded leaf lamina samples of the species Melinis minutiflora Pal. de Beauv (Molassesgrass), Hyparrhenia rufa (Nees) Stapf. (Jaraguagrass), Brachiaria decumbens Stapf. (Signalgrass), Imperata brasilienses Trin. (Sapegrass), and foliar laminas of Medicago sativa L. (Alfalfa) and Schinus terebenthifolius Raddi (Aroeira), sampled in the rainy and dry seasons, were digested in vitro and prepared according to the microhistological technique. The digestion process caused change of 19 units in the percentage of identifiable fragments whose values varied among forage species. The season did not influence the percentage of identifiable fragments for most species; the presence of pigments and adherence of epidermis to internal tissues of the leaf hindered the identification of fragments. The digestion improved the identification of sapegrass fragments, jaraguagrass and Schinus terebenthifolius Raddi, but hindered identification of signalgrass fragments and mainly those of alfalfa