21 research outputs found

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

    Get PDF
    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

    APPLICATION OF A NEW TECHNIQUE TO STUDY THE DYNAMIC TENSILE FAILURE OF CONCRETE

    No full text
    Une nouvelle technique pour soumettre le béton à la traction dynamique est décrite. Les résultats d'un essai sont interprétés à l'aide de simulations numériques.A new technique to test concrete in dynamic tension is described. The results of an experiment are interpreted using numerical simulations

    Rat hepatic natural killer cells (pit cells) express mRNA and protein similar to in vitro interleukin-2 activated spleen natural killer cells.

    No full text
    Pit cells are liver-specific natural killer (NK) cells that can be divided into high- (HD) and low-density (LD) subpopulations. The characteristics of pit cells were further investigated in this report. LD and HD pit cells express the specific NK-activation markers gp42, CD25, and ANK44 antigen. LD cells and IL-2-activated NK cells have a high mRNA expression of perforin, granzymes, interferon-gamma, and tumor necrosis factor-alpha. LD pit cells, unlike spleen NK cells, have a weak response to IL-2 with regard to proliferation, cytotoxicity, and production of NK-related molecules. The characteristics of HD cells are intermediate between LD and spleen NK cells. These results show that pit cells, especially LD cells, possess characteristics similar to IL-2-activated NK cells. This is the first evidence on a molecular level that pit cells could be considered in vivo activated NK cells.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe
    corecore