23 research outputs found
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
Recommended from our members
Interferometric reconstruction of electron number densities in laser- induced plasmas
Recommended from our members
2660 A holographic interferometry of laser produced plasmas from tilted disk targets
Using double exposure holographic interferometry, an investigation has been made of the Nd laser produced plasmas surrounding disk targets irradiated at different angles of incidence. Measurements have produced a detailed description of the plasma profile necessary for realistic simulations of resonance absorption. A 2660A 15 psec probe pulse is produced by frequency quadrupling a fraction of the main Nd laser pulse from the Janus laser. F/1 and f/10 lenses were utilized to irradiate the targets with intensities ranging from 10/sup 13/ w/cm/sup 2/ to 10/sup 16/ w/cm/sup 2/. Measurements have produced the shape of the electron density profile near critical, the direction of the plasma blowoff, and revealed transverse rippling of the isodensity surfaces
Recommended from our members
Extreme Ultraviolet Lithography for 0.1 {micro}m Devices
Extreme Ultraviolet Lithography (EUVL) has emerged as one of the leading successors to optics for 0.1 {micro}m IC fabrication. Its strongest attribute is the potential to scale to much finer resolution at high throughput. As such, this technique could meet the lithography needs for Si ULSI down to fundamental device limits. In the US, Lawrence Livermore, Sandia, and Lawrence Berkeley National Laboratories are participating in an industry funded research effort to evolve EUV technology and build a prototype camera for lithographic exposure. More recently, both Europe and Japan have initiated government/industry sponsored programs in EUVL development. This talk will focus on our program successes to date, and highlight some of the challenges that still lie ahead
Recommended from our members
Confirmation of radiation pressure effects in laser--plasma interactions
Interferometric data resolved in 1..mu..m and 15 psec confirms the dominant role of radiation pressure during high intensity laser-plasma interactions. Specifically observed manifestations include electron density profiles steepened to 1 ..mu..m scale length, clearly defined upper and lower density shelves, and small and large scale deformation of transverse isodensity surfaces