11 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
Gamma Ray Measurement Information Barriers for the FMTT Demonstration System
The gamma ray attribute measurement information barrier discussion directly complements the discussion of gamma ray measurement, presented in the measurements paper by Gosnell and the general discussion of information barriers (IBs) by MacArthur. It focuses on the information barrier features applied specifically to the gamma-ray measurement and attribute analysis system. The FMTT demonstration instrument represents the second application of an IB design paradigm developed in conjunction with the Joint DOE/DoD Information Barriers Working Group (IBWG) as well as representatives from the Russian Federation's delegations to the Trilateral Initiative and meetings on the agreement for transparency at the Mayak Fissile Storage Facility (FMSF). It is also the second evolutionary step in constructing hardware to embody these jointly developed ideas. The first step was the prototype instrument developed for the Trilateral Initiative, the so-called Attribute Verification System with Information Barriers for Plutonium with Classified Characteristics utilizing Neutron Multiplicity Counting and High-Resolution Gamma-ray Spectroscopy (AVNG), that was demonstrated at Los Alamos National Laboratory in June 1999. Several improvements are evident in this second effort, and will be discussed. Improved, though this information barrier may be, it is still a prototype meant only for demonstration purposes. Its evolving specification and design are appropriately a subject for joint discussion and development. Part of that development must include creating components that the respective governments can trust enough to certify
Recommended from our members
Advanced array techniques for unattended ground sensor applications
Sensor arrays offer opportunities to beam form, and time-frequency analyses offer additional insights to the wavefield data. Data collected while monitoring three different sources with unattended ground sensors in a 16-element, small-aperture (approximately 5 meters) geophone array are used as examples of model-based seismic signal processing on actual geophone array data. The three sources monitored were: (Source 01). A frequency-modulated chirp of an electromechanical shaker mounted on the floor of an underground bunker. Three 60-second time-windows corresponding to (a) 50 Hz to 55 Hz sweep, (b) 60 Hz to 70 Hz sweep, and (c) 80 Hz to 90 Hz sweep. (Source 02). A single transient impact of a hammer striking the floor of the bunker. Twenty seconds of data (with the transient event approximately mid-point in the time window.(Source 11)). The transient event of a diesel generator turning on, including a few seconds before the turn-on time and a few seconds after the generator reaches steady-state conditions. The high-frequency seismic array was positioned at the surface of the ground at a distance of 150 meters (North) of the underground bunker. Four Y-shaped subarrays (each with 2-meter apertures) in a Y-shaped pattern (with a 6-meter aperture) using a total of 16 3-component, high-frequency geophones were deployed. These 48 channels of seismic data were recorded at 6000 and 12000 samples per second on 16-bit data loggers. Representative examples of the data and analyses illustrate the results of this experiment
The use of robustness analysis for planning actions in a poor Brazilian community
This paper reports on the use of Robustness Analysis for planning actions in a poor Brazilian community. The focus is on food and agricultural production and the project is based on a participatory approach incorporating both community-driven development and sustainability in food production. A comparison is made with other soft Operations Research (OR) methodologies and first actions and results are reported