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

A modular ducted rocket missile model for threat and performance assessment

A model was developed to predict the thrust of throttled ramjet propelled missiles. The model is called DRCORE and fulfils the growing need to predict the performance of air breathing missiles. Each subsystem of the propulsion unit of this model is coded by using engineering formulae and enables the prediction of the thrust of air breathing missiles during on- and off-design operation. DRCORE is able to use experimental data or results from external studies (for example CFD) as input. During several threat analyses, the capabilities of the DRCORE model have been proven to be crucial for accurate performance prediction of air breathing supersonic weapon systems. DRCORE was developed in an international collaboration between TNO (The Netherlands) and Defence R&D Canada. Copyright © 2005 by TNO

Proof-of-principle experiment of a shock-induced combustion ramjet

By injecting and mixing the fuel upstream of the combustor and initiating the combustion of the fuel-air mixture by a shock wave in the combustor, shock-induced combustion ramjets offer the potential to drastically reduce the length and mass of scramjet propulsion systems. Based on extensive numerical gas dynamic and thermo-mechanical analysis, an axi-symmetric dual cone test object was designed and manufactured to demonstrate that it is possible to inject hydrogen into a high enthalpy supersonic air flow without causing premature ignition and subsequently induce combustion of this mixture by a strong oblique shock wave. The test object was instrumented with 16 thermocouples and a shadowgraph technique was used to visualize density changes in the flow field. A test series was executed in the TNO Free Jet Test Facility using the Mach 3.25 free jet nozzle in which the air flow stagnation temperature and the injected hydrogen mass flow rate was varied. Due to thermal expansion of the strut holding the test object, a small angle-of-attack was induced and resulted in different types of combustion occurring at the top and bottom sides of the test object. At the bottom, hydrogen was captured and subsequently burned in the boundary layer separation zone resulting in very high local heat loads. At the top side of the test object, shock-induced combustion occurred in the inviscid flow field only at a higher level of stagnation temperature with a peak heat load clearly downstream of the boundary layer separation zone. This experimental result is an important step in demonstrating the feasibility of a shock-induced combustion ramjet as a future hypersonic propulsion system

Two phase flow combustion modelling of a ducted rocket

Under a co-operative program, the Defence Research Establishment Valcartier and Université Laval in Canada and the TNO Prins Maurits Laboratory in the Netherlands have studied the use of a ducted rocket for missile propulsion. Hot-flow direct-connect combustion experiments using both simulated and solid fuels have been carried out on a wide range of configurations to identify the geometries and flow rates necessary for good combustor performance. The experiments using a simulated ducted rocket fuel, a reacted mixture of ethylene and air, have all been modelled using reacting flow Computational Fluid Dynamics (CFD) with the goal of being able to analyze and predict combustor performance. The combustion was modelled with onestream and twostream PDF (Probability Density Function) models. With the onestream model, all of the fuel components, both gaseous and solid carbon, were injected together and were assumed to react instantaneously in the presence of the oxidizer. Because of this, the onestream model overpredicted the combustion efficiency with respect to the experimental results for most of the combustor configurations examined. With the twostream model, however, the fuel stream was separated into gaseous and solid carbon components, with the carbon injected as a series of 75 nm particles. These particles decompose gradually into carbon monoxide gas, based on a model using both the kinetics of the surface reactions and the diffusion of oxygen to the surface of the particles. For the majority of the configurations, better predictions of combustion efficiency were obtained with the twostream approach when compared to the experimental results than for the onestream PDF model. © 2001 by the Department of National Defence, Canada and TNO Prins Maurits Laboratory, the Netherlands

Optimization of fermentation conditions for P450 BM-3 monooxygenase production by hybrid design methodology

Factorial design and response surface techniques were used to design and optimize increasing P450 BM-3 expression in E. coli. Operational conditions for maximum production were determined with twelve parameters under consideration: the concentration of FeCl(3), induction at OD(578) (optical density measured at 578 nm), induction time and inoculum concentration. Initially, Plackett-Burman (PB) design was used to evaluate the process variables relevant in relation to P450 BM-3 production. Four statistically significant parameters for response were selected and utilized in order to optimize the process. With the 416C model of hybrid design, response surfaces were generated, and P450 BM-3 production was improved to 57.90×10(−3) U/ml by the best combinations of the physicochemical parameters at optimum levels of 0.12 mg/L FeCl(3), inoculum concentration of 2.10%, induction at OD(578) equal to 1.07, and with 6.05 h of induction