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

Super-resolution imaging and performance optimization for single- and multi-layer silver superlenses

For conventional optical imaging and projection lithography the resolution is limited to approximately half the exposing wavelength. The trend in semiconductor manufacturing has therefore been to use shorter wavelengths, with 193 nm ArF laser sources being used currently. Another way to improve resolution is to go into the near field region, where conventional resolution limits no longer apply. We have used our Evanescent Near Field Optical Lithography (ENFOL) technique to demonstrate resolution down to λ/7 in a hard-contact lithography experiment [1], with λ/20 resolution predicted for thinner resists [2]. A problem with ENFOL and related techniques is that they require intimate mask/resist contact, which may be undesirable in a manufacturing environment. Following Pendry’s proposal that a planar metal film can act as a plasmon-mediated near-field superlens [3] a near-field planar lens lithography (PLL) technique has been developed in which a planar metallic film is inserted between the mask and imaging photoresist [4]. Using PLL we have provided the first experimental demonstration of sub-wavelength imaging using a silver planar lens illuminated at the i-line wavelength of a Mercury lamp [5]. We have gone on to show that this technique is capable of producing sub-diffraction-limited near-field images [6], as have another group using a related technique [7]. Further improvements in the imaging properties of silver superlenses have been proposed by going from singlelayer to multi-layer lens structures [8]. If the same total thickness of silver and dielectric spacer layers is used, then the lamination of these materials provides resolution enhancements by the introduction of additional metal surfaces between the object and image planes; as the imaging in these silver superlenses is strongly mediated by surface plasmons, the incorporation of additional layers on which such plasmons can be generated allows higher spatial frequency components to be efficiently transferred through the system. The resolution enhancements provided in going to multi-layer superlenses have been experimentally tested very recently [9]. This work showed that super-resolution can also be achieved through a double-layer silver superlens, with enhanced transmission compared to a single-layer lens. We review this work here and present the main experimental findings. Analytical and simulation results are then given to show how the performance of multi-layer superlenses can be optimized by changing the relative layer thicknesses in the lens stack

Experimental comparison of resolution and pattern fidelity in single- and double-layer planar lens lithography

An experimental comparison of the performance of single- and double-layer planar lens lithography (PLL) has been carried out. A direct comparison is made with a single 50nm silver lens and a double silver lens with two 30nm layers. Sub-diffraction-limited features have been imaged in both cases, with dense grating periods down to 145nm and 170nm for the single- and double-layered stacks, respectively. For the same total thickness of silver the resolution limit is qualitatively better for a double layer stack. However, pattern fidelity is reduced in the double layer experiments due to increased surface roughness. Finite-difference time-domain simulations are also presented to back up the experimental results

Nanometre-scale electrochemical switches fabricated using a plasma-based sulphidation technique

©2006 IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE.Solid-state electrochemical switches are new devices that may find application in low power logic or memory circuits. The reversible electrochemical oxidation and reduction of a sub 10nm-thick silver sulphide layer is the critical process for these devices’ operation, which determines the switching speed and the OFF/ON resistance ratio. A new process has been developed for fabricating QCAS devices, including a novel SF6 plasma sulphidation technique for forming the critical silver sulphide switchable insulator layer. QCAS devices were successfully created with OFF/ON resistance ratios of up to 106, with switching speeds comparable to previous devices and far less problematic yields

Magnetic properties of Gd-Y and Gd-Sc alloys

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Exploring phase-transfer catalysis with molecular dynamics and 3D/4D quantitative structure−selectivity relationships

Quantitative Structure−Selectivity Relationships (QSSR) are developed for a library of 40 phase-transfer asymmetric catalysts, based around quaternary ammonium salts, using Comparative Molecular Field Analysis (CoMFA) and closely related variants. Due to the flexibility of these catalysts, we use molecular dynamics (MD) with an implicit Generalized Born solvent model to explore their conformational space. Comparison with crystal data indicates that relevant conformations are obtained and that, furthermore, the correct biphenyl twist conformation is predicted, as illustrated by the superiority of the resulting model (leave-one-out q2 = 0.78) compared to a random choice of low-energy conformations for each catalyst (average q2 = 0.22). We extend this model by incorporating the MD trajectory directly into a 4D QSSR and by Boltzmann-weighting the contribution of selected minimized conformations, which we refer to as ‘3.5D' QSSR. The latter method improves on the predictive ability of the 3D QSSR (leave-one-out q2 = 0.83), as confirmed by repeated training/test splits