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

The Bound Structures of 17β-Estradiol-Binding Aptamers

DNA aptamers can exhibit high affinity and selectivity towards their targets, but the aptamer–target complex structures are rarely available from crystallography and often difficult to elucidate. This is particularly true of small molecule targets, including 17β-estradiol (E2), which is becoming one of the most widely encountered endocrine-disrupting chemicals in the environment. Using molecular dynamics simulations, we demonstrate that E2 binds to a thymine loop region common to all E2-specific aptamers in the literature. Analyzing these structures allows us to design new E2 binding sequences. As well as illuminating the essential sequence and structural factors for generating specificity for E2, we demonstrate the effectiveness of molecular dynamics simulations for aptamer science

Methyl group influence on the formation of CuI complexes with thio-pyridine ligands

In order to investigate the effect of methyl group substitution adjacent to a pyridyl N donor, three ligands were synthesised and complexed with CuI in a 1:2 ratio. The crystal structures of three CuI complexes were determined. The dimethylated ligand bis(6-methyl-2-pyridylmethyl)sulfide (L-1) gave rise to a tetranuclear complex with two Cu2I2 bridges in which the Cu centres were four-coordinate. The asymmetric ligand 2-(6-methylpyridyl) methyl(2-pyridyl) methylsulfide (L-2) gave a tetranuclear complex which contained two parallel Cu2I2 bridges. In each Cu2I2 bridge, one Cu centre was three- and the other four-coordinate. In contrast, the ligand bis(2-pyridylmethyl) sulfide (L-3), with no Me substitution, gave rise to a one-dimensional coordination polymer with CuI chains. It was found that the differences in the complexes were a result of both the electronic and steric effects arising from the Me substitution of the pyridine donors and that no one effect completely dominated

Impact of Acceptor Fluorination on the Performance of All-Polymer Solar Cells

Here, we systematically study the effect of fluorination on the performance of all-polymer solar cells by employing a naphthalene diimide (NDI)-based polymer acceptor with thiophene-flanked phenyl co-monomer. Fluorination of the phenyl co-monomer with either two or four fluorine units is used to create a series of acceptor polymers with either no fluorination (PNDITPhT), bifluorination (PNDITF2T), or tetrafluorination (PNDITF4T). In blends with the donor polymer PTB7-Th, fluorination results in an increase in power conversion efficiency from 3.1 to 4.6% despite a decrease in open-circuit voltage from 0.86 V (unfluorinated) to 0.78 V (tetrafluorinated). Countering this decrease in open-circuit voltage is an increase in short-circuit current from 7.7 to 11.7 mA/cm2 as well as an increase in fill factor from 0.45 to 0.53. The origin of the improvement in performance with fluorination is explored using a combination of morphological, photophysical, and charge-transport studies. Interestingly, fluorination is found not to affect the ultrafast charge-generation kinetics, but instead is found to improve charge-collection yield subsequent to charge generation, linked to improved electron mobility and improved phase separation. Fluorination also leads to improved light absorption, with the blue-shifted absorption profile of the fluorinated polymers complementing the absorption profile of the low-band gap PTB7-Th.C.R.M. acknowledges support from the Australian Research Council (FT100100275). J.M.H. and S.K.K.P. acknowledge support from a Rutherford Discovery Fellowship to J.M.H. The Advanced Light Source was supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02- 05CH11231. R.M. and M.S. acknowledge funding from the DFG (IRTG SOMAS 1642)