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

Phosphorylation of SAF-A/hnRNP-U Serine 59 by polo-like kinase 1 is required for mitosis

Scaffold attachment factor A (SAF-A), also called heterogenous nuclear ribonuclear protein U (hnRNP-U), is phosphorylated on serine 59 by the DNA-dependent protein kinase (DNA-PK) in response to DNA damage. Since SAF-A, DNA-PK catalytic subunit (DNA-PKcs), and protein phosphatase 6 (PP6), which interacts with DNA-PKcs, have all been shown to have roles in mitosis, we asked whether DNA-PKcs phosphorylates SAF-A in mitosis. We show that SAF-A is phosphorylated on serine 59 in mitosis, that phosphorylation requires polo-like kinase 1 (PLK1) rather than DNA-PKcs, that SAF-A interacts with PLK1 in nocodazole-treated cells, and that serine 59 is dephosphorylated by protein phosphatase 2A (PP2A) in mitosis. Moreover, cells expressing SAF-A in which serine 59 is mutated to alanine have multiple characteristics of aberrant mitoses, including misaligned chromosomes, lagging chromosomes, polylobed nuclei, and delayed passage through mitosis. Our findings identify serine 59 of SAF-A as a new target of both PLK1 and PP2A in mitosis and reveal that both phosphorylation and dephosphorylation of SAF-A serine 59 by PLK1 and PP2A, respectively, are required for accurate and timely exit from mitosis

Retention of inherited Ar by alkali fedspar xenocrysts in a magma: Kinetic constraints from Ba zoning profiles

40Ar/39Ar dating of volcanic alkali feldspars provides critical age constraints on many geological phenomena. A key assumption is that alkali feldspar phenocrysts in magmas contain no initial radiogenic 40Ar (40Ar*), and begin to accumulate 40Ar* only after eruption. This assumption is shown to fail dramatically in the case of a phonolitic lava from southern Tanzania that contains partially resorbed xenocrystic cores which host inherited 40Ar manifest in 40Ar/39Ar age spectra. Magmatic overgrowths on the xenocrysts display variable oscillatory zoning with pisodic pulses of Ba enrichment and intervals of resorption. Ba concentration profiles across contrasting compositional zones are interpreted as diffusion couples. Inferred temperature time histories recorded by these profiles reveal significant variations between phenocrysts. Combined with Ar diffusion kinetics for alkali feldspars and magma temperature inferred from two feldspar thermometry, the results indicate that >1% inherited 40Ar can be retained in such xenocrysts despite immersion in magma at ~900°C for tens to >100 years. In cases where the age contrast between inherited and magmatic feldspars is less pronounced, the age biasing effect of incompletely degassed xenocrysts may easily go undetected

Polarized point sources in LOTSS-HETDEX

Item does not contain fulltextVisibility data taken from LOTSS, imaged in polarization, and had RM synthesis applied. Resulting RM spectra were searched for polarization peaks. Detected peaks that were determined to not be foreground or instrumental effects were collected in this catalog. Source locations (for peak searches) were selected from TGSS-ADR1 (J/A+A/598/A78). Due to overlap between fields, some sources were detected multiple times, as recorded in the Ndet column. Polarized sources were cross-matched with the high-resolution LOTSS images (Shimwell+, in prep), and WISE and PanSTARRS images, which were used to determine the source classification and morphology. (1 data file)

Polarized point sources in the LOFAR Two-meter Sky Survey: A preliminary catalog

The polarization properties of radio sources at very low frequencies (<200 MHz) have not been widely measured, but the new generation of low-frequency radio telescopes, including the Low Frequency Array (LOFAR: a Square Kilometre Array Low pathfinder), now gives us the opportunity to investigate these properties. In this paper, we report on the preliminary development of a data reduction pipeline to carry out polarization processing and Faraday tomography for data from the LOFAR Two-meter Sky Survey (LOTSS) and present the results of this pipeline from the LOTSS preliminary data release region (10h45m–15h30m right ascension, 45°–57° declination, 570 square degrees). We have produced a catalog of 92 polarized radio sources at 150 MHz at 4.′3 resolution and 1 mJy rms sensitivity, which is the largest catalog of polarized sources at such low frequencies. We estimate a lower limit to the polarized source surface density at 150 MHz, with our resolution and sensitivity, of 1 source per 6.2 square degrees. We find that our Faraday depth measurements are in agreement with previous measurements and have significantly smaller errors. Most of our sources show significant depolarization compared to 1.4 GHz, but there is a small population of sources with low depolarization indicating that their polarized emission is highly localized in Faraday depth. We predict that an extension of this work to the full LOTSS data would detect at least 3400 polarized sources using the same methods, and probably considerably more with improved data processing

Polarized point sources in LOTSS-HETDEX

Visibility data taken from LOTSS, imaged in polarization, and had RM synthesis applied. Resulting RM spectra were searched for polarization peaks. Detected peaks that were determined to not be foreground or instrumental effects were collected in this catalog. Source locations (for peak searches) were selected from TGSS-ADR1 (J/A+A/598/A78). Due to overlap between fields, some sources were detected multiple times, as recorded in the Ndet column. Polarized sources were cross-matched with the high-resolution LOTSS images (Shimwell+, in prep), and WISE and PanSTARRS images, which were used to determine the source classification and morphology. (1 data file)