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A genome-wide association study highlights a variant in DOCK2, which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.

A single-cell multiomic immune cell atlas from 235 Japanese, including patients with COVID-19 and healthy individuals, linked with host genetics including germline and somatic mutation, plasma proteomics and metagenomics data reveals that immune cells are dynamically regulated in a cell state-dependent manner.

The tumor suppressor p53 prevents malignant transformation and regulates stem cell function and differentiation. Here, the authors discover a p53-induced lncRNA, LOC644656, that regulates genotoxic stress-induced stem cell maldifferentiation and chemoresistance in cancer cells.

Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.

Many bacteria release DNA and membrane vesicles through unclear mechanisms. Here, the authors show that a prophage endolysin is involved in the explosive lysis of a sub-population of cells in Pseudomonas aeruginosa, releasing cytoplasmic content and membrane fragments that rapidly form membrane vesicles.

The cell polarity regulator aPKC is associated with cell proliferation but the precise mechanism are unknown. Here, the authors find that aPKC lambda phosphorylates the FoxO1 transcription factor, a gatekeeper of endothelial growth, during both angiogenesis and angiosarcomas.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

While biallelic mutations of the SLC26A4 gene cause non-syndromic hearing loss with enlarged vestibular aqueducts or Pendred syndrome, a considerable number of patients carry mono-allelic mutations. Here the authors identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4.

Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.

Peripheral blood mononuclear cells from 73 Japanese patients with coronavirus disease 2019 (COVID-19) and 75 healthy controls were analyzed using single-cell transcriptomics. Combining these data with genotyping data highlights the interplay between host genetics and the immune response in modulating disease severity.

The sprouting activity of filopodia emerging from endothelial sprouting cells needs to be compensated for in mature stable vessels. Adams and colleagues find that sprouting cells in mouse retinal vasculature show high VEGF uptake and VEGF receptor turnover, both essential for sprouting. These are inhibited by an aPKC-mediated decrease in VEGF receptor endocytosis in mature vessels, through a mechanism implicating clathrin-associated proteins, the transmembrane protein ephrin-B2 and the polarity factor PAR-3.

CENP-E regulates chromosome alignment during mitosis to distribute chromosomes equally into daughter cells. Here, the authors show that CENP-E inhibition causes p53-mediated post-mitotic apoptosis in tumours where the spindle assembly checkpoint is compromised, suggesting that CENP-E is a therapeutic target for these cancers.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Takayanagi and colleagues show that thymic medullary fibroblasts can contribute to central tolerance mechanisms by expressing cell-type-specific antigens distinct from those expressed by medullary thymic epithelial cells.

The protein ephrin-B2 is known to be upregulated during angiogenesis — the growth of new blood vessels — but its precise function has been unclear. Here it is shown that signalling through ephrin-B2 controls vessel sprouting. Mechanistically, ephrin-B2 seems to function in part by regulating the internalization of vascular endothelial growth factor receptors (VEGFRs). The results indicate that blocking ephrin-B2 signalling might be an alternative to blocking VEGFR function to disrupt angiogenesis in tumours.

The role of integrin β1 in angiogenesis is poorly understood. Here, the authors show that integrin β1 regulates murine angiogenesis and adherens junction integrity by controlling VE-cadherin localization, myosin light chain phosphorylation and the function of the Rap1/MRCK and Rho/Rho-kinase pathways.

The two homoeologous subgenomes in the allotetraploid frog Xenopus laevis evolved asymmetrically; one often retained the ancestral state, whereas the other experienced gene loss, deletion, rearrangement and reduced gene expression.

Pericytes are essential for the development, maintenance and function of vascular networks. Here, Eilken and colleagues show that expression of the decoy receptor VEGFR1 by pericytes spatially restricts VEGF signalling, thus regulating VEGF-induced endothelial cell sprouting in developing tissues.

IgA is necessary for maintaining gut homeostasis, and its production depends on microbial sampling by the gut-associated lymphoid tissue (GALT). Takayanagi and colleagues identify a novel population of mesenchymal cells in the GALT that control M cell differentiation and function of gut epithelium.

Asano et al. dissect the functional difference between the soluble and membrane-bound forms of RANKL. Membrane-bound RANKL is sufficient for most physiological RANKL functions, whereas soluble RANKL promotes bone metastases by stimulating tumour cell migration to bone, without affecting tumour cell growth or osteoclast differentiation.

Genotype-biochemical phenotype correlation suggests protein misfolding plays a key role in pathogenesis of fructose-1,6-bisphosphatase deficiency for one functional class of missense mutations reported in the associated enzyme.