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An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

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.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

Dengue is a major public health concern in the Americas, and the Caribbean can be a source for reintroduction and spread. Here, the authors use travel surveillance data and genomic epidemiology to reconstruct Dengue epidemic dynamics in the Caribbean from 2009-2022.

In a previous clinical trial, the authors reported that SCFA-yielding biotherapy in adults with type 1 diabetes remodels the gut proteome and metabolome. Here, the show that colonization of the post-therapy microbiome into mice delayed diabetes and increased aryl-hydrocarbon receptor ligand and IgA production in the gut.

Crackdown on illegal border crossings puts endangered species at further risk.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Ancient DNA has allowed researchers to trace the origins of 4,000-year-old mummies in China. Plus: Bacteria imaged in unprecedented detail, and plans for Africa’s first synchrotron.

People are volunteering to be infected with coronavirus in an effort to speed up vaccine development. Plus: astronomers might have detected an elusive exoplanet, and cancer biologists are harnessing the power of AI.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Despite being highly toxic, carbon monoxide (CO) is also essential as an intracellular signalling molecule, but CO-dependent signalling is poorly understood. Here, authors employ spectroscopic and electrophysiology methods and find that CO activates K_ATP channels via SUR2A, a heme-regulated receptor.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Here, using in vitro assays and structural analysis, the authors characterize the anti-SARS-CoV-2 properties of two small molcules, showing these to bind and target the virus main protease (M^pro), and to exhibit a synergistic antiviral effect when combined with remdesivir in vitro.

BRG1 and BRM are central components of the BAF (mSWI/SNF) chromatin remodelling complex, which is critical for regulation of chromatin structure. Here, the authors provide evidence that both the BRG1 and hBRM bromodomains have DNA-binding activity and bind to both DNA and H3K14ac simultaneously.

Multi-ancestry genome-wide association analyses and systematic variant-to-gene mapping strategies implicate new genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Diversity within terrestrial tetrapod communities has risen by at most threefold over the last 300 million years, consistent with a constrained model of diversification.

Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

NMR and single molecule FRET experiments show that antiparallel EmrE dimers interconvert between two identical but oppositely oriented conformations that are each open only to one side of the membrane.

The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.

Non-human primates are important animal models for studying SARS-CoV-2 infection. Here, Salguero et al. directly compare rhesus and cynomolgus macaques and show that both species represent COVID-19 disease of mild clinical cases, and provide a lung histopathology scoring system.

The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.

A single dose of the ChAdOx1 nCoV-19 vaccine elicits antibodies and cytokine-producing T cells that might help control or prevent SARS-CoV-2 infection.

Douglas Easton and colleagues report a comprehensive analysis of SNP associations to prostate cancer across the 8q24 region. They report 8 SNPs in 5 blocks independently associated to prostate cancer risk.

Direct imaging of the lung microcirculation in mice indicates that it is a major site of mature platelet production from megakaryocytes.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

Axl is a TAM receptor that can inhibit Toll-like receptor (TLR) -induced pro-inflammatory production by dendritic cells (DC). Here the authors show that miR-34a targets Axl to control CD1c+ DC activity in mice, and that miR-34a-deficient mice are resistant to collagen-induced arthritis, whereas DCs from patients with rheumatoid arthritis have high levels of miR- 34a.

Recovery of neurotransmitter involves the endocytic retrieval of vesicles from the plasma membrane. Jonas and colleagues show that in hippocampal synapses, the anti-apoptotic protein Bcl-x_L enhances the recovery of a vesicle pool. It does this independently of its mitochondrial function, through its calmodulin-stimulated translocation to clathrin-coated pits and recruitment of the dynamin-related protein Drp1.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Aicardi-Goutieres syndrome is a genetically determined encephalopathy that is associated with an increased production of interferon alpha, which in turn is central to the pathogenesis of systemic lupus erythematosus. Yanick Crow and colleagues now identify homozygous mutations in an interferon-inducible nuclear gene encoding SAMHD1 in AGS-affected individuals across several pedigrees and characterize its function in modulating an innate immune response.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Rosalind Eeles and colleagues present a genome-wide association study for prostate cancer. They report seven loci newly associated with prostate cancer susceptibility.

Rosalind Eeles and colleagues report a multistage genome-wide association study of prostate cancer, identifying seven new prostate cancer susceptibility loci.

Rare truncating mutations in the p53-inducible protein phosphatase PPM1D are shown to be associated with predisposition to breast cancer and ovarian cancer; notably, all of the mutations are mosaic in white blood cells but are not present in tumours, and probably have a gain-of-function effect.

Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers.