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A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.

In an ongoing phase 1 trial, the combination of two new immunotherapies targeting CTLA-4 and PD-1 was overall well tolerated and elicited encouraging clinical responses in patients with relapsed/refractory microsatellite stable colorectal cancer, a tumor type typically unresponsive to immune checkpoint blockade.

JWST observations of a strongly lensed low-mass galaxy in a 600-million-year-old Universe show massive star clusters (the Firefly Sparkle) cocooned in a diffuse arc in the Canadian Unbiased Cluster Survey.

The infrared view of JWST has opened up the early Universe to study. This Perspective summarizes the key developments in our understanding of the high-redshift Universe from the first 18 months of JWST observations.

In a post-approval study including more than 17,000 patients on the safety of pulsed field ablation, a new method for treatment of atrial fibrillation, the procedure was found to have a low rate of adverse events but was associated with some unexpected rare complications that will need further study.

The authors analyse tree responses to an extreme heat and drought event across South America to understand long-term climate resistance. While no more sensitive to this than previous lesser events, forests in drier climates showed the greatest impacts and thus vulnerability to climate extremes.

Alternative stable states in forests have implications for the biosphere. Here, the authors combine forest biodiversity observations and simulations revealing that leaf types across temperate regions of the NH follow a bimodal distribution suggesting signatures of alternative forest states.

Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.

The hepatocyte growth factor receptor MET is a receptor tyrosine kinase involved in cellular processes such as proliferation, migration, and survival. Here the authors combine molecular dynamics simulations and smFRET in cells, to investigate the early stages of MET activation.

Dimethyl fumarate (DMF) is an anti-inflammatory drug proposed as a treatment for COVID19. Here the results are reported from a randomised trial testing DMF treatment in 713 patients hospitalised with COVID-19. DMF was not associated with any improvement in day 5 outcomes.

Respiratory syncytial virus is a major pathogen with burden observed and associated with childhood infection. Here the authors characterise a cationic adjuvant formulation and show single immunisation results in protection in a murine neonate model of respiratory syncytial virus infection.

‘Commercial fisheries have decimated keystone species, including oysters in the past 200 years. Here, the authors examine how Indigenous oyster harvest in North America and Australia was managed across 10,000 years, advocating for effective future stewardship of oyster reefs by centering Indigenous peoples.’

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Ferritin, the cellular iron storage complex, binds NCOA4 and is trafficked to the lysosome for degradation and iron release. Here, authors present the cryo-EM structure of the NCOA4-Ferritin complex with biophysical and cellular characterization.

Ancient microbiomes from palaeofaeces are more similar to non-industrialized than industrialized human gut microbiomes regardless of geography, but 39% of their de novo reconstructed genomes represent previously undescribed microbial species.

Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating widely in birds and have recently caused large outbreaks in mammals. Here, Furey et al. develop a clade 2.3.4.4b HA-expressing mRNA-LNP vaccine and show that it elicits strong protective immune responses in mice and ferrets.

Vertebral column length and shape exhibits remarkable robustness within a species but diversity across species. Here the authors reveal the molecular logic constraining vertebral number in mouse and a novel role for posterior Hox genes in this context.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.

Case report of an individual heterozygous for a rare RELN-COLBOS variant that confers resilience, via a gain-of-function mechanism, to Alzheimer’s disease.

Epithelioids are genetically stable, self-sustaining three-dimensional cultures. They may be used to investigate various aspects of epithelial biology over several months without need for passaging. In this paper, mouse epithelioids are used to identify drivers of clonal expansion in the esophagus.

Inflammatory intestinal lesions are often hypoxic, which results in the stabilization and activation of hypoxia-inducible-factors (HIF). Here authors show that in a mouse model of colitis, HIF-2α is specifically stabilized in CD4+ type 1T helper (T_H1) cells, leading to the upregulation of miR-29a expression and suppression of T_H1 cell function, which pathway is potentially targetable for therapeutic purposes.

Children often show milder COVID-19 symptoms, but the underlying mechanistic insights are still lacking. Here the authors profile both pediatric and adult cohorts of COVID-19 patients in Brazil to find that children exhibit higher viral load but stronger and biased cellular immunity, thereby serving clues for the differential responses in children.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Brazil has operated a conditional cash transfer program to support families living in precarious conditions since 2004. Here, the authors use linked administrative and health data to investigate the impacts of the program on HIV/AIDS-related outcomes, demonstrating strong positive associations.

An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary.

Exploring genomic data from contemporary and 191 Arabidopsis thaliana herbarium specimens collected over 193 years, the authors identify signs of local adaptation in regulators of stomatal development in contemporary samples from different geographic regions, then use functional scoring to identify a genetic component contributing to this change.

The relative risk of COVID-19-associated death for younger individuals (under 65) is consistent across countries and can be used to robustly compare the underlying number of infections in each country.

Here, the authors describe biallelic loss-of-function variants in human SHARPIN in individuals with autoinflammation and immunodeficiency, termed sharpenia. They also successfully treat one of these individuals with TNF inhibitors.

Treatment of diffuse anaplastic Wilms tumours (DAWT) remains a challenge. Here, the authors perform multi-omic analysis and identify a desert-like DAWT subtype accounting for one third of DAWT cases and suggest treating them with HDAC and/or WEE1 inhibitors.