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BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

By deciphering the molecular fingerprint of cells treated with host-directed therapies targeting protein translation, the authors identified a rational approach to select for broad-spectrum antivirals with potential to counteract future pandemic viruses.

The ventral tegmental area (VTA) is key to processing value. Rather than molecularly grouping VTA neurons, the authors functionally parse two neuronal ensembles (reward/stress), and show their indispensability for approach/avoidance behavior.

Temporary bioelectronics can complement classical therapies in non-chronic treatments. Here, the authors describe the minimally invasive implantation of bioresorbable electrodes in the brain that form in situ from water-dispersed nanoparticles and show no tissue damage after bioresorption.

Symbiont-housing structures are well-studied in multicellular eukaryotes but rarely in unicellular protists. This study shows that low-oxygen-adapted Anaeramoebae have symbiosomes positioning sulfate-reducing bacteria near hydrogenosomes, with genomic analyses suggesting likely metabolic interactions.

Temporal multi-omic analysis of tissues from rats undergoing up to eight weeks of endurance exercise training reveals widespread shared, tissue-specific and sex-specific changes, including immune, metabolic, stress response and mitochondrial pathways.

Calorie restriction extends lifespan in many animal models; however, the effects in humans and the mechanisms of action are not clear. This Review summarizes evidence regarding potential adverse effects of calorie restriction and highlights the complexity of extrapolating findings from animal studies to humans.

A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 (GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

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.

The authors provide the first anellovirus-like particle structure determined by CryoEM. The authors propose hypervariable regions on the spike domains extending from the particle surface contribute to the immune evasion properties of anelloviruses.

Leukemias with ambiguous lineage require further characterisation. Here, the authors perform epigenomic and transcriptomic analysis of a subgroup of such leukemias with CpG Island Methylator Phenotype and propose that epigenetic dysregulation and not genetic lesions explains their mixed phenotype.

The extinction of the ichthyosaurs had previously been attributed to increasing competition or to the loss of their main prey. Here, Fischer et al.analyse phylogenetic and ecological patterns of ichthyosaur diversification and extinction, and find that the decline of the group is more likely due to climatic volatility.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Geiger and colleagues use SILAC and mass spectrometry to study protein turnover in human T cells and examine how naive T cells maintain their quiescence and transition to activated cells.

Genetic variants at the FTO gene are associated with obesity in humans. Now, Roger Cox and colleagues analyze mice globally overexpressing Fto and show that increased Fto expression leads to obesity in mice.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Gonzalez et al. use a viral evolutionary approach to generate cross-species compatible AAV (ccAAVs) vectors. They describe a highly potent new variant, AAV.cc47, with enhanced transduction efficiency over AAV serotype 9 and show its efficacy in different mouse models, pigs and non-human primates.

HIV-1 can be transmitted by infected cells in body fluids and an efficient prophylaxis should prevent this. Here the authors show that the HIV-1 antibody 10-1074, when applied as topical vaginal gel, inhibits cell-associated transmission in non-human primates.

Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.

Unimolecular integration of NMDA receptor antagonism with GLP-1 receptor agonism effectively reverses obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Chromium tellurides are a particularly promising family of quasi-2D magnetic materials; towards the single van der Waals layer limit, they preserve magnetic ordering, some even above room temperature, and exhibit a variety of intrinsic topological properties. Here, Hang Chi, Yunbo Ou and co-authors demonstrate a strain tunable Berry curvature induced reversal of the anomalous Hall effect in Cr₂Te₃.

The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.

ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic pontine glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours.

A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G_i reveals structural determinants of its G protein-binding specificity.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.