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Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

In wildlife tagging, stress from capture and handling can alter post- release behavior and potentially study interpretations. This study of 42 mammal species shows that these effects diminish within 4–7 days, and quicker for animals in high human activity areas indicating adaptation to disturbance.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

The antisense oligonucleotide rugonersen has acceptable safety and tolerability in children with Angelman syndrome and shows partial normalization of electroencephalogram abnormalities and clinical improvements relative to natural history.

Transplantation of glia-enriched organoids into the mouse brain enables the study of astrocyte subtypes.

Human Staufen1 (STAU1) functions in mRNA decay and other cellular processes. Structural and functional studies reveal that a new, conserved motif together with a degenerate double-stranded RNA–binding domain mediate STAU1 dimerization through a 'domain-swapping' interaction and that dimerization is important for efficient STAU1-mediated decay in vivo.

Bacterial type IV pilus-like systems catalyse the formation of pilin fibres but it is unknown how they are powered. Here, the authors present crystal and cryo-EM structures of the hexameric motor ATPases PilB and PilT from Type IVa Pilus that reveal different conformational states, classify the conformations of all PilT-like ATPase structures and propose a model for PilT function.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Genetic analysis in mice selected for leanness has identified thiosulfate sulfurtransferase as a target for the treatment of diabetes.

REM-sleep behavior disorder often precedes Parkinson’s disease or dementia. Here, the authors perform a genome-wide association study for REM-sleep behavior disorder, and discover how it potentially affects gene expression in the brain.

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.

Deep waters of the Atlantic, Pacific and Indian Oceans upwell in the Southern Oceanbut the exact pathways are not fully characterized. Here the authors present a three dimensional view showing a spiralling southward path, with enhanced upwelling by eddy-transport at topographic hotspots.

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.

A genome-wide association study in ~3 million individuals identifies 3,952 independent variants associated with educational attainment. A polygenic index explains 12–16% of variance for this trait and contributes to risk prediction for ten diseases.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

This study shows that adult neurogenesis requires canonical Wnt signaling to trigger transcription of pro-neural NeuroD1. Wnt signaling activates β-catenin, which in complex with TCF/LEF displaces the repressor Sox2 from a previously unknown combined Sox/LEF element in the Neurod1 promoter. Similar Sox/LEF elements activated by Wnt signaling were found in LINE-1 retrotransposons.

Suchacki et al. show that serotonin suppresses human brown adipose tissue (BAT) activation, and that inhibition of the serotonin transporter (SERT) potentiates the suppressive action of extracellular serotonin on BAT by preventing serotonin uptake.

A genetic study identifies hundreds of loci associated with risk tolerance and risky behaviors, finds evidence of substantial shared genetic influences across these phenotypes, and implicates genes involved in neurotransmission.

Cell type–specific expression and activation of channelrhodopsin-2 in the dorsomedial striatum shows that stimulation of dopamine D1 receptor–expressing direct pathway medium spiny neurons (MSNs) can reinforce operant behavior in awake behaving mice, whereas activation of D2 receptor–expressing indirect pathway MSNs punishes operant behavior.

Directed evolution of the final enzyme in the lovastatin biosynthetic pathway yields a variant with 29 mutations that does not require a carrier protein and displays altered dynamics of the catalytic residues, spending more time in the catalytically active conformation.

Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.

The pathogen Pseudomonas aeruginosa uses a synthase-dependent secretion system for production of the exopolysaccharide alginate, which is associated with lung infection severity. Here, Gheorghita et al. determine the crystal structure of one of the secretion system components (the AlgKX complex) and show that it binds alginate oligosaccharides and is required for polymer production and biofilm attachment.

Stig Bojesen, Georgia Chenevix-Trench, Alison Dunning and colleagues report common variants at the TERT-CLPTM1L locus associated with mean telomere length measured in whole blood. They also identify associations at this locus to breast or ovarian cancer susceptibility and report functional studies in breast and ovarian cancer tissue and cell lines.

Combining fungal-resistance genes into a single cassette enables the generation of highly resistant wheat lines.

A chemically synthesized analog of Bacillus cereus secondary cell wall polysaccharide (SCWP) facilitates the identification of PatB1 as a SCWP O-acetyltransferase, and the structure of PatB1 provides insights into its catalytic mechanism.

The remoteness and paucity of historic observations of the Southern Ocean limit understanding of the effects of climate change on circulation. Using observations, CMIP6 and eddy-resolving models, this Article shows that acceleration of its zonal flow emerged in recent decades as a result of uneven ocean warming.

SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca²⁺ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

The authors generate a genome-wide dataset of 102 individuals who lived in Crete, the Greek mainland and the Aegean islands between the Neolithic and the Iron Age, identifying high levels of biological and cultural connectedness within the ancient Aegean.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Observations of ZTF SLRN-2020, a short-lived optical outburst in the Galactic disk accompanied by bright, long-lived infrared emission, show that the resulting light curve and spectra are consistent with the signatures of a planet being engulfed by its host star.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Simon Gayther and colleagues report 3 new risk variants for mucinous ovarian carcinoma (MOC) on the basis of an analysis of 1,644 MOC cases and 21,693 controls. They confirm an eQTL association between the HOXD9 promoter and risk SNPs at 2q31.1 using chromosome conformation capture analysis and show that HOXD9 overexpression associates with neoplastic transformation.

Auxin is perceived by a co-receptor complex that contains a TIR1 F-box protein and an Aux/IAA transcriptional repressor. The combinatorial diversity of auxin co-receptor complexes and their distinct spectra of affinities offer a means to tune plant cell sensitivity to a wide range of auxin concentrations.

Experiments in mice provide insight into the dynamic relationship between dopamine and acetylcholine in the ventrolateral striatum and how this signalling circuit affects decision-making and behaviour.

Bone marrow adipose tissue (BMAT) comprises over 10% of total fat mass but its systemic metabolic role is unclear. Here, the authors show that BMAT glucose uptake is not insulin or cold responsive; however, BMAT basal glucose uptake is higher than in white adipose tissue or skeletal muscle, underscoring BMAT’s potential to influence systemic glucose homeostasis.

mTORC1 is shown to regulate a translational program that requires the rapamycin-resistant 4E-BP family of translational repressors and consists almost entirely of mRNAs containing 5′ terminal oligopyrimidine or related motifs.

Using TEA-seq, Thomson et al. detail transcriptional and epigenetic alterations in the T cell compartment between healthy children and older adults, leading to the discovery of a novel pediatric CD8αα⁺ population poised for rapid effector responses.