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Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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.

CAR-T cells engineered with αPD-L1–IL-12 fusion proteins show antitumour activity in mouse models of prostate and ovarian cancer.

A phase 1 feasibility trial shows that bilateral deep brain stimulation within the central lateral thalamus can be safely applied and is associated with improved executive control.

The Global Flourishing Study provides a comprehensive view of the distribution and determinants of well-being by assessing domains such as health, happiness, meaning, character, relationships and financial security. Initial findings reveal significant variations in flourishing across countries and demographic groups, with factors such as age, marital status and religious service attendance showing strong associations with well-being.

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).

HORNET, a method that uses unsupervised machine learning and deep neural networks to analyse atomic force microscopy data enables structural determination of RNA molecules in multiple conformations.

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

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

Flash droughts can have devastating impacts but are notoriously difficult to predict. This study identifies global hotspots of flash drought, driven by evaporative demand and precipitation deficits across varying geographic regions and crop-type, providing a framework for flash drought prediction.

This Consensus Statement presents the standards for technical reporting in environmental and host-associated microbiome studies (STREAMS) guidelines.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

Using upgraded hardware of the multiuser Cold Atom Lab (CAL) aboard the International Space Station (ISS), Bose–Einstein condensates (BECs) of two atomic isotopes are simultaneously created and used to demonstrate interspecies interactions and dual species atom interferometry in space.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Transplants of consortia with limited numbers of strains of commensal bacteria derived from healthy human stool samples are able to suppress intestinal Enterobacteriaceae by regulating gluconate availability, suggesting potential therapies for infectious and inflammatory diseases.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Strain richness of gut microbiota ecosystems is a key characteristic underpinning engraftment in faecal microbiota transplantation, and could improve the design of defined live biotherapeutic products with predictable outcomes.

Results of multi-omic profiling of the microbiome and host immunity of individuals treated with VE303 to prevent recurrent Clostridioides difficile infection in the context of a phase 2 trial show robust colonization of VE303 and indicate potential biomarkers of response.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

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 Bose–Einstein condensate prepared in low Earth orbit shows a free-expansion time greater than one second, demonstrating the advantages of a microgravity environment for such studies.

NASA’s Cold Atom Lab has operated on the International Space Station since 2018 to study quantum gases and mature quantum technologies in Earth’s orbit. Here, Williams et al., report on a series of pathfinding experiments exploring the first quantum sensor using atom interferometry in space.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Colonization of trypsin-degrading commensal bacteria may contribute to the maintenance of intestinal homeostasis and protection against pathogen infection in humans and mice.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

In chickens, influenza A virus relies on host protein ANP32A. Here the authors use CRISPR/Cas9 to generate homozygous gene edited chickens containing two ANP32A amino acid substitutions that prevent viral polymerase interaction.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

The genome of the biofuel crop switchgrass (Panicum virgatum) reveals climate–gene–biomass associations that underlie adaptation in nature and will facilitate improvements of the yield of this crop for bioenergy production.

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

A consortium of 11 bacterial strains from the healthy human gut microbiota can strongly induce interferon-γ-producing CD8 T cells in the intestine, and enhance both resistance to bacterial infection and the therapeutic efficacy of immune checkpoint inhibitors.

The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.

JWST observations of the planetary nebula NGC 3132 reveal a rich molecular environment containing evidence of multiple stellar interactions on a variety of scales.

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.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

DNA analysis of 6 individuals from eastern and south-central Africa spanning the past approximately 18,000 years, and of 28 previously published ancient individuals, provides genetic evidence supporting hypotheses of increasing regionalization at the end of the Pleistocene.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Understanding the relationship between aridity and ecosystem N-cycling is important in predicting the effects of global climate change. Here, the authors present N isotopes across an aridity gradient and identify a tipping point, which marks a divergence in N-cycling controlling factors and mechanisms.

Constraints on the cratering history of the Moon from the modelled production and removal of crustal porosity by impacts are inconsistent with an extended period of bombardment.

LaNiO₃ is a strange metal, for reasons that are not well understood. Here, Liu et al. report evidence for scattering of charge carriers by antiferromagnetic quantum fluctuations in high-purity epitaxial thin films of LaNiO₃, suggesting it is close to an antiferromagnetic quantum critical point.

Martin Tobin and colleagues report a meta-analysis of 23 genome-wide association studies for pulmonary function. They identify 16 loci newly associated with variation in two cross-sectional measures of lung function, used to define airway obstruction and to grade the severity of obstruction.