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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.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Speckle patterns are a manifestation of decoherence and can result from two-particle interference. Here, the authors image atomic speckle for guided matter waves and link this to atom bunching in the second-order correlation function, suggesting potential use in squeezed-atom interferometry applications.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

A comparative analysis of trait data combined with a mathematical model suggests that dietary specialization drives selection towards the smallest and largest body sizes in terrestrial mammals, as generalists outcompete specialists at intermediate sizes.

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

Chlorpyrifos is a widely-used pesticide and a common residue on vegetables and fruits. Here the authors show that at non-neurotoxic doses, chlorpyrifos reduces energy expenditure, by inhibiting diet induced thermogenesis, and promotes obesity and insulin resistance.

Atmospheric short-wave absorption due to wildfire smoke is caused predominantly by dark brown carbon particles, according to observations from smoke plumes in the United States.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

MATTERIX, a multiscale graphics processing unit-accelerated framework for high-fidelity digital twins and workflows of chemistry laboratories, is presented, simulating robot and device operation, fluids and powders, and processes such as heat transfer and chemical kinetics.

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).

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.

CLASSIC is a high-throughput genetic profiling platform that combines long- and short-read next-generation-sequencing modalities to quantitatively assess pools of constructs of arbitrary length containing diverse genetic part compositions.

With its attribution to Paranthropus, a 2.6-million-year-old partial mandible expands the range of the genus into the Afar region of Ethiopia and adds to our understanding of hominin evolution in eastern Africa.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

This study examines long-term changes in species richness across tropical forests in the Andes and Amazon. Hotter, drier and more seasonal forests in the eastern and southern Amazon are losing species, while Northern Andean forests are accumulating species, acting as a refuge for climate-displaced species.

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.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

Hiraike et al. identify nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat. NFIA activates cell-type-specific enhancers prior to differentiation and facilitates PPARγ binding to regulate the brown fat gene program.

Kinematic measurements of the Perseus galaxy cluster reveal two drivers of gas motions: a small-scale driver in the inner core associated with black-hole feedback and a large-scale driver in the outer core powered by mergers.

Baked sediment, heat-shattered artefacts and introduced pyrite in a 400,000-year-old Palaeolithic occupation site in Suffolk, UK provide evidence of intentional fire-making, marking a pivotal moment in human development.

Brown adipose tissue (BAT) burns, rather than stores, energy and has thus been explored as a way to combat obesity. Aaron Cypess and his colleagues isolate neck fat from adult humans and show that BAT exists in this region, define its anatomical localization in the neck relative to white adipose tissue and demonstrate that it is functional.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

The oncogenic potential of interfollicular stem and progenitor cells in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Here, the authors modelled rapidly growing cSCC driven by the hyperactivation of the MAPK signalling pathway in mice and showed that SOX2 overexpression renders progenitor cells prone to transformation.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Human brown and white preadipocyte clones from neck fat depots have been isolated and used to identify genetic biomarkers that predict their thermogenic capacity.

Structurally resolving glycans remains a challenge. Here, the authors analyse influenza H3 hemagglutinin glycan evolution to show that over five decades of glycan incorporation highly impact structural stability and epitope accessibility, particularly in the head domain, providing key insights for vaccine design.

A member of the family of bone morphogenetic proteins, BMP-7, promotes the differentiation of brown, not white, fat cells. BMP-7 switches on regulators of brown fat, among which there is PRDM16, adipogenic transcription factors, and mitochondrial biogenesis. BMP-7 can persuade mesenchymal progenitor cells to become brown adipocytes. Without BMP-7 less brown fat develops.

Genetic mapping in mice identified Homer1a as a key modifier of attention. Developmental downregulation in the prefrontal cortex enhances inhibitory tone, neural signal to noise and adult attentional performance, revealing a new control mechanism and target.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

Obesity is a major risk factor for chronic disease. A new study in mice reveals that lowering levels of the signaling molecule serotonin outside of the brain reduces obesity and its complications by increasing brown adipose tissue (BAT) energy expenditure.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

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.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Combining high-resolution mapping of foliar and herbivore faecal sodium concentrations across Africa, the authors show that plant-derived sodium availability constrains megaherbivore densities at a continental scale.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Andrew Robinson reviews five of the best science picks.

Improved vaccines and antivirals are needed for many enveloped viruses. Here, the authors identify sulfur-based small molecules that disrupt viral membrane properties, inhibiting fusion and entry, and safely inactivate influenza virus. The resulting inactivated influenza vaccine is protective in mice.

As presented at the ESMO Congress 2025: In patients with locally advanced or metastatic solid tumours, including mesothelioma, treatment with a first-in-class inhibitor of the Hippo−YAP−TEAD pathway was safe and led to encouraging clinical response rates in patients with mesothelioma.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.