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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.

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

An Earth-mass planet is found to have a white dwarf host—the final evolutionary stage of Sun-like stars. This system suggests that terrestrial planets in Earth-like orbits may avoid being engulfed during the red-giant phases of their host stars.

Inhibition of haem synthesis is shown to lead to the accumulation of branched-chain amino acids in the brown adipose tissue of mice, which reduces UCP1 levels and impairs thermogenesis.

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.

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.

Chemical language models trained on known metabolites can identify previously unknown metabolites from mass spectrometry-based metabolomics data with high accuracy.

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.

A paleogenome from an approximately 100,000-year-old polar bear shows massive prehistoric, and largely unidirectional, gene flow from polar bears into brown bears at a time of climate change-induced overlap in the ranges of the two species. This admixture event cannot be detected using genomic data from living polar bears.

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.

Liquid charge density wave order is thought to occur in many correlated electron systems but has not been observed experimentally. Now, a liquid-like electronic state is shown to emerge in a transition metal dichalcogenide on photoexcitation.

Geminin regulates DNA replication by binding CDT1 and preventing MCM helicase loading. Using a reconstituted system and structural modelling, the authors find geminin inhibits via steric clash with MCM, not by blocking the CDT1–MCM interface. Combined with CDK activity, it fully halts licensing.

A giant planet candidate roughly the size of Jupiter but more than 14 times as massive is observed by TESS and other instruments to be transiting the white dwarf star WD 1856+534.

Whole-ecosystem manipulations of Caribbean islands occupied by brown anoles, involving the addition of competitors (green anoles) and/or top predators (curly-tailed lizards), demonstrate that predator introductions can alter the ecological niches and destabilize the coexistence of competing prey species.

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.

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.

The vagus nerve is known to promote rest and digest, to counter physiologic stresses. Here, authors show that insulin signaling plays a critical role in optimizing autonomic function to maintain metabolic and inflammatory homeostasis.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of frataxin-stimulated NFS1 activity.

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.

Coulomb explosion imaging can map positions of atoms and their motion in molecules. Here the authors extend it to detect up to eight ions in coincidence and develop a machine-learning framework for automated differentiation of reaction pathways.

Liver and adipose tissue are shown to use different metabolic routes to generate NADPH for de novo lipogenesis, with the liver relying on a unique cytosolic serine catabolic pathway involving the enzyme SHMT1.

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.

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.

Saccharomyces cerevisiae bearing engineered alginate and mannitol catabolic pathways can ferment sugars from brown macroalgae to produce ethanol, potentially allowing the use of brown macroalgae as a viable feedstock for the production of biofuels and renewable chemicals.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Here, the authors show people with high trait anxiety display stable, parvocellular-specific visual cortical hyperactivity linked to disrupted cortical excitation–inhibition modulation. Trait anxiety thus alters sensory encoding from the earliest stages of cortical processing.

An Fe^III/V redox mechanism in Li₄FeSbO₆ on delithiation without Fe^IV or oxygen formation with resistance to aging, high operating potential and low voltage hysteresis is demonstrated, with implications for Fe-based high-voltage applications.

Terahertz-frequency communications promise ultra-high data rates and stable latency, yet current systems lag behind infrared technologies. Here, the authors demonstrate a pioneering multi-gigabit-per-second free-space optical communication using a terahertz quantum cascade laser, setting the stage for advanced wireless networks with significant implications for high-speed data transmission.

Variants of adeno-associated viruses displaying robust and widespread transduction in murine, porcine and non-human-primate kidneys, and in human kidney organoids, can be obtained via the cross-species cycling of capsid libraries in the different kidney models.

Mirusviruses were detected in metagenomic datasets, but little is known about how they infect their hosts. Here, the authors characterize mirusviruses in the marine protist Aurantiochytrium, detecting virions, viral genes and proteins, and establishing this as a valuable model system.

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.

Hominin fossils from the Ledi-Geraru Research Project area, Ethiopia, suggest that early Homo and Australopithecus species co-existed in the region more than 2.5 million years ago.

In this disease mapping study, the authors estimate disability-adjusted life year rates for three of the major causes of mortality for children under five 43 countries in sub-Saharan Africa. They identify significant heterogeneity at the subnational level, highlighting the need for a targeted intervention approach.

Laboratory simulation experiments with isomer selective photoionization detection techniques reveal that octasulfur (S₈) and sulfanes can be easily formed in low temperature H₂S interstellar ice analogues exposed to ionizing radiation, suggesting a critical link between sulfur chemistry on ice coated nanoparticles in molecular clouds and the inventory of sulfur compounds in our Solar System.

High pathogenicity avian influenza virus has a wide host range and has been detected across a large geographic area. Here, the authors present evidence of spread to the Antarctic and sub-Antarctic regions, with signs of clinical infection and positive virus detection in birds and elephant seals.

This Perspective proposes the Population Neuroscience-Dementia Syndemics Framework and model to develop knowledge of how multiple factors may interact to perpetuate inequities in dementia, especially for women in low- and middle-income countries.

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).

Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.

Metamorphic soles beneath ophiolites record rapid subduction initiation, with high-temperature metamorphism that may be driven by relative motion across the plate interface, according to diffusion speedometry of garnets combined with isotopic data.

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.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.