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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.

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.

The bacterial anti-phage defense systems known as ‘Zorya’ consist of a membrane protein complex (ZorAB) and soluble components of unclear function. Here, the authors solve cryo-EM structures of the ZorAB complex and show that the soluble component ZorE displays nickase activity and acts as an effector module.

The heteromeric insect TRPV channel, Nanchung-Inactive, is a previously structurally uncharacterized insecticide target. Here, Fedor et al. provide insights into how an insecticide and a natural agonist modulate channel behavior, paving the way for future insecticide development.

The authors theoretically delineate the maximal increases in tree growth that can be expected from increases in plant intrinsic water-use efficiency, which increases with rising CO₂. They highlight environmental and physiological limits on growth in the context of experimental data.

The results from a state-of-the-art suite of hydrodynamical cosmological zoom-in simulations show how globular clusters naturally emerge in the Standard Cosmology and also reveal the existence of a new class of object called globular-cluster-like dwarfs.

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.

In this study, Wrigth et al. use structural, medicinal chemistry, and behavioral approaches to examine how equilibrative nucleoside transporter subtype 1 (ENT1) exerts its functions; and their findings reveal ENT1 as a potential target for analgesia.

In this attempt at xenotransplantation of a lung from a genetically modified pig into a brain-dead recipient, although the grafted lung initially maintained viability and functionality, antibody-mediated rejection rapidly occurred, contributing to xenograft damage.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

T cell activation is a process that requires extra nutrients, which could be difficult to source from the tumor microenvironment in competition with tumor cells. Here authors increase the metabolic fitness of CAR-T cells by stable overexpression of the glucose transporter GLUT1, which allows them to increase their glucose intake and enhances their antitumour function.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

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.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

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.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

URAT1 is the target for gout drugs that block urate reuptake in the kidneys, however current treatments have limitations. Here, authors show how urate-lowering drugs inhibit URAT1, facilitating antigout drug development.

Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining neuroendocrine–tuft heterogeneity and offering new perspectives for targeting lineage plasticity.

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

Faecal carbon:nitrogen measurements and manipulation of nitrogen availability via diet and host secretions in a murine model suggest that intestinal nitrogen limitation occurs due to host absorption and microbial use, leading to benefits for specific taxa.

How Japanese encephalitis virus (JEV) penetrates the blood-brain barrier (BBB) remains unclear. Here, using a genetic mouse model and a virulent JEV strain, the authors show that perivascular mast cells (MC) mediate JEV neuroinvasion and identify the MC-protease chymase as a potential therapeutic target.

Interpreting untargeted mass spectrometry (MS) data is challenging due to incomplete reference libraries. Here, the authors created the nearest neighbor suspect spectral library from largescale public MS data, significantly enhancing the ability to hypothesize structures for unknown mass spectra.

Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.

Buchanan, Rupprecht, Kaelberer and colleagues show that the preference for sugar over sweetener in mice depends on gut neuropod cells. Akin to other sensor cells, neuropod cells swiftly communicate the precise identity of stimuli to drive food choices.

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).

Aeneas, a generative neural network trained on ancient texts, helps historians contextualize inscriptions and perform epigraphic tasks, offering an improved starting point for historical research.

The functions of small nucleolar RNAs (snoRNAs) in cancer remain to be studied. Here the authors show that the snoRNA Snord67 promotes lymph node metastasis of breast cancer cells through guiding modifications of the spliceosome and regulating the splicing landscape.

Examining drivers of the latitudinal biodiversity gradient in a global database of local tree species richness, the authors show that co-limitation by multiple environmental and anthropogenic factors causes steeper increases in richness with latitude in tropical versus temperate and boreal zones.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.