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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.

Rullman et al. explore skeletal muscle gene-expression in patients with severe heart failure. They identify upregulation of p53 signaling, a process linked to aging and cell damage to be associated with mortality, highlighting the need to separate inactivity effects from disease-specific changes and cell-cycle control as a disease mechanism.

How landscapes are arranged affects soil pathogenic fungi worldwide. The authors reveal the global pattern and pronounced scale-dependency of landscape complexity and land-cover quantity on soil pathogenic fungal diversity.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Manipulating chemical reactions using laser pulses to control electron transfer is an attractive goal, however much of the underlying physics remains unexplored. Here the authors analyse and explain the intramolecular electronic transfer occurring during charge-separation in acetylene, a model donor-bridge-acceptor molecule.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

The potential of mammogram-based biological age predictors remains to be fully explored. Here this group introduces a deep learning model to estimate the biological age of the breast using healthy mammograms.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Large language models (LLMs) are emerging as powerful tools in healthcare, with a growing role in global health, particularly in low- and middle-income countries. This Perspective examines the current progress, challenges and prospects of LLMs in addressing health system disparities and supporting achievement of the Sustainable Development Goals.

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.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

A pooling–deconvolution algorithm identifies cooperative catalyst behaviours with low experimental cost while accommodating potential inhibitory effects between catalyst candidates.

Across 13 longitudinal studies (3,737 adults), the authors show that brain atrophy parallels memory loss, with a stronger coupling in later life. APOE ε4 increases decline, yet genetic risk does not modify the brain–memory relationship.

Singlet oxygen relaxes in water to its triplet ground state. Here, the authors show that heavy-atom tunnelling speeds up this reaction from time scales longer than the age of the universe to microseconds.

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.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Tolododekin alfa is an anchored interleukin-12 conjugate enhancing tumour retention. Here, this group reports a Phase 1 trial evaluating the safety and biological activity of tolododekin alfa in patients with different advanced solid tumours.

An expert-elicitation process identifies current methodological barriers for monitoring terrestrial biodiversity, and how technological and procedural development of robotic and autonomous systems may contribute to overcoming these challenges.

As presented at the ESMO Congress 2025: Results of the phase 2/3 AGITG DYNAMIC-III trial show that de-escalated chemotherapy based on ctDNA-negative status in patients with stage III colon cancer did not meet non-inferiority for 3-year recurrence-free survival when compared to standard of care, although it enables better informed treatment decisions.

In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.

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.

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.

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.

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.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

While important for solar energy conversion, it is unclear whether electron transfer at molecular–semiconductor interfaces is influenced only by the distance over which the injected electron tunnels and whether specific through-bond pathways are active. Now, a pathway for electron transfer has been identified through comparative analysis of compounds with phenyl- or xylyl-thiophene bridges.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

ChReef is an optogenetic actuator for sustained optogenetic control of excitable cells in a variety of preclinical applications.

Hesitation—pausing in the face of uncertainty—is ubiquitous in daily life and disrupted in several psychiatric disorders. Unlike other forms of response inhibition, hesitation is mediated by indirect, but not direct, pathway striatal neurons.

In this epidemiological analysis, Marcus et al. show that acute alcohol consumption is associated with a higher risk of discrete atrial fibrillation episodes, as well as for new-onset (incident) atrial fibrillation, in the general population.

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.

Recent ultrafast measurements shed light on the nature of charge carrier dissociation in organic heterojunctions, but a mechanistic understanding is still incomplete. Bittner and Silva address the role of quantum coherence in this process and propose a direct tunnelling to current-producing states.

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.

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.

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.

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.

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.

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.

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.

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.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

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.