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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.

In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

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.

The growing market demand for peptides is drawing more attention to their industrial synthetic procedures, which rely on large amounts of toxic solvents. Here the authors suggest practical steps that bring fully water-based peptide synthesis closer to reality.

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

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

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

Single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing profiling of human retinal samples from diverse ancestries create an epitranscriptomic atlas characterizing over 130 cell types. Integration with genome-wide association study and expression quantitative trait loci data provides further insights into gene regulation and disease etiology.

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.

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.

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.

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.

Gram-negative bacteria use a multiprotein complex, LptB₂FGC, to transport lipopolysaccharides (LPS) to the outer membrane. Here, Fiorentino et al. present cryo-EM structures of the complex from Pseudomonas aeruginosa, revealing species-specific features and providing insights into LPS transport mechanisms.

Differentiating DCs express ALDH1A2, which produces retinoic acid and suppresses DC activity. Blocking this pathway with a new inhibitor, KyA33, enhances immune responses and boosts the effectiveness of DC cancer vaccines in mouse models.

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.

The interactions of CAR-T cells and solid tumors are modeled on a chip.

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.

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.

Here the authors perform a gene knockout screen in myeloid cells, identifying 295 genes regulating interleukin-1β production, of which 57 lie in regions associated with inflammatory disease risk. The study sheds light on genetic control of interleukin-1β in inflammation, beyond previously known factors.

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.

A deep-learning-based de novo design strategy was developed that enables simultaneous scaffolding of three distinct epitopes derived from respiratory syncytial virus within small single-domain immunogens. Crystallographic analyses confirmed precise presentation of the designed motifs. The multiepitope constructs elicited enhanced cross-reactive and neutralizing antibody responses, demonstrating the potential of generative models for complex multisite protein engineering.

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.

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.

A long-period radio transient with coincident radio and X-ray emission and observational properties unlike any known Galactic object has been observed by the Australian Square Kilometre Array Pathfinder.

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.

The authors present a scalable mass spectral search tool that identifies both known molecules and structural variants by estimating match significance. The method revealed biosynthetic pathways in Streptomyces, expanding the scope of metabolite discovery.

Here, the authors show that methylphenidate alters brain organization by compressing the hierarchy between sensory and association areas. This dopamine-driven shift predicts improved attention, revealing how stimulants reorganize brain networks to enhance cognitive function.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

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.

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.

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

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.

Padawer-Curry et al. show that the hallucinogenic 5-HT2A receptor agonist DOI alters neurovascular coupling in mice, with implications for the interpretation of human fMRI studies of psychedelics.

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.

The NINJ1 protein regulates plasma membrane rupture by altering membrane biomechanical properties, independent of cell death programs.

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.

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.

Myocardial infarction disrupts cardiac repair mechanisms, limiting regeneration. Here, the authors show that extracellular matrix therapies activate spatial and cell-specific pro reparative programs, revealed through spatial transcriptomics and snRNA-seq.

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.

Automated iterative small-molecule synthesis has generally been limited to around one carbon–carbon bond-forming step per day. Now, a next-generation automated synthesizer enables rapid, automated, iterative synthesis of a variety of small molecules. Improvements to chemistry and automation leads to a tenfold decrease in reaction time over previous automated platforms.

A long-lived photoinduced metastable state in a quasi-one-dimensional cuprate, Sr₁₄Cu₂₄O₄₁, is reported.

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.

Sustainable aviation fuel enables decarbonization of the aviation industry. Here the authors report a hydrothermal liquefaction pathway for sustainable aviation fuel from food waste, meeting fuel property standards and improving circularity index.

The chemotherapeutic efficacy of prodrug is limited by its cancer-targeting ability. Here this group reports an engineered commensal Lactobacillus plantarum strain with anticancer prodrugs loading on the surface for nasopharyngeal carcinoma cell-targeting and growth inhibition.

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 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.