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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.

Using the 2008 Wenchuan Earthquake, the authors show that earthquake-triggered landslides increased mountain carbon storage by ~10% from 2008 to 2020, as vegetation recovery and sediment burial retained carbon, revealing earthquakes and landslides function as long-term carbon capacitors.

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.

Nuzum et al. used cross-sectional data from the UK PROTECT study to evaluate the relationship between high autistic traits and suicidality in older adults.

Data on immune response to the SARS-COV-2 AZD1222 vaccine are limited in African populations. Here, the authors show immunogenicity of the AZD1222 vaccine in two independent cohorts from West Africa, including seroprevalence levels prior to vaccine rollout in January 2021.

Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is important for early detection and treatment. Here, the authors use a multigene next-generation sequencing panel to identify genomic differences in Nigerian CRCs compared to those from TCGA and MSKCC cohorts.

Experts, regulators mull how to foster technologies without posing undue risk to patients.

Coastal west Greenland ice caps fluctuated strongly compared to the interior in response to rapid Common Era changes in snow accumulation, according to modelling of proxy records developed from a Nuussuaq Peninsula ice core covering the last 2,000 years.

Analysis of a continuous record of water-isotope ratios from the West Antarctic Ice Sheet Divide ice core reveals a dominant role for annual maximum insolation in determining West Antarctic summer temperature during the Holocene.

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.

Global-health researcher Joshua Vogel describes challenges in maternal and newborn health and how to translate research into practice.

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.

Although ordered membrane nanodomains, also known as lipid rafts, have many proposed cellular functions, pharmacological tools to modulate protein affinity for rafts and to manipulate raft formation are currently lacking. Here, the authors screened 24,000 small molecules for compounds that impact the raft affinity of a known raft-preferring model protein, peripheral myelin protein 22 (PMP22), in giant plasma membrane vesicles, identifying three chemically distinct tools for modulating raft formation in a protein-independent manner by altering lipid–lipid interactions and membrane fluidity in biophysical experiments and in living 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.

Strontium isotope analysis can be applied to animal and plant tissues to help determine their provenance. Here, the authors generate a strontium isoscape of sub-Saharan Africa using data from 2266 environmental samples and demonstrate its efficacy by tracing the African roots of individuals from historic slavery contexts.

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.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

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.

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.

Optineurin is linked to ALS and glaucoma, but the mechanism is unknown. Here, the authors show that optineurin mutation causes deficits in axonal mitochondria transport and neurodegeneration, enhancing of which achieves axon protection and regeneration.

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.

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.

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.

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.

Dual cyclin A/B RxL inhibitors selectively kill small cell lung cancer cells and other cancer cells with high E2F activity.

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).

Frequent dispersal and short-lived local transmission clusters fuelled the 2013–2016 Ebola virus epidemic in Guinea, Liberia and Sierra Leone.

Efficient statistical emulation of melting land ice under various climate scenarios to 2100 indicates a contribution from melting land ice to sea level increase of at least 13 centimetres sea level equivalent.

Single cell transcriptomics can be used to identify genes associated with type 2 diabetes (T2D) and computational models can be used to identify gene networks. Here the authors identify networks of dysregulated genes in T2D and the biological processes involved, further demonstrating the functional context of the identified genes.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.

Tanguy Chouard rates a film probing the psyches of Indonesia's paramilitary killers.

Modulating mitochondrial NAD⁺ levels by changing the expression of the mitochondrial NAD⁺ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD⁺ levels are a key determinant of the rate of liver regeneration.

Monitoring of western chimpanzee populations in Guinea-Bissau and Côte d’Ivoire reveals the presence of rare and different genotypes of Mycobacterium leprae, suggesting greater circulation in wild animals than previously thought.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Here, the authors report the characterization of stable few-layer PdSe₂ transistors encapsulated in hexagonal boron nitride, showing field effect mobilities up to 700 cm²/Vs at room temperature and signatures of an 8-fold spin-valley degeneracy of the magnetotransport quantum oscillations at cryogenic temperatures.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

Analysis of shallow-water marine carbonate samples from 101 stratigraphic units allows construction of a record of lithium isotopes from the past 3 billion years, tracking the evolution of the global carbon and silicon cycles.

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.

Structural and single-molecule analyses show the CTPase, KorB, is a sliding DNA clamp that interacts with a clamp-locking protein KorA to inhibit gene expression over distances of more than 1 kb in the multi-drug resistance RK2 plasmid.

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.

Circulating tumor cell (CTC) clusters are much more likely to produce viable metastasis than single CTCs. Here the authors find that the transmembrane protein Plexin-B2 (PLXNB2) mediates homotypic and heterotypic CTC cluster formation, driving lung metastasis in breast cancer mouse models.

Double Asteroid Redirection Test (DART) mission impact on asteroid Dimophos resulted in an elliptical ejecta plume. Here, the authors show that this elliptical ejecta is due to the curvature of the asteroid and makes kinetic momentum transfer less efficient.