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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.

TEAD transcription factors are critical effectors and druggable sites of the Hippo pathway in cancer, however, the development of small molecule inhibitors and degraders remains underexplored. Here, the authors identify and characterize bifunctional IAP-based degraders targeting TEAD1 via a lipid pocket and recruit different members of the inhibitor of apoptosis proteins (IAPs) family, offering a comprehensive toolkit for structural, biophysical and cellular profiling.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate. Through integrated laboratory and clinical studies, the authors identify significant ERBB2 (the gene that encodes the HER2 protein) mutational heterogeneity in patients with urothelial cancer and co-mutation and amplification of ERBB2 as a potential biomarker of exceptional response to T-DXd.

Natural products and their synthesis have always fascinated organic chemists, frequently providing the inspiration and testing ground for new synthetic methods. This Review considers examples of natural products that were prepared first synthetically and predicted to be natural products prior to their isolation from nature.

As presented at the ESMO Congress 2025: In patients with locally advanced or metastatic solid tumours, including mesothelioma, treatment with a first-in-class inhibitor of the Hippo−YAP−TEAD pathway was safe and led to encouraging clinical response rates in patients with mesothelioma.

Melanoma cells lacking SOX10 are tolerant to MAPK inhibition (MAPKi) due to elevated TAZ-driven TEAD signaling. Here, the authors develop two inhibitors of TEAD, capable of resensitising SOX10 knockout melanoma cells to MAPKi and offering a strategy to overcome drug tolerance and improve treatment response.

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.

Catalytic metals dissolved in a liquid gallium solvent remain atomically dispersed. Alignments among the liquid atoms and reactants facilitate selective propylene synthesis from various hydrocarbon feedstocks.

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.

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.

Nitrogen and phosphorus fertilization is an effective pathway to increase soil carbon sequestration through microbial necromass accumulation and plant-derived carbon inputs, as shown by a 180-year soil fertilization experiment, ¹⁴C labelling, metagenomics and metabolomics.

Achieving nonlinear optical response of free-space planar solid devices in the few-photon regime will provide several technological advances. Here, the authors demonstrate a self-hybridised perovskite metasurface with strong nonlinear absorption at record low incident powers, by means of cavity critical coupling engineering

Otopetrins form proton channels in animals ranging from nematodes to humans. Here, authors identify small molecule inhibitors and characterize their binding in the intrasubunit interface region, thus highlighting the area for pharmacological targeting for channel modulation.

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.

Plasmid copy number heterogeneity can be used as a tool to build synthetic microbial populations that adapt to changing environments due to specific plasmid-encoded fitness effects.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

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.

Friction consolidation transforms brittle Sm–Co powders into dense magnets via shear-driven redox reactions and localized heating, enabling phase-selective refinement and enhanced magnetization in a single-step, low-temperature process.

Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.

Wong Chi-huey was accused of accepting a bribe for helping a company gain the rights to use his technology.

In the CheckMate 142 study, nivolumab (anti-PD-1) alone and in combination with ipilimumab (anti-CTLA-4) was shown to induce durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Here, the authors perform exploratory biomarker analysis of the CheckMate 142 study.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Molten Sn as a metallic solvent presents economic feasibility and offers unique surface atomic structures, expanding the concept of liquid metal catalysis. As a demonstration, SnIn_0.1034Cu_0.0094 enables selective H₂ production from hydrocarbons.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Analysis of samples from the asteroid Ryugu provide evidence of late fluid flow in a carbonaceous asteroid, indicating that such bodies may have retained two to three times more water than previously thought.

The chemistry of group 13 metals (M) is dominated by +1 and +3 oxidation states, so MX₂ species are typically metal–metal-bonded dimers, M(II)₂X₄ or mixed-valence species M(I)M(III)X₄. Now, monomeric M(II)(boryl)₂ radicals have been prepared for gallium, indium and thallium. The compounds — structurally characterized by X-ray crystallography — are stable up to 130 °C and exhibit dominant metal-centred radical character.

Porous materials are technologically important for a wide range of applications, such as catalysis and separation. Covalently bonded organic cages can now be assembled into crystalline microporous materials, and their porosity is found to be intrinsic to their molecular cage structure.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Cells under environmental stress, including viral infections, accumulate RNA molecules stalled in pre-initiation complexes known as stress granules (SG). Here the authors show that the viral protein Gag counters anti-viral stress responses by inhibiting SG assembly during HIV-1 infection.

The Cancer Genome Atlas Research Network report integrated genomic and molecular analyses of 164 squamous cell carcinomas and adenocarcinomas of the oesophagus; they find genomic and molecular features that differentiate squamous and adenocarcinomas of the oesophagus, and strong similarities between oesophageal adenocarcinomas and the chromosomally unstable variant of gastric adenocarcinoma, suggesting that gastroesophageal adenocarcinoma is a single disease entity.

The gene Pirtencodes a transmembrane domain protein that is expressed in sensory neurons. Tang and colleagues use calcium imaging and electrophysiology to show that Pirt positively regulates the transient receptor potential channel TRPM8, and that deletion of this protein results in impaired cold sensitivity.

Studies have shown that placental aneuploidy is correlated with adverse pregnancy outcomes, though few causative data are available. Here they show that chromosomal instability is an inherent feature of trophoblasts and normal human placentas, without functional compromise, and provide mechanisms for how this damage is tolerated.

Andrew Futreal and colleagues report inactivating somatic mutations in the histone lysine demethylase gene UTX in human cancers, including multiple myelomas, esophageal squamous carcinomas, renal clear cell carcinomas, acute and chronic myeloid leukemias, breast and colorectal cancers and glioblastomas, identifying UTX as a new tumor suppressor gene.

Analysis of whole-genome sequencing data from hematopoietic stem and progenitor cells taken from patients with myeloma shows how treatment shapes clonal architecture and sheds light on the evolution of treatment-related myeloid neoplasms.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.

A purely organic crystalline two-dimensional mechanically interlocked polymer comprising [c2]daisy chain units forms via preorganized crystallization and thiol–ene click chemistry. This polymer network can be exfoliated to give nanosheets with a 47-fold stiffness enhancement relative to the bulk parent.