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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.

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.

Ribas and colleagues report the results of a phase 2 clinical trial of neoadjuvant PD-1 blockade in patients with surgically resectable desmoplastic melanoma.

Generation of orbital currents in a non-magnetic material can be useful to build efficient orbitronic devices. Now, the interplay of chiral phonons and electrons is shown to produce orbital currents in α-quartz.

High-resolution flare footpoint observations in the extreme ultraviolet and X-rays were taken by Solar Orbiter. Combined with simulations, the results reveal that the dominant mechanism carrying flare energy through the Sun’s atmosphere can vary on small spatial scales.

Andrew P. Ingersoll relishes a study of scientific discoveries on hot, toxic Venus.

Chemical inhomogeneities between the two members of a binary star system, where the stars presumably are formed from the same material, could be due to planetary engulfment. Such a fate has befallen planets around a quarter of Sun-like (in temperature and surface gravity) stars, according to this sample of more than 100 binary systems.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Achieving tight Cas9 regulation without sacrificing activity remains difficult. Here, the authors design multi-level circuits combining anti-CRISPRs, splice sites, chemical induction, and degron control to enable ultra-high dynamic range and precise, on-demand genome editing across contexts.

The MOUNTAINEER phase 2 trial demonstrated the efficacy and safety of tucatinib (HER2-targeted TKI) and trastuzumab (anti-HER2 antibody) in patients with HER2 + , RAS wildtype unresectable or metastatic colorectal cancer that had progressed on chemotherapy, resulting in the approval of the regimen. Here, the authors report the updated analysis of the MOUNTAINEER trial.

Andrew Robinson reviews five of the best science picks.

CLASSIC is a high-throughput genetic profiling platform that combines long- and short-read next-generation-sequencing modalities to quantitatively assess pools of constructs of arbitrary length containing diverse genetic part compositions.

Psoriasis is a difficult to treat chronic skin condition that could be limiting to quality of life. Here, authors present results of the phase 2 randomized clinical trial KNOCKOUT (NCT05283135) in which they treated patients with moderate-to-severe plaque psoriasis with higher-than-approved doses of risankizumab, an interleukin-23 inhibitor, to show high skin clearance rates and decreased tissue resident memory T cell numbers in the lesional skin.

MatterGen is a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints.

Here, the authors show that pre-infection gastrointestinal microbial composition predicts parasite levels in rhesus macaques infected with P. fragile and humans infected with P. falciparum in a controlled human malaria infection (CHMI) study.

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).

This Review provides a comprehensive overview of epidemiology and molecular determinants of relapsed rhabdoid and other non-nephroblastoma childhood and adolescent kidney tumours, which are usually rare and challenging to cure. The most updated results in this field are discussed to highlight how understanding tumour biology can be used to inform therapeutic strategies in these patient populations.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

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.

Double Asteroid Redirection Test (DART) mission’s impact on asteroid Dimorphos has led to various impact related features. Here, the authors show that those features result naturally from the dynamical interaction of the ejecta with the binary system and solar radiation pressure.

Exploring active and durable catalysts for seawater electrolysis is crucial for sustainable hydrogen production. Here, the authors report a strategy for designing a nickel-molybdenum catalyst for photothermal-promoted anion exchange membrane seawater electrolysis.

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.

Swathi Kumar, Lakshmi Sujeesh, Lois Hong, Jennifer Young and Andrew Holle discuss how scientists can work with communities in low- and middle-income countries to address health-related challenges.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

Zonal positioning in the liver determines whether the CTNNB1 oncogene can induce liver cancer.

The combination of computational design, laboratory-based screening and biophysical validation enables the de novo generation of variable heavy-chain antibody fragments and antibodies that precisely target chosen disease-related molecules.

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.

The J2 antibody is widely used for detecting double-stranded RNAs. Here, Bou-Nader et al. define its nucleic acid specificity and recognition mechanism by solving its co-crystal structure bound to dsRNA, establishing a framework for its reliable use in RNA detection.

Cells must sense heat quickly to protect their proteins and membranes. Here, the authors show that membrane stretch detected by the membrane sensor Mid2 promotes rapid phosphorylation of the Hsp70 chaperone to coordinate gene activity, protein synthesis and resolution of stress-induced protein droplets during heat shock.

Kopal et al. analyze MRI data from a Parkinson’s Disease cohort to assess how LRRK2 gene variants shape brain structure. They find that LRRK2-associated Parkinson’s Disease shows a milder and anatomically distinct pattern of neurodegeneration compared to non LRRK2-associated Parkinson’s Disease.

Dye-sensitized solar cells combining electrolytes based on the ferrocene/ferrocenium redox couple with a metal-free organic donor–acceptor sensitizer are reported to achieve a record 7.5% energy conversion efficiency, revealing the great potential of ferrocene-based electrolytes for future dye-sensitized solar cell applications.

R9AP is a key receptor for entry of Epstein–Barr virus into human epithelial and B cells, and interacts directly with the viral glycoprotein gH/gL complex to mediate virus–host membrane fusion.

Ultraviolet radiation (UVR) increases melanoma incidence. Here, the authors report that UVR-damaged dermal fibroblasts upregulate MMP1 to degrade collagen which inhibits melanoma invasion and that aged primary melanomas in skin with degraded collagen have a better prognosis, while new collagen synthesis restores invasion and leads to death.

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.

Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

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.

As presented at the ASCO 2025 Annual Meeting and the ESMO Congress 2025: In RELATIVITY-098, treatment of patients with stage III/IV resected melanoma with nivolumab and relatlimab compared to nivolumab alone did not significantly change recurrence-free survival, with correlative data pointing to the absence of tumor-infiltrating LAG3⁺ T cells as a potential reason.

Stacking multiple junctions with different bandgaps and operating under concentrated light allows solar cells to reach efficiencies beyond the limits of standard devices. Geisz et al. present a six-junction solar cell based on III–V materials with a 47.1% efficiency—the highest reported to date.

A combination of clonal expansion and DNA amplification is used to sequence genetic material from individual melanocytes, shedding light on the mutational landscape of these cells and the development of melanomas.

Known to augment host innate immunity, Zhou and Ahearn et al. shows that a SARS-CoV2 NSP15 mutant also increases viral recombination and reduces sub-genomic message. Results articulate a novel role for NSP15 in viral transcription and recombination.

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.