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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.

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.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Functional and structural characterization of PtmA2 reveals that it is an unusual non-adenylating acyl-CoA ligase and part of a system wherein the canonical acyl-CoA ligase reaction is separated into two half-reactions performed by distinct enzymes.

Owing to electron localization, two-dimensional materials are not expected to be metallic at low temperatures, but a field-induced quantum metal phase emerges in NbSe₂, whose behaviour is consistent with the Bose-metal model.

A protein biomarker, the NOTCH3 extracellular domain, identifies individuals with idiopathic pulmonary hypertension, correlates with disease progression, improves mortality risk prediction and provides a readily implementable, noninvasive blood test for this disease.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

Vaccinations against the SARS-CoV-2 KP.2 variant were introduced for the 2024-25 season in the United States. Here, the authors investigate the effectiveness of these vaccines up to April 2025 through a target trial emulation study using electronic health record data.

The ALICE Collaboration provides details on the microscopic mechanism that ends up creating antideuteron in high-energy proton–proton collisions at the Large Hadron Collider.

The CMS Collaboration reports the measurement of the spin, parity, and charge conjugation properties of all-charm tetraquarks, exotic fleeting particles formed in proton–proton collisions at the Large Hadron Collider.

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.

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

Artificial neural networks face challenges of robustness and efficiency as they scale. Here, the authors show that incoherent network motifs provide greater stability and resilience to noise than coherent network motifs, offering new structural insights for designing stronger neural networks.

The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

The quark structure of the f₀(980) hadron is still unknown after 50 years of its discovery. Here, the CMS Collaboration reports a measurement of the elliptic flow of the f₀(980) state in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of 8.16 TeV, providing strong evidence that the state is an ordinary meson.

SPACEc offers a user-friendly, expert-curated workflow for multiplexed image analysis, enabling researchers to easily perform advanced spatial biology studies and streamline the path from experiment to discovery.

Yuan et al. present crossNN, an explainable machine learning tool to classify tumors based on DNA methylation data from several platforms with different epigenome coverage and sequencing depth, benchmark against other models and validate externally.

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.

CRISPR-Cas9 technology holds the potential to treat a wide spectrum of genetic diseases. Here, the authors describe a modular platform for extracellular vesicle-based Cas9 delivery, using MS2-based RNA-binding domains and UV-cleavable linkers, suitable for various Cas9-based moieties.

Through fine-root nutrient chemistry, it is possible to study ecosystem-scale biogeochemical cycling. Compiling data from 211 studies measuring nitrogen and phosphorus in plant roots, Yuanet al. find that tropical ecosystems are more phosphorous-limited than higher latitudes.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

While Bell inequalities have been violated several times—mostly in photonic systems—their violations within particle physics experiments are less explored. Here, the BESIII Collaboration showcases Bell-violating nonlocal correlations between entangled hyperon pairs.

The developmental dynamics of distinct cell types across brain regions remain poorly understood. Here authors generate DevAtlas, a high-resolution developmental 3D atlas, mapping region and cell type-specific growth in GABAergic cells and microglia in early postnatal mouse brains.

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.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Observations of a fast X-ray transient reveal that it is a gamma-ray-burst explosion from a very distant galaxy that emits light with the wavelength necessary to drive cosmic reionization, the last major phase change in the history of the Universe.

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.

It remains unclear whether machine learning methods can accurately identify cancer driver alterations. Here, the authors compare machine learning-based approaches to other computational methods to determine their utility for annotating variants of unknown significance and identifying driver alterations in real-world cancer patient data, demonstrating superior performance.

Topological lasers often suffer from low directionality, and/or complex design requirements hindering operation at small wavelengths. Here, by using a few monolayers of perovskite quantum dots, the authors demonstrate a lithography-free, vertical-emitting, single-mode laser emitting in the green.

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.

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.

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.

This global study shows that short-term exposure to landscape fire sourced PM_2.5 increases hospital admissions for multiple diseases in children, especially those aged 5-9 years and in low-SES areas, highlighting the need for targeted protection.

In two cohorts of patients with glioblastoma who received anti-PD-1, Sonabend and colleagues show that ERK1/2 phosphorylation, detected by immunohistochemistry, provides a biomarker for MAPK/ERK pathway activity and better survival on this therapy.

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.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

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 genetic susceptibility to breast cancer remains understudied in non-European populations. Here, the authors analyse pathogenic variants associated with breast cancer susceptibility in Hispanic/Latina women using genomics, and find that loss of function variants in FANCM are strongly associated with ER-negative breast cancer risk.

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 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.

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.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

Inactivating PPP2R1A mutations correlate with better survival after immune checkpoint blockade in patients with ovarian clear cell carcinoma, suggesting that targeting the phosphatase 2A (PP2A) pathway may represent an effective startegy for improving responses to immunotherapy.

The semileptonic decay channels of the Λc baryon can give important insights into weak interaction, but decay into a neutron, positron and electron neutrino has not been reported so far, due to difficulties in the final products’ identification. Here, the BESIII Collaboration reports its observation in e+e- collision data, exploiting machine-learning-based identification techniques.

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.

Here the authors provide new radiocarbon, U-series, and OSL dates for Homo sapiens fossils from Tongtianyan cave, southern China, placing them at 33-23 thousand years ago and indicating widespread presence of Homo sapiens across eastern Asia in the Late Pleistocene.