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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.

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.

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.

A global synthesis of >600 studies finds that across agro-ecosystems, grasslands and forests in temperate and tropical zones, increasing plant diversity has a consistently positive effect on plant performance and the suppression of antagonists.

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

Personal names vary across cultures. Here, the authors show how historical name systems share a common information structure, reflecting pressure for efficient communication, as well as laws changing these systems and introducing systematic bias.

JWST’s COSMOS-Web survey is used to create an ultra-high-detail dark matter map, revealing hidden filaments, clusters and distant structures. By tracing features out to z = 2, this map shows how dark and luminous matter build the cosmic web across cosmic time.

GPR99/OXGR1 is a GPCR activated by both oxoglutarate and leukotriene E4, implicated in asthma and inflammation. The authors report here the cryo-EM structures of GPR99-Gq bound to both ligands, demonstrating two distinct binding sites.

piR48444 targets METTL7A to inhibit BMP2 mRNA m6A methylation and METTL7A/eIF4E complex-mediated BMP2 mRNA stability and translation, ultimately inhibiting osteogenic differentiation of MSCs and bone regeneration.

FAME is a biobank-scale method that tests whether the effect of an SNP on a quantitative trait is modulated by an individual’s polygenic background. FAME can also be used to estimate of the proportion of variance explained by such marginal epistasis effects

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.

Ensuring accurate state monitoring is vital for battery safety and efficiency in electric vehicles. Here, authors present mechanistically guided residual learners that integrate mechanistic knowledge and machine learning to enable continuous, reliable battery state tracking over the entire lifespan.

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.

PropMolFlow is a flow-matching method for property-guided molecule generation that matches diffusion model performance while generating stable, valid structures more quickly and enabling the discovery of molecules with under-represented property values.

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.

Drug combination discovery remains slow and challenging. Here, the authors introduce Combocat, an open-source framework that combines acoustic liquid handling protocols with machine learning to achieve ultrahigh-throughput drug combination screening; as proof of concept, they use Combocat to screen 9,045 drug combinations in a neuroblastoma cell line.

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.

Liu and colleagues demonstrate that biomimetic fractal patterns derived from glomerular histology can enhance the maturation of podocytes (highly differentiated glomerular cells) that are grown in culture. This work presents a bioengineered platform for improved cell culture fidelity.

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 ambiphilic reactivity of alkyl sulfonyl fluorides in stereoselective cyclopropanation under Pd(II) catalysis is reported. The method provides convenient access to cis-disubstituted cyclopropanes that are otherwise challenging to access. A representative carboxylic acid cyclopropane building block is scaled up to 100 mmol, demonstrating the practicality of this transformation.

Erbium quantum emitters operating in the telecom C band are promising for spin-photon interfaces but achieving both optical and spin coherence has been challenging. Gupta et al. report two types of erbium dopants in epitaxial Y₂O₃ thin films occupying distinct lattice sites and exhibiting long spin and optical coherence times

It is uncertain how much life expectancy of the Chinese population would improve under current and greater policy targets on lifestyle-based risk factors for chronic diseases and mortality behaviours. Here we report a simulation of how improvements in four risk factors, namely smoking, alcohol use, physical activity and diet, could affect mortality. We show that in the ideal scenario, that is, all people who currently smokers quit smoking, excessive alcohol userswas reduced to moderate intake, people under 65 increased moderate physical activity by one hour and those aged 65 and older increased by half an hour per day, and all participants ate 200 g more fresh fruits and 50 g more fish/seafood per day, life expectancy at age 30 would increase by 4.83 and 5.39 years for men and women, respectively. In a more moderate risk reduction scenario referred to as the practical scenario, where improvements in each lifestyle factor were approximately halved, the gains in life expectancy at age 30 could be half those of the ideal scenario. However, the validity of these estimates in practise may be influenced by population-wide adherence to lifestyle recommendations. Our findings suggest that the current policy targets set by the Healthy China Initiative could be adjusted dynamically, and a greater increase in life expectancy would be achieved.

The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

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.

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 phase 3 STEER trial showed that a single intrathecal dose of onasemnogene abeparvovec significantly improved motor function in children and adolescents with spinal muscular atrophy versus sham, with a similar and acceptable safety profile.

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.

A comparison of alpha diversity (number of plant species) and dark diversity (species that are currently absent from a site despite being ecologically suitable) demonstrates the negative effects of regional-scale anthropogenic activity on plant diversity.

Electron distributions exhibit velocity-space signatures indicative of the rapid energy released by magnetic reconnection explosions occurring in Earth’s magnetosphere and in plasmas throughout the universe. Here, the authors discover a smile-shaped signature in the electron gradient distribution associated with reconnection occurring at Earth’s dayside magnetopause boundary.

Crystal growth is visualized inside non-transparent liquid metals, while preserving their original state, using X-ray micro-computed tomography to reveal how liquid metal solvent composition and cooling conditions influence crystal formation.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

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.

The valorization of glycerol to propylene glycol is economically attractive but involves high hydrogen pressures. Here, the authors report a thermo-electroreduction strategy using a cobalt-cluster-on-copper catalyst, which enables propylene glycol production even at ampere level current density.

To turn on and obtain emission from lanthanide-doped insulating nanoparticles, an electrical excitation pathway coupling them to organic optical molecules to form nanohybrids is described, enabling tunable electroluminescence properties of LEDs fabricated from such materials.

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 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.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

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.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

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.

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.

This study identifies four distinct polycystic ovary syndrome (PCOS) subtypes using unsupervised clustering analysis on data from 11,908 women and validated across five diverse cohorts. The subtypes show unique clinical features and suggest that subtype-specific management could enhance treatment precision for PCOS.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.