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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.

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.

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.

Transcriptional memory is a phenomenon that enables cells to memorize transient gene activation. A study now sheds light on epigenetic mechanisms conveying mitotic-heritable memory in the context of the IFNγ model.

Using cryo-EM, the authors identified 42 MIPs, including outer junction protein CFAP77 and outer dense fibers, in native doublet microtubules of Tetrahymena thermophila. Knockout of CFAP77 reduced ciliary beat frequency and led to outer junction damage.

Short-circuiting during fast charging through lithium dendrite intrusion into electrolytes is a major challenge in solid-state batteries. Here, using thermally annealed 3-nm-thick Ag coatings, lithium penetration into brittle electrolyte Li_6.6La₃Zr_1.6Ta_0.4O₁₂ is inhibited at local current densities of 250 mA cm⁻² due to an increase in surface fracture toughness.

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.

Proton-exchange membrane water electrolysers rely on iridium to catalyse their anodic reaction, and while ruthenium is a less costly alternative due to its similar activity, it is not as stable. Now, a hierarchical machine-learning catalyst discovery workflow, termed mixed acceleration, is put forward to predict catalyst synthesis, activity and stability, and identify promising RuO_x-based water oxidation catalysts.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

The use of nucleic acid-based nanostructures as synthetic biological tools remains challenging. Here they present synthetic RNA structures that fold and self-assemble inside human cell nuclei, offering a platform for imaging, sensing, and future therapeutic applications.

A multimodal deep learning model combines molecular sequence, structure and biochemical properties to predict immunogenicity in an interpretable way, providing a framework for smarter molecular prediction and hypothesis generation.

Li et al. propose a conceptual framework to study the phenomenon of falling asleep based on electroencephalogram data. They show that a tipping point marks the brain’s nonlinear wake-to-sleep transition and that the unfolding process can be tracked in real time.

An Fe^III/V redox mechanism in Li₄FeSbO₆ on delithiation without Fe^IV or oxygen formation with resistance to aging, high operating potential and low voltage hysteresis is demonstrated, with implications for Fe-based high-voltage applications.

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

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.

Xenotransplantation of a genetically edited pig kidney with a thymic autograft into a brain-dead human for 61 days with immunosuppression resulted in stable kidney function without proteinuria, and xenograft rejection was treated and reversed by the end of the 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).

Here, combining structural, proteomics and biochemical analyses, the authors elucidate how the keystone gut bacterium Ruminococcus bromii assembles a specialized enzyme complex, the amylosome, to efficiently break down resistant starch, a cardinal dietary fiber that influences gut microbiome function and health.

The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.

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.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

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.

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.

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.

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.

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 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.

TARPs are tetraspanins that are claudin-like but regulate glutamate receptors. Here, the moieties that define TARP function and distinguish them from claudins are uncovered through cryo-EM, structure prediction, and electrophysiology.

Together with a companion paper, molecular details of immune responses in a pig-to-human xenotransplantation are identified through dense longitudinal multi-omics profiling of the xenograft and the host recipient, across the 61-day procedure.

Here, the authors sample air and surfaces in hospital rooms of COVID-19 patients, detect SARS-CoV-2 RNA in air samples of two of three tested airborne infection isolation rooms, and find surface contamination in 66.7% of tested rooms during the first week of illness and 20% beyond the first week of illness.

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.

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.

Converting low-cost inorganic chemicals into value-added organic chemicals is a longstanding goal in chemistry. Here the authors describe a silver-catalysed chemoselective carbene N−H insertion reaction, providing access to primary amines from aqueous ammonia and diazo compounds.

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.

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.

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.

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.

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.

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.