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ATRX mutations are associated with developmental disorders and cancer, but how they affect gene regulation is unclear. Here, the authors report that ATRX loss can perturb alpha-globin gene expression by promoting G4- and R-loop-associated DNA damage via a G-rich repeat.

Mass-wasting deposits that accumulated against mid-ocean ridge faults have high porosity in which calcium carbonate precipitated, storing seawater carbon dioxide, as revealed by cores of a 61-million-year-old seafloor talus deposit.

Black-hole masses are estimated from broad emission-line widths and luminosity. Here, the authors show that over decades the luminosity varies while line widths remain constant biasing mass estimates, but using narrow-line luminosity corrects this.

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.

Gravitational lens modelling of a million-solar-mass dark object reveals that it cannot be a free-floating black hole or dark-matter halo as predicted by cold dark matter, instead indicating a peculiar and highly concentrated mass distribution.

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.

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.

Atomic force microscopy is used to investigate the adsorption and organization of ions on charged surfaces. Trivalent ions adopt complex networks, clusters and layers associated with overcharging, whereas divalent ions follow classical predictions.

Coordinated X-ray and radio observations reveal that disk winds and jets occur mutually exclusively in 4U 1630–472, providing new observational constraints on the interplay between different modes of outflow in X-ray binaries.

MK-7762 is a new oxazolidinone antitubercular agent that is structurally similar to linezolid, and demonstrated in vivo efficacy, lesion penetration and limited toxicity compared to linezolid, indicating it could be used in broad tuberculosis regimens.

Water can be extracted from the atmosphere via adsorption-evaporation or dewing, but these methods require prohibitively high energy use. Here, the authors report a forty-five-fold increase in energy efficiency via ultrasonic extraction, making atmospheric water harvesting technology economically feasible for large-scale adoption.

Rider, Grantham, Smith, Watson et al. integrate multiomic data from patients with psoriasis using dimensionality reduction and machine learning techniques. This approach identifies biological relationships between genetic background, clinical features and disease severity, providing insight into disease variability across individuals.

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.

Materials with tunable modulus, viscosity, and complex viscoelastic spectra are crucial in various applications but it remains challenging to design polymer networks with predicted hierarchical relaxation processes. Here, the authors synthesize networks with both pendant and telechelic architectures using mixed orthogonal dynamic bonds to understand how the network connectivity and bond exchange mechanisms govern the overall relaxation spectrum.

This Resource paper presents a global SARS-CoV-2 phylogenetic tree of 4,471,579 high-quality genomes consistently constructed by Viridian, an efficient amplicon-aware assembler.

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.

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

SpaceX’s Inspiration4 mission sent an all-civilian crew into orbit to study physiological, neurovestibular and neurocognitive changes in the astronauts and found that short-duration civilian space missions do not pose a major health risk.

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.

Researchers identify the cancer drug LY2090314 as a potent inhibitor of Toxoplasma gondii and Cryptosporidium and report the first crystal structure of the parasite kinase TgGSK3 bound to it, validating TgGSK3 as a therapeutic target.

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.

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.

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.

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.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

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.

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.

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.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

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.

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.

The evolutionary mechanisms leading to symbiont replacement in insects are not well understood. Zhou et al. show that genome degradation results in nested symbiosis and endosymbiont replacement in cicadas, offering insight into the endosymbiotic origins of cellular organelles.

Laboratory automation, machine learning, and metabolic engineering may be combined to quickly and efficiently build productive microbial strains. Here the authors used these techniques in P. putida to boost isoprenol titers 5-fold over six DBTL cycles while sampling a reduced design space.

Free-space meta-optics with ultrahigh quality(Q)-factor at visible wavelengths is demanded but very challenging to achieve due to the fabrication imperfections. Here, the authors design an etch-free metasurface with minimized fabrication defects and experimentally demonstrate a million-Q resonance at 779 nm wavelength.

Forest ecotypes of deer mice have longer tails than prairie ecotypes. This study shows that this difference is adaptive and involves changes in six genomic regions, one of which is an allele-specific reduction in Hoxd13 expression that leads to tail elongation.

Magnetic skyrmions are promising objects for future spintronic devices. However, a better understanding of their dynamics is required. Here, the authors show that in contrast to predictions the skyrmion Hall angle is independent of their diameter and motion is dominated by disorder and skyrmion-skyrmion interactions in the system.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

Spatially resolved transcriptomic, metabolomic and proteomic analyses of human liver samples highlight the role of lipid-associated macrophages in metabolic dysfunction-associated steatotic liver disease.

REMETA is a method for meta-analyzing gene-based associations using summary statistics, integrating with REGENIE and improving computational efficiency for large studies with many phenotypes.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.