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The functional impact of most missense variants remains unknown. Here the authors perform deep mutational scanning of the tumor suppressor SMARCB1 and find missense mutations that retain detectable protein expression but disrupt function similar to protein-null mutations

Global Burden of Disease analysis found that in 2023, suboptimal diet was estimated to be responsible for 4 million deaths and 97 million morbidity burdens from ischemic heart disease.

The genomewide meta-analysis of lumbar spinal stenosis LSS identifies 73 previously unreported loci in addition to 15 known loci and highlights spinal degeneration as a key pathogenic mechanism. Overall, the findings expand knowledge of the genetic background of LSS.

Lethal heatwaves are traditionally identified using wet-bulb temperature thresholds, which fail to capture vulnerability and adaptability. Here, a model using thermo-temporal trends and public health predicts lethal heat with more than 10x accuracy.

When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

The authors have applied an eight-tissue rat multi-omic dataset to analyze the gene regulatory landscape of endurance exercise training, identifying tissue-specific regulatory patterns involved in muscle function, metabolism and immune response.

Fear generalization allows learned threats to extend to similar stimuli, but the early sensory mechanisms involved are unclear. Here, authors show that fear conditioning reduces GABAB inhibition in the olfactory bulb scaled to odor similarity, and that bidirectional manipulation of this inhibition controls breadth of fear generalization.

A large-scale study on the replicability of claims from social and behavioural science journals reports that about half of the results replicate in the same patterns as the original study.

The molecular mechanisms underlying natural transformation remain poorly understood. Here, the authors use optical tweezers to show how the periplasmic DNA receptor ComEA drives the inward pulling of DNA by switching between oligomerization states.

Exposome analyses across 34 countries showed that social exposures were associated with faster functional brain aging and physical exposures with faster structural brain aging.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

A mummified fossil of the early Permian reptile Captorhinus reveals the potential ancestral amniote breathing mechanism and its impact on terrestrial vertebrate evolution.

Decreased brain volumes and increased NfL levels can be observed earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Analysis combining multiple global tree databases reveals that whether a location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

In a phase 1 basket trial, the small interfering RNA zodasiran, targeting ANGPTL3, lowered triglycerides in patients with severe hypertriglyceridemia and lowered both triglycerides and low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolemia.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

Androgen activity in the male embryonic hindbrain prolongs hindbrain differentiation in male individuals and drives sex differences in the incidence and prognosis of posterior fossa type A (PFA) ependymoma, an aggressive childhood brain tumour.

The CMS experiment at CERN reports one of the highest-precision measurements of the W boson mass, finding it in line with standard model predictions and at odds with recent anomalous measurements.

Appel et al. found that deceptive networks reached over 37 million Facebook and 3 million Instagram users during the 2020 US elections, with the majority of this exposure driven by 3 networks and amplified by ordinary users resharing the content.

Assessment of how 16 taxonomic groups in a lowland tropical forest resist and recover from anthropogenic disturbance shows the potential of protecting naturally regenerating secondary forests to reverse biodiversity losses.

A single-cell multiomic atlas of the human maternal–fetal interface across pregnancy reveals cell types, states and spatial niches, developmental tissue architectures and transcriptional programmes, and identifies cell types with roles in pre-eclampsia, spontaneous preterm birth and miscarriage.

A study of reproducibility in a stratified random sample of 600 papers published from 2009 to 2018 in 62 journals spanning the social and behavioural sciences finds higher reproducibility among more recent papers and papers from journals that require data sharing.

A global analysis of 1,412 studies shows that one in five women and one in six men experienced sexual violence as children, highlighting the urgent need for evidence-based prevention and intervention programmes worldwide.

Identification of genetic variants associated with the efficacy and side effects of GLP1 medications could underpin development of precision medicine approaches in the treatment of obesity.

Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.

ATP-binding cassette transporters use ATP to move peptides across membranes, but how ATP binding drives transport is unclear. Here, authors visualize single transport events and show that ATP binding alone triggers peptide translocation via a conformational switch.

Genome-wide analysis coupled with long-read sequencing identifies a repeat expansion in GOLGA8A associated with high risk for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.

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.

An analysis of whole-exome sequencing data linked to longitudinal electronic health records from 44,028 British South Asians finds new gene–phenotype associations and identifies 2,991 genes with rare biallelic predicted loss-of-function genotypes.

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.

An artificial intelligence system can produce research papers with minimal human involvement, even passing the first round of peer review for the workshop of a main machine learning conference.

Over five years, implementation of the NHS England Lung Cancer Screening Programme achieved high early-stage detection rates and demonstrated that the programme is both feasible and scalable for reaching high-risk and underserved populations.

Here, the authors present aDNA from 49 grape pips spanning the Bronze Age to Medieval period in France and surrounding areas. They find evidence of long-distance exchange of domestic varieties through vegetative clones and one Medieval sample that is nearly identical to modern Pinot Noir.

Alsulami et al. present PrePR-CT, a computational approach that predicts how different cell types respond to drug-like compounds using limited data. By integrating biological networks with machine learning, it improves accuracy, interpretability and efficiency in early drug discovery.

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.

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.

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.

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

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.

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.

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.

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.