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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.

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.

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.

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.

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.

A first-in-human phase 1 trial shows that intravitreal photoswitch therapy can be administered safely in advanced retinitis pigmentosa, with exploratory signals compatible with light responsiveness following treatment.

The long-term natural history of long-COVID is not well understood. In this population-based cohort study from Scotland, the authors describe symptom prevalence and health-related quality of life up to 18 months after a positive SARS-CoV-2 test and compare with matched test-negative controls.

Applying proteomics to longitudinal plasma samples from calorically restricted participants of the CALERIE trial, Mishra, Kim and colleagues link complement protein C3a to inflammaging. In aged mice, visceral fat macrophages produce C3a, and neutralization of C3a blocks inflammaging.

HORMAD1 expression is typically restricted to germline cells where it has an important role in meiotic recombination but has been shown to be upregulated in triple negative breast cancer (TNBC). Here, the authors report that aberrant HORMAD1 expression weakens the spindle assembly checkpoint, driving sensitivity to AURORA kinase inhibition.

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

At single-cell resolution, Tarkhov et al. delineate stochastic and co-regulated components of epigenetic aging, revealing a simultaneous loss of regulation at the epigenetic and transcriptional levels in aging.

Analysis of sequencing data from rare disease cohorts identifies biallelic variants in RNU2-2 underlying a developmental and epileptic encephalopathy associated with reduced U2-2 abundance and clinically distinct from the dominant RNU2-2 disorder.

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.

A high-resolution spectroscopic analysis reveals ultralow amounts of heavy elements in the star SDSS J0715−7334. The star originates from the Large Magellanic Cloud and probably formed directly after the first stars through dust cooling.

Most advanced triple-negative breast cancers remain resistant to immunotherapy. Here, the authors discover that RIPK1-driven necroptosis in both tumor and stromal compartments is essential for effective immunogenic cell death-based therapy and immune checkpoint blockade.

From 2014–2017, marine heatwaves caused global mass coral bleaching, where the corals lose their symbiotic algae. The authors find, this event exceeded the severity of all prior global bleaching events in recorded history, with approximately half the world’s reefs bleaching and 15% experiencing substantial mortality.

Using active and passive genomic surveillance, researchers observed the rapid spread of high pathogenicity avian influenza H5N1 D1.1 viruses in wild birds during the 2024 migratory season, which coincided with detection in humans, but did not identify mammalian adaptive markers in viruses from wild birds.

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.

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.

Orientia tsutsugamushi utilizes a unique, conserved domain in Ank effector proteins to bind lamin A and inhibit NF-κB, which is linked to global alterations in chromatin accessibility during infection.

Three endoplasmic reticulum luminal mannosyltransferases ALG3, ALG9 and ALG12 catalyze the synthesis of the branched mannose core in N-glycans in four distinct steps. Now, cryo-electron microscopy structures and characterization of ALG3, ALG9 and ALG12 reveal the molecular logic of oligomannose core assembly.

Soil fauna is an important but often neglected component of terrestrial food webs. Here the authors use a large dataset of stable isotope observations to analyse how soil animal trophic diversity varies across climates and land-use types and identify potential biotic mechanisms.

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.

Longitudinal tracking of mice reveals that stable, specialized social roles emerge spontaneously within groups during a foraging task, with dopaminergic activity in the ventral tegmental area driving sex-divergent patterns of specialization.

The excitatory neuron diversity and specialized connectivity of complex, multilayered mammalian neocortex are driven by mammalian-specific cis-regulatory elements bound by ZBTB18, deletion of which disrupts gene expression and results in projection patterns resembling those of non-mammalian brains.

In this phase 1, open-label dose-escalation study in healthy adults found that the mRNA vaccine (mRNA-1215), encoding the Nipah virus Malaysian strain chimeric pre-fusion F protein linked to glycoprotein G, was safe and induced elevated immune responses at 1 year of follow-up, indicating that this is a promising vaccine candidate for further development.

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.

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).

Artificial intelligence (AI) could help improve risk predictions in acute leukaemia and reduce systemic health disparities in the diagnostic process. Here, the authors assemble a diverse, international cohort of 6,206 patients with acute leukaemias and deploy an AI tool to support diagnosis based on standard laboratory results, with refinements for both adult and peadiatric leukaemias.

Sedimentary time-series data of Lake Yoa in Chad covering the past 10.25 thousand years (kyr) show that the mid-Holocene African Humid Period experienced several decadal-scale droughts, caused by sudden inputs of freshwater into the North Atlantic.

Plasma ctDNA testing for FGFR alterations in metastatic urothelial carcinoma shows high concordance with tissue testing and identifies additional patients with actionable alterations. Here, the authors show that clinical uptake of ctDNA FGFR testing can be combined with tissue-based approaches.

This study analyses whole-genome sequencing data of cancer samples from 10,983 patients and explores relationships among mutational signatures, various biomarkers and clinical outcomes.

Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

The transcription factor TOX is well studied in the context of CD8⁺ T cell functionality, but less is known about its role in CD4⁺ T cells. Here the authors show that TOX drives T_H1 cell differentiation and effector function that can drive antitumor immunity and autoimmune pathology.

Neuromodulation via epidural electrical stimulation both below and above the lesion in three participants with complete spinal cord injury could enable respectively motor activation and sensory perception.

Many GPCRs signal from endosomes, which requires active G proteins at this location. Here, the authors describe how active Gα_s accumulates on endosomes and reveal location-biased selectivity in GPCR-mediated G protein activation.

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.

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.

The ~200-Myr-old star TOI-2076 hosts a young four-planet system, the orbits and atmospheres of which are still evolving, showing signs of early dynamical reshaping and atmospheric sculpting and offering a rare glimpse of how planetary systems form and transform in their youth.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

Using 63 globally distributed grassland and shrubland sites from the International Drought Experiment, this study identified plant traits linked to drought resistance after 1 year of extreme drought across growth forms, lifespans and climate.

A new platform making use of hexagonal boron nitride interfaced with the molecular superconductor κ-(BEDT-TTF)₂Cu[N(CN)₂]Br is demonstrated for realizing cavity-altered materials, confirmed by magnetic force microscopy and nano-optical measurements.

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.

Most GWAS have focused on common variants or rare protein coding variants. Here, the authors interrogate the contribution of rare non-coding variants for anthropometric traits, identifying new genes associated with increased BMI and height.

Analysing the causal links of gene expression and protein abundance on type 2 diabetes risk in blood and seven tissues related to the disease from individuals of four ancestries, the authors advance our understanding of the genetic architecture of type 2 diabetes

In a randomized, double-blind, placebo-controlled trial comparing autologous mRNA-engineered BCMA-targeting CAR T cell therapy versus placebo in patients with generalized myasthenia gravis, a significantly higher percentage of patients exhibited a reduction in disease activity in the treatment arm than in the placebo arm.

This multidisciplinary response to investigate the large outbreak of unknown febrile illness in the Panzi Health Zone in the Democratic Republic of the Congo in late 2024 suggests that the outbreak was largely associated with malarial cases and concurrent viral respiratory infections.