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Here the authors perturb genes linked to schizophrenia risk in human neurons. They find that single perturbations share common downstream effects on gene networks, while joint perturbations result in downstream effects being saturated.

A prospective nationwide genomic screening pilot for ten genes in young adults in Australia detected pathogenic variants in 2% of the population, most of whom were ineligible for government-funded genomic testing.

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.

The MOUNTAINEER phase 2 trial demonstrated the efficacy and safety of tucatinib (HER2-targeted TKI) and trastuzumab (anti-HER2 antibody) in patients with HER2 + , RAS wildtype unresectable or metastatic colorectal cancer that had progressed on chemotherapy, resulting in the approval of the regimen. Here, the authors report the updated analysis of the MOUNTAINEER trial.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Activity-based protein profiling identifies covalent small molecules that potentiate the activity of the METTL5:TRMT112 complex through binding to a complexoform-restricted allosteric pocket absent in other TRMT112:methyltransferase complexes

CLASSIC is a high-throughput genetic profiling platform that combines long- and short-read next-generation-sequencing modalities to quantitatively assess pools of constructs of arbitrary length containing diverse genetic part compositions.

Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.

Enhanced label-free multiphoton skin imaging uses phasor analysis to unmix key endogenous fluorophores, enabling mapping of molecular components in skin of varying pigmentation and metabolic states.

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.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

High-resolution kelp canopy maps from a convolutional neural network showed that kelp persistence after a marine heatwave was linked to pre-heatwave persistence, cooler sea surface temperatures, shallow habitats that are often missed by coarser satellite sensors, and lower levels of fragmentation.

In this Viewpoint, past attendees and organizers of the Little Brain Big Brain share their experience with this unique meeting and their insights into the field of enteric neuroscience and neurogastroenterology.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

Crosslinking mass spectrometry offers direct PPI mapping but suffers from low yields. Here, the authors develop a two-step click-linking strategy that improves crosslinking efficiency and interactome coverage in fixed cells, outperforming conventional methods.

The study advances the use of serological surveys to guide trachoma elimination program decisions and provides a way to set thresholds for whether or not to continue an intervention program.

This study demonstrates that brain functional network imbalance appears linked to progressive brain atrophy and cognitive decline across the dementia spectrum.

Across 13 longitudinal studies (3,737 adults), the authors show that brain atrophy parallels memory loss, with a stronger coupling in later life. APOE ε4 increases decline, yet genetic risk does not modify the brain–memory relationship.

Age-related macular degeneration (AMD) is a leading cause of blindness. Here, the authors identify a role for apolipoprotein M in AMD that may present a therapeutic target.

Breaking waves on the ocean surface generate air bubbles that yield sea spray aerosols when released to the atmosphere. Measurements of sea spray aerosols in the North Atlantic Ocean and the coastal waters of California suggest that the surface water organic carbon reservoir is responsible for the organic carbon enrichment of freshly emitted sea spray aerosol.

Head motion is an artifact in structural and functional MRI signals, and some traits or groups are more strongly correlated with motion than others. Here the authors describe a method to attribute a motion impact score to specific trait-functional connectivity relationships.

Narrow river gorges are often short-lived features. Images of a bedrock gorge in Taiwan, which was carved after 1999, reveal rapid widening where the upstream floodplain meets the gorge, an erosional front that propagates downstream as the gorge is erased.

The BioDIGS project is a nationwide initiative involving students, researchers and educators across more than 40 research and teaching institutions. Participants lead sample collection, computational analysis and results interpretation to understand the relationships between the soil microbiome, environment and health.

Epigenetic regulators have been proposed to be modulators of chemoresistance in acute lymphoblastic leukaemia. Here, the authors find enrichment of mutations in epigenetic regulators at relapse, including somatic mutations in SETD2.

The ability to visualise stochastic invasion events is limited in murine models of metastatic cancers. Here the authors use a transparent zebrafish epidermis model to follow the invasion events of K-Ras transformed epithelial cells and show that these cells invade through basal cell extrusion.

Dendritic cells are supplied antigens by other cells such as lymphatic endothelial cells (LEC) at late time points after immunization. Here the authors show antigen archiving is defined by a transcriptional program that can predict antigen archiving depending on the priming pathogen, and that boosting of immune responses increases the archiving.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

SARS-CoV-2 infection can lead to sustained increased macrophage numbers and formation of enlarged lipid-laden macrophages after viral clearance. This can be prevented with antiviral treatment in mice.

Lowering the levels of coagulation factor XII may prevent thrombosis without increasing the risk of bleeding. Here, Haj et al. use a large human dataset to show that this is the case for people carrying mutations that lower the levels of factor XII.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Observations from the JWST MIRI-MRS instrument reveal the detection of rotational emission from molecular hydrogen near the only O-type star in the 3% solar metallicity galaxy Leo P, providing confirmation that significant quantities of molecular gas can form in such metal- and dust-poor environments.

The antiviral protein SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of the immune regulator RESIST.

Anagnostou et al. present an improved predictor of response to immune checkpoint blockade that integrates estimates of tumor mutational burden corrected for tumor purity, RTK genomic alterations, a smoking-related mutational signature and HLA status.

The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.

Preclinical studies indicate that simultaneous HER2 and VEGF blockade may be beneficial in gastroesophageal adenocarcinoma (GEA). Here, the authors report the efficacy and biomarker analysis of a phase II clinical trial investigating the combination of bevacizumab (anti-VEGF) and standard-of-care CAPOX (capecitabine, oxaliplatin) and trastuzumab in previously untreated advanced HER2 + GEA.