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The immune response to SARS-CoV-2 infection is variable but has been linked to prognosis and the development of severe immunopathology. Here the authors assess a range of immune parameters in both peripheral blood and respiratory samples, providing a comparative assessment of the immune response between these compartments and their potential impact on immune-pathogenesis.

Park, Davis et al. evaluate candidate biomarkers of cancer-associated cachexia in a diverse cohort of pancreatic ductal adenocarcinoma individuals. GDF-15 is better at classifying cachexia than standard biomarkers for non-Hispanic White and Hispanic/Latinx individuals, but not for non-Hispanic Black individuals.

A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.

Understanding the role of coherent structures in the dynamics of turbulent flows is of high relevance for fluid dynamics, climate systems, and aerodynamics. The authors propose a deep learning approach to evaluate the importance of various types of coherent structure in the flow, to uncover main mechanisms of wall-bounded turbulence and develop techniques for its control.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Parity induces an accumulation of CD8⁺ T cells, including cells with a tissue-resident-memory-like phenotype within human normal breast tissue, offering long-term protection against triple-negative breast cancer.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

Analysing camera-trap data of 163 mammal species before and after the onset of COVID-19 lockdowns, the authors show that responses to human activity are dependent on the degree to which the landscape is modified by humans, with carnivores being especially sensitive.

Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

KLHDC2 is a promising E3 ligase for targeted protein degradation (TPD). In this study, the authors demonstrate that heterobifunctional degraders induce cooperative ternary complexes with KLHDC2 and BRD3. They highlight exit vector, neo-substrate, E3 ligase selectivity, and prodrug choice can effectively leverage C-degron E3s for TPD.

The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Seo et al. present an approach to regulate the formation and optoelectronic quality of the SnO₂ electrodes, improving electroluminescence and efficiency in perovskite solar cells.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

The impact of senescent cells on remyelination is unknown. Here, the authors show that treatment with senolytics following demyelination enhances remyelination in young, but not aged mice, and these effects are mediated by senescence-associated secretory phenotype factors including CCL11.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.

GIANT, a genetically informed brain atlas, integrates genetic heritability with neuroanatomy. It shows strong neuroanatomical validity and surpasses traditional atlases in discovery power for brain imaging genomics.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

Fruitflies require Sestrin to regulate mTORC1 signalling in response to dietary leucine, survive a diet low in leucine, and control leucine-sensitive physiological characteristics, which establishes Sestrin as a physiologically relevant leucine sensor.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

By using gene expression data, gastric cancer is divided into subtypes associated with distinct molecular alterations and clinical prognosis.

Strong yet releasable metamaterial adhesives are fabricated using nonlinear cut architectures to achieve control of the crack propagation interface for programmable, directional and spatially selective adhesion.

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Pain experience is highly individual, but its individual-specific brain features remain unclear. The authors identify brain regions with consistent versus variable representations of pain across a large sample of individuals.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

The Global Flourishing Study provides a comprehensive view of the distribution and determinants of well-being by assessing domains such as health, happiness, meaning, character, relationships and financial security. Initial findings reveal significant variations in flourishing across countries and demographic groups, with factors such as age, marital status and religious service attendance showing strong associations with well-being.

Gastric cancer has two distinct morphologic subtypes, intestinal and diffuse, that differ in genetic composition and clinical manifestation. Here, the authors carry out whole-genome sequencing of diffuse and intestinal gastric cancer samples and characterize the mutational landscape of these different subtypes.

Functional CRISPR screens in patient-matched pre-treatment and post-treatment glioblastoma models identify the PTP4A–ROBO1 axis as a driver of tumorigenicity and enriched ROBO1 expression in recurrent glioblastoma that can be targeted with CAR T cell therapy.

Barnes et al. report a dynamic and reciprocal crosstalk between tissue tension and glycocalyx bulkiness that promotes a mesenchymal, stem-like phenotype in GBM.

Leveraging RNA-targeting dCas13d enables selective interference with phage protein translation and facilitates measurement of phage gene fitness at a transcriptome-wide scale.

Here the authors show that lowering IGF-1R levels in endothelial cells improves insulin sensitivity, boosts energy use, and supports beneficial changes in adipose tissue, offering insights into potential treatments for obesity-related metabolic disorders.

The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

A device architecture based on indium arsenide–aluminium heterostructures with a gate-defined superconducting nanowire allows single-shot interferometric measurement of fermion parity and demonstrates an assignment error probability of 1%.

Metabolic liver disease is highly prevalent in subjects with obesity and involves inflammation, insulin resistance, and fibrosis, leading to cirrhosis. Here, the authors show the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and playing a major role in the pathogenesis of metabolic liver disease.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

EBV (Epstein-Barr virus)-targeted therapy is limited by efficient agents inducing lytic cycle in cancer cells. Here they report a transcriptional activator incorporated into lipid nanoparticles that could specifically activate endogenous BZLF1 and induce lytic reactivation in EBV-positive cancer cells thereby suppress tumor progression.