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

Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.

Genome-wide association studies incorporating data for populations of African ancestry provide an expanded view of the genetic basis of schizophrenia, which has previously been studied mainly in European and East Asian cohorts.

The authors uncover a direct, BAI1-dependent, role for C1q in the control of neural stem cell proliferation and quiescence via MDM2–p53 and p32, a complement cascade-independent mechanism of C1q action that has implications for central nervous system health and disease.

A specialized, open-source, retrieval-augmented language model is introduced for answering scientific queries and synthesizing literature, the responses of which are shown to be preferred by human evaluations over expert-written answers.

Projected impacts of climate change on malaria burden in Africa by 2050 highlight the urgent need for climate-resilient malaria control strategies and robust emergency response systems to safeguard progress towards malaria eradication.

This study uses single-cell DNA sequencing to analyze genomic evolution in pancreatic cancer using a cohort of multiregionally and longitudinally sampled patients’ tissues across various clinical contexts.

Ribas and colleagues report the results of a phase 2 clinical trial of neoadjuvant PD-1 blockade in patients with surgically resectable desmoplastic melanoma.

Human–artificial intelligence (AI) dialogues can meaningfully impact voters’ attitudes towards presidential candidates and policy, demonstrating the potential of conversational AI to influence political decision-making.

Feng et al. unravel the structural basis of TDP-43 higher-order assemblies with mRNA and the structural changes leading to TDP-43 aggregation, which are associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis.

Some surveys of intelligence have suggested that the mean IQ is rising; others, that it is decreasing alarmingly. The explanation seems to be that the educational level of the populations has changed.

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.

Pre-treatment dual immune checkpoint blockade in cervical cancer remains understudied. In this trial, the authors show that neoadjuvant immune checkpoint blockade enhances immune activation and correlates with improved response to subsequent chemoradiation in patients with cervical carcinoma.

In the adrenal cortex, cholesterol used for steroid production is stored in lipid droplets. The authors demonstrate here the importance of the transcription factor HHEX in maintaining glucocorticoid levels and protecting lipid droplets from androgen-induced lipid depletion.

Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.

Multi-trait genome-wide analyses identify variants associated with comorbid lung diseases. Polygenic scores leveraging shared components of heritable risk improve prediction of asthma, chronic obstructive pulmonary disease and lung cancer in a multi-ancestry cohort.

CAR-T cell therapy has been shown to be effective in immunotherapy for treatment of several different tumours. Here the authors show pre-specified interim outcomes from a P-BCMA-ALLO1 trial with BCMA targeted CAR-T therapy in multiple myeloma.

A protein biomarker, the NOTCH3 extracellular domain, identifies individuals with idiopathic pulmonary hypertension, correlates with disease progression, improves mortality risk prediction and provides a readily implementable, noninvasive blood test for this disease.

Piol et al. uncover that impaired eukaryotic initiation factor 5a (Eif5a) hypusination disrupts axonal translation and neuronal activity in fused in sarcoma-amyotrophic lateral sclerosis (FUS-ALS) by applying spatial transcriptomics in motor axons. In vitro and in vivo targeting Eif5a hypusination via spermidine supplementation improves ALS model phenotypes.

Luppi et al. identify transcriptomic and connectomic controllers of information integration and its breakdown induced by anaesthesia in humans, macaques, marmosets and mice.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

A preregistered systematic review, meta-analysis, and multiverse meta-analysis of 32 RCTs (5704 patients) shows that psychosocial interventions consistently prolong cancer survival and clarifies sources of prior inconsistent findings.

Following its internalisation, active endosomal GLP-1R engages with VAPB and SPHKAP at ER membrane contact sites to assemble a local cAMP/PKA condensate for the control of MICOS complex phosphorylation, mitochondrial remodelling and β-cell function.

Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4⁺ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.

Estimates of infection rates from the UK COVID-19 Infection Survey may have been biased by the characteristics of people who chose to take part. Here, the authors show that the survey population had unusually high vaccination rates and adjust infection estimates taking this into account.

Hematopoiesis influences the progression of cardiovascular disease, yet the influence of cardiovascular disease on the bone vasculature is unknown. Hoffmann, Luxán, Abplanalp et al. describe the response of the bone cell composition to myocardial infarction and provide a rationale for using anti-inflammatory therapies to prevent the deterioration of the bone vascular niche

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.

In this multicenter phase 1 trial of patients with advanced solid tumors resistant to anti-PD-1 therapy, treatment with the anti-latent TGFβ1 antibody linavonkibart with or without pembrolizumab was safe, and encouraging clinical response rates were associated with T cell infiltration and immune activation.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Jang and colleagues demonstrate that GDF3 reshapes the chromatin landscape of inflammatory adipose tissue macrophages and drives endotoxic inflammation with age. Pharmacological inhibition of the GDF3–SMAD2/3 axis alleviates endotoxemia lethality in old mice.

The basic features of dopamine release sites are still largely unknown. Here, the authors determine the ultrastructure of fluorescent dopaminergic and glutamatergic synaptosomes in mouse striatum using cryo-correlative light and electron microscopy.

Data collected from zoos and aquariums worldwide show that hormonal contraception or permanent surgical sterilization in mammals increase life expectancy, with different mechanisms in males and females.

Cryptococcal meningitis is a common infection in patients with compromised CD4 T cell function. Using a CD4 T cell activation tracking mouse the authors show the localisation and activation of CD4 T cells in the brain after cryptococcus infection and how these cells interact with MHCII expressing microglia which may increase pathologic brain inflammation.

This study demonstrates that 16p11.2 hemideletion, a genetic deletion linked to neurodevelopmental disorders, affects male and female mice differently, altering specific striatal neuronal circuits and driving sex-specific behavioral changes.

Elebsiran plus PEG-IFNα improved hepatitis B surface antigen (HBsAg) loss rates compared with PEG-IFNα alone in patients with chronic hepatitis B virus infection. Furthermore, prior response to the BRII-179 vaccine was associated with higher HBsAg clearance, suggesting its potential as a predictive tool for identifying patients more likely to benefit from therapies.

Sivanandan, Leitmann, and colleagues present the CellPaint-POSH platform, which combines pooled CRISPR screening with Cell Painting. Using self-supervised deep learning on cell images, the method enables discovery of gene function and biological networks.

Post-acute sequelae of SARS-CoV-2 (PASC) is still not well understood. Here the authors provide patient reported outcomes from 590 hospitalized COVID-19 patients and show association of PASC with higher respiratory SARS-CoV-2 load and circulating antibody titers, and in some an elevation in circulating fibroblast growth factor 21.

Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

Recent MPXV outbreaks underscore the need for better vaccines and treatments. Here, the authors isolate and structurally characterize potent antibodies interacting with A28 that they identify as a key viral surface protein essential for viral entry and that induces strong, protective antibody response in mice.

Liver-restricted viral infection in mice results in secondary lymphoid organ dormancy and the compensatory induction of specialized lymphoid tissue in the liver, the structural features and functional outputs of which are closely mirrored in humans.

Varicella zoster virus (VZV) infection causes varicella and herpes zoster and, rarely, severe central nervous system (CNS) complications, including encephalitis. Ogunjimi et al. review the evidence linking herpes zoster with stroke and dementia, summarize innate and adaptive immune responses to VZV-related CNS disease, and debate the consequences of vaccination.