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A single-cell epigenomic atlas of human immune cells highlights cell-type-specific features associated with genetic or environmental exposures.

Disease heterogeneity complicates precision medicine, which focuses on single conditions and ignores shared mechanisms. Here the authors introduce ‘pan-disease’ analysis using a deep learning model on multi-organ data, identifying 11 AI-derived biomarkers that reveal new therapeutic targets and pathways, enhancing patient stratification for disease risk monitoring and drug discovery.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

Pretrained using 335,645 whole-slide images, a foundation model is developed to provide representations for slide- and patient-level tasks. It is capable of performing clinical tasks and generating reports even in data-scarce scenarios, such as rare cancer diagnosis and survival prediction, without requiring further fine-tuning.

The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

The oncogenic potential of interfollicular stem and progenitor cells in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Here, the authors modelled rapidly growing cSCC driven by the hyperactivation of the MAPK signalling pathway in mice and showed that SOX2 overexpression renders progenitor cells prone to transformation.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

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.

Artifact mutations from FFPE are a major barrier blocking WGS adoption in clinical oncology. FFPErase, a machine learning framework, eliminates these with high accuracy in multiinstitutional datasets, delivering clinical-grade variant reports.

Clade 2.3.4.4b highly pathogenic H5N1 is currently causing a panzootic and has the potential to become a pandemic. Here, Peña Alzua and colleagues develop specific monoclonal antibodies against this virus that could be used to prevent or treat human infections.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

H5N1 avian influenza viruses caused an outbreak in dairy cattle. We show that the potential for avian viruses to replicate in cow cells varies across H5N1 evolution, suggesting that the risk of spillover into mammals differs between variants.

Here the authors show that lab mice have retained ancient gut bacterial symbionts that diversified in parallel with rodent species, but the genomes of these gut bugs have accumulated mutational burdens over the past ~ 120 years of inbreeding in captivity.

u-Segment3D is a universal framework that translates and enhances 2D instance segmentations to a 3D consensus instance segmentation without training data. It performs well across diverse datasets, including cells with complex morphologies.

Influenza A virus infection causes a dramatic upregulation of ADP-ribosylation that as part of the cellular antiviral response, a process that is counteracted by the viral NS1 protein.

Otopetrins form proton channels in animals ranging from nematodes to humans. Here, authors identify small molecule inhibitors and characterize their binding in the intrasubunit interface region, thus highlighting the area for pharmacological targeting for channel modulation.

Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.

Semaglutide, a GLP-1 receptor agonist, may offer neuroprotective benefits after stroke, but its effects in large vessel occlusion (LVO) are unknown. Here the authors show, in a phase 2 randomized trial, that semaglutide is safe after endovascular therapy and may improve recovery in patients not receiving intravenous thrombolysis.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate. Through integrated laboratory and clinical studies, the authors identify significant ERBB2 (the gene that encodes the HER2 protein) mutational heterogeneity in patients with urothelial cancer and co-mutation and amplification of ERBB2 as a potential biomarker of exceptional response to T-DXd.

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

Mastomys natalensis is a rodent species native to West Africa that is the primary reservoir host for Lassa virus. Here, the authors investigate whether the invasive rodent Rattus rattus decreases M. natalensis density and could therefore indirectly decrease zoonotic transmission of Lassa virus to humans.

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.

Rossi and colleagues assemble an in vitro enzymatic pipeline using enzymes from distinct domains of life to recapitulate eukaryotic N-glycosylation. This work advances the synthesis of bespoke glycopeptides with biomedical and biotechnological applications.

Here the authors report NiGa₂O_4–x(OH)_y for light-driven CO₂ hydrogenation to methanol. The surface Lewis acid–base pairs and -OH groups act as conduits for H^- /H⁺ transport to active sites, enhancing photocatalytic methanol production.

Cells must sense heat quickly to protect their proteins and membranes. Here, the authors show that membrane stretch detected by the membrane sensor Mid2 promotes rapid phosphorylation of the Hsp70 chaperone to coordinate gene activity, protein synthesis and resolution of stress-induced protein droplets during heat shock.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.

Chemically induced protein degradation is a powerful alternative to classical inhibition, but some proteins have deeply masked binding pockets that make the development of degrader molecules difficult. Here, the authors discover an alternate site on nuclear receptors that can be targeted by degraders.

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.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here the authors report the results of a phase II clinical trial of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in RMC, associating the activation of a myeloid mimicry program in tumor cells to the rapid disease progression and hyper-progression observed in treated patients.

Cheng et al., use non-infectious stable viral replicon cell lines in genome-wide CRISPR KO screens across diverse viral pathogens to identify host factors specifically involved in the intracellular stages of viral replication.

Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

Allogenic mesenchymal stem cells are engineered with three mRNAs to bind to multiple myeloma B cells while activating T cells for cancer therapy.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Claudin 18.2 (CLDN18.2) has emerged as a target for gastrointestinal cancer, however, on-target/off-tumor toxicities have been also reported. Here, after reporting evidence of erosive gastritis in patients treated with CLDN18.2 targeted immunotherapies, the authors develop and characterize CLDN18.2 fully-human VH-only single domain CARs, showing that a lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor efficacy in gastric cancer models.

There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

In a post-hoc analysis of circulating tumor DNA (ctDNA) features from patients with metastatic prostate cancer treated with [¹⁷⁷Lu]Lu–PSMA-617 or cabazitaxel in the randomized phase 2 TheraP trial, low ctDNA levels at baseline were predictive of clinical benefit from [¹⁷⁷Lu]Lu–PSMA-617, and PTEN or ATM alterations were identified as potential biomarkers of response.

MAP-X is used to map protein complexes in P. falciparum, identifying previously undescribed interactions, revealing stage-specific dynamics and predicting moonlighting behaviour of subunits.

This work presents a fully implantable wireless optogenetic device that delivers spatiotemporally patterned cortical stimulation through the skull and generates artificial perception in mice.

Pretrained using over 100,000 diagnostic histopathological slides across 20 major tissue types, a self-supervised model is shown to outperform existing baselines across various clinically relevant computational pathology tasks.

How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.

Female embryonic stem cells (ESCs) are the ideal model to study X chromosome inactivation (XCI) establishment; however, these cells are challenging to keep in culture. Here the authors create fluorescent ‘Xmas’ reporter mice as a renewable source of ESCs and show nucleosome remodelers Smarcc1 and Smarca4 create a nucleosome-free promoter region prior to the establishment of silencing.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

In this work, Wilson et al., examined sharing of Salmonella between humans, animals and the environment using household samples from Malawi. They revealed an interconnected web of Salmonella circulation, underscoring the importance of the One Health concept.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.