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In mice, DHPS supports the maturation, maintenance and function of tissue-resident macrophages via the polyamine–hypusine axis, with implications for macrophage-targeting therapies.

The authors developed an LXR inverse agonist, TLC-2716, and show it is effective in reducing triglycerides and cholesterol in dysmetabolic preclinical models. Additionally, a phase 1 trial in healthy participants shows that TLC-2716 is well tolerated and reduces plasma triglycerides and postprandial remnant cholesterol, highlighting its potential for managing cardiovascular risk.

This study detects Chlamydia pneumoniae in human retina and brain, increasing with AD severity. Retinal pathogen load with Aβ₄₂ may predict AD stage. In models, infection drives Aβ deposition and NLRP3 activation, worsening pathology and cognition.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

An ultrasmall particle adjuvant therapy reprogrammes the tumour microenvironment of a resistant melanoma to a pro-inflammatory state, enhances antitumour immunity and synergizes with immune checkpoint inhibitors to prolong survival in murine models.

The use of nucleic acid-based nanostructures as synthetic biological tools remains challenging. Here they present synthetic RNA structures that fold and self-assemble inside human cell nuclei, offering a platform for imaging, sensing, and future therapeutic applications.

Mu opioid receptor agonists with a preference for the non-GTP-bound state of the G protein promote GTP release, thereby potentiating antinociceptive effects of drugs such as morphine and fentanyl without also increasing their respiratory or cardiac effects.

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.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Activin receptor-like kinase 4 (ALK4) is frequently downregulated or mutated in cancers. Here the authors find that ALK4 loss promotes canonical TGF-β signaling and cancer progression through increasing TGF-β receptor N-linked glycosylation and subsequently stabilizing these receptors at the cell surface.

Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.

Virus-like particles are engineered to edit human hematopoietic cells in vivo.

Barnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.

The authors identify a Cys→Ser transformation (C19S) in insulin leading to neoepitope presentation and CD4⁺ T cell autoreactivity in type 1 diabetes. Inflammation and oxidative stress enhanced C19S transformation in β cells and antigen-presenting cells, resulting in C19S-specific CD4⁺ T cells with an activated memory phenotype linked to disease progression.

Aging-related Meibomian gland shrinkage is associated with dry eye disease. Here, the authors identify Meibomian gland stem cell populations and identify regulatory pathways altered in aging, suggesting new therapeutic targets for Meibomian gland dysfunction.

The authors provide a comprehensive characterization of how glutamine uptake and utilization regulate macrophage function in atherosclerosis.

The blood ApoM-S1P complex regulates vascular functions, but its role in neurogenic niches remains unclear. Here, the authors show that the blood ApoM-S1P complex preserves V-SVZ homeostasis and protects against early features of Alzheimer’s disease.

Quintana and colleagues describe the engineering of oncolytic viruses armed with multiple immunomodulators and with targeted tropism for tumor cells for glioblastoma immunotherapy.

PD-1 blockade interferes with the selective expansion and maintenance of high-affinity TCR stem-like clones that have a critical role in effective checkpoint blockade therapy.

CAR T cell therapies have been developed to treat paediatric diffuse intrinsic pontine glioma (DIPG), however, clinical efficacy remains limited. Here, the authors report that engineering B7-H3-targeting CAR T cells to express the chemokine receptor CXCR3-A enhances their trafficking and efficacy in DIPG preclinical models.

Some transcription factors can organize into different structural states, from small nanoscale clusters to macrophases. Here authors show that NHA9 undergoes differential conformational expansion across these states and exhibits micelle-like organization with non-fixed stoichiometry.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Pathogens often persist within granulomas which form to control infection. Here, Harvest et al describe an innate granuloma that eradicates a ubiquitous environmental pathogen without inducing adaptive immunity.

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).

Shaking evoked by wet fur or plumage is reproduced by a synthetic agonist of the cold and menthol receptor TRPM8, in rats, mice, and chickens. In water sprayed mice, the onset of the shaking behavior depends on water temperature and TRPM8 expression.

Merghoub, Wolchok and colleagues reveal a role of the extracellular matrix protein thrombospondin-1 (TSP-1) and CD47 in promoting T cell exhaustion during tumor progression in mice and humans.

Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.

Chronic stress is a risk factor for depression, yet the mechanisms are unclear. Here, the authors show in mice that stress drives interferon-mediated neutrophil recruitment from the skull to the brain’s outer membranes, contributing to depressive behaviors.

Fibrodysplasia ossificans progressiva is an ultra-rare genetic disorder with progressive heterotopic ossification. Yang et al develop different gene therapy approaches and show their efficacy in mouse models and in human induced pluripotent stem cells.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Caspase-7 cleaves and activates acid sphingomyelinase (ASM), which promotes the repair of gasdermin pores and thereby delays pore-driven lysis to allow other processes such as extrusion or apoptosis to occur before cell death.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

HCMV rearranges the host cell to produce infectious virus but molecular details are still unclear. Here, the authors analyze the transcriptome of infected cells and show that HCMV turns on dormant neuronal genes through chromatin manipulation to achieve this goal.

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.

SEUDO is a tool for detecting and correcting errors introduced by automated processing of calcium imaging data.

Acid sphingomyelinase (ASM) is a sphingolipid metabolizing enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide, and previous work has shown it is upregulated in models of Alzheimer’s disease. Here the authors demonstrate in a mouse model of Alzheimer’s disease that antibody-based immunotherapy targeting plasma ASM resulted in attenuated neuropathological features by suppressing pathogenic Th17 cells.

A study reveals a gut–brain sensory pathway through which the microbial component flagellin activates neuropod cells in the colon to signal the brain and reduce feeding in mice.

In Drosophila, the physical structure of the eye has a key role in the directional tuning of motion-sensitive neurons, showing how navigational behaviour is tightly associated with anatomy.

Commensal Candida albicans enhances the virulence and dissemination of Salmonella enterica subsp. enterica serovar Typhimurium.