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A follow-up analysis of a clinical trial that evaluated anti-PD-1 therapy in patients with cancer who are living with HIV provides mechanistic insights into transcriptomic, cellular and cytokine changes related to immune checkpoint inhibitor treatment and identifies a signature associated with clinical response.

DNA methylation and gene expression data integration identify aging-related genes in blood that predict health outcomes, offering new insights into aging biology and potential therapeutic targets.

To humanize models of liver metabolic disease research, authors develop a microfluidic platform leveraging human hepatic spheroids integrated with microvasculature and circulating monocytes to model hepatic insulin resistance.

Thendral et al. describe a mitophagic programme that removes deleterious mtDNA during the oocyte-to-zygote transition in Caenorhabditis elegans, promoting mitochondrial health and offspring survival. Loss of this mitophagy leads to mutant mtDNA accumulation.

Butyrophilin 2A2 is a member of the B7 costimulatory family that is expressed on antigen presenting cells and is linked to the regulation of T cells. Here the authors implicate butyrophilin 2A2 in enhancement of CD45 phosphatase activity within the immunological synapse during T cell activation, leading to expansion of regulatory T cells and reduction of proinflammatory Th17 CD4 T cells.

This study analyses whole-genome sequencing data of cancer samples from 10,983 patients and explores relationships among mutational signatures, various biomarkers and clinical outcomes.

At single-cell resolution, Tarkhov et al. delineate stochastic and co-regulated components of epigenetic aging, revealing a simultaneous loss of regulation at the epigenetic and transcriptional levels in aging.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.

Primary cutaneous B-cell lymphoma encompass clinically heterogeneous entities, including indolent and aggressive subtypes. Here, the authors show that the two indolent subtypes exhibit a persistent germinal centre reaction and thus may be driven by (a yet unknown) antigen.

This paper uses multiomics to profile a large cohort of meningioma samples to highlight the role of the tumor microenvironment in driving the epigenetic changes underpinning tumor classification and prediction of outcome.

Two groups of ammonia-oxidizing archaea drive marine nitrification. Stuehrenberg et al. reveal that their distribution reflects substrate use, with one relying on urea and the other on ammonia to maintain nitrification in open-ocean waters.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

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.

Rathmell and colleagues show that metabolic reprograming of regulatory T cells is associated with severity of critical illness in patients with and without sepsis.

Huang et al. analyzed serial samples from participants with metastatic non-small cell lung cancer treated with radiotherapy followed by immunotherapy and report improved clinical outcomes and enhanced antitumor responses in immunologically cold tumors.

Smc5/6 association with DNA junctions can support genomic functions. Here, the authors show that Smc5/6 junction polarity preferences, targeting, and dwell times are determined by its structural modules as well as the RPA and PCNA genomic factors.

Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

With whole-genome sequencing of longitudinal Staphylococcus aureus isolates collected from long-term urinary catheters, authors show that the same strain of multidrug resistant S. aureus persists asymptomatically long-term despite antibiotic exposures.

The long-term natural history of long-COVID is not well understood. In this population-based cohort study from Scotland, the authors describe symptom prevalence and health-related quality of life up to 18 months after a positive SARS-CoV-2 test and compare with matched test-negative controls.

The authors show how Vγ1⁺ γδ T cells produce IL-4 to drive early CD8⁺ T cell and dendritic cell responses to malaria infection in mice.

Here the authors functionally test and resolve the spatial genome organization of cis-regulatory elements and genetic variants in atrial, ventricular, and failing human cardiomyocytes and linked them to heart disease traits, including QT syndrome.

Microflora Danica—an atlas of Danish environmental microbiomes—reveals that although human-disturbed habitats have high alpha diversity, species reoccur, revealing hidden homogeneity.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Non-invasive strategies to detect and track activated myeloid cells will facilitate disease diagnosis and monitoring in patients affected by neuroinflammatory disorders. Here, the authors present 18F-FMD, a dendrimer-based PET tracer that detects and monitors activated myeloid cells at different stages (presymptomatic and symptomatic) of Experimental Autoimmune Encephalomyelitis (EAE) in mice and in response to disease-modifying therapies.

Age-related decline of chaperone-mediated autophagy blunts the regenerative capacity of muscle stem cells, partly due to impaired glycolytic shift required for normal stem cell expansion.

PCNA–PAF15 has a key role in determining replisome dynamics during genome replication and protecting against genome instability.

Ramaglia and colleagues show that aberrant formation of B cell-rich lymphoid structures in the brain meninges is associated with high CXCL13:BAFF ratios. Inhibiting the kinase BTK reduces the lymphotoxin signaling needed to sustain such structures, lowers CXCL13:BAFF ratios and reduces cortical tissue injury.

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.

Here, the authors report that combining Army Liposome Formulation with QS21 saponin (ALFQ) and Alum to formulate the ΔV1gp120 boost decreases the risk of simian immunodeficiency virus (SIV) mac251 acquisition in female macaques.

Zhao et al. used single-cell and spatial multiomics data analysis of human and mouse lung adenocarcinoma tumors and cell lines to reveal TP53 mutation-associated changes in cancer cells and their microenvironment.

Treatment with 4′-fluorouridine (also known as EIDD-2749) in an African green monkey (Chlorocebus aethiops) model of Lassa disease resulted in complete clearance of infectious virus in a high proportion of cases and prolonged survival to the pre-determined study end-point in all cases.

How synaptic plasticity rules lead to diverse neural responses in a spiking neural network model remains poorly understood. Here, the authors show how a diversity of response types contributes to network function and task performance.

A comprehensive atlas platform integrating transcriptional and epigenetic data enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.

Vaccines inducing mucosal immunity may provide better protection from respiratory viruses. Here, Ykema et al. demonstrate the utility of a bivalent, mucosally delivered nanostructured lipid carrier-replicon vaccine for induction of mucosal and systemic immunity and protection against morbidity and mortality from H5N1 and H7N9 influenza.

Veiga-Fernandes and colleagues show that neuroepithelial interactions differentially control type 1 and type 2 enteric immunity via VIP–VIPR1 signaling.

Plasmodium falciparum proteins were engineered to create a nanoparticle vaccine platform capable of displaying multiple antigens at 48 sites. Displaying a designed malaria circumsporozoite protein immunogen on this platform achieves full sterile protection in mice.

Mathematical modelling and experimental tests reveal principles that govern displacement of a resident strain by an invader in microbial communities.

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.

The inability of intrinsically photosensitive retinal ganglion cells to shift the circadian clock in the suprachiasmatic nucleus during daytime is caused by light-dependent depolarization block of these cells.

Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

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.

Colorectal cancer is often diagnosed at later stages, leading to poor prognosis. Here, the authors utilise analysis of rectal mucus specimens using host and microbial analysis to detect cancer lesions.

Engineered mucus-tethering bispecific nanobodies neutralize and entrap viruses to enhance mucosal immunity, preventing influenza infection and limiting SARS-CoV-2 transmission.

The CMS Collaboration reports the measurement of the spin, parity, and charge conjugation properties of all-charm tetraquarks, exotic fleeting particles formed in proton–proton collisions at the Large Hadron Collider.

Here, using a mouse model, the authors show that a lysine-restricted diet counteracts obesity via the enrichment of Parabacteroides goldsteinii and its metabolite MIAA, which in turn leads to suppressed fat accumulation by modulating the FTO-YTHDC1-SLC2A4 pathway.

Specific pain-sensing nociceptors and chemosensory tuft cells form a circuit to promote type 2 immune responses in the intestine.

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.