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N-terminal acetylation shapes protein fate during protein biosynthesis at the ribosome. Here the authors show that the NatA enzyme forms dynamic multi-factor complexes at the ribosome, acting as an interaction hub that coordinates cotranslational protein maturation.

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 use a mouse model of multiple sclerosis to show that CD38⁺Foxp3⁺ T_reg cells persist in postinflammatory CNS tissues and are needed for maintaining immune homeostasis. These localized stress-tolerant T_reg cells have developed mechanisms to exploit the limited availability of IL-2 in this tissue.

Estimating respiratory infection rates in the community is challenging as testing is usually limited to people with more severe infections. Here, the authors develop a statistical method to estimate infection rates using data from a community survey that performed lateral flow testing in England and Scotland in 2023-24.

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

Stable adipocytes resist lipolysis in healthy states but are highly susceptible to a catecholamine-independent, neurosystemic pathway-driven catabolic state.

One of three back-to-back papers to show that dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance CAR T cell therapies for cancer.

Although antiretroviral therapies (ART) have expanded the life expectancy of patients with HIV, they are not curative due to the presence of latently infected cells. Here, the authors present IMC-M113V, a bispecific soluble TCR targeting the HIV peptide Gag_77-85 complexed to HLA-A*02:01 as an approach for targeting HIV reservoirs and test safety, tolerability and pharmacodynamics in a first-in-human clinical trial on 12 HLA-A*02:01-positive male individuals on ART.

Here the authors show that endogenous or therapeutically delivered GDF-15 activates brainstem neurons that trigger splenic β-adrenergic signaling. This, in turn, suppresses autoreactive T cells and reduces neuroinflammation, identifying a possible target for multiple sclerosis treatment.

Oat consumption, particularly a short-term, high-dose oat diet, improves metabolic health in individuals with metabolic syndrome by increasing microbially produced phenolic metabolites, leading to lower blood cholesterol levels.

Different agonists produce equilibria of at least four distinct active states of the G-protein-bound M2 muscarinic acetylcholine receptor, each with a different ability to activate G proteins.

Lamin A/C in the nuclear lamina is identified as a regulator of cysteine catabolic flux, necessary for cell fate decisions and function.

Here the authors show that transient cell cycle arrest reprograms CD8⁺ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.

In a randomized, double-blind, placebo-controlled trial comparing autologous mRNA-engineered BCMA-targeting CAR T cell therapy versus placebo in patients with generalized myasthenia gravis, a significantly higher percentage of patients exhibited a reduction in disease activity in the treatment arm than in the placebo arm.

The PhenoSphere is a unique plant cultivation facility in which field-like environments can be simulated. Here, the authors find that a single season simulation is superior to an averaged season and to a climatized glasshouse cultivation to elicit field-like phenotypes evaluated in 11 maize lines.

In a phase 2 trial evaluating healthy donor fecal microbial transplantation plus either anti-PD-1 in patients with non-small cell lung cancer or anti-PD-1 and anti-CTLA-4 in patients with melanoma, encouraging efficacy was seen in both cohorts, with responses linked to significantly greater loss of baseline bacterial species.

The use of antimicrobial agents can exacerbate the proliferation of antimicrobial resistance genes, which can put public health at risk; evaluating this risk requires proper monitoring. An extensive investigation of Australian wastewater reveals a distinct correlation between the type of antimicrobial used and the socioeconomic status of the population.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

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.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

In a double-blind, placebo-controlled phase 2 trial in patients with metastatic renal cell carcinoma treated with anti-PD-1 plus a VEGFR tyrosine kinase inhibitor, donor fecal microbial transplantation (FMT) from complete responders to immunotherapy did not significantly improve the primary endpoint of 12-month progression-free survival (PFS) but did significantly improve median PFS versus placebo FMT.

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.

The chimeric candidate Zika virus vaccine YF-ZIK has been previously shown to confer protection in mice after a single dose regimen. Here the authors further characterise the response to YF-ZIK and show induction of immunity and protection in non-human primates.

Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.

Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

In an arm of an ongoing multicenter phase 2 trial testing different therapies in patients with genetically profiled grade 2 or 3 meningiomas, treatment with an oral CDK4/6 inhibitor met the primary endpoint for progression-free survival at 6 months in patients with CDK or NF2 alterations.

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

Transcriptomic and clinical data analyses from multiple cohorts of patients with cancer receiving immunotherapy find that PD-1 blockade potentiates tumor-specific IgG1 plasma cell responses that complement cellular immunity and contribute to clinical benefit.

MedHELM, an extensible evaluation framework including a new taxonomy for classifying medical tasks and a benchmark of many datasets across these categories, enables the evaluation of large language models on real-world clinical tasks.

Using a mouse model with a macrophage-specific DNA repair defect, Niotis, Arvanitaki et al. identify DNA damage-induced autophagy in macrophages as a link from aging to autoimmunity.

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.

Mitochondria that are transported from satellite glial cells in dorsal root ganglia to peripheral sensory neurons through tunneling nanotube-like structures provide protection against peripheral neuropathy.

Using inbred medaka strains, the authors mapped 59 genetic loci linked to heart rate. Gene editing validated conserved genes affecting heart rate and morphology, highlighting the power of isogenic strains in uncovering mechanisms of cardiac traits and disease.

Early results from the phase 2b VIBRANT-HD trial of the oral splicing modulator branaplam in Huntington’s disease suggested reduced cerebrospinal fluid huntingtin levels, but safety monitoring revealed signs of peripheral neurotoxicity, prompting early termination of the study.

Many biological systems appear to organize their dynamics close to a critical point. Now it is shown that the protein array mediating Escherichia coli chemosensing is near-critical, enabling large signal amplification without compromising response speeds.

New hominin fossils from the Grotte à Hominidés at Thomas Quarry I (ThI-GH) in Casablanca, Morocco, dated to around 773 thousand years ago are similar in age to Homo antecessor, yet are morphologically distinct.

Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals, suggesting that a tailored therapeutic strategy is needed to target each subset.

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.

The genetic distance between parents influences hybrid performance in plants. Here Miller et al. show that Arabidopsishybrids produced from diverse parental ecotypes have reduced expression of stress responsive genes at certain times of the day and this correlates with greater biomass production.

The R21/Matrix-M vaccine, but not the ME-TRAP vaccine, was protective against intradermal challenge with Plasmodium falciparum sporozoites, while neither was protective against direct venous inoculation, potentially explaining previously observed differences in protection.

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

TCR-engineered T cells have shown limited efficacy in part due to the absence of co-stimulation leading to limited accumulation in solid tumors. The authors here show engineering the CD8β coreceptor with an intracellular CD28 domain enhances cytokine production, persistence, and tumor control in vivo independent of tumor-associated co-stimulatory ligand encounter.

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.

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.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.