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The impact of variants of uncertain significance (VUS) on protein function and cancer risk remain unclear. Here, the authors focus on the functional impact of VUS of the PALB2 gene and identify defects in DNA damage repair by homologous recombination associated with increased risk of breast cancer.

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 authors report a trial subset analysis of the immune responses induced by two inactivated quadrivalent influenza vaccines (QIVs): Sinovac QIV and Vaxigrip-Tetra™. Both vaccines elicit robust humoral responses and distinct T cell profiles.

Components of the glycocalyx have been shown to impair immune cell functions, including of CAR-T cells. Here the authors show that CAR-T cell mediated cytotoxicity in pancreatic cancer models can be enhanced by incorporating non-signalling binding domains that target the glycocalyx.

Promising clinical activity of Claudin (CLDN) 18.2-directed CAR-T cell therapy in patients with gastric cancer has been recently reported, however gastrointestinal toxicities have also been described. Here the authors recapitulate the on-target off-tumor toxicity of CLDN18.2-directed CAR-T cells due to gastric mucosa damage in preclinical models, suggesting an AND-gate strategy targeting CLDN18.2 and mesothelin to overcome CAR-T cell toxicity

Data provided by Amazonian peoples are used to estimate the value of wild animals as a source of food, including its spatial distribution and nutritional value, providing information that will be key for improved management of forest ecosystems in the region.

Mucosal influenza vaccines promise enhanced protection but lack defined immune correlates of protection. Here, the authors conduct a phase I trial of an intranasal recombinant influenza A/H5 vaccine with a nanoemulsion adjuvant, demonstrating successful mucosal priming and broad cross-clade immune responses, advancing the development of intranasal influenza vaccines.

Clinical trials in Europe must become far more efficient to support the needs of investigators and their patients. The way trials are designed, conducted and regulated should be attuned first and foremost to the needs of patients, to ensure timely and equitable access to safe, effective and innovative treatments.

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 an integrated analysis of transcriptomic data from the SUBSPACE consortium and public datasets of patients with sepsis, acute respiratory distress syndrome, trauma and burns, dysregulation within four consensus molecular clusters related to myeloid and lymphoid cells is associated with mortality and illness severity.

In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

Optimising plant-rhizobium interactions can enhance nitrogen fixation, improving sustainability in agriculture. This study identified four groups of faba bean symbionts that show growth-promoting characteristics and whose diversity across root nodules is under plant genetic control.

This study reveals how a cancer-associated mutation in CHD1 leads to the loss of its C-terminal intrinsically disordered region, disrupting condensate formation. This impairment causes improper genome distribution and gene expression, driving cancer development.

Kallies and colleagues examine the role of the chromatin regulator SATB1 in CD8⁺ T cell differentiation during viral infection and cancer. They show that SATB1 is a negative regulator of exhausted CD8⁺ T cell expansion and effector differentiation.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Cibula et al. present survival results of the SENTIX trial and demonstrate that SLN biopsy alone does not increase the risk of disease recurrence in patients with early-stage cervical cancer.

Bhattacharjee and Schaeffer et al. map exclusive breastfeeding (EBF) in 94 low- and middle-income countries (LMICs), finding increased EBF practice and reduced subnational variation across the majority of LMICs from 2000 to 2018. However, only six LMICs will meet WHO’s target of ≥70% EBF by 2030 nationally, and only three will achieve this in all districts.

Analysis of data on 971 bird species in natural habitat and cattle pasture in Colombia finds that near-national-scale losses of bird diversity greatly exceed losses recorded at the local scale, suggesting that extrapolations from local studies will severely underestimate biodiversity losses.

Here the authors show a function for lymph nodes in the maintenance of effector T cell differentiation and function during chronic infection and checkpoint blockade, identifying a spatial component in the regulation of exhausted T cell fitness.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Redox signalling is emerging as an important regulator of metabolism and physiology, which is dysregulated in ageing and disease. Here, the authors show that redox regulation of a key redox sensitive cysteine in Atg4a induces autophagy in vivo and extends lifespan in female Drosophila.

ZeoBind is developed for high-throughput molecule screening in zeolite synthesis. Here 2.3 million organic structure-directing agents are enumerated and predictive models for binding affinity are developed; the screening is experimentally validated for two zeolites.

Food biodiversity is likely to benefit both human health and agrifood systems. To assess food biodiversity, this epidemiological study proposes the use of dietary species richness, which is highly heterogeneous—both between and within countries—and is associated with lower rates of mortality in Europe and similar levels of micronutrient adequacy in low- and middle-income countries, as opposed to other classical indices.

Integration of multiomics data with functional analysis of pancreatic tissues from individuals with early-stage type 2 diabetes indicates that the genetic risk converges on RFX6, which regulates chromatin architecture at multiple risk loci.

Robust bioanalytical and modeling methods are needed for covalent drug discovery. Here, the authors demonstrate a mass spectrometry (MS) assay to measure target engagement of any drug-target protein complex, a universal PK/PD model for covalent drugs, and a decision tree to guide research.

Establishment of antiviral immune responses depends on dendritic cells (DCs), but how transitional DCs compare with other DC subsets in this regard is unclear. Here the authors show the origins of these cells and their proinflammatory function during viral infection.

Anoxic marine zones are expanding and intensifying with climate change. Here the authors show that microbial dark carbon fixation influences the carbonate system and the stable isotope composition in waters off Chile, contributing up to 35% of the organic carbon reaching the mesopelagic region.

CD4⁺ T cells are known to be important in Plasmodium infection. Here the authors use mouse models to track antigen-experienced TCR transgenic and polyclonal CD4⁺ T cells during Plasmodium re-infection, and show different T cell phenotypes and varied responses in different areas of the spleen.

A single-cell transcriptomic analysis of endometriosis, endometriomas, eutopic endometrial samples and uninvolved ovary tissues highlights cell populations characteristic of these tissue types. Transcriptional and cellular heterogeneity across tissues suggests novel therapeutic targets and biomarkers for this disease.

Moreno-Loaiza et al. found that interleukin-1β, acting upon cardiac resident macrophages, promotes atrial fibrillation in mice, and this mechanism may represent a common pathway connecting various risk factors to this arrhythmia.

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).

Ruivo et al uncover a Toxoplasma survival mechanism conserved across different cell types and species. By repressing NF-kB activation and lytic host cell death pathways, the rhoptry protein ROP55, promotes parasite survival and host immune evasion.

Equal affinities of competing reactions at an energetic convergence node demonstrated a metabolic transition in the high-altitude Lirima hydrothermal system of Chile, according to combined geochemistry, thermodynamic modeling, stable isotope analysis, microbial activity measurements, and metagenomics.

Camera-trap data for 159 mammalian species at 1,002 sites across 16 tropical-forest protected areas show how local survival and colonization probabilities of specialist and generalist species are differently affected by human-induced stressors at different spatial scales, such as human population density and forest fragmentation.

How different cell types in primary motor cortex contribute to movement during learning and/or execution is not fully understood. Here authors show that corticothalamic neurons of the primary motor cortex are silent during movement and that this activity signature is critical for proficient movement generation.

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.