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Exhaustion is a functional state that hampers anti-cancer and antiviral CD8 T cell activity, and is preceded by a stem-like state, maintained by the transcription factor TCF1. Here authors develop mouse models that allow a precise understanding of the developmental trajectory between the stem-cell-like and exhausted states of CD8 T cells and find that while constitutive overexpression of TCF1 expands the stem-like T cell pool, TCF1 expression specifically in already exhausted cells is unable to promote dedifferentiation.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

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.

Liquid crystal skyrmions are quasiparticle structures whose interactions at large separations can be understood in terms of elastic multipoles. Here, the authors derive these multipole interactions analytically and show how they drive the formation of chains and clusters under oscillating electric fields.

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.

The neural mechanisms underlying the diversity of hippocampal replay dynamics remain unclear. Here, using computational modelling, the authors show that modulation of firing-rate adaptation accounts for distinct replay modes and their relationships to behavioral state and oscillatory activity.

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.

During development of eutherian females, one of the X-chromosomes is silenced. Here, authors show that alleles on the inactive X-chromosome are dynamically expressed along neural differentiation enhancing resilience of female neural tissue.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

Mislocalized and aggregated TDP-43 drives neurodegeneration in several diseases. The current work shows that RAD23A contributes to TDP-43 toxicity by driving pathological re-distribution of key proteins into an insoluble fraction of cells and thereby leading to loss of function phenotypes.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

Glioblastoma is characterised by high levels of intratumoural heterogeneity and plasticity, hindering treatment. Here, the authors develop an analytical framework, scFOCAL, to predict the sensitivity of glioblastoma cell subpopulations to therapies based on reversal of disease transcriptional signatures to identify synergistic therapeutic combinations.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

Organisms vary in their nitrogen and phosphorus content, shaping ecological and evolutionary processes. This study shows that nitrogen deposition is a consistent global factor associated with plant and animal stoichiometry.

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.

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.

89ZED88082A is a zirconium-89-labeled one-armed anti-CD8α antibody for the non-invasive whole-body visualization of CD8 + T-cells by positron emission tomography (PET). Here the authors report the results of a phase 2 study of 89ZED88082A for whole-body CD8 + T-cell PET imaging in patients with large B-cell lymphoma before and during CD19-directed CAR T-cell therapy.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Deep-sea mining in the Clarion-Clipperton Zone may release waste into midwaters that support diverse marine life. This study finds such discharges could dilute key food particles and disrupt trophic links from zooplankton to large marine predators.

Arctic ground squirrels recycle microbially-liberated urea-nitrogen into anabolic amino acids during subzero hibernation, potentially supporting protein and nitrogen balance during prolonged fasting.

Myotonic dystrophy type 1 affects both muscle and neuronal function, but its synaptic pathology is poorly understood. Here, the authors show that upregulation of FasII (NCAM1) in both pre- and postsynaptic cells synergistically drives neuropathological and behavioral DM1 phenotypes, which can be rescued by FasII knockdown or specific isoform modulation.

How cells respond to replication-derived DNA damage that is carried over into mitosis is not well understood. Here, the authors show that CIP2A with TOPBP1 mediates the mitotic recruitment of the SLX4/MUS81/XPF nuclease complex to replication stress-induced DNA lesions to maintain genome integrity.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

T-cell acute lymphoblastic leukemia is a highly aggressive disease with varying recurrence rates. Here, the authors build a single cell transcriptomic atlas of childhood T-cell acute lymphoblastic leukaemia (T-ALL). They identified a distinctive cancer cell state that correlates with high risk, treatment refractory T-ALL.

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.

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.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Ferromagnetism has been known as a material property of solids since the time of the ancient Greeks. Here, Shuai et al. report that magnetic nanoplates suspended in a simple solvent can spontaneously align to form a ferromagnetic liquid, capable of both producing and sensing magnetic fields.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.