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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.

Ultraviolet light damages DNA and drives skin cancer. Here, the authors show that the DNA replication factor And-1 coordinates with DNA polymerase δ to repair UV-induced lesions, and that loss of And-1 phosphorylation impairs repair and promotes skin tumorigenesis.

PARP inhibitors, either alone or in combination with bevacizumab, have regulatory approval as maintenance therapy following response to first-line platinum-based chemotherapy. Here this group reports SOLACE2 trial investigating whether combining olaparib with low dose cyclophosphamide treatment improves progression-free survival, comparing to olaparib monotherapy alone, in platinum-sensitive recurrent ovarian cancer.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Small cell lung cancer cells form functional synapses with glutamatergic neurons, receiving synaptic transmissions and deriving a proliferative advantage from these interactions.

In a meta-analysis of 48 randomized trials of chronic kidney disease progression, reduction in the 6-month urinary albumin:creatinine ratio was associated with lower hazard ratios of established kidney disease endpoints, supporting the use of albuminuria change as a surrogate endpoint in clinical trials for chronic kidney disease.

Here, the authors present archaeology of the Namorotukunan site in Kenya’s Turkana Basin that demonstrates adaptive shifts in hominin tool-making behaviour spanning 300,000 years and increasing environmental variability. They contextualize these findings with paleoenvironmental proxies, dating, and geological descriptions.

Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

Here the authors map the dynamics of human NK cell residency and recirculation, showing that CD56^bright NK cells transiently occupy tissues and recirculate via lymphatics, whereas CD56^dim NK cells remain vascular except during inflammation.

Proteomic data from natural isolates of Saccharomyces cerevisiae provide insight into how these cells tolerate aneuploidy (an imbalance in the number of chromosomes), and reveal differences between lab-engineered aneuploids and diverse natural yeasts.

Melanoma cells lacking SOX10 are tolerant to MAPK inhibition (MAPKi) due to elevated TAZ-driven TEAD signaling. Here, the authors develop two inhibitors of TEAD, capable of resensitising SOX10 knockout melanoma cells to MAPKi and offering a strategy to overcome drug tolerance and improve treatment response.

In this work, authors present an AI framework to detect pediatric tuberculosis by using both frontal and lateral chest X-rays, showing robust performance across several age groups and settings.

High near-surface nitrogen-fixation rates that promoted the recent growth of the Great Atlantic Sargassum Belt were tied to greater upwelling of phosphorus from the equatorial Atlantic, according to coral-bound nitrogen isotope records from the Caribbean.

In this work, authors show that Salmonella uses its SPI-1 injectisome to infect macrophages, triggering rapid translational upregulation of transcription factors, such as EGR1 which suppresses the inflammatory response, aiding the bacteria in establishing systemic infection

This study nominates immune escape as an early event in colorectal cancer and shows how this can be driven through both genetic and epigenetic changes.

Surfaces are the stage for vital catalytic reactions, but accurately simulating them is computationally expensive. Here, the authors introduce an efficient method using GPUs to model large, complex surfaces with exceptionally high, experiment-matching accuracy

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.

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.

Hybrid gRNAs significantly increase targeted editing in the liver while simultaneously reducing unwanted bystander editing in humanized mouse models.

Multimodal AI combines different types of data to improve decision-making in fields such as healthcare and engineering, but work so far has focused on vision and language models. To make these systems more usable in the real world, Liu et al. discuss the need to develop approaches with deployment in mind from the start, working closely with experts across relevant disciplines.

This study identifies status dystonicus as a distinct brain state characterized by excessive beta-band activity with implications for the diagnosis and treatment of this poorly known neurological emergency

Functional and structural characterization of PtmA2 reveals that it is an unusual non-adenylating acyl-CoA ligase and part of a system wherein the canonical acyl-CoA ligase reaction is separated into two half-reactions performed by distinct enzymes.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

Understanding molecular arrangements in mechanistic studies of complex materials is critical but challenging. Here, the authors develop a hierarchical incremental learning protocol to uncover microscopic patterns, improving mechanistic insights obtained

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

Different types of SETBP1 variants cause variable developmental syndromes with only partial clinical and functional overlaps. Here, the authors report that SETBP1 variants outside the degron region impair DNA-binding, transcription, and neuronal differentiation capacity and morphologies.

Yoon et al present super-resolution panoramic integration, a microscopy method that instantly captures super-resolution images with high throughput, enabling detailed biological study of cells beyond traditional optical limits

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.

In a randomized trial of patients with a previous myocardial infarction and with residual inflammation, a monoclonal antibody targeting the LOX-1 receptor, thought to contribute to atherosclerotic plaque progression and inflammation, reduced soluble LOX-1 and interleukin-6 levels but did not lead to a substantial reduction in coronary plaque volume.

In this multicentered observational study, Rotavac, an indigenous, monovalent, live, attenuated, oral rotavirus vaccine, had an adjusted vaccine efficacy of 54% and protected against severe gastroenteritis in Indian children during its rollout between 2016 and 2020.

The authors conducted prospective multimodal monitoring of simultaneous brain and heart function to define physiological changes during the human dying process leading to circulatory arrest.

In this study, the authors determine the structure of a Type I-A retron from E. coli FORC82 and reveal the functional interplay between Reverse Transcriptases (RTs) and Structural Maintenance of Chromosomes (SMC) ATPases.’

African ancestry is a known risk factor for prostate cancer development, but the genetic determinants of this are incompletely understood. Here, the authors identify 172 potentially pathogenic variants which are enriched in an African population.

Type 2 diabetes predisposes individuals to multiple comorbidities, but causal mechanisms are unclear. Here, the authors use Mendelian randomisation to show that distinct genetic pathways underlie diabetes-related risks, with ancestry-specific differences.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Confocal microscopy enables high-resolution, high-plex 3D cyclic immunofluorescence of 30- to 50-µm-thick tissue sections. The approach allows for rich phenotypic assessments of intact cells and intercellular interactions with subcellular resolution.

This study explores the relationship between telomere length and clonal hematopoiesis. Splicing factor and PPM1D gene mutations are more frequent in people with genetically predicted shorter telomere lengths, suggesting that these mutations protect against the consequences of telomere attrition.

This study shows that p300/CBP-dependent H2B acetylation is crucial for maintaining transcription of oncogenic gene programs in androgen receptor-driven prostate cancer.

Literature produced inconsistent findings regarding the links between extreme weather events and climate policy support across regions, populations and events. This global study offers a holistic assessment of these relationships and highlights the role of subjective attribution.

This study introduces the Cattle Cell Atlas, a single-cell expression resource including 1,793,854 cells from 59 tissues. Integrative analyses leveraging this atlas provide insights into the biology underlying bovine monogenic and complex traits.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

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.

In a phase 3 trial for Huntington’s disease, pridopidine did not meet its primary endpoints but was safe and favored in some prespecified subgroup analyses.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with anti-inflammatory interventions.

Natural products have historically made a major contribution to pharmacotherapy, but also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization. This Review discusses recent technological developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — that are enabling a revitalization of natural product-based drug discovery.

The predicted increase in frequency of droughts and rising temperatures in Europe will lead core populations of a temperate plant to an evolutionary dead-end unless they acquire genetic alleles that are present only in extreme edge Mediterranean, Scandinavian, or Siberian populations.

Understanding how local distortions affect the functional properties of high entropy materials remains an open challenge. This work found element-specific distortions beyond nearest neighbors and a flexible cationic sublattice in spinel oxides, linking mean-field magnetism to bond lengths.