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This study develops and validates a prognostic staging framework for Alzheimer’s disease by integrating cognitive status with blood-based biomarkers, and neuroimaging data, to improve risk stratification across the disease continuum.

Protein C-terminal diversity is widespread, yet its proteome-wide impact remains unclear. Here, the authors show that C-terminal variations influence the stability of canonical and disease associated mutant proteins and define the sequence features and degradative mechanisms underlying this regulation.

Tan and colleagues present “cycling molecular assemblies” that borrow cellular lipidation machinery to build nanostructures inside the Golgi apparatus. These tools enable rapid organelle imaging and selective destruction of cancer cells.

Phosphorylation-dephosphorylation and ubiquitination tune TCR signaling to avoid self-reactivity. Kim and colleagues show that acetylation also modulates TCR signaling.

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.

Genome-wide association meta-analysis identifies 58 independent risk loci for major anxiety disorders among individuals of European ancestry and implicates GABAergic signaling as a potential mechanism underlying genetic risk for these disorders.

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.

Genetic variants of TREX1, a negative regulator of type I interferon responses, have been linked previously to non-monogenic systemic lupus erythematosus (SLE). Here the authors analyze UK Biobank multi-omics data to show that, while a derived oligoprotein interferon signature associates with increased SLE risk, TREX1 variants do not.

Genomic and transcriptomic analysis of samples from patients with multiple myeloma, followed by in vitro validation, indicate mechanisms of antigen escape in response to GPRC5D T cell-engager talquetamab, including biallelic deletions, small nucleotide variants, insertion-deletions and chromatin silencing.

Authors report drug repurposing screens against O-GlcNAc cycling enzymes, finding kinase inhibitors that act as splicing modulators to disrupt O-GlcNAc homeostasis and downregulate OGT and OGA. These findings reveal splicing modulator chemotypes and approaches to disrupt O-GlcNAc homeostasis.

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.

Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4⁺ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.

“This randomized controlled trial in adults with central obesity found that high-intensity interval training, performed once or thrice weekly, reduced body fat mass compared with control, highlighting the benefits of “weekend warrior” interventions.”

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.

Infective endocarditis (IE) is an understudied biofilm-associated infection. Here, analyses of preclinical and clinical data reveal that the Fsr quorum sensing (QS) system of Enterococcus faecalis is a negative regulator of IE pathogenesis.

Accurately predicting enzyme functions remains challenging, especially for underrepresented enzyme commission (EC) classes. Here, the authors introduce HIT-EC, a hierarchical interpretable transformer that improves EC number prediction and provides insight into sequence-function relationships.

In the adrenal cortex, cholesterol used for steroid production is stored in lipid droplets. The authors demonstrate here the importance of the transcription factor HHEX in maintaining glucocorticoid levels and protecting lipid droplets from androgen-induced lipid depletion.

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

The relative contribution of lipid catabolism on fasting-induced longevity was unknown. Authors showed lifespan extension from fasting depend on silencing lipid catabolism upon nutrient replenishment through phosphorylation of NHR-49 by KIN-19.

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.

Elevated triglyceride-rich lipoproteins (TRLs), long linked to cardiovascular disease, were thought to be harmful mainly in their remnant form. Here, the authors show that intact TRLs, not just their remnants, promote atherosclerosis and vascular inflammation in a mouse model.

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.

Application of multiancestry and ensemble-based approaches yields improved polygenic risk prediction models for breast cancer and its subtypes among women of African ancestry.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Short-circuiting during fast charging through lithium dendrite intrusion into electrolytes is a major challenge in solid-state batteries. Here, using thermally annealed 3-nm-thick Ag coatings, lithium penetration into brittle electrolyte Li_6.6La₃Zr_1.6Ta_0.4O₁₂ is inhibited at local current densities of 250 mA cm⁻² due to an increase in surface fracture toughness.

Silicon anodes promise much higher battery capacity but are limited by poor storage life. This work identifies key ageing mechanisms and suggests ways to improve long-term stability.

Crystal structures of HIV Env trimer with native glycosylation in complex with neutralizing antibodies reveal a glycan shield of high-mannose and complex-type N-glycan and indicate a path for germline-targeting vaccine design.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

Here the authors show that PARP inhibition activates SIRT-1–FOXO1 signaling to drive transcriptional and metabolic reprogramming of CD8⁺ T cells into central memory T cells with superior recall capacity and efficacy in adoptive therapy.

This study detects Chlamydia pneumoniae in human retina and brain, increasing with AD severity. Retinal pathogen load with Aβ₄₂ may predict AD stage. In models, infection drives Aβ deposition and NLRP3 activation, worsening pathology and cognition.

Using infant fMRI, the authors show that, by 2 months of age, representations in high-level visual cortex encode visual categories that align with deep neural networks, and lateral object-selective regions are later to develop.

Ribas and colleagues report the results of a phase 2 clinical trial of neoadjuvant PD-1 blockade in patients with surgically resectable desmoplastic melanoma.

The nuclear clock transition of ^229mTh in ²²⁹Th:CaF₂ crystals is characterized as a function of doping concentration, temperature and time, demonstrating high reproducibility and identifying ideal operating characteristics of these crystals as nuclear clocks.

In mice, DHPS supports the maturation, maintenance and function of tissue-resident macrophages via the polyamine–hypusine axis, with implications for macrophage-targeting therapies.

Human genetic loci that associate with composition of the oral microbiome are identified using saliva-derived DNA, where the same host genetics also shapes oral health and genetic variation in oral bacteria.

The formation of glycylglycine, a simple peptide molecule, is possible under non-aqueous interstellar conditions, according to laboratory experiments. Thus, complex organics with biological relevance may predate planetary accretion.

Several recent publications have attempted to detect novel unannotated microproteins using mass spectrometry proteomics. Here, the authors reassess these claimed microprotein detections, finding that many are poorly supported, while a subset represents likely genuine discoveries of novel proteins.

Whole-genome and transcriptome analysis of 1,364 cases of breast cancer from South Korea broadens our understanding of breast cancer biology and reveals genomic features that connect tumour biology with treatment responses and clinical outcomes.

Here the authors perform longitudinal sampling of lymphoid organs along with fate mapping and matched single-cell RNA sequencing and TCR sequencing to define the developmental dynamics of follicular regulatory T (T_FR) cells. They find that T_FR cells undergo clonal expansion and progressive differentiation in a process that requires follicular helper T cells.

Whole genomes of 185 atypical enteropathogenic Escherichia coli (aEPEC) isolates reveal 30 LEE (locus of enterocyte effacement) subtypes in 3 major lineages, varying in insertion site preference and their complement of non-LEE encoded effector genes.

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.

Nanoparticles sensing glycosaminoglycan loss in osteoarthritis enable disease-severity-responsive delivery of ghrelin messenger RNA to cartilage lesions, reducing cartilage damage, bone thickening and pain in animal models.

Objective indicators for distinguishing subtypes of depressive-like behavior remain unclear. Here, the authors characterize semantic syllables of naturalistic mouse behavior to delineate state manifestations across stressors, sexes, stages, and treatment types.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

Large-scale molecular dynamics simulations show that the crystal–melt interfacial energies of MgSiO₃ bridgmanite increase substantially with pressure, potentially forming unusually large bridgmanite crystals and suggesting a new physical mechanism driving magma ocean segregation.

The Taiwan Precision Medicine Initiative (TPMI) has built a cohort of more than half a million individuals with Han Chinese ancestry, providing a rich resource of genetic and medical data for this group.