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Loss-of-function variants of ABCA7, associated with Alzheimer’s disease, result in disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways in the human brain.

Lipid nanoparticles (LNPs) are a versatile class of clinically approved drug delivery vehicles, particularly for nucleic acid cargoes, but they often suffer from instability issues. Here, the authors report that the room temperature stability of small interfering RNA LNPs formulated with unsaturated ionizable lipids can be improved by inclusion of mildly acidic, antioxidant-containing buffers.

In multiple sclerosis, smoldering inflammation contributes to clinical progression. Using multi-omics data, here the authors link chronic inflammation to senescence-like processes and cellular network changes, suggesting a potential therapeutic target.

Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining neuroendocrine–tuft heterogeneity and offering new perspectives for targeting lineage plasticity.

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 authors report spectral hole burning with a record hole lifetime in a Er³⁺ doped scheelite crystal CaWO₄ at mK temperatures. This can benefit applications in classical and quantum information processing.

Foetal haematopoiesis takes place in the liver before the bone marrow is seeded. Here the authors used imaging analysis and mouse genetics to look at nascent bone marrow formation and show that yolk-sac-derived myeloid cells promote haematopoiesis by promoting specification of a VCAM1⁺ sinusoidal colonisation niche.

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.

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.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

This study discovers human SERF2 as a key partner in stress granule formation by binding specific RNA G-quadruplexes. SERF2 and these RNAs provide a detailed structural model of protein-RNA interactions driving liquid-liquid phase separation in condensates.

Broad-spectrum vaccines have been proposed as a tool for rapid response to emerging infectious disease threats and are in pre-clinical development. Here, the authors use mathematical modelling to assess the potential impacts of broadly protective sarbecovirus vaccines for a hypothetical “SARS-X” outbreak.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Let-7 microRNA (miRNA) and its target gene lin-28 regulate pluripotency. A second Let-7 target, lin-41, controls miRNA function in stem cells by regulating the turnover of the miRNA effector Argonaute2 through its ubiquitin ligase activity.

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

Brain-restricted allogeneic transplantation of myeloid progenitors enables microglia replacement without the need for genetic engineering or systemic cytotoxic preconditioning.

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.

Fish retinal regeneration starts with the dedifferentiation of glia cells into progenitors. Following injury, the proneural transcription factor, Ascl1a, upregulates the pluripotency factor Lin-28, which in turn prevents let-7 microRNA-mediated inhibition of regeneration-associated genes.

Multiple energy system models are used under jointly adopted deep decarbonisation scenarios to conclude that the direct penetration of electricity and hydrogen in final energy consumption may rise to shares of, respectively, 60% and 6%, in Europe by 2050.

At equilibrium, the ferroelectric polarization is proportional to the strain. At ultrafast timescales, an above-bandgap laser excitation decouples strain and polarization, which, out of equilibrium, is mainly determined by the photoexcited electrons.

Haematopoietic stem cell numbers are restricted at both systemic and local levels.

Understanding the mechanisms of chemoresistance in multiple myeloma (MM) remains elusive. Here, the authors identify a long non-coding RNA termed as PLUM that is overexpressed in NF-ĸB mutant high-risk MM and interacts with EZH2 to mediate PRC2 complex formation promoting chemoresistance via the activation of the UPR pathway.

Immune tolerance to food is mediated by CD4⁺ T cells forming subsets of T helper cells lacking the capacity to trigger gut pathology but able to produce regulatory T cells that may suppress it.

Myeloid cells contribute to the etiology of multiple sclerosis (MS), but the dynamics of myelopoiesis during disease progression is still unclear. Here the authors show, in both mouse models and clinical data, that myelopoiesis is differentially regulated via M-CSF modulation in different organs at distinct stages of MS, with diet and lifestyle being potential modifiers.

Reservoir computers are artificial neural networks that can be trained on small data sets, but require large random matrices and numerous metaparameters. The authors propose an improved reservoir computer that overcomes these limitations and shows advantageous performance for complex forecasting tasks

A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a promising candidate for tuberculosis treatment regimens.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.

A reinforcement learning-based virtual reality system, implementing a series of sport sessions with coaching, was as effective as standard physical activity in reducing fat mass in adolescents, with positive effects on cognition.

ADP-heptose binds to ALPK1, triggering transcriptional reprogramming and NF-κB activation, endowing pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Efficient electro-optic conversion is central to photonic computing, and thin-film lithium niobate (TFLN) offers this capability. Here, the authors demonstrate computing circuits on the TFLN platform, enabling the next generation of photonic computing systems featuring both high-speed and low-power.

Genetic and genome-wide analysis of a catalytically deficient SETDB1-like enzyme, MET-2, in Caenorhabditis elegans reveals that MET-2 promotes transcriptional silencing and fertility through both H3K9 methylation and focus formation, which blocks histone acetylation.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

China’s rapid e-commerce growth has driven a 12-fold surge in express delivery, yet cross-regional emissions and health impacts remain poorly quantified. Road transport emitted 23.9-Mt CO₂-equivalent and caused approximately 5,100 premature deaths in 2021, revealing stark transit-region health inequities and guiding sustainable logistics pathways.

Previously undescribed hierarchical arrangements in haematopoietic stem cells and their niches that mediate both regenerative potential and immune privilege are identified.

Electron hopping in geometrically frustrated lattices can result in a rich variety of unusual behaviours. Now, the orbital arrangement in a van der Waals metal with a non-frustrated, primitive lattice is found to show similar effects.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Mechanisms for generating spin-polarized currents may be helpful for applications. Now one such mechanism that uses the unusual Landau-level spectrum of WSe₂ under a strong magnetic field is demonstrated.

The diagnosis and prognosis of chronic kidney disease (CKD) relies on invasive renal biopsies, which can be clinically constrained. Here, the authors develop a non-invasive model using retinal images that can be used to screen for CKD and identify five common pathological types of CKD.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Whereas epidermal growth factor-induced dimerization is considered essential for EGFR signalling, the structurally related insulin receptor is a disulfide-linked dimer. Here the authors show that C. elegansEGFR is constitutively dimeric and undergoes subtle structural changes upon ligand binding that likely underlie allosteric activation.

A combination of large-scale phylogenomic analysis, mouse lethality experiments and bacterial growth assays shows that gene loss in the putrescine utilization pathway has enhanced biofilm formation and transmission-related characteristics in the pandemic clone of a bacterial pathogen, Vibrio parahaemolyticus, promoting successive waves of global transmission events.

Here, the authors leverage whole-genome sequencing from >88,000 diverse individuals to uncover 18 BMI-related genetic signals, including novel variants in participants of African genetic ancestry, highlighting the value of diversity in genetic discovery.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Several parameters in the bone marrow (BM) niche regulate leukaemic stem cell status and disease progression. Here, the authors show that calcium-sensing receptor affects the location of acute myeloid leukaemia (AML) cells in the BM niche which influences self-renewal of leukaemic stem cells and AML development