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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

High-elevation meteorological observations and reanalysis data indicate local cooling and drying near Himalayan glaciers due to enhanced katabatic winds in response to global warming.

An expert-elicitation process identifies current methodological barriers for monitoring terrestrial biodiversity, and how technological and procedural development of robotic and autonomous systems may contribute to overcoming these challenges.

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

It has been argued that air temperatures over mountain glaciers are decoupled from surrounding warming, which could slow down melting. Here the authors show that this effect will weaken with future glacier retreat, leading to a recoupling of temperatures from the 2030s onwards.

Estimating the contribution of different age groups to COVID-19 epidemic dynamics is complicated by changing variants, non-pharmaceutical interventions, and vaccination levels. Here, the authors use longitudinal social contact data from Belgium to characterise the contribution of age groups to transmission during different phases of the pandemic.

The primary cilium is required for the autophagic response to shear stress. Here, the authors show that PI3KC2α has a role in ciliogenesis and promotes local PI3P production upon shear stress to induce autophagy that is distinct from VPS34-driven starvation-induced autophagy.

T follicular regulatory cells control the magnitude of the germinal centre response. Here the authors show that these cells display specificity to self as well as foreign antigens, and can arise from Foxp3-negative precursors at early stages of immunization in a PD-L1 dependent manner.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

How nicotine impacts the adolescent development of neural circuitry is not fully understood. Here authors show that early adolescent nicotine exposure in male mice blocked the maturation of nicotine-evoked dopamine signaling, causing an immature, vulnerable behavioral response in adult mice. Restoring their adult-like nicotine-evoked signaling unmasks a mature behavioral response in male mice.

Combined analysis of new genomic data from 116 ancient hunter-gatherer individuals together with previously published data provides insights into the genetic structure and demographic shifts of west Eurasian forager populations over a period of 30,000 years.

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.

Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

Analyses of 475 ancient horse genomes show modern horses emerged around 2200 bce, coinciding with sudden expansion across Eurasia, refuting the narrative of large horse herds accompanying earlier migrations of steppe peoples across Europe.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The second Global Amphibian Assessment finds that the status of amphibians is continuing to deteriorate globally, driven predominantly by climate change, disease and habitat loss.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

The syndecan binding protein syntenin promotes the budding of intraluminal vesicles from the endosomal membrane, resulting in increased exosome secretion. Ghossoub et al.show that syntenin activates a pathway including ADP-ribsoylation factor 6 and phospholipase D to stimulate budding.

Zhou et al. investigate the molecular events that follow neoadjuvant treatment in PDAC patients, explore signatures of heterogeneous response and persister phenotypes, identify a CYP3A link to resistance and suggest that it is useful in predicting response.

A deleterious mutation in the tomato transcription factor SSP2 was enriched during domestication. Repairing the deleterious mutation in cultivated tomato by base editing leads to compact growth and early fruit yield.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.

This Review discusses multiomic approaches for the characterization and biological understanding of cellular senescence, including detailed case studies on skeletal muscle and adipose tissue that highlight current outstanding issues in the field.

Reductive carboxylation of glutamine by isocitrate dehydrogenase 2 (IDH2) has a role in determining the fate of T cells, and inhibiting this enzyme promotes the differentiation of memory T cells.

Piwi-associated RNAs (piRNAs) are small RNAs with several functions in the germline, such as repressing transposable elements and helping to maintain germline stem cells. Now, a function for piRNAs has been discovered outside the germline, in the fruitfly embryo. Specifically, piRNAs are required for the decay of the messenger RNA encoding the posterior morphogen Nanos. When piRNA-induced regulation is impaired, this mRNA is stabilized and developmental defects ensue.

Ultra-high-energy gamma-ray emission from the microquasar V4641 Sagittarii is reported, suggesting that large-scale jets from microquasars could be more common than previously thought and also could be a notable source of galactic cosmic rays.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) remains poorly understood. Here, the authors analyse over 2700 micro-dissected samples using transcriptomics to identify genes that characterise different stages of DCIS to IDC progression, and identify IDC-associated markers within early-stage lesions.

Morphological and electrophysiological understanding of cerebrospinal fluid-contacting neurons (CSF-cNs) is extended by analysis in the mouse, revealing that they express PKD2L1 and ASICs along with ligand- and voltage-gated channels modulated by metabotropic receptors.

Multimodal DNA methylation and transcriptome profiling of single glioma cells links tumor cell transcriptional states to epigenetics via interaction with PRC2 and shows that these states are heritable and important for tumor plasticity.

Analysis of a multicenter cohort of kidney transplants shows that mismatches in the MICA locus and the presence of anti-MICA donor-specific antibodies are associated with reduced graft survival and increased rejection.

Deletion of the transcription factor Irf5 in macrophages leads to expansion of the subcutaneous fat depot but restriction of the visceral fat during obesity, resulting in improved insulin sensitivity

Acetaminophen-induced liver injury is one of the most common causes of liver failure and has to be treated within hours of the overdose. Here Barbier-Torres et al. show that targeting MCJ, a mitochondrial negative regulator, even 24 h after the overdose protects liver from acetaminophen-induced damage.

RNA editing by the adenosine deaminase ADAR1 controls cathepsin S expression in endothelial cells, a mechanism that is implicated in determining cathepsin S levels in patients with atherosclerotic vascular diseases.

The Patagonian ice sheet not only responded to climate change but also actively influenced it regionally, highlighting the role of topographic forcing in shaping atmospheric circulation during glacial-interglacial cycles, according to a modeling study.

The global rush to develop the ‘blue economy’ risks harming both the marine environment and human wellbeing. Bold policies and actions are urgently needed. We identify five priorities to chart a course towards an environmentally sustainable and socially equitable blue economy.