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This study shows that historical precipitation variability shapes current and future record-breaking precipitation probabilities, with regions with low current records being more at risk. High-risk regions are abundant around the world, leading to a quarter billion people facing potential precipitation disasters by 2050.

Antisense oligonucleotide (ASO) cellular activity requires endosomal escape. Here, the authors show that disrupting Golgi-endosome protein AP1M1 enhances ASO activity by prolonging ASO endosomal residence and increasing the likelihood of endosomal escape.

Hydrocarbons are challenging to functionalize. Here, the authors present an electrochemical oxo-functionalization of cyclic alkanes and alkenes to ketones and dicarboxylic acids via mediating nitrate-based supporting electrolyte and molecular oxygen.

Portugal-Calisto et al report the discovery of a 14-residue inhibitory segment, I-patch, present within G-patch activators, Tma23 and Pxr1, that restrains the ATPase activity of the DEAH-RNA helicase Prp43 during ribosome assembly.

Flash droughts that are accompanied by extreme heat drive more severe and prolonged impacts on global ecosystems, according to analysis of global reanalysis data and satellite observations.

Climate models, impact models and demographic data are used to estimate the number of people projected to experience unprecedented lifetime exposure to extreme climate events across multiple dimensions, including birth year, warming scenario and vulnerability.

The risk of heat-mortality is increasing sharply. The authors report that heat-mortality levels of a 1-in-100-year summer in the climate of 2000 can be expected once every ten to twenty years in the current climate and at least once in five years with 2 °C of global warming.

An initial draft of the human pangenome is presented and made publicly available by the Human Pangenome Reference Consortium; the draft contains 94 de novo haplotype assemblies from 47 ancestrally diverse individuals.

Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.

The conventional cocoa value chain has important environmental, nutritional and socio-economic implications. This study presents a chocolate formulation that combines the cocoa pod endocarp and pulp juice to create a sweetening gel that replaces refined sugar, offering improved nutritional value and reduced environmental impact while also contributing to income diversification for smallholder farmers.

Independent statistical reconstructions of the global mean surface temperature from either ocean or land data show that existing estimates of early-twentieth-century ocean surface temperatures are too cold.

Record-breaking heatwaves in 2003 and 2010 surprised both the public and experts. Observations provide new insights into how temperatures escalated to unprecedented values through the interaction of boundary-layer dynamics and land surface drying.

Arctic warming has reduced cold-season temperature variability in the northern mid- to high-latitudes. Thus, the coldest autumn and winter days have warmed more than the warmest days, contrary to recent speculations.

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 re-wiring of the metabolic machinery is a common feature in cancer. Here, the authors show, using paired normal and prostate cancer samples that the cancer samples exhibit a shift to succinate respiration, which is associated with elevated levels of mitochondrial DNA mutations.

Changes in extreme heat are often calculated as anomalies above a reference climatology. A different definition—week-day heatwaves surpassing the current record by large margins—shows that their occurrence probabilities depend on warming rate, not level, and are higher than during recent decades.

Silicate weathering reactions remove carbon dioxide from the atmosphere and store it in carbonate minerals. During the high atmospheric carbon dioxide conditions of the Early Eocene Climatic Optimum, rates of chemical weathering, physical erosion and denudation in the western USA were equivalent to the highest recorded rates in the non-glacial Quaternary.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Ceramics are very brittle and hard to be plastically deformed. Here, the authors report a unit-cell scale disturbance mechanism to improve the deformation ability of ceramics and ultimately achieve large mechanical property enhancement.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

We uncover key processes of the genomic evolution of small cell lung cancer under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with drug response.

Comparisons within the human pangenome establish that homologous regions on short arms of heterologous human acrocentric chromosomes actively recombine, leading to the high rate of Robertsonian translocation breakpoints in these regions.

Heat extremes in Western Europe have increased by an outstanding amount in the last 70 years. Climate models simulate weaker trends. This is largely due to atmospheric circulation trends, favouring heat, missed by climate models.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Climate projections at km-scale show that local hourly precipitation extremes in the UK become 4-times more frequent by 2070, while they do not intensify gradually with warming, but tend to cluster in time.

Jeanette Erdmann and colleagues identify a locus on chromosome 3q22.3 associated with coronary artery disease. The SNP with the strongest association is in MRAS, which encodes a membrane-anchored GTP-binding protein.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

Erik Ingelsson and colleagues report a large-scale genome-wide meta-analysis for associations to the extremes of anthropometric traits, including body mass index, height, waist-to-hip ratio and clinical obesity. They identify four loci newly associated with height and seven loci newly associated with clinical obesity and find overlap in the genetic structure and distribution of variants identified for these extremes of the trait distributions and for the general population.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Based on coupled climate model simulations the authors show that changes to the Earth’s surface energy balance following global-scale forestation and deforestation may change the strength of the jet stream, the Hadley cell, and the ocean circulation, which alters remote climate patterns across the globe

Constructing genome graphs directly from genome assemblies overcomes single-reference bias.

How the effects of irrigation on the climate conditions compare to other anthropogenic forcings is not well known. Observational and model evidence show that expanding irrigation has dampened historical anthropogenic warming during hot days, an effect that is particularly strong over South Asia.

Kathryn Lunetta and colleagues report a meta-analysis of 22 genome-wide association studies for age at menopause. They identify 13 loci newly associated with age at natural menopause, including several candidate genes with roles in DNA repair and immune function.

Kinetochores must interact with both polymerizing (straight) and depolymerizing (curved) microtubules to ensure correct mitotic chromosome segregation. Abad et al. reveal how this flexibility is achieved through structural characterization of the interactions between microtubules and the kinetochore protein Ska1.

Multiple record-breaking climate events have been observed, posing socioeconomic risks. This Review outlines observed and projected changes in record-breaking events, revealing 300–350% increases in the frequency of daily record heat in 2016–2024 relative to a stationary climate.

Myocardial tissue undergoes steady functional decline when cultured in vitro. Here, the authors report a protocol for culture of human cardiac slices that allows maintenance of contractility for up to four months, and show that the model is suitable for evaluation of drug safety, as exemplified for drugs interfering with cardiomyocyte repolarization.

A study comparing the pattern of single-nucleotide variation between unique and duplicated regions of the human genome shows that mutation rate and interlocus gene conversion are elevated in duplicated regions.

This study investigates uncertainties in impact assessments when using climate projections. The uncertainties in health-related metrics combining temperature and humidity are much smaller than if the uncertainties in the two variables were independent. The finding reveals the potential for joint assessment of projection uncertainties in other variables used in impact studies.

Karsten Suhre and colleagues report a genome-wide association study of metabolic traits in human urine, using NMR spectrometry to measure 59 metabolites in urine from participants. They identify five loci influencing urine metabolite levels and point to a missense variant in AGXT2 as the likely cause of hyper-β-aminoisobutyric aciduria, a common inborn error of metabolism.