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Mutation of positively charged binding sites on the eastern equine encephalitis virus (EEEV) E2 glycoprotein affects both heparan sulfate and protein receptor binding, identifying an unexpected linkage between engagement of these two receptor types.

Auditory processing is an important component of mosquito behaviour including mating. Here the authors demonstrate substantial sex- and also species-specific variation in mosquito auditory transduction, amplification and gain control.

Polyubiquitin chains form a “ubiquitin code” to control protein functions. Here, the authors develop linkage-selective enDUBs to study this in live cells. Applied to Kv7.1 ion channel, enDUBs reveal distinct roles for K11, K29/33, K48, and K63 chains in regulating channel abundance and trafficking.

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.

The signaling-specific inhibitor AEF0117 selectively inhibits CB₁ activation by THC and reduces self-administration and subjective effects of cannabis in clinical trials, making it a potential treatment for cannabis use disorder.

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

Effective treatments for atopic dermatitis (AD) are highly sought after. Here the authors develop ucenprubart (LY3454738) for treating AD and find, in a randomized, multiple arms, multicenter, placebo controlled, and dose-escalating phase 1 trial (NCT03750643) trial, ucenprubart to be safe and showing preliminary efficacy when compared with placebo at 12 weeks post treatment.

A large-scale genome-wide meta-analysis conducted across different platforms identifies genetic loci regulating levels of circulating metabolites.

The second messenger cAMP modulates a wide range of important biological processes. Here, the authors developed a fluorescent indicator termed G-Flamp1, which can accurately report levels of cAMP in living cells.

The SIGNAL Phase 2 study of pepinemab immunotherapy in early Huntington’s disease (HD) did not meet its coprimary clinical efficacy endpoints, but had a favorable safety profile and showed a significant treatment-related reduction in caudate brain atrophy and reversal of the characteristic decline in brain metabolic activity that is typical of HD progression.

Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), can progress to liver fibrosis. Here, the authors develop a peripheral 5HT_2A antagonist for the treatment of MASLD and MASH.

Acrasis kona is a solitary amoeba which builds a multicellular fruiting body, despite being a distant relative of other multicellular eukaryotes. This study analysed A. kona’s genome and developmental transcriptomes and find extensive similarity with common developmental pathways of other multicellular taxa.

While the organelle genome is commonly considered to be a single circular DNA molecule, extensive variation exists. Here, the authors report multipartite minicircular genomes in red algae and indicate an origin driven by recombination due to loss of DNA replication, recombination, and repair genes.

Infection with any one of the four dengue virus serotypes can cause disease that ranges from a mild febrile illness through to haemorrhagic fever and shock. This Primer outlines the epidemiology, pathogenesis, diagnosis and management of dengue infection.

Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.

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.

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.

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.

Whole-genome sequence analysis of 172 indigenous African cattle from 16 breeds identifies 16 loci linked to environmental adaptations among crossbred animals, including a highly divergent locus in African taurine cattle putatively linked to trypanotolerance.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

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.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

Xia et al. provide a method for deep learning of 3D facial images to predict biological age with an accuracy of ±2.8 yr from chronological age and its correlation with lifestyle indicators and blood transcriptomic age.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.