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An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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.

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.

Despite extensive structural studies elucidating how antigens are anchored to antigen-presenting molecules and presented to T cells, little is known about the display mechanism of the lipid-antigen-presenting molecule CD1c. Here, by combining structural immunology, lipidomics, and biophysical analysis, the authors reveal that the CD1c binding cleft accommodates two different lipids, one of them with a bulky headgroup positioned sideways for display to T cells, rather than upwards, different from the conventional upright antigen-presentation mode

The authors synthesize bee assemblage data from 681 crop fields across three continents, finding that local pesticide hazards and decreasing adjacent semi-natural habitats both negatively affected wild bee abundance and species richness in crop fields, while pesticides also reduced functional diversity.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

High-resolution geospatial mapping found that the annual incidence of cholera shifted from western to central and eastern Africa between 2011 and 2020, with the latter regions more likely to report cholera in 2022–2023, reflecting instability in cholera burden patterns that can impact progress in disease control.

In this study, the authors describe SANA, a nitroalkene derivative of salicylate, as a potential activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue. Preclinical and clinical data from this paper also suggest that SANA improves glucose homeostasis and promotes weight loss in mice and humans.

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.

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.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

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.

Infection may induce multi-organ thrombosis, but the underlying inflammatory mechanism remains elusive. Here, using Salmonella Typhimurium infectious mouse model, the authors reveal organ specific and broad inflammatory events like TNF for thrombosis in liver and spleen.

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.

Zhang et al. show that Egr1 regulates transient senescence during neonatal heart regeneration and upon agrin-mediated cardiac repair in adult mice, acting downstream of the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts.

Spatial multi-omics analysis tools have lagged behind advancements in single-cell technologies. Here, authors introduce TACIT, a scalable tool for automated cell type and state deconvolution from spatial multi-omics datasets, improving accuracy and efficiency over existing methods.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

A comprehensive meta-analysis of global terrestrial and marine genetic diversity covering more than three decades of research demonstrates rapid loss of genetic diversity and identifies conservation interventions that could mitigate this process.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

Sharks and rays are vital coral reef species. This study shows that nearly two thirds (59%) of the 134 coral-reef associated species are threatened with extinction. The main cause of their decline is found to be overfishing, both targeted and unintentional, and extinction risk is greater for larger species found in nations with higher fishing pressure and weaker governance.

Rodin and Dou et al. characterized genome-wide somatic mutation in autistic and control brains, revealing that even unaffected individuals may possess dozens of brain somatic mutations and providing insight into the role of somatic mutation in autism.

Osimo et al. developed two models to predict the risk of treatment-resistant schizophrenia in patients with a first-episode psychosis using blood-based biomarkers and sociodemographic data routinely collected at psychosis onset in psychosis early intervention services in the United Kingdom. They used clozapine treatment as a proxy for treatment-resistant schizophrenia using data from 785 patients for model development and 1,110 patients for external validation.

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.

Offshore wind and wave energy may play a key role in the energy transition. Here, authors identify cost targets for these technologies to become cost effective and show how the grid’s installed capacity decreases, and generation and transmission change as offshore energy deployment increase.

Artificial intelligence holds great promise to improve diagnosis of numerous immune-related or infectious diseases. Here, the authors show that machine learning can be used to identify HIV-1 specific broad neutralising antibody.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

In a prespecified 3-year analysis of the KEN SHE trial, single-dose HPV vaccination was shown to be well tolerated and provided durable protection against cervical HPV infection in Kenyan women aged 15–20 years.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Whole-genome sequencing of lung cancer in never smokers identifies different copy number subtypes and shows a lack of tobacco smoking signatures, even in cases exposed to secondhand smoke.

Shakked et al. highlight the importance of cardiomyocytes’ redifferentiation after dedifferentiation and proliferation in cardiac repair and show that redifferentiation depends on negative feedback signaling and LATS1/2 Hippo pathway activity. Cardiomyocyte redifferentiation not only promotes the restoration of cardiac function but also protects against future insult.

The CRISPR–Cas9 system is widely studied for its role as a phage defence system and for gene editing applications, but its evolutionary origins are poorly understood. Here the authors use ancestral sequence reconstruction to determine the evolutionary history and ancient protein sequences of Streptococcus pyogenes Cas9 ancestors.

Quantitative multimodal 3D reconstruction of human pancreatic tissue at single-cell resolution reveals a high burden of multifocal, genetically heterogeneous pancreatic intraepithelial neoplasias in the normal adult pancreas.

Newly evolved Xanthomonas citri pv. malvacearum isolates triggers recent bacterial blight outbreaks in cotton. Here, the authors show that a recently evolved TALE, Tal7b, activates host susceptibility genes GhSWEET14a and GhSWEET14b rather than GhSWEET10 to confer pathogenicity in these new isolates.

Biocatalytic methods to access thioesters, such as acyl-coenzyme A, from carboxylic acids are underdeveloped. Now, it is shown that the adenylation domain of a carboxylic acid reductase enzyme can be exploited as a promiscuous thioester synthetase and combination with acyltransferases facilitates the synthesis of amides and peptide labelling.

The growth plate cartilage supports long bone growth. Here the authors identify FoxA2+ long term stem cells in the growth plate that are stratified with short term PTHrP+ cells, participate in production of hyaline cartilage, expand in response to trauma, and whose ablation impairs cartilage regeneration.

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.

The response to infectious and inflammatory challenges differs among people but the reasons for this are poorly understood. Here the authors explore the impact of variables such as age, sex, and the capacity for controlling inflammation and maintaining immunocompetence, linking this capacity to favourable health outcomes and lifespan.