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Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

Direct interaction between the small GTPase Rab7a and the cation channel TPC2 has been reported but the functional regulation is less clear. Here, the authors show that Rab7a enhances the activity of TPC2 to promote melanoma progression through the GSK3β/β-Catenin/MITF axis.

Current approaches to detect allograft damages non-invasively are limited and do not differentiate between cellular mechanisms. Here, the authors show that the composition of cell-free DNA in blood samples can reveal cellular causes of allograft injury after liver transplant.

The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.

The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.

Montserrat Garcia-Closas and colleagues report a meta-analysis of three genome-wide association studies for estrogen receptor (ER)-negative breast cancer, including 4,193 ER-negative breast cancer cases and 35,194 controls, with replication using the iCOGS custom genotyping array in 40 studies, including 6,514 cases and 41,455 controls. They identify four loci associated with ER-negative but not ER-positive breast cancer.

Jayavelu, Samaha et al., apply machine learning models on hospital admission data, including antibody titers and viral load, to identify patients at high risk for Long COVID. Low antibody levels, high viral loads, chronic diseases, and female sex are key predictors, supporting early, targeted interventions.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

Whole-genome sequencing of more than 2,000 colorectal carcinoma samples provides a highly detailed view of the genomic landscape of this cancer and identifies new driver mutations.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

In a phase 1 trial, patients with pancreatic ductal adenocarcinoma who were treated with surgery and bespoke neoantigen mRNA vaccines combined with anti-PD-L1 and chemotherapy exhibited marked long-lived persistence of neoantigen-specific CD8⁺ T cell clones, which correlated with prolonged recurrence-free survival at a 3.2-year follow-up.

Evolutionarily conserved gene modules mediate neurodegenerative dementia in a variety of mouse models and in postmortem brain tissue from patients.

Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

A multi-ancestry genome-wide gene–smoking interaction study identifies 13 new loci associated with serum lipids.

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.

Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis-regulatory elements, particularly in vascular endothelial cells.

Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.

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.

Whole-genome sequence data for 108 individuals representing 28 language groups across Australia and five language groups for Papua New Guinea suggests that Aboriginal Australians and Papuans diverged from Eurasian populations approximately 60–100 thousand years ago, following a single out-of-Africa dispersal and subsequent admixture with archaic populations.

Genome-wide association analyses of two oral glucose tolerance test-derived measures of postprandial insulin resistance discover ten new loci. Functional characterization identifies nine candidate genes implicated in the regulation of GLUT4.

Angelman syndrome is a neurodevelopmental disorder caused by the deletion of a single gene. Here, researchers discovered a small molecule that could be delivered peripherally to activate a dormant copy of the gene throughout the brain, providing a potential treatment opportunity.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

Rheumatoid arthritis patients respond differently to anti-TNF treatment. Using community-based challenge, the authors show that currently available data does not reveal meaningful genetic predictors of response to anti-TNF therapy, thus confirming clinical observations.

G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.

Green hydrogen production via water electrolysis requires a low-cost solution to provide efficient catalysts. Here, the authors report an industrially scalable method for synthesizing NiFe layered double hydroxide at room temperature and atmospheric pressure, enhancing alkaline electrolysis.

Super-resolution imaging of whole mammalian cells is often hampered by high fluorescence background and slow acquisition speeds. Here, the authors present soTILT3D, a platform based on a steerable single-objective light sheet with nanoprinted microfluidics for flexible whole-cell, multi-target, 3D single-molecule imaging.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-β signalling which could promote the anti-tumour response.

Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Chirality plays a central role in molecular recognition, and systems combining multiple, interdependent chiral elements can offer enhanced enantioselectivity. Here, the authors show that covalent tethering of a dihydroxy-pillar[5]arene with meso-2,11-dibromododecanedioate affords diastereomeric pseudo[1]catenanes that combine three stereogenic features, enabling enantioselective chiroptical sensing.

Luo et al. conducted a multinational cohort study examining the trends in mortality risk among 1,272,495 individuals with incident dementia between 2000 and 2018. There is a consistent decline in mortality risk following dementia diagnosis in the UK, Canada, South Korea, Taiwan and Hong Kong, indicating potential advancements in dementia care.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

Lung adenocarcinoma is often curable when diagnosed at an early stage, but a subsection of patients will progress. Here, the authors use multi-omics profiling to show that gene expression data can predict clinical outcome.

Lenardo and colleagues identify a new human genetic disease, GISELL, whereby ceramide lipid homeostasis is disrupted, thereby altering T cell longevity. Deficiency of GTPase of the immunity-associated protein 5 (GIMAP5) in patients leads to cellular senescence, immunodeficiency and early mortality.

How arable farming affects soil fungal biogeography is poorly understood. Here, the authors find that prevalent fungal groups become more abundant, whereas rare groups become fewer or absent in arable lands across Europe, suggesting a biotic homogenization due to arable farming.

Magneto-ionics are a promising approach for controlling magnetism via electric fields, but most studies have been limited to thin films, rather than the nanostructures that would form the basis of a magneto-ionic memory unit. Here, Spasojevic et al demonstrate magneto-ionic control over transitions among paramagnetic, single domain, and vortex states in an array of nanodots.

Ancient DNA analyses reveal that Viking Age migrations from Scandinavia resulted in differential influxes of ancestry to different parts of Europe, and the increased presence of non-local ancestry within Scandinavia.

Cardiomyocyte transplantation after heart attack improves contractile function in monkeys.

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.

A catalogue of the vascular flora of New Guinea indicates that this island is the most floristically diverse in the world, and that 68% of the species identified are endemic to New Guinea.

A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2 diabetes.

Z. Liu, Y. Liu and Z. Yu et al. discovered a subtype of valve interstitial cells underneath the valve endothelial cells sensing unidirectional flow. These cells express high levels of APOE, which is responsible for JAG1–NOTCH2-mediated fetal elastogenesis.

A 1.5 °C climate target implies total emissions of carbon from the start of 2017 must fall below 195 to 205 PgC, according to an observationally constrained very large ensemble of simulations with an efficient Earth system model.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.