Search

EDI048 is a gastrointestinal-targeted Cryptosporidium PI(4)K inhibitor that undergoes a predictable metabolism and limits systemic exposure without compromising its anti-parasitic activity.

Here a Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I) redox sequence is revealed in copper-catalysed aryl iodide coupling, capturing intermediate species and redefining the mechanistic understanding of the reaction.

Ewing sarcoma (ES) is driven by the oncogenic fusion-protein EWSR1::FLI1. Here the authors identify that a galactosyltransferase C1GALT1 stabilizes Smoothened protein to activate Hedgehog signaling and promote EWSR1::FLI1 transcription in ES cells, which could be therapeutically targeted by an anti-fungal drug itraconazole that inhibits C1GALT1.

Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context.

The mechanisms that impact tumorigenesis during aging are incompletely understood. Here Shuldiner et al. show that in mice, aging represses KRAS-driven lung tumorigenesis and dampens the impact of inactivating many tumor suppressor genes, which may contribute to the deceleration in cancer incidence with extreme age in humans.

ANKLE1 senses DNA tension and negative supercoiling, enhancing cleavage of stretched, supercoiled DNA to resolve chromatin bridges, highlighting its unique mechanosensitive role in maintaining genome stability during cell division.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Clear cell renal cell carcinoma (ccRCC) bears the hallmark loss of VHL but remains incurable. Here, the authors identify the SLC1A1 dicarboxylic amino acid transporter as an actionable, oncogenic, HIF-independent, metabolic dependency in VHL-deficient ccRCCs.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

A 15-year prospective cohort study found that during times of social unrest in Hong Kong, people experienced more conflicts with family and friends and this coincided with the use of social media—these factors were also associated with higher levels of depression.

The mechanisms of intratumoral subtype heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, the authors analyse PDAC tumours and preclinical models using multi-omics and imaging; they demonstrate that AP1 dichotomy influences tumor plasticity, heterogeneity, and immune response, with potential therapeutic implications.

Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth muscle dysfunction syndrome.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Small RNAs such as snaR-A (small NF90-associated RNA isoform A) may contribute to cancer-related phenotypes. Here the authors find that snaR-A interacts with mRNA splicing factors in subnuclear foci and causes splicing defects in mRNA subpopulations, which is associated with increased cell proliferation, and poor outcomes in cancer patients.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

The authors show that the CD4 mimetic CJF-III-288 stabilizes HIV-1 Env in an asymmetric “open” State-3 conformation, guiding anti-CoRBS antibodies to boost ADCC against infected cells and delay viral rebound in vivo, underscoring therapeutic promise.

Many premalignant colorectal polyps in familial adenomatous polyposis arise polyclonally rather than from a single mutated cell, showing diverse early evolutionary trajectories that frequently occur without clonal APC or KRAS driver events.

Somatic mutations in blood cells (CHIP) are linked to diseases like heart disease, but the mechanisms are unclear. Here, the authors show that different CHIP driver genes alter unique sets of plasma proteins, some of which are validated in mouse models.

Scale-invariant magnetic anisotropy in RuCl₃ has been revealed through measurements of its magnetotropic coefficient, providing evidence for a high degree of exchange frustration that favours the formation of a spin liquid state.

The existing ENCODE registry of candidate human and mouse cis-regulatory elements is expanded with the addition of new ENCODE data, integrating new functional data as well as new cell and tissue types.

In a large multinational cohort study, maternal, gestational or pregestational diabetes was associated with only a small-to-moderate risk of ADHD in offspring, contrary to previous estimates that showed stronger effect sizes, attributing the differences in findings to confounding by shared genetic and familial factors.

Standard approaches for identifying pleiotropic genetic variants may lead to spurious results. Here the authors present a new statistical method and show that it uncovers five genes linked to metabolites in METSIM participants, which were previously undetected by existing methods.

When a superconductor is in contact with a normal metal, Cooper pairs from the superconductor ‘leak’ into the metal, causing local superconductivity. When in contact with a ferromagnet, however, Cooper pairs do not stray very far. Therefore, the discovery that a ferromagnetic nanowire goes completely superconducting when placed between two superconducting electrodes is surprising indeed.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

The understudied lipid kinase PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced autophagic flux impairment, suppressing viral protein degradation. PIP4K2C inhibition is a candidate strategy to combat emerging viruses.

Quantifying the degree of correlation required to drive a Mott insulator transition is a crucial aspect in understanding and manipulating correlated electrons. Here, the authors introduce a thallium-based cuprate system and use resonant inelastic X-ray scattering, combined with Hubbard-Heisenberg modeling, to establish a universal relation between electron interactions and magnon dispersion, suggesting optimal superconductivity at intermediate correlation strength.

Structures of the growing peptide chain on and off the ribosome reveal that the ribosome destabilizes the unfolded nascent chain, promoting the formation of partially folded intermediate states.

Embryonal tumour with multilayered rosettes (ETMR) is a rare and aggressive paediatric brain tumour. Here, the authors analyse intratumour heterogeneity and the tumour microenvironment in ETMR using single-cell and spatial transcriptomics, in vitro cultures, and a 3D forebrain organoid model, finding important aspects – such as the communication with pericytes – for ETMR development and response to therapy.

The efficacy of CAR-T cells against solid tumors is still limited by immunosuppressive factors. Here, the authors show that engineering of CAR T cells with A1R enhances their efficacy against solid tumors in vitro and in vivo.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

The identification of broken symmetry states in underdoped cuprate superconductors via quantum oscillation measurements remains inconclusive. Here, Chan et al. report the reconstructed Fermi surface of HgBa₂CuO_4+δ comprises only a single pocket indicating a biaxial charge-density-wave order within each CuO₂plane.

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.

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

This study reveals that during human gait development, neuromotor modules (muscle synergies) and limb biomechanical properties co-evolve toward bilateral symmetry, which enhances locomotor stability. By combining longitudinal EMG, kinematic, and neuromusculoskeletal modeling data from infants, adults, and elders, the authors demonstrate that functional symmetrization of these modules underlies efficient and stable gait control across the lifespan.

Reboldi and colleagues show that high-cholesterol diets influence IgA secretion. Cholesterol-derived metabolites act on plasma cell GPR183 receptors to alter cell positioning of IgA⁺ plasma cells within the lamina propria and suppress antibody responses to intestinal pathogens.

In the cuprates, antiferromagnetic correlations might be the cause of the pseudogap phenomenon. Here the authors use neutron scattering on the tetragonal cuprate HgBa₂CuO_4+δrevealing commensurate antiferromagnetic excitations as a signature of the pseudogap state.

Surgical sterilization alone cannot control global stray and feral domestic cat populations. Here, Godin et al. show that a single-dose injectable female sterilant administered before puberty safely and completely prevents pregnancy after maturity.

Although ice plays a crucial role in shaping our ecosphere, its microstructures formed by freezing water remain unclear. Here, the authors employ cryogenic liquid-cell TEM to gain atomic-level insights into ice defects frozen from liquid water.

In genome-wide association meta-analysis, it is often difficult to find an independent dataset of sufficient size to replicate associations. Here, the authors have developed MAMBA to calculate the probability of replicability based on consistency between datasets within the meta-analysis.

A single dose of an adeno-associated virus vector encoding an HIV-1 broadly neutralizing antibody given shortly after birth results in persistent antibody expression and protection from infection in rhesus macaque models of human HIV-1 transmission through breastfeeding and sexual intercourse.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Confocal microscopy enables high-resolution, high-plex 3D cyclic immunofluorescence of 30- to 50-µm-thick tissue sections. The approach allows for rich phenotypic assessments of intact cells and intercellular interactions with subcellular resolution.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

An analysis of cell-type diversity in brain samples from a variety of mammalian species, both during development and in adult animals, reveals that the TAC3 initial class of striatal interneurons is conserved across placental mammals and is homologous to Th striatal interneurons in rodents.