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Distal gene regulation is increasingly recognised as a major contributor to complex trait variability. Here, the authors show that a heritable, biologically interpretable transcriptome signature driven by distal regulation predicts metabolic traits across mice and humans.

Monomethylation of histone H4 lysine 20 (H4K20me1) contributes to DNA replication but the mechanism is not well understood. Here, the authors identify a conserved tandem Tudor ___domain of BAHCC1 as a H4K20me1-specific reader, which promotes the recruitment of MCM complex to chromatin for efficient DNA replication.

PIEZO1 is critical in numerous physiological processes, but monitoring its activity and localization in cells can be challenging. Here, the authors present a chemogenetic platform to visualize endogenous human PIEZO1 localization and activity in native cellular conditions, expanding the knowledge on mechanotransduction across single cells and tissue organoids.

A red blood cell haemostatic mechanism induced by dying ECs functions independently of platelets and fibrin.

Exome sequencing of 851 trios from more than 2,500 individuals finds 187 genes with de novo mutations that contribute to meningomyelocele (spina bifida) and highlights critical pathways required for neural tube closure.

A novel covalent inhibitor, ISM3312, targets the main protease of multiple human coronaviruses, including drug-resistant strains, and shows broad antiviral activity. It offers a promising therapeutic strategy against current and future coronavirus threats.

Conditional cysteine restriction in mice causes substantial weight loss, exceeding that seen with essential amino acid restriction, by activating the integrated stress and oxidative stress responses, and by unexpectedly depleting coenzyme A, leading to metabolic inefficiency.

Nerve injury activates microglia to remove spinal synapses, disrupting spinal sensory processing and contributing to chronic pain. Blocking complement protein C1q preserves synapses, highlighting a potential therapeutic target for neuropathic pain.

The role of the immune system in tissue regeneration remains poorly understood. Here, in bone marrow transplantation and organoid culture models, T-cell-derived Interferon-γ is shown to promote STAT1-dependent intestinal stem cell c-MYC expression and epithelial regeneration.

Fidler et al. show that anti-IL-1β treatment of atherosclerotic Ldlr-null mice with clonal expansion of Tet2-null or Jak2^VF hematopoietic stem cells promotes the recruitment of fibroblast-like cells to the plaque fibrous cap, leading to cap thickening and increased plaque stability. Conversely, the removal of fibroblast-like cells during atherosclerosis progression results in reduced fibrous cap formation in mice receiving anti-IL-1β antibody treatment.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

Sialoglycan receptor binding promotes the D2 ___domain up conformation in the HKU1 coronavirus spike protein. Here the authors show that this conformational change is driven fundamentally by the full structuring of the canonical embecovirus binding site.

IL-27 promotes tumour control by preventing dysfunction and enhancing cytotoxicity of tumour-specific CD8⁺ T cells.

In response to acute thermal challenge, thermosensing glutamatergic neurons of the parabrachial nucleus in mouse brain activate tanycytes, which reduce the excitability of Flt1-expressing dopamine and agouti-related peptide-containing neurons, thus suppressing appetite.

Simultaneous inhibition of LSD1 and GSK3 kinase promotes cell differentiation, providing a therapeutic strategy for treating acute myeloid leukaemia.

Accelerated atherosclerosis in a mouse model of clonal haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β.

Mother's milk contains a number of protective factors, such as the anti-inflammatory enzyme PAFAH. Here, Duet al. show that the VLDL receptor protects nursing newborns from systemic inflammation by maintaining secretion of PAFAH from maternal macrophages into mother's milk.

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 large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

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.

A non-invasive in vivo positron emission tomography imaging approach detects inflammatory disease using various preclinical models.

Exposure to a novel experience can ‘reset’ connections between the hippocampus and prefrontal cortex in mice, allowing them to overcome an existing learned behaviour and to replace it with a new one.

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.

V-___domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.

Yang et al. identify and characterize distinct sugar- and fat-responsive neuronal populations in the dorsal hippocampus and their contribution to the development of obesity.

Caspase-7 cleaves and activates acid sphingomyelinase (ASM), which promotes the repair of gasdermin pores and thereby delays pore-driven lysis to allow other processes such as extrusion or apoptosis to occur before cell death.

Bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes alterations in local haemodynamic contrast.

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.

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.

Inhibition of haem synthesis is shown to lead to the accumulation of branched-chain amino acids in the brown adipose tissue of mice, which reduces UCP1 levels and impairs thermogenesis.

A sensor for oxytocin reveals mechanisms of oxytocin action with high spatiotemporal precision.