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DNA damage burden and inadequate repair in CUX2⁺ cortical layer 2/3 excitatory neurons contributes to selective vulnerability in neuroinflammatory injury.

The genetically encoded voltage indicators JEDI3sub and JEDI3hyp enhance monitoring of subthreshold neuronal activity in the awake mouse brain using a variety of two-photon microscopy techniques.

In vivo adenine base editing corrects a common Pex1 pathogenic allele in mouse models of Zellweger spectrum disorder, rescuing liver pathology, fatty acid levels, body weight and peroxisome function.

Neurotrophic factor Nerve Growth Factor (NGF) is involved in bladder physiopathology. Here the authors report that mast-cell derived NGF sustains the pro-tumoral functions of ILC2s in bladder cancer (BC), showing that selective targeting of the NGF receptor TrkA improves survival and response to immune checkpoint blockade in BC models.

The transcription factor ATF4 is shown to regulate double-stranded DNA repair within vulnerable CUX2⁺ upper-layer 2/3 cortical neurons, enabling their survival during development.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

Following its internalisation, active endosomal GLP-1R engages with VAPB and SPHKAP at ER membrane contact sites to assemble a local cAMP/PKA condensate for the control of MICOS complex phosphorylation, mitochondrial remodelling and β-cell function.

The factors contributing to the onset of Barrett’s esophagus, a precancerous stage of the highly lethal esophageal cancer, remain elusive. Here, the authors identify inherited mutations in the VSIG10L gene as a key etiologic determinant affecting esophageal biology and facilitating the development of Barrett’s esophagus.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

The anterior cingulate cortex encodes affective pain behaviours modulated by opioids; targeting opioid-sensitive neurons through a new chemogenetic gene therapy replicates the analgesic effects of morphine, providing precise chronic pain relief without affecting sensory detection.

Leveraging pythons as an extreme model of feeding and fasting behaviour, this study uncovers para-tyramine-O-sulphate as a conserved postprandial metabolite that links nutrient intake to energy balance by activating hypothalamic neurons and suppressing food intake in pythons and mice.

The cytochrome bc₁ oxidase of Mycobacterium tuberculosis is a potential target in the fight against tuberculosis. Here, the authors evaluate the potential of cytochrome bc₁ inhibitors as partner drugs in tuberculosis treatment regimens.

In this work, the authors reveal that three non-ribosomal peptides targeting a common protein quality system differentially alter the Mycobacterium tuberculosis proteome, providing new insight into the molecular mechanisms behind their antimycobacterial activity.

Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here the authors described a role for the TGFβ superfamily protein GDF3 in the regulation of lipolysis, glucose tolerance and glycemic variability in mice.

Cupedo and colleagues show that neutrophils promote a tumor-supportive microenvironment via a self-amplifying interaction between neutrophils and bone marrow stromal cells. This scenario creates a promyeloma niche that is difficult to treat despite targeted therapies directed at the myeloma cells.

Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of Na_V1.7.

Electrochemical reduction of carbon dioxide to more useful products is an industrially important process. Here, the authors report a nanoporous silver catalyst that efficiently and selectively reduces carbon dioxide due to its high surface area and intrinsically high activity.

Lee et al. identify SHMT and one-carbon metabolism as a metabolic vulnerability conferred by LKB1 and KEAP1 loss in KRAS-mutant lung cancer.

CRISPR–Cas9 screening identifies CLCC1 as a factor that increases neutral lipid flux to prevent hepatic steatosis and promotes nuclear pore complex assembly by promoting membrane bending and fusion.

TNF is an important driver of many inflammatory diseases. Zhou et al. demonstrate ILC3 production of the growth factor HB-EGF protects against TNF-mediated injury of the gut epithelium in inflammatory bowel disease.

Sadhu et al. identify and functionally validate ferredoxin-1 (FDX1) as a determinant of cholesterol metabolism and cardiovascular risk in Asian populations.

Psilocybin may help treat chronic pain, possibly due to direct analgesic effects. Here, authors tested psilocybin on acute and chronic pain in three mouse models of pain and found minimal effects on sensory, affective, or functional pain measures.

Precise and efficient CRISPR genome editing requires specialized delivery systems. Here, the authors develop Coomassie lipidoids that deliver purified adenine base editors into retinal tissues, making it possible to achieve robust genome editing with a defined, non-viral nanomedicine.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Directed evolution is a process of mutation and artificial selection to breed biomolecules with new or improved activity. Here the authors develop a directed evolution platform (PROTein Evolution Using Selection; PROTEUS) that enables the generation of proteins with enhanced or novel activities within a mammalian context.

Hamidzada et al. show that human pluripotent stem cell–derived macrophages are educated into a tissue-resident fate within human cardiac microtissues, enhancing its function via efferocytic ingestion of stressed cardiomyocyte cargo.

Disordered rock-salt positive electrodes are promising for nickel- and cobalt-free lithium-ion batteries. Here, the authors demonstrate a synthesis method that yields highly crystalline, sub-200 nm dispersed single particles, enabling improved electrochemical cycling stability.

It remains unknown why only some sickle cell disease (SCD) patients develop lung thrombosis. Here, the authors show that an extracellular vesicle-dependent mechanism prevents lung thrombosis in SCD and how a CD39 polymorphism impairs this protection to promote lung thrombosis in subset of patients.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Tubulin conservation presents a challenge to understanding microtubules’ diverse functions in eukaryotes. Here, the authors characterize the structures of P. falciparum microtubules to show how evolutionary adaptation of tubulin modulates the material properties of the cytoskeleton.

Anxiety-like behaviour in mice, as a result of psychological stress, is shown to be mediated by GDF15 release in response to adipose tissue lipolysis.

The development of a new genetic tool to selectively deplete or modify group 2 innate lymphoid cells (ILC2s) addresses the debate regarding the non-redundant functions of this immune cell type.

In vivo gene editing hinges on identifying an ideal delivery vehicle from numerous candidates. Here, authors establish the GFP-on mouse model capable of translating successful adenine base editing to a fluorescent readout thus enabling the rapid evaluation of genome editing delivery vehicles.

Actin filament polymerization is crucial for building sound-sensitive stereocilia in the cochlea. Here, the authors show that a myosin motor can nucleate actin filaments, revealing a mechanism for stereocilia growth and hereditary hearing loss.

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.

The adhesion of meningococci to endothelial cells relies on type IV pili, which induce the formation of long tubular structures on the host cell membrane. Here, the authors show that the tubular structures accumulate and trap host membrane-associated proteins, which facilitates their interaction with bacterial ligands and the activation of adhesion and signaling receptors.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

The anti-tuberculosis drug bedaquiline targets ATP synthase, but there is controversy about the precise mechanisms leading to mycobacterial death. Here, the authors show that the apparent ‘uncoupling’ activity of bedaquiline is, in fact, a redirection of electron flux to the CydAB oxidase, induced to mitigate the deleterious consequences of ATP synthase inhibition.

Circular RNAs are exported from the nucleus by Ran-GTP, exportin-2 and IGF2BP1 in a mechanism analogous to protein export rather than mRNA export.

Dietary protein influences metabolic health and ageing. Here Solon-Biet et al. show that, rather than having a direct toxic effect, dietary branched-chain amino acids (BCAAs) appear to induce hyperphagia, owing to an imbalance between BCAAs and other amino acids, which reduces lifespan as a consequence of obesity.

Perovskite nanocrystal LEDs featuring long-chain ammonium cations offer improved stability and efficiency.

A study using mouse models of food allergy shows that allergic sensitization drives antigen-specific avoidance behaviour mediated by immunoglobulin E antibodies and mast cells.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

Ultra-high-capacity Li–air batteries have low Coulombic efficiency and degrade during re-charging, resulting in a poor cycle life. Redox mediators enable improvements but only at undesirably high potentials. The origin of this high potential and the impact of purported reactive intermediates has now been elucidated by resolving the charging mechanism using Marcus theory.

Dietary inulin fibre alters the composition and metabolism of gut microbiota, resulting in elevated levels of bile acids that subsequently trigger mucosal type 2 inflammation characterized by eosinophilia, with clinical implications for allergy and anti-helminth defence.

Utilizing single-cell RNA sequencing, the authors here find that IL1B gene expression in peripheral blood monocytes associates with smaller HIV-1 reservoir size in people treated during acute infection, suggesting IL1B may be a natural latency reversing factor decreasing the reservoir via NF-κB activation.

Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Bio-inspired assembly of mesoscale materials presents a unique challenge due to complex machinery or labor-intensive processing involved in engineering. Barber et al. report chiral filaments self-assembled into free-standing, anisotropic bundles through pre-programmed, light-mediated structural deformations.