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Base editors (BEs) enable precise base substitutions but are limited by their large size. Here, the authors engineer a split BE system utilizing coiled-coil heterodimers (CC-BE) and demonstrate that CC-BEs maintain or even enhance efficiency, enabling gene therapy applications via dual AAV.

Crohn’s disease is associated with disturbances in the B-cell compartment and secreted antibodies. Here, the authors reveal impaired colonic dimeric IgA responses in patients with Crohn’s disease and verify this phenotype in murine models, demonstrating that mitochondrial dysfunction drives defective mucosal humoral immunity.

Grain chalkiness is an undesirable trait that severely compromises rice quality. Here, the authors report the cloning of an E3 ubiquitin ligase encoding gene Chalk9 and reveal its crucial role in regulating grain chalkiness through mediating the ubiquitination-dependent degradation of OsEBP89.

Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

In vivo base editing of a causative mutation that leads to the neurodevelopmental disorder Snijders Blok–Campeau syndrome restores protein dosage and ameliorates molecular and behavioural deficits in a humanized mouse model of the condition.

Here the authors report NiGa₂O_4–x(OH)_y for light-driven CO₂ hydrogenation to methanol. The surface Lewis acid–base pairs and -OH groups act as conduits for H^- /H⁺ transport to active sites, enhancing photocatalytic methanol production.

Endosomal sequestration of lipid-based nanoparticles is a barrier to delivery of nucleic acids. Here the authors test an array of cholesterol variants and perform in-depth investigation of nanoparticle shape, internal structure and intracellular trafficking.

Ubiquitin chains direct post-ER membrane proteins toward different degradation routes. Here, the authors show that K63 chains promote lysosomal sorting, whereas K48 chains trigger “CUTUP”, a protein shearing pathway mediated by two ubiquitin-dependent proteases, Ddi1 and Rbd2, and the proteasome.

Taniuchi and colleagues show that differential phosphorylation of the terminal Y residue in Runx proteins connect MHC restriction with the helper versus cytotoxic T cell lineage choice.

Zhang, Huang, Wang, Long et al. report that NAT10 enhances serine uptake and biosynthesis in an ac4C-dependent mechanism, thereby promoting stemness and progression in acute myeloid leukaemia.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

Huang, Rigau and colleagues observe major changes in how DNA is organized in early germ cells before they start developing into sperm or eggs. These results show that germline removes structural ‘memory’ of DNA folding to start fresh for the next generation.

Maurice et al. examine how cytokines regulate antigen-independent activation of memory CD8⁺ T cells. They show that IL-4 signaling changes the quality of the bystander T cell response by antagonizing IL-18 sensing and subsequent IFNγ production, but increasing granzyme B expression without changing perforin, thereby limiting bystander-mediated protection.

Drug-controlled DROP-CARs enable reversible extracellular control of CAR T cell function via human-derived protein switches that modulate cell–cell interactions and support dual-antigen targeting as well as logic-gated signaling.

Self-DNA has been implicated in the activation of cGAS/STING/IFN-I responses in autoimmunity and inflammatory diseases. Here the authors show that macrophage uses a process termed ‘nucleocytosis’ to extract nuclear DNA from lysosome-impaired, dying target cells, thereby activating downstream cGAS-STING signaling and IFN-I production.

Insights into regulatory T cell biology are accelerating therapeutic innovation in cancer immunotherapy, autoimmune diseases and transplant rejection.

Sabatino and colleagues examine expanded CD8⁺ T cell clonotypes from a small cohort of multiple sclerosis patients. They identified several cognate peptide epitopes that derive from Epstein–Barr virus, suggesting EBV reactivation may drive pathogenesis in these patients.

Mucosal administration of a multivalent, adjuvanted vaccine against Clostridioides difficile promoted bacterial clearance and protected against morbidity, mortality, tissue damage and recurrence in mice.

Wang, Zheng, Qian, Pan, Tian et al. characterize the crosstalk between peritumoural visceral adipose tissue and colorectal tumour microenvironment and report an immune escape mechanism, which may be potentially targeted for improved immunotherapy.

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDegs—are identified to inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs prime apo-IDO1 ubiquitination and subsequent degradation using its native proteolytic pathway.

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 ZFTA–RELA fusion, an oncogene for ependymomas, promotes the production of itaconate, and its dependence on this metabolite represents a new therapeutic target for this cancer.

Antigen presentation in skull bone marrow by hematopoietic stem and progenitor cells induces myelopoiesis and generates CD4⁺ regulatory T cells in a mouse model of ependymoma, promoting immune tolerance. Treatment with anti-GM-CSF antibody has antitumor effects that are augmented by immunotherapy.

The authors show how Vγ1⁺ γδ T cells produce IL-4 to drive early CD8⁺ T cell and dendritic cell responses to malaria infection in mice.

A human spinal cord organoid model can replicate two different types of spinal cord injury and can be used as an in vitro system to evaluate therapeutics and inflammatory reactions to treatments.

Here they demonstrate a therapeutic intervention elevating levels of CYP450-derived lipids to control the expansion of intermediate monocytes in tissue and peripheral blood, presenting a first in class therapeutic approach for treating chronic inflammatory disease.

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

Post-transcriptional regulation of mRNA translation was explored using Ribo-STAMP and single-cell RNA sequencing to reveal cell-type-specific and isoform-specific translation patterns across hippocampal neuronal and non-neuronal cell types, highlighting functional differences between CA1 and CA3.

A follow-up analysis of a clinical trial that evaluated anti-PD-1 therapy in patients with cancer who are living with HIV provides mechanistic insights into transcriptomic, cellular and cytokine changes related to immune checkpoint inhibitor treatment and identifies a signature associated with clinical response.

Here, the authors use a mouse model of multiple sclerosis to show that CD38⁺Foxp3⁺ T_reg cells persist in postinflammatory CNS tissues and are needed for maintaining immune homeostasis. These localized stress-tolerant T_reg cells have developed mechanisms to exploit the limited availability of IL-2 in this tissue.

The Neurospora circadian clock keeps time through a negative feedback loop involving a protein complex of FRQ bound to FRH. Here, the authors show that slow, stochastic phosphorylation of these proteins dissociates and activates them via two precisely timed switches.

Functional studies of O-GlcNAcylation have often focused on individual modifications. Now, a systems-level approach has identified simultaneous O-GlcNAcylation events that coordinate cellular activities and tissue-specific functions.

Phosphorylation-dephosphorylation and ubiquitination tune TCR signaling to avoid self-reactivity. Kim and colleagues show that acetylation also modulates TCR signaling.

Cryo-electron microscopy structures of three large ornate natural bacterial RNA molecules reveal their quaternary structures and intra- and intermolecular interactions that stabilize them.

Here they show that the adhesion GPCR Gpr126/Adgrg6 regulates trabeculation during heart development. Its N-terminal fragment is required for maintaining cell adhesion and compact wall integrity while its C-terminal fragment is essential to provide trabecular identity.

ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

Eosinophils enhance granuloma-mediated control of persistent Salmonella infection in mice through CCL11-driven recruitment and MBP-dependent modulation of macrophage polarization and bacterial clearance.

In a phase 1 trial, personalized mRNA vaccines tailored to individual tumour mutations in triple-negative breast cancer induced robust, long-lasting T cell responses and improved prognosis.

Using a deep generative model, CellBender models and denoises droplet-based single-cell data and improves multiple downstream analyses.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

Rapid immune activation requires tight control of mRNA stability in CD8⁺ T cells. Here, the authors show that a compositive RNA motif – m⁶A sites positioned next to AU-rich elements - marks mRNAs for rapid decay during activation, revealing a coordinated mechanism that shapes T-cell immunity.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

Large-scale computational and in vitro analyses identify commensal type III secretion systems and substrates in the human gut microbiome that can interact with human proteins to modulate immune pathways.

This study provides a comprehensive profile of human fetal midbrain development and its comparison with lab-grown midbrain cultures. These findings demonstrate that midbrain organoids recapitulate fetal developmental stages while capturing essential spatial and molecular characteristics, relevant to dopamine-related disorders.

Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

This study uncovers genetic links between plant roots and their microbiome in Brassica napus, identifying microbe-associated loci and a beneficial bacterium, Sphingopyxis, that promotes nitrogen uptake.

Evolutionarily related ‘proto-point’ centromeres providing resolution to the evolutionary origins of point centromeres are identified in yeast, and comparison shows they evolved in an ancestor with retrotransposon-rich centromeres and that long-terminal-repeat retrotransposons are the genetic substrate.

Langstein-Skora, Schmid, Huth et al. propose that intrinsically disordered region functionality can be driven by the interplay between linear binding motifs and contextual chemical characteristics such as charge and hydrophobicity.