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RNA polymerase II (RNAPII) is typically considered as an essential enzyme. Here the authors show that natural degradation of RNAPII drives chromatin reorganization in growing oocytes, preparing the chromatin for genome activation after fertilization.

CRISPR–Cas9 in Streptococcus pyogenes prevents self-cleavage through abasic CRISPR RNA oxidations that suppress off-target activity. Inspired by a natural mechanism, Gu and Kim et al. designed chemically modified abasic guide RNAs to enhance genome-editing specificity of SpCas9, suppressing off-target toxicity in in vivo applications.

Here, the authors show that 2’-O-methylated RNA fragments from ribosomal RNA naturally block TLR7 and TLR8, helping to avoid avoid harmful self-RNA detection and autoimmunity.

Da Pra, Boriati and colleagues show that physiological glucocorticoids suppress growth-factor-induced cardiomyocyte regeneration by inhibiting ERK signaling and propose glucocorticoid receptor antagonism as a strategy to enhance their protective and regenerative effects.

The authors find that distinct radial glia subtypes generate and support midbrain dopaminergic neurons, revealing specialized function and lineage relationships among the diverse cell types that shape dopamine neuron development.

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.

Population-level analyses and in vitro experiments show that a specific genetic variant of cyclin D3 inhibits the growth of the malaria-causing parasite Plasmodium falciparum in erythrocytes, and suggest that its high frequency in Sardinia was driven by past endemic malaria.

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.

Long-term, continuous tracking of biomarkers, such as inflammatory cytokines, is key for disease prevention. By leveraging the natural high selectivity and sensitivity of keratinocyte stem cells, the authors genetically engineered cells to express fluorescent proteins in response to specific biomarkers.

Bång-Rudenstam et al. report that the acidic tumour microenvironment facilitates the assembly of chondroitin sulfate-enriched glycocalyx to disrupt lipid scavenging and prevent ferroptosis, thereby providing an adaptive mechanism upon tumour acidosis.

Dai and colleagues implicate defective dendritic cell migration in impaired vaccine responses in aged mice. Oral delivery of yeast-derived nanoparticles promotes migration of dendritic cells from the gut to lymph nodes and restores vaccine efficacy in aged mice.

Heparan sulfate proteoglycans facilitate the assembly of clusters of glycoRNAs and cell surface RNA-binding proteins, which negatively modulate VEGF-A signalling and angiogenesis.

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.

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.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

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.

In vitro methods for thymic organoid cultures are useful to examine requirements for T cell development and for generating large numbers of cells for therapeutic purposes. Here the authors use human induced pluripotent stem cells, differentiate these into thymic epithelial organoid cultures and utilise haematopoietic progenitors to show development of T cells in vitro.

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.

The Akt-mTOR axis influences cell activation, differentiation and metabolism. Jordan and colleagues show that thymic and inducible T_H17 cells exhibit different requirements for mTORC1 and mTORC2 as well as Akt isoforms.

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.

A protein biomarker, the NOTCH3 extracellular domain, identifies individuals with idiopathic pulmonary hypertension, correlates with disease progression, improves mortality risk prediction and provides a readily implementable, noninvasive blood test for this disease.

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.

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

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.

Here, the authors show that early-life high-fat/high-sugar diet induces sex-specific alterations in adult feeding behavior, hypothalamic transcriptome and blood metabolome, with Bifidobacterium longum and prebiotic FOS + GOS administration restoring these effects via distinct mechanisms, highlighting their therapeutic potential.

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.

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 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.

A 3D soft electronic mesh allows high-resolution electrical recording and stimulation across the full surface of neural organoids, enabling long-term studies, drug testing and optogenetic control without compromising their viability owing to its porous design.

Myeloid derived suppressor cells (MDSC) use different metabolic mechanisms to adapt to the tumour microenvironment. Here the authors show that 6-phosphogluconate dehydrogenase (6PGD) is important for MSDC function and that blockade of 6PGD impaired MDSC function and suppresses tumour growth leading to metabolic and functional changes in the MDSC and a more pro-inflammatory phenotype.

Avian influenza jumped from wild birds into dairy cattle. Here, the authors report that two mutations in the viral polymerase helped the virus to quickly adapt to cattle. Mutations increased the polymerase activity and made the virus better at replicating in human cells.

Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

The meningeal compartment communicates with the brain to modulate homeostatic functions. Here, the authors demonstrate that natural killer (NK) cells and innate lymphoid cells (ILC) 1 shape synaptic neuronal transmission and affect mouse behavior.

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.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.

Mouse models show that lymphoedema caused by impaired lymphatic drainage is ameliorated by removal of cholesterol deposits, which promotes the regeneration of lymphatic vessels.

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.

Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.

Hepatocyte organoids derived directly from human tissue enable long-term hepatocyte expansion and can be combined with portal mesenchyme and cholangiocyte organoids to form a donor-specific periportal liver assembloid system.

Mouse models demonstrate that vagal sensory neurons transmit signals from lung adenocarcinoma to the brain, increasing sympathetic efferent activity in the tumour microenvironment and thereby creating a immunologically permissive environment for tumour growth.

Mapping of the neutrophil compartment using single-cell transcriptional data from multiple physiological and patological states reveals its organizational architecture and how cell state dynamics and trajectories vary during health, inflammation and cancer.

I-motifs are non-canonical secondary DNA structures that form dynamically in certain C-rich DNA regions. Here, the authors show that PCBP1 binds and unfolds i-motifs in a protonation- and structure-dependent manner, controlling their formation during the cell cycle to maintain genomic stability.

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.

Robust protein synthesis by the ribosome is required for rapid cancer growth. Here authors present interdictors, small molecule inhibitors of protein synthesis with context-dependent activity that inhibit MYC-driven cancer cell growth in a mouse model.

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.

Recent work has revealed that dendritic cells (DCs) are more heterogeneous than previously thought, yet the functional roles of these newly described DC subsets remain unclear. Here, Li et al. find that in mice, TSLP from keratinocytes activates transitional DC-derived DC2 to promote GATA3⁺ regulatory T cells and mediate immunosuppression during inflammation and cancer.