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MAU2’s role in Cornelia de Lange syndrome was unclear. Here, the authors identify pathogenic MAU2 variants that disrupt NIPBL–MAU2 function, define MAU2‑specific episignatures, and show variable CdLS‑related phenotypes, supported by a Mau2 knockout mouse model.

Single-nucleus chromatin and RNA sequencing identifies epigenetic chromatin domains that confer vulnerability to paediatric brain tumours such as ependymomas, providing insight into the development of such tumours despite ‘quiet’ genomes.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

The DNA origami vaccine platform DoriVac is shown to support multiplexed nanoparticles carrying diverse antigens against emerging infectious diseases and variants.

Early-life exposure to allergens triggers a distinct local mode of dendritic cell activation in neonatal skin without requiring migration to lymph nodes, which shapes responses to allergens in later life.

Oncolytic viruses, including Zika virus, have been proposed as therapeutic option for glioblastoma (GBM) treatment, however, efficacy in patients remains suboptimal. Here, the authors show that expanding peripheral T cells with long-acting IL7 prior to intratumoral oncolytic treatment improves survival in GBM preclinical models.

Moral-Sanz, Fernández-Carrasco and colleagues identify senolytic properties of sea anemone-derived pore-forming toxins, with selectivity mediated by senescence-associated lipid profiles. An optimized senotoxin improves the efficacy of chemotherapy in mouse models.

Bacteria are able to covalently incorporate n:3 polyfluoroalkyl carboxylates into phosphatidylethanolamine and phosphatidylglycerol, two major components of bacterial lipid bilayers.

Integration of mosquito and non-human primate surveillance and viral metagenomics reveals yellow fever virus outbreak dynamics at an urban–forest interface in Brazil.

Preclinical studies indicate a synergistic effect of radiotherapy treatment (RT) and Immune checkpoint inhibitors (ICI) on tumor growth and metastasis. However, little is known about the immunomodulatory performance of different radioisotopes on the tumor microenvironment. Here, the authors employ alpha- versus beta-particle emitting radiopharmaceuticals in combination with dual ICI therapy and dissect mechanisms of in vivo immunomodulation and timing of ICI administration relative to RT, by comparing responses in immunogenic and non-immunogenic preclinical mouse models.

Longitudinal metatranscriptomics in a prospective cohort of 1,164 adults hospitalized for COVID-19 reveals that azithromycin offered no apparent anti-inflammatory benefit but enriched the respiratory microbiome with potential pathogens and antimicrobial resistance genes.

One of three back-to-back papers to show that dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance CAR T cell therapies for cancer.

Lipid nanoparticles incorporating a crosslinked ionizable lipid are shown to promote efficient endosomal escape of antigen mRNA and glycolysis stimulation in dendritic cells, to elicit robust vaccination against viruses and cancer.

Rhine et al. find that neuronal aging leads to widespread dysregulation of RNA biology, including mislocalization of splicing proteins like TDP-43, chronic cellular stress and reduced resiliency.

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.

Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

Insect venom can cause severe allergic reactions including anaphylaxis. Here, the authors report structural and functional evidence that nanobody-based inhibitors can limit the allergenic and toxic activity of the major honeybee venom allergen and that passive administration prevents anaphylaxis in vivo.

Sepsis is a heterogeneous inflammatory disease and it is believed treatment requires suitable stratification based on the underlying disease pathology and immunology. Here the authors show genetic variation in the regulatory elements of MTOR can impact neutrophil-T cell cross talk in the context of pneumonia associated sepsis, highlighting a genetic framework for targeted patient stratification.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Analysis of the somatic and transcriptomic profile of 123 acral melanoma samples from Mexican patients helps understand tumour origins and prognosis, and highlights the importance of including samples from diverse ancestries in cancer genomics studies.

Conventional type 1 dendritic cells (cDC1) can boost the precursor exhausted T cell population thought to be essential for efficacy of immune checkpoint therapy. Here the authors enhance this cellular network using Flt3L to expand cDC1s and then map the movement of T cells and DCs between tumors and lymph nodes.

Mitochondrial respiration provides reducing power to the electron transport chain (ETC), driving proton pumping and ATP synthesis required for T cell activation and differentiation. Here, the authors use alternative oxidase (AOX) as a mechanistic probe to bypass cytochrome c oxidase deficiency and thereby isolate the role of respiration and demonstrate that intact mitochondrial respiration is important for T cell proliferation, effector function, memory formation, and regulation of apoptotic and metabolic signaling pathways.

Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

The cell states and lineage connections underlying the progression from Barrett’s esophagus to esophageal adenocarcinoma remain unresolved. Here, the authors use single-cell lineage tracing and transcriptomics to analyse patient samples from the gastroesophageal junction and identify cellular relationships in the progression of Barrett’s esophagus to cancer.

Extracellular vesicles have been implicated in the transmission of pathogens from the arthropod to the human host. Here the authors show that tick-derived extracellular vesicles play a role in feeding and modulate the outcome of bacterial infection.

Synthetic fibril strain 1B is a pathogen that is capable of self-replication and inducing glial cytoplasmic inclusions in vivo in mice, and the structural features of 1B may underlie the pathology of individuals with multiple-system atrophy.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

In a phase 1 trial, intramuscular injection of synthetic plasmid DNA encoding monoclonal antibodies against SARS-CoV-2 was safe and well tolerated and did not elicit antidrug antibodies.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Here the authors report that colonoids from children with ulcerative colitis exhibit hypermetabolism and cellular stress primarily driven by lipid dysregulation. Pharmacological inhibition of PPAR-a, a transcriptional regulator of lipid metabolism, alleviates epithelial stress and inflammation.

There are currently no licensed vaccines to prevent Group A Streptococcus (GAS) infections. In this study, the authors evaluate the immune response and preclinical efficacy of a multicomponent mRNA lipid-nanoparticle vaccine against GAS.

The relevance of mitochondrial cysteine metabolism to ferroptosis is unknown. Here, Ward et al. show that mitochondrial Fe-S cluster synthesis persists under cysteine limitation via the catabolism of glutathione and at the expense of cell viability.

Intelectin-2 defends mucosal interfaces by crosslinking mucus and blocking microbial growth. This study reveals that mouse and human intelectin-2 recognizes galactose-rich glycans to bind and target diverse bacteria—uncovering a potent, dual-action lectin that shapes host–microbe balance.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

Analyses of clinical and genomic data from a cohort of 2,336 patients with pancreatic adenocarcinoma find that KRAS dosage gains are a hallmark of disease progression and are predictive of poor outcomes across different disease stages.

In this protocol, the authors present straightforward and efficient methods to genetically modify corals and study gene function throughout various life-history stages using CRISPR–Cas9-based mutagenesis.

High-content protein arrays were used to identify cysteine dioxygenase (CDO1) as a small-molecule glue target for the von Hippel–Lindau (VHL) E3 ubiquitin ligase and induces VHL-dependent proteasomal degradation of CDO1 in cells.

Injectable biomaterial vaccines designed to magnetically capture pathogen-associated molecular patterns protect mice and pigs against septic shock from lethal bacterial infections.

A multiancestry phenome-wide analysis of copy number variants in the UK Biobank genomes increases power to detect genetic associations with complex traits across human populations.

Components of the glycocalyx have been shown to impair immune cell functions, including of CAR-T cells. Here the authors show that CAR-T cell mediated cytotoxicity in pancreatic cancer models can be enhanced by incorporating non-signalling binding domains that target the glycocalyx.

ATP synthase powers cells by converting proton translocation into energy. Here, authors reveal distinct structural features of the P. aeruginosa ATP synthase that regulate activity and may serve as targets for new antimicrobial therapies.

In mice, prolonged consumption of a high-fat diet decreases interest in calorie-rich foods as a result of reduced neurotensin expression and signalling, which uncouples hedonic feeding behaviour linked to neurons projecting from lateral nucleus accumbens to ventral tegmental area.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer’s disease who have the APOE4 genotype.

Molecular glue degraders eliminate cellular proteins by promoting their interaction with E3 ubiquitin ligases. Here, the authors identify molecular glue degraders targeting the E3 ligase TRIM21 and synthesize a heterobifunctional degrader that recruits TRIM21 to degrade an engineered protein aggregate.

Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.

Cholera remains a significant public health burden in sub-Saharan Africa, but the mechanisms of continental and regional spread remain undefined. Here, the authors investigate recent patterns of spread using Vibrio cholerae genomic surveillance data collected by a consortium of seven African Union member states from 2019-2024.

Successful skeletal muscle regeneration involves a complex and finely tuned inter-cellular response. Here, by using spatial transcriptomics, the authors identify an intercellular communication axis between fibro-adipogenic progenitors and macrophages to enhance macrophage-mediated tissue repair.