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Semaglutide-induced weight loss is shown to depend on G_s-coupled signalling in GLP1R-expressing hindbrain neurons, with a critical role for cAMP in mediating neuronal activation and downstream effects.

Bioinformatic, structural and functional analyses characterize Streptomyces antiquus insecticidal protein (SAIP) as a diphtheria toxin homologue that is lethal to insect cells and targets the Flower protein as a receptor

The transcription factor TOX is well studied in the context of CD8⁺ T cell functionality, but less is known about its role in CD4⁺ T cells. Here the authors show that TOX drives T_H1 cell differentiation and effector function that can drive antitumor immunity and autoimmune pathology.

Global analysis of obesity trends from 1980 to 2024 in 200 countries and territories using data from 4,050 population-based studies reveals that framing obesity as a single global epidemic masks the highly varied dynamics across countries and age groups.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

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.

Cheng et al., use non-infectious stable viral replicon cell lines in genome-wide CRISPR KO screens across diverse viral pathogens to identify host factors specifically involved in the intracellular stages of viral replication.

Circulating tumor cell (CTC) clusters are much more likely to produce viable metastasis than single CTCs. Here the authors find that the transmembrane protein Plexin-B2 (PLXNB2) mediates homotypic and heterotypic CTC cluster formation, driving lung metastasis in breast cancer mouse models.

The excitatory neuron diversity and specialized connectivity of complex, multilayered mammalian neocortex are driven by mammalian-specific cis-regulatory elements bound by ZBTB18, deletion of which disrupts gene expression and results in projection patterns resembling those of non-mammalian brains.

Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.

LRFN2 in cone photoreceptors is vital for building the OFF pathway. Here authors report this cell-adhesion molecule stabilizes contacts with OFF bipolar cells, clusters their ionotropic receptors, and is required for negative-contrast vision and predator-detection behaviors.

Melanoma cells lacking SOX10 are tolerant to MAPK inhibition (MAPKi) due to elevated TAZ-driven TEAD signaling. Here, the authors develop two inhibitors of TEAD, capable of resensitising SOX10 knockout melanoma cells to MAPKi and offering a strategy to overcome drug tolerance and improve treatment response.

Here the authors show thatMETTL9 enzyme sustains neural development in vertebrates by maintaining the secretory pathway, mainly independently of METTL9 catalytic activity. METTL9 loss in cells leads to Golgi fragmentation.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

Cytidine nucleotide triphosphate (CTP) is a key precursor involved in the metabolism of DNA, RNA and phospholipids. In this study, the authors examine the physiological consequences of CTP synthase (Ctps) 1 and 2 deletion in vivo and demonstrate that Ctps1 protects mice from fatal autoimmunity.

Fibrosis is the final common pathway in chronic kidney disease and a potential target for therapeutic interventions. Here, the authors use intravital imaging to show that pyrimidinergic calcium signaling links tubular injury to fibroblast activation, and that blocking this pathway reduces fibrosis

Fucosylation of host glycoproteins is revealed to sensitize cells to cholera intoxication while fucosylation of host glycolipids is protective. The glycosyltransferases encoded by B3GALT5 and B3GNT5 are identified as key regulators of this phenomenon.

Simon, Bugos and colleagues report the design and characterization of monospecific and bispecific synthetic chimeric T cell receptors, conferring increased antigen sensitivity and antitumor activity in B cell malignancies and multiple myeloma models.

The orphan enzyme phosphotriesterase-related (PTER) is identified as a mammalian N-acetyltaurine hydrolase that has roles in regulating body weight and energy balance.

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

Savan and colleagues show that distinct isoforms of the RNA-binding protein ZAP function as an antiviral restriction factor or as an interferon-resolution factor, based on differences in their intracellular localization.

The epigenetic mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) are not fully elucidated. Here, the authors reveal a druggable super-enhancer-mediated RNA-binding protein cascade that supports PDAC growth through enhanced mRNA translation.

The Src-family kinase Lyn plays multiple roles in myeloid and B cell development; thus, conventional or cell-type specific genomic deletion of Lyn does not allow clear functional readouts regarding specific mature B cell functions. Here the authors establish a mouse model in which Lyn is acutely deleted in a Tamoxifen inducible manner in B cells and find that Lyn plays a role in the anergy of DNA reactive Ars/A1 B cells via providing continuous inhibitory signalling.

Rapid methods to identify antigen-specific T cells are essential for developing targeted immunotherapies. Here the authors present a high-throughput MHC class II single-chain trimer platform for the comprehensive profiling of CD4⁺ T cells, enabling the rapid identification and characterization of virus- and tumour-specific T cell receptors (TCR) at single-cell resolution.

Here, the authors elucidate TMPRSS2 protease recognition of the SARS-CoV-2 spike S₂′ cleavage site, revealing the molecular basis of activation of membrane fusion, and show that antibodies recognizing the S₂′ site or TMPRSS2 block viral entry by interfering with TMPRSS2 access.

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.

Hodgson, Huang, Lang et al. show that TDP-43 limits ribonucleoprotein particle condensation into paraspeckles in a concentration- and polymerization-dependent manner. They also link paraspeckle condensation to stress response and neuroprotection.

This study highlights that IFITM3 deficiency lowers the minimum infectious dose of influenza virus, enhances adaptation of influenza viruses to a new host species, and broadly increases infection of human cells by avian and swine influenza viruses.

The tumor suppressor proteins DAXX and ATRX are frequently mutated in cancers with alternative lengthening of telomeres (ALT). This study shows that DAXX-ATRX regulates p53 chromatin accessibility and DNA damage response and that disruption of this pathway is critical for ALT cell survival.

Kaposi’s sarcoma-associated herpesvirus changes mitochondrial architecture via vBcl-2 interaction with a host NDP kinase, which triggers mitochondrial fission and inhibition of MAVS allowing for virus production.

Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

Although IFN-γ is known to regulate T cell function and expansion during virus-specific responses, its impact on T cells with varying avidity for antigen remains unclear. Here, the authors demonstrate that IFN-γ promotes the expansion of low-avidity CD8⁺ T cells during the effector phase, but favours those with high avidity in the memory pool.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

Many viral vaccine antigen candidates are transmembrane glycoproteins, and their development requires methods which allow their biophysical characterization. Here authors present an optimized nanodisc assembly platform which provides reproducible, scalable, and accurate replication of the vaccine candidates for detailed analysis.

USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.

Most advanced triple-negative breast cancers remain resistant to immunotherapy. Here, the authors discover that RIPK1-driven necroptosis in both tumor and stromal compartments is essential for effective immunogenic cell death-based therapy and immune checkpoint blockade.

HSC mutations lead to diverse clonal hematopoiesis outcomes. This study shows how epigenetic traits can predispose clones for dominance. Sox4 increases sensitivity to Tet2 KO, offering insights into variable phenotypes despite identical mutations.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

Zhu et al show that LRRK2 kinase promotes invagination of the plasma membrane to create ‘reservoirs’, which dynamically store or release excess membrane. Salmonella can exploit these membrane reservoirs during invasion of host cells by controlling the activity of LRRK2.

Cancer cell-derived small extracellular vesicles bind to therapeutic nanoparticles leading them from tumours to the liver for degradation. This mechanism is another barrier for the development of efficient nanoparticle-based cancer therapies.

Endothelial Sirtuin1 downregulation in metabolic disorders causes vascular dysfunction and inflammation. Here, the authors show that deficiency of endothelial Sirtuin1, while having deleterious effects on the vasculature, stimulates skeletal muscle insulin sensitivity and improves glucose disposal.

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.

A distinct population of CD4 T cells resides in specific regions of the steady-state brain, and these T cells are programmed in the periphery by the microbiome to coordinate adaptive behaviour.

Three BRAF inhibitors are used to treat melanoma and colorectal cancer. Here, the authors demonstrate that these drugs bind and activate the protein kinase GCN2, a previously unappreciated off-target effect that may modulate tumour cell responses.

The mitochondrial phosphatase PPTC7 has previously been linked to the maintenance of mitochondrial content, but the mechanisms underlying this phenotype remain unclear. Here, the authors demonstrate that loss of Pptc7 results in metabolic defects and further suggest that PPTC7 is a regulator of receptor-mediated mitophagy.

Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.

Romero-Becerra et al. report that stress kinases p38γ and p38δ are activated in ventricles of old mice and in arrhythmogenic conditions, and they demonstrate that p38γ/δ -driven phosphorylation of RyR2 and SAP97 is a trigger for ventricular fibrillation.