Biology subjects

Arrieta, M.

Publications and source records attributed to Arrieta, M..

4 recordsLinked to original sources

bioRxiv2025

Endothelin Signaling via EDNRB receptor Reduces Proliferation and Promotes Proneural-to-Mesenchymal Transition in Gliomas

Diffuse gliomas are incurable primary brain tumors encompassing three histo-molecular subtypes: glioblastomas (GB), astrocytomas, and oligodendrogliomas. The latter two harbor IDH1 mutations and exhibit slower progression than glioblastomas. Diffuse gliomas are composed of highly plastic tumor cells capable of transitioning between astrocyte-like, oligodendrocyte-like, progenitor-like, and mesenchymal-like states, driven by genetic alterations and microenvironmental cues. The proneural-to-mesenchymal transition (PMT), associated with increased malignancy, is notably influenced by cytokines in the tumor microenvironment. Endothelin cytokines (ET-1, ET-2, ET-3), primarily secreted by vascular cells, regulate not only vascular tone but also astrocyte and neural stem cell proliferation via the G-protein-coupled receptors EDNRA and EDNRB. Prior studies using serum-cultured glioma lines suggested pro-proliferative effects of endothelins; however, such models poorly recapitulate the in vivo glioma context. In this study, we comprehensively revisited endothelin signaling - covering receptor expression, regulation, downstream pathways, and cellular responses-using eleven serum-free, patient-derived glioma lines (glioblastomas, IDH-wt and IDH-mutant oligodendrogliomas and astrocytomas), along with primary tumor samples. Multi-omics and electrophysiological analyses revealed EDNRB as the predominant receptor, enriched in astrocyte-like cells, upregulated by BMPs or growth factor withdrawal, and downregulated by interferons, IL-6 cytokines, endothelins, and Hippo/YAP activation. In contrast, EDNRA was expressed by a perivascular tumor subpopulation and induced by Notch signaling in glioblastomas but not in IDH1-mutant cells. Functionally, endothelins reduced proliferation across all models while promoting migration and PMT. Mechanistically, EDNRB activation increased intracellular Ca{superscript 2} and activated ERK, STAT3, and apamin-sensitive SK2/SK3 potassium channels. These findings identify endothelin signaling as an important regulator of glioma cell plasticity and behavior. HighlightsO_LIEDNRB is the predominant endothelin receptor expressed in glioma cells, with a small subset of tumor cells expressing EDNRA in close proximity to blood vessels C_LIO_LIEndothelin signaling reduces proliferation while promoting cell migration and Proneural-to-Mesenchymal transition C_LIO_LIEndothelin activates downstream Ca2+, K+, ERK, and STAT3 signaling pathways C_LIO_LIEDNRB expression is both positively and negatively regulated by inflammatory cytokines and the Hippo/YAP1 pathway, whereas EDNRA is upregulated by Notch signaling and hypoxia C_LI

cancer biology↗

bioRxiv2025

Targeting Pseudomonas aeruginosa Ventilator-associated pneumonia with a non-antibiotic and biolfilm-disrupting Live Biotherapeutic: Preclinical Safety and Efficacy study

Background.Ventilator-associated pneumonia (VAP) is the second most common hospital-acquired infection and is associated with high morbidity and mortality. The insertion of the endotracheal tube (ETT) compromises the hosts bronchial defenses and facilitates the formation of microbial biofilms and VAP. Although antibiotics remain the cornerstone treatment, their efficacy is often compromised by poor biofilm penetration and the prevalence of multidrug-resistant bacteria. This reveals the need to develop novel non-antibiotic therapeutic strategies. We engineered a non-pathogenic strain of the pulmonary bacteria Mycoplasma pneumoniae CV2 to express anti-biofilm and bactericidal enzymes (VAP platform). The therapeutic effect was validated in a murine model of Pseudomonas aeruginosa infection and ex vivo in ETTs of patients with P. aeruginosa-induced VAP. Methods.We evaluated the safety of an improved version of CV2 (CV8, Mycochassis) in a miniature pig model, and its efficacy with the VAP therapeutic platform (CV8_VAP) in a piglet model of P. aeruginosa-induced VAP. CV8_VAP was administered via intralobe instillation or nebulization. We assessed the platforms ability to degrade biofilms formed on ETTs in vivo and its impact on the airway microbiota. We evaluated bacterial load in the lungs, inflammatory responses, histopathological and the clinical outcomes to provide a comprehensive characterization of therapeutic efficacy and safety. Findings.VAP platform reduced biofilm thickness and P. aeruginosa load in ETTs and lungs, with the nebulized route showing enhanced efficacy. CV8_VAP contributed on microbiome diversity restoration. Inflammatory markers in the lung were markedly decreased, suggesting a local immunomodulatory effect. Interpretation.These findings support that CV8_VAP as a promising, non-antibiotic therapeutic strategy for treating VAP caused by P. aeruginosa. Funding.The project that gave rise to these results has received funding from "La Caixa" Foundation (HR18-00058), and the European Research Council under the European Unions Horizon 2020 research and innovation program (670216).

synthetic biology↗

bioRxiv2023

The RAD51 paralogue HvXRCC2 regulates meiosis and recombination in barley

Using a positional candidate-gene approach we show that semi-sterile desynaptic8 mutants are associated with deletions in or complete knockout of the barley homolog of XRCC2 (X-Ray Repair Cross Complementing 2). In barley XRCC2 mutants, the initial meiotic progression is normal, albeit with a small delay in initiation, with completion of synapsis. However, the absence of HvXRCC2 subsequently leads to a dramatic reduction in the number of crossovers, chromosome mis-segregation, and infertility, suggesting that HvXRCC2 plays a major role in recombination. This mutant phenotype is congruent with that reported in mammalian studies but contrasts with the XRCC2 mutant in Arabidopsis which is fertile, exhibits normal chromosome pairing and correct chromosome segregation, and is associated with an increased rate of crossovers. This indicates that the XRCC2 mutant phenotype in Arabidopsis is not representative of all plants and that XRCC2 is not a good candidate for the modulation of recombination in barley. HighlightThe mutants of the barley homolog of XRCC2 exhibit delays in replication leading to defective meiosis, altered RAD51 orthologue behaviour, and significant reduction in the number of crossovers as in canonical mammalian XRCC2 mutants but unlike those in Arabidopsis.

plant biology↗

bioRxiv2020

Time-resolved transcriptome of barley anthers and meiocytes reveals robust and largely stable gene expression changes at meiosis entry

In flowering plants, successful germinal cell development and meiotic recombination depend upon a combination of environmental and genetic factors. To gain insights into this specialised reproductive development programme we used short- and long-read RNA-sequencing (RNA-seq) to study the temporal dynamics of transcript abundance in immuno-cytologically staged barley (Hordeum vulgare) anthers and meiocytes. We show that the most significant transcriptional changes occur at the transition from pre-meiosis to leptotene-zygotene, which is followed by largely stable transcript abundance throughout prophase I. Our analysis reveals that the developing anthers and meiocytes are enriched in long non-coding RNAs (lncRNAs) and that entry to meiosis is characterized by their robust and significant down regulation. Intriguingly, only 24% of a collection of putative meiotic gene orthologues showed differential transcript abundance in at least one stage or tissue comparison. Changes in the abundance of numerous transcription factors, representatives of the small RNA processing machinery, and post-translational modification pathways highlight the complexity of the regulatory networks involved. These developmental, time-resolved, and dynamic transcriptomes increase our understanding of anther and meiocyte development and will help guide future research. One sentence summaryAnalysis of RNA-seq data from meiotically staged barley anthers and meiocytes highlights the role of lncRNAs within a complex network of transcriptional and post-transcriptional regulation accompanied by a hiatus in differential gene expression during prophase I. The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: Robbie Waugh (robbie.waugh@hutton.ac.uk)

developmental biology↗