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Articles publicats en revistes (Patologia i Terapèutica Experimental)

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/8283

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    Variability vs. phenotype: Multimodal analysis of Dravet syndrome brain organoids powered by deep learning
    (Elsevier, 2025-11-21) Lao, Oscar; Acosta, Sandra; Turpin, Isabel; Modrego, Adriana; Martí Sarrias, Andrea; Ortega Gascó, Alba; Haeb, Anna-Christina; García González, Laura; Soriano i Fradera, Jordi; Ruiz, Núria; Peñuelas Haro, Irene; Espinet, Elisa; Tornero, Daniel
    Dravet syndrome (DS) is a developmental epileptic encephalopathy (DEE) driven by pathogenic variants in the SCN1A gene. Brain organoids (BOs) have emerged as reliable models for neurodevelopmental genetic disorders, reproducing human brain developmental milestones and rising as a promising drug testing tool. Here, we determined the underlying molecular DS pathophysiology affecting neuronal connectivity, revealing an early onset excitatory-inhibitory imbalance in maturing DS organoid circuitry. However, neuronal circuitry modeling in BOs remains hampered by the notorious inter- and intra-organoid variability. Thus, leveraging deep learning (DL), we developed ImPheNet, a predictive tool grounded in BO live imaging datasets, to overcome the limitations of the intrinsic BOs variability. ImPheNet accurately classified healthy and DS phenotypes at early onset stages, revealing differences between genotypes and upon antiseizure drug exposure. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool to accelerate DEEs research and advance toward treatment discovery in a time- and cost-efficient manner.
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    Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3
    (Elsevier, 2024-01-04) Ruiz-Gabarre, Daniel; Vallés Saiz, Laura; Carnero-Espejo, Almudena; Ferrer, Isidro (Ferrer Abizanda); Hernández, Félix; Ávila, Jesús; García-Escudero, Vega; Garcia-Escudero, Ramon
    Background: Tau is a microtubule-binding protein encoded by the MAPT gene. Tau is essential for several physiological functions and associated with pathological processes, including Alzheimer's disease (AD). Six tau isoforms are typically described in the central nervous system, but current research paints a more diverse landscape and a more nuanced balance between isoforms. Recent work has described tau isoforms generated by intron 11 and intron 12 retention. This work adds to that evidence, proving the existence of MAPT transcripts retaining intron 3. Our aim is to demonstrate the existence of mature MAPT RNA species that retain intron 3 in human brain samples and to study its correlation with Alzheimer's disease across different regions. Methods: Initial evidence of intron-3-retaining MAPT species come from in silico analysis of RNA-seq databases. We further demonstrate the existence of these mature RNA species in a human neuroepithelioma cell line and human brain samples by quantitative PCR. We also use digital droplet PCR to demonstrate the existence of RNA species that retain either intron 3, intron 12 or both introns. Findings: Intron-3-retaining species are even more prominently present that intron-12-retaining ones. We show the presence of MAPT transcripts that retain both introns 3 and 12. These intron-retaining species are diminished in brain samples of patients with Alzheimer's disease with respect to individuals without dementia. Conversely, relative abundance of intron-3- or intron-12-retaining MAPT species with respect to double-retaining species as well as their percentage of expression with respect to total MAPT are increased in patients with Alzheimer's disease, especially in hippocampal samples. Among these TIR-MAPT species, TIR3+12 double truncation allows better classification potential of Alzheimer's disease samples. Moreover, we find a significant increase in intron-3- or intron-12-retaining species and its relative abundance with respect to double-retaining MAPT species in cerebellum in contrast to frontal lateral cortex and hippocampus in individuals with no signs of dementia. Interpretation: Intron retention constitutes a potential mechanism to generate Tau isoforms whose mature RNA expression levels correlate with Alzheimer's pathology showing its potential as a biomarker associated to the disease.
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    Thrombospondin-1 regulates synaptic transmission in hippocampal field CA2 and social behavior in mice
    (Elsevier, 2025-11-19) Leana-Sandoval, Gerardo; Madrid, Alexis; Extrémet, Johanna; Aso Pérez, Ester; Díaz-Alonso, Javier
    Thrombospondin 1 (TSP1) is a secreted extracellular matrix glycoprotein, which mediates cell-to-cell and cell-to-matrix interactions. In humans, mutations in THBS1, which encodes TSP1, are associated with neurodevelopmental disorders, but the underlying neurobiological mechanisms are unclear. TSP1 is secreted by astrocytes, and has been shown to promote synaptogenesis in vitro, but knowledge about its function in vivo is limited. In this study, we assessed TSP1's modulation of synaptic function and cognitive and emotional processes using TSP1 knockout mice. Deletion of TSP1 led to decreased perineuronal net density and strengthened synaptic transmission in hippocampal field CA2, but not CA1. Accordingly, TSP1 KO mice showed severely disrupted social interaction, as well as emotional alterations, but normal spatial memory. Collectively, our findings identify TSP1 as a crucial modulator of synaptic function in CA2 and social and emotional processes. Furthermore, our work delineates a mechanism linking altered TSP1 signaling with psychiatric conditions with altered social and emotional function.
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    Adenosine A2A receptor activation regulates Niemann-Pick C1 expression and localization in macrophages
    (MDPI, 2023-06-07) Skopál, Adrienn; Újlaki, Gyula; Gerencsér, Attila Tibor; Bankó, Csaba; Bacsó, Zsolt; Ciruela Alférez, Francisco; Virág, László; Haskó, György; Kókai, Endre
    Adenosine plays an important role in modulating immune cell function, particularly T cells and myeloid cells, such as macrophages and dendritic cells. Cell surface adenosine A2A receptors (A2AR) regulate the production of pro-inflammatory cytokines and chemokines, as well as the proliferation, differentiation, and migration of immune cells. In the present study, we expanded the A2AR interactome and provided evidence for the interaction between the receptor and the Niemann-Pick type C intracellular cholesterol transporter 1 (NPC1) protein. The NPC1 protein was identified to interact with the C-terminal tail of A2AR in RAW 264.7 and IPMФ cells by two independent and parallel proteomic approaches. The interaction between the NPC1 protein and the full-length A2AR was further validated in HEK-293 cells that permanently express the receptor and RAW264.7 cells that endogenously express A2AR. A2AR activation reduces the expression of NPC1 mRNA and protein density in LPS-activated mouse IPMФ cells. Additionally, stimulation of A2AR negatively regulates the cell surface expression of NPC1 in LPS-stimulated macrophages. Furthermore, stimulation of A2AR also altered the density of lysosome-associated membrane protein 2 (LAMP2) and early endosome antigen 1 (EEA1), two endosomal markers associated with the NPC1 protein. Collectively, these results suggested a putative A2AR-mediated regulation of NPC1 protein function in macrophages, potentially relevant for the Niemann-Pick type C disease when mutations in NPC1 protein result in the accumulation of cholesterol and other lipids in lysosomes.
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    Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies
    (Elsevier Masson SAS, 2025-01-01) Benítez García, Cristina; Martínez García, David; Kotev, Martin; Pérez Hernández, Marta; Westermaier, Yvonne; Díaz, Lucía; Korrodi-Gregório, Luis; Fontova, Pere; Torres, Ana Aurora; Pérez Tomás, Ricardo E.; García Valverde, María; Quesada, Roberto; Soliva, Robert; Soto Cerrato, Vanessa
    Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy. Therefore, we focused on identifying and validating a novel specific, directly binding survivin inhibitor for cancer treatment and tumor sensitization to conventional proapoptotic therapies. In this work, we conducted a structure-based high-throughput virtual screening at the survivin homodimerization domain. Asenapine Maleate (AM), an approved drug for central nervous system diseases, was identified as a direct binder of the survivin homodimerization domain and it significantly affected cell viability of lung, colon, and brain cancer cell lines. Direct interaction of AM to survivin protein was corroborated by surface plasmon resonance and a specific survivin protein decrease was observed in cancer cells, compared to other inhibitors of apoptosis proteins. Therapeutic in vivo studies showed an impairment of tumor growth in AM-treated mice. Finally, a synergistic anticancer effect was detected in vitro when combined with different conventional chemotherapies, and in vivo studies showed higher antitumor effects when combined with cisplatin. Altogether, our results identify AM as a specific direct binding inhibitor of survivin, showing anticancer properties in vitro and in vivo and sensitizing effects when combined with cisplatin, opening the possibility of repositioning this approved drug for cancer treatment.
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    Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503
    (Nature Publishing Group, 2025-10-06) Vidal Sabanés, Maria; Navaridas, Raúl; Egea, Joaquim; Encinas, Mario; Rodriguez Barrueco, Ruth; Silva, Jose M.; Matias-Guiu, Xavier, 1958-; Llobet Navas, David; Dolcet, Xavier; Bonifaci Cano, Núria
    Endometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGFβ-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGFβ stimulation. The miR-424(322)~503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)~503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)~503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)~503 knock-out mice. We demonstrate that loss of miR-424(322)~503 impairs proliferation of both wild type or Pten deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)~503 restores TGFβ-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo, Pten/miR-424(322)~503 knock-out mice exhibit reduced endometrial cancer progression compared to Pten deficient mice through a cell-autonomous mechanism.
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    Intraoperative brain mapping in multilingual patients: what do we know and where are we going?
    (MDPI, 2022-04-27) Martín Fernández, Jesús; Gabarrós, Andreu; Fernández Coello, Alejandro
    In this review, we evaluate the knowledge gained so far about the neural bases of multilingual language processing obtained mainly through imaging and electrical stimulation mapping (ESM). We attempt to answer some key questions about multilingualism in the light of recent literature evidence, such as the degree of anatomical-functional integration of two or more languages in a multilingual brain, how the age of L2-acquisition affects language organization in the human brain, or how the brain controls more than one language. Finally, we highlight the future trends in multilingual language mapping.
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    Beta-blocker treatment of patients with atrial fibrillation attenuates abnormal electrical activity induced by spontaneous calcium release
    (Elsevier Masson SAS, 2023-02-01) Jiménez Sábado, Verónica; Casabella-Ramón, Sergi; Llach, Anna; Gich, Ignasi; Casellas, Sandra; Ciruela Alférez, Francisco; Chen, S.R. Wayne; Guerra, José María; Ginel, Antonino; Benítez, Raul; Cinca, Juan; Tarifa, Carmen; Hove-Madsen, Leif
    Aims: Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because β-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with β-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI). Methods: The impact of treatment with commonly used β-blockers was analyzed in human atrial myocytes from 371 patients using patch-clamp technique, confocal calcium imaging or immunofluorescent labeling. Data were analyzed using multivariate regression analysis taking into account potentially confounding effects of relevant clinical factors RESULTS: The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with β-blockers did not affect ICa density in any group. By contrast, the ITI frequency was elevated in patients with either paroxysmal or chronic AF that did not receive treatment, and β-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that β-blocker treatment also reduced the calcium spark frequency in patients with AF to levels observed in those without AF. Furthermore, phosphorylation of the ryanodine receptor (RyR2) at Ser-2808 and phospholamban at Ser-16 was significantly lower in patients with AF that received β-blockers. Conclusion: Together, our findings demonstrate that β-blocker treatment may be of therapeutic utility to prevent spontaneous calcium release-induced atrial electrical activity; especially in patients with a history of paroxysmal AF displaying preserved ICa density.
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    Genetic adaptation and acquisition of macrolide resistance in haemophilus spp. during persistent respiratory tract colonization in chronic obstructive pulmonary disease (COPD) patients receiving long-term azithromycin treatment
    (American Society for Microbiology, 2022-12-08) Carrera Salinas, Anna; González-Díaz, Aaida; Ehrlich, Rachel L.; Berbel, Dàmaris; Tubau, Fe; Domínguez Luzón, Ma. Ángeles (María Ángeles); Pomares, Xavier; Garmendia, Junkal; Ardanuy Tisaire, María Carmen; Huertas, Daniel; Marín, Alicia; Montón, Conchita; Mell, Joshua Chang; Santos Pérez, Salud; Martí Martí, Sara
    Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones.
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    Photoswitching endogenous glutamate receptors in neural ensembles and single synapses in vivo
    (Elsevier, 2025-09-11) Garrido Charles, Aida; Bosch Pita, Miquel; Lee, Hyojung; Rovira, Xavier; Pittolo, Silvia; Llobet Berenguer, Artur, 1972-; Wong, Hovy Ho-Wai; Trapero, Ana; Matera, Carlo; Papotto, Claudio; Serra, Carme; Llebaria Soldevila, Amadeu; Soriano García, Eduardo; Sánchez-Vives, María Victoria; Holt, Christine E.; Gorostiza Langa, Pablo Ignacio
    Purpose: To interrogate animal physiology in vivo, there is a lack of non-genetic methods to control the activity of endogenous proteins with pharmacological and spatiotemporal precision. To address this need, we recently developed targeted covalent photoswitchable (TCP) compounds that enable the remote control of endogenous glutamate receptors (GluRs) using light. Methods: We combine the photopharmacological effector TCP9 with neuronal activity sensors to demonstrate all-optical reversible control of endogenous GluRs across multiple spatiotemporal scales in rat brain tissue ex vivo and in Xenopus tadpole brains in vivo. Findings: TCP9 allows photoactivation of neuronal ensembles, individual neurons, and single synapses in ex vivo tissue and in intact brain in vivo, which is challenging using optogenetics and neurotransmitter uncaging. TCP9 covalently targets AMPA and kainate receptors, maintaining their functionality and photoswitchability for extended periods (>8 h) after a single compound application. This allows tracking endogenous receptor physiology during synaptic plasticity events such as the reduction of functional AMPA receptors during long-term depression in hippocampal neurons. Conclusion: TCP9 is a unique non-invasive tool for durable labeling, reversible photoswitching, and functional tracking of native receptors in brain tissue without genetic manipulation.
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    CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness
    (Springer Nature, 2025-09-15) Romero Moya, Damià; Torralba-Sales, Eric; Calvo, Cristina; Marin-Bejar, Oskar; Magallon-Mosella, Maria; Distefano, Maximiliano; Pera, Joan; Castaño, Julio; De Giorgio, Francesca; González, Jessica; Iglesias, Arnau; Berenguer Balaguer, Clara; Schilling, Marcel; Plass, Mireya; Pasquali, Lorenzo; Català, Albert; Molina, Òscar; Wlodarski, Marcin W.; Bigas Salvans, Anna; Giorgetti, Alessandra
    GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34+ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.
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    Use of adenoviral vectors with a minimal cytomegalovirus promoter
    (Eaton Pub. Co.], 2018-09-24) Ferrer-Martínez, Andreu; García Martínez, Celia; Gómez Foix, Anna Maria
    E1-deleted recombinant adenoviruses 5 are widely used as gene vectors for basic and clinical research. Most adenoviral constructions bear an expression cassette inserted into the E1 region of their genome close to the 5′ end and include a heterologous promoter. The major immediate early human cytomegalovirus (hCMV) and the Rous sarcoma virus promoters, which have fairly high and consistent activity, are among the most extensively used. Nevertheless, expression of delivered protein from these promoters is often excessive, and weaker transcriptional activity would be desirable.
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    Editorial: Purinergic Signaling 2020: the State-of-The-Art commented by the members of the Italian Purine Club
    (Frontiers Media, 2021-09-14) Ciruela Alférez, Francisco; Fuxe, Kjell; Illes, Peter; Ulrich, Henning; Caciagli, Francesco
    The “purinergic signaling” term was coined in 1972 by Geoffrey Burnstock Burnstock et al. after demonstrating that adenosine 5’-triphosphate (ATP) is a transmitter in nonadrenergic, noncholinergic inhibitory nerves innervating the guinea-pig taenia coli (Burnstock et al., 1966). This signaling system, which is ubiquitously expressed in every organ and system of the body, comprises various ecto-, soluble and intracellularly localized enzymes, nucleoside transporters, and G protein-coupled and ligand-gated cation channel receptors. Through the purinergic signaling system cells can maintain basal adenine and guanine-based purines at certain steady-state levels, thereby contributing to preserve the purines-dependent cellular homeostasis.
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    Investigation of mobile genetic elements and their association with antibiotic resistance genes in clinical pathogens worldwide
    (Public Library of Science (PLoS), 2025-08-18) Johansson, Markus H.K.; Petersen, Thomas N.; Nag, Sidsel; Lagermann, Timmie M.R.; Birkedahl, Laura E.K.; Tafaj, Silva; Bradbury, Susan; Collignon, Peter; Daley, Denise; Dougnon, Victorien; Fabiyi, Kafayath; Coulibaly, Boubacar; Dembélé, Réné; Magloire, Natama; Ouindgueta, Isidore J.; Hossain, Zenat Z.; Begoum, Anowara; Donchev, Deyan; Diggle, Mathew; Turnbull, LeeAnn; Lévesque, Simon; Berlinger, Livia; Søgaard, Kristine K.; Diaz Guevara, Paula; Duarte, Carolina; Maikanti, Panagiota; Amlerova, Jana; Drevinek, Pavel; Tkadlec, Jan; Dilas, Milica; Kaasch, Achim; Westh, Henrik T.; Bachtarzi, Mohamed A.; Amhis, Wahiba; Salazar, Carolina E.S.; Villacis, José E.; Domínguez Luzón, Ma. Ángeles (María Ángeles); Berbel, Dàmaris; Duployez, Claire; Paluche, Maxime; Asante-Sefa, Solomon; Møller, Mie; Ip, Margaret; Mareković, Ivana; Pál-Sonnevend, Agnes; Cocuzza, Clementiza E.; Dambrauskiene, Asta; Macanze, Alexandre; Cossa, Anelsio; Mandomando, Inácio; Nwajiobi-Princewill, Philip; Okeke, Iruka N.; Kehinde, Aderemi O.; Adebiyi, Ini; Akintayo, Ifeoluwa; Popoola, Oluwafemi; Onipede, Anthony; Blomfeldt, Anita; Nyquist, Nora E.; Bocker, Kiri; Ussher, James; Ali, Amjad; Ullah, Nimat; Khan, Habibullah; Gustafson, Natalie W.; Jarrar, Ikhlas; Al-Hamad, Arif; Luvira, Viravarn; Paveenkittiporn, Wantana; Baran, Irmak; Mwansa, James C.L.; Sikakwa, Linda; Yamba, Kaunda; Aarestrup, Frank M.
    Objectives: Antimicrobial-resistant bacteria are a major global health threat. Mobile genetic elements (MGEs) have been crucial for spreading resistance to new bacterial species, including human pathogens. Understanding how MGEs promote resistance could be essential for prevention. Here we present an investigation of MGEs and their association with resistance genes in pathogenic bacteria collected from 59 diagnostic units during 2020, representing a snapshot of clinical infections from 35 counties worldwide. Methods: We analysed 3,095 whole-genome sequenced clinical bacterial isolates from over 100 species to study the relationship between resistance genes and MGEs. The mobiliome of Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Klebsiella pneumoniae were further examined for geographic differences, as these species were prevalent in all countries. Genes potentially mobilized by MGEs were identified by finding DNA segments containing MGEs and ARGs preserved in multiple species. Network analysis was used to investigate potential MGE interactions, host range, and transmission pathways. Results: The prevalence and diversity of MGEs and resistance genes varied among species, with E. coli and S. aureus carrying more diverse elements. MGE composition differed between bacterial lineages, indicating strong vertical inheritance. 102 MGEs associated with resistance were found in multiple species, and four of these elements seemed to be highly transmissible as they were found in different phyla. We identified 21 genomic regions containing resistance genes potentially mobilized by MGEs, highlighting their importance in transmitting genes to clinically significant bacteria. Conclusion: Resistance genes are spread through various MGEs, including plasmids and transposons. Our findings suggest that multiple factors influence MGE prevalence and their transposability, thereby shaping the MGE population and transmission pathways. Some MGEs have a wider host range, which could make them more important for mobilizing genes. We also identified 103 resistance genes potentially mobilised by MGEs, which could increase their transmissibility to unrelated bacteria.
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    TRESK background potassium channel regulates MrgprA3+ pruriceptor excitability, acute and chronic itch
    (Wolters Kluwer Health, 2025-03-06) Pallás, Irene; Llimós-Aubach, Júlia; Andrés-Bilbé, Alba; Pujol-Coma, Anna; Castellanos, Aida; Bahamonde, Maria Isabel; Anta i Vinyals, Josep Maria de; Soler Prat, Concepció; Comes i Beltrán, Núria; Callejo, Gerard; Gasull Casanova, Xavier
    A subset of peripheral sensory neurons expressing specific Mas-related G-protein-coupled receptors and transient receptor potential channels mediate pruritogen-induced chemical itch. However, the molecular mechanisms that regulate the excitability of these cells, and consequently itch sensation, are poorly understood. TWIK-related spinal cord K + channel (TRESK) is a background K + channel that modulates the resting membrane potential, action potential firing, and neuronal excitability, and it has been involved in somatosensation and pain transduction. Here, we demonstrate that this channel contributes to pruritic transduction and it is a potential target for treating chronic itch pathologies. TRESK channel coexpress with Mas-related G-protein-coupled receptor A3, MrgprC11 and MrgprD in mouse sensory neurons, and with MrgprX1 in human ones. Genetic ablation of TRESK enhances firing of MrgprA3-expressing pruriceptors and acute itch in response to intradermal injection of chloroquine, while the response to histamine, BAM8-22, or leukotriene C4 remains unaffected. TRESK deletion also exacerbates chronic itch in mouse models of allergic contact dermatitis, dry skin, and imiquimod-induced psoriasiform dermatitis, resulting in a significantly increased scratching behavior that develops earlier and is more robust. Moreover, pharmacologically enhancing TRESK function diminishes both acute and chronic itch in wild-type mice but not in TRESK knockout (KO) animals. In summary, our data indicate that TRESK plays a role in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators represents a promising antipruritic therapeutic approach that can be combined with other compounds for the treatment of nonhistaminergic itch, which currently lack adequate treatment options.
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    Photoswitchable diazocine derivative for adenosine A3 receptor activation in psoriasis
    (American Chemical Society, 2025-01-08) Tosh, Diliip K.; López-Cano, Marc; Scortichini, Mirko; Salmaso, Veronica; Ko, Tongil; Salort, Glòria; Filgaira Enri, Ingrid; Soler Prat, Concepció; Trauner, Dirk; Hernando, Jordi; Jacobson, Kenneth A.; Ciruela Alférez, Francisco
    Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A3 receptor (A3R) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5′-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive Z agonist form and a photoinduced, pharmacologically active E configuration. As a result, our photoswitchable agonist allowed the precise modulation of A3R function both in vitro and in vivo, which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for in vivo photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action.
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    LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson’s disease model
    (Springer Science and Business Media LLC, 2025-08-12) Blasco Agell, Lucas; Pons Espinal, Meritxell; Testa, Veronica; Roch, Gerard; Montero-Muñoz, Jara; Fernández Carasa, Irene; Baruffi, Valentina; Gonzalez-Sepulveda, Marta; Richaud-Patin, Yvonne; Jimenez, Senda; Cuadros, Thais; Cladera-Sastre, Joana M.; Compte, Joan; Manglano-Artuñedo, Zoe; Ventura, Salvador; Juan, Manel; Tolosa, Eduardo; Raya Chamorro, Ángel; Vila, Miquel; Consiglio, Antonella
    Parkinson's disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not alpha-synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglia's role in PD progression, and provides a model for testing therapeutic targets.
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    Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
    (Springer Nature, 2025-12-01) Kotmayer, Lili; Kozyra, Emilia; Kang, Guolian; Strahm, Brigitte; Yoshimi, Ayami; Sahoo, Sushree S.; Pastor, Victor B.; Attardi, Enrico; Voss, Rebecca; Vinci, Luca; Kaiser, Max; Dworzak, Michael N.; De Moerloose, Barbara; Sukova, Martina; Stary, Jan; Hasle, Henrik; Jahnukainen, Kirsi; Polychronopoulou, Sophia; Kállay, Krisztián; Smith, Owen P.; Malone, Andrea; Barzilai Birenboim, Shlomit; Masetti, Riccardo; Buechner, Jochen; Ussowicz, Marek; Kjöllerström, Paula; Bodova, Ivana; Kavcic, Marko; Català, Albert; Turkiewicz, Dominik; Schmugge, Markus; de Haas, Valerie; Okhomina, Victoria I.; Sotomayor, Cristian; Catalán, Paula; Wehr, Claudia; Salzer, Ulrich; Germing, Ulrich; Gattermann, Norbert; Bödör, Csaba; Gray, Nathan; Lewis, Sara; Shimamura, Akiko; Giorgetti, Alessandra; Erlacher, Miriam; Niemeyer, Charlotte M.; Wlodarski, Marcin W.
    GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.
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    Pirfenidone in post-COVID-19 pulmonary fibrosis (FIBRO-COVID): a phase 2 randomised clinical trial
    (European Respiratory Society, 2025-04-24) Bermudo-Peloche, Guadalupe; Del Rio, Belén; Vicens-Zygmunt, Vanesa; Bordas Martínez, Jaume; Hernández, Marta; Valenzuela, Claudia; Laporta, Rosalía; Rigual Bobillo, Juan; Portillo, Karina; Millán-Billi, Paloma; Balcells, Eva; Badenes Bonet, Diana; Bolivar, Santi; Rodríguez-Portal, José Antonio; López Ramirez, Cecilia; Tomás, Laura; Fernández de Roitegi, Koral; Sellarés Torres, Jacobo; Castillo Villegas, Diego; Gonzalez-Cabrera, Joaquín; Barril, Silvia; Gutiérrez Rodríguez, Yasmina; Caballero, Paloma; Alarcon, Javier; Peñafiel, Judith; Sanz-Santos, Jose; Blavia, Rosana; Caupena, Cristina; Segovia, Pilar; Santos-Pérez, Salud; Ferrer-Artola, Anna; Badia, Maria B.; Hereu Boher, Pilar; Fuentes Prado, Mireya; Montes Worboys, Ana; Franquet, Tomás; Luburich Hernaiz, Patricio; Molina Molina, María
    Background: Patients with severe COVID-19 may develop lung fibrosis. Pirfenidone is an anti-fibrotic drug approved for idiopathic pulmonary fibrosis. The efficacy and safety of pirfenidone in patients with fibrotic interstitial lung changes after recovery from severe COVID-19 pneumonia were evaluated. Methods: This was a phase 2, double-blind, placebo-controlled, Spanish multicentre clinical trial. Patients were randomised to receive pirfenidone or placebo (2:1) for 24 weeks. The primary end-point was the proportion of patients that improved, considered when percentage change in forced vital capacity (FVC) was ≥10% and/or any reduction in the fibrotic score on chest high-resolution computed tomography (HRCT). Secondary end-points included health-related quality of life (HRQoL), exercise capacity and drug safety profile. Results: From 119 eligible patients, 113 were randomised and 103 were analysed (pirfenidone n=69 and placebo n=34). Most patients were male (73.5%) and were receiving low-dose prednisone; mean age was 63.7 years and mean body mass index was 29 kg·m-2. The percentage of patients that improved was similar in the pirfenidone and placebo groups (79.7% versus 82.3%, respectively). The mean predicted FVC increased by 12.74±20.6% with pirfenidone and 4.35±22.3% with placebo (p=0.071), and the HRCT (%) fibrotic score decreased by 5.44±3.69% with pirfenidone and 2.57±2.59% with placebo (p=0.52). Clinically meaningful improvement in HRQoL was not statistically different (55.2% in the pirfenidone group and 39.4% in the placebo group). Exercise capacity, adverse events and hospitalisations were similar between groups. No deaths were reported. Conclusions: The overall improvements in lung function and HRCT fibrotic score after 6 months with pirfenidone were not significantly different than with placebo.
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    Long-lasting behavioral, molecular and functional connectivity alterations after chronic THC exposure during adolescence in mice
    (Elsevier BV, 2025-06-16) Gómez Acero, Laura; Varriano, Federico; Sánchez Fernández, Nuria; Ciruela Alférez, Francisco; Soria, Guadalupe; Aso Pérez, Ester
    Heavy and daily use of cannabis with high contents of Delta 9-tetrahydrocannabinol (THC) during adolescence is associated with an increased risk of developing psychotic disorders later in life. Here, we treated mice with THC during adolescence and found that this exposure impaired social interaction and increased vulnerability to develop sensorimotor gating deficiencies comparable to those previously described among heavy cannabis consumers. Importantly, we provide evidence on long-term cortico-striatal dysconnectivity induced by exposure to THC during adolescence and its correlation with impaired social interactions occurring later in adulthood. Moreover, we have observed long-lasting molecular alterations in key elements that regulate the mesolimbic dopaminergic system, namely on the balance between dopamine D2, adenosine A2A, and cannabinoid CB1 receptors in the striatum of treated mice. Together, these findings contribute to a better understanding of the neurobiological bases of the deleterious effects associated with cannabis abuse during adolescence.