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Articles publicats en revistes (Biomedicina)

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    Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin's lymphoma and characterization of the loss of the target antigen. 
    (BMJ Publishing Group, 2024-12-18) Esquinas, Esperanza; Moreno-Sanz, Álvaro; Sandá, Víctor; Stodulski-Ciesla, Damian; Borregón, Jennifer; Peña-Blanque, Virginia; Fernández Calles, Javier; Fernandez-Fuentes, Narcís; Serrano-Lopez, Juana; Juan, Manel; Engel Rocamora, Pablo; Llamas-Sillero, Pilar; Solán-Blanco, Laura; Martin-Antonio, Beatriz
    Background: Infusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin's lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results. Methods: We designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen's expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)). Results: We found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19- relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen. Conclusions: Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.
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    Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington’s Disease
    (Elsevier, 2025-09-24) Sitjà Roqueta, Laia; Ngum, Neville M.; Zherebstov, Evgenii; Küçükerden, Melike; Givehchi, Maryam; Bova, Valentina; Delicata, Francis; Anaya Cubero, Elena; Santamaria, Enrique; Fernández Irigoyen, Joaquín; Conde-Berriozabal, Sara; Castañé, Anna; Sokolovski, Sergei; Rafailov, Edik; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959-; Dalkara, Deniz; Möglich, Andreas; Bykov,Alexander; Meglinski, Igor; Rheinallt Parri, Harri; Masana Nadal, Mercè
    Coordinated neuron-astrocyte interactions are crucial for synaptic plasticity and brain function. Cyclic adenosine monophosphate (cAMP) pathways have a key role in modulating plasticity and are disrupted in neurodegenerative diseases. Yet, the role of astrocytic cAMP remains unclear. We addressed this by expressing the photoactivatable adenylyl cyclase DdPAC in cortical astrocytes, enabling cAMP synthesis under red light stimulation. Using electrophysiological and comprehensive proteomic analyses, we determined its effects in wild-type mice. The modulation of astrocytic cAMP triggered long-term synaptic potentiation and rapidly induced the phosphorylation of proteins involved in synaptic transmission, including PKA. In Huntington's Disease (HD) models, DdPAC activation in cortical astrocytes differentially enhanced brain hemodynamics and induced motor learning, while specifically increasing grooming and impairing coordination in HD mice. Thus, we reveal a mechanism of astrocyte-driven plasticity mediated by cAMP elevation and underscore the alterations in astrocytic cAMP signaling associated with HD.
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    MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors
    (Springer Nature, 2025-10-31) Proaño Pérez, Elizabeth; Serrano Candelas, Eva, 1982-; Guerrero, Mario; Gómez Peregrina, David; Llorens, Carlos; Soriano, Beatriz; Gámez Valero, Ana; Herrero Lorenzo, Marina; Martí, Eulalia; Serrano, César; Martín Andorrà, Margarita
    The role of Microphthalmia-associated Transcription Factor (MITF) in gastrointestinal stromal tumors (GISTs) remains unclear, although previous studies suggest it contributes to tumor growth regulation. Previously, we demonstrated that MITF depletion reduces GIST cell proliferation and viability, accompanied by decreased expression of BCL-2 and CDK2. To elucidate the mechanisms underlying MITF function in GISTs, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) as well as RNA sequencing. Integrated analyses revealed that MITF directly regulates genes involved in lysosome biogenesis, vesicle trafficking, autophagy, and the mTOR signaling pathway. Transcriptomic profiling following MITF silencing further demonstrated enrichment of differentially expressed genes in PI3K/ mTOR signaling, with downstream effects on tumor growth and autophagy. We next examined the functional consequences of MITF loss on mTOR inhibition-induced autophagy and on extracellular vesicle (EV) content and secretion, given their known interplay in tumor progression. MITF depletion reduced LC3-II levels and impaired autophagy flux, confirming its role in regulating autophagy in GISTs. EV size and number remained unaffected; however, silencing MITF altered EV cargo and notably decreased KIT expression in both cells and EVs. As KIT-containing EVs have been implicated in GIST invasion, these findings suggest that MITF contributes to tumor progression through coordinated regulation of autophagy and EV-mediated signaling. Collectively, our results identify MITF as a key regulator of GIST biology, highlighting its potential as a therapeutic target to limit tumor growth and metastasis.
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    Obese Asthma Syndrome: Multiple Inflammatory Patterns and A Key Solution
    (Esmon Publicidad S.A., 2025-12-01) Bantulà, Marina; Picado Vallés, César; García, A.; Arismendi, Ebymar
    Obesity frequently complicates the pathobiology, diagnosis, and management of asthma. Traditionally, obese asthma patients have been classified as presenting either early-onset obese asthma, characterized by atopy and type 2 inflammation, or late-onset, noneosinophilic, obese asthma
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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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    Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth
    (Elsevier, 2025-10-01) Recalde Percaz, Leire; de la Guía López, Inés; Linzoain-Agos, Paula; Noguera Castells, Aleix; Rodrigo-Faus, María; Jauregui, Patricia; López Plana, Anna; Fernández Nogueira, Patricia; Iniesta-González, Minerva; Cueto-Remacha, Mateo; Manzano, Sara; Alonso, Rodrigo; Moragas, Núria; Baquero, Cristina; Palao, Nerea; Dalla, Erica; Avilés Jurado, Francesc Xavier; Vilaseca González, Isabel; Leon Vintro, Xavier; Camacho, Mercedes; Fuster Orellana, Gemma; Alcaraz Casademunt, Jordi; Aguirre-Ghiso, Julio; Gascón, Pere; Porras, Almudena; Gutiérrez-Uzquiza, Álvaro; Carbó Carbó, Neus; Bragado Domingo, Paloma
    Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.
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    Mediterranean Diet Pattern: Potential Impact on the Different Altered Pathways Related to Cardiovascular Risk in Advanced Chronic Kidney Disease
    (MDPI, 2024-10-31) Rovira, Jordi; Ramírez Bajo, María José; Bañón Maneus, Elisenda; Ventura Aguiar, Pedro; Arias Guillén, Marta; Romano Andrioni, Bárbara; Ojeda, Raquel; Revuelta, Ignacio; García Calderó, Héctor; Barberà i Mir, Joan Albert; Dantas, Ana Paula; Diaz Ricart, M. Isabel; Crispi Brillas, Fàtima; García Pagán, Juan Carlos; Campistol Plana, Josep M.; Diekmann, Fritz
    Background: Cardiovascular disease (CVD) remains the most common cause of mortality in chronic kidney disease (CKD) patients. Several studies suggest that the Mediterranean diet reduces the risk of CVD due to its influence on endothelial function, inflammation, lipid profile, and blood pressure. Integrating metabolomic and proteomic analyses of CKD could provide insights into the pathways involved in uremia-induced CVD and those pathways modifiable by the Mediterranean diet. Methods: We performed metabolomic and proteomic analyses on serum samples from 19 patients with advanced CKD (aCKD) and 27 healthy volunteers. The metabolites were quantified using four different approaches, based on their properties. Proteomic analysis was performed after depletion of seven abundant serum proteins (Albumin, IgG, antitrypsin, IgA, transferrin, haptoglobin, and fibrinogen). Integrative analysis was performed using MetaboAnalyst 4.0 and STRING 11.0 software to identify the dysregulated pathways and biomarkers. Results: A total of 135 metabolites and 75 proteins were differentially expressed in aCKD patients, compared to the controls. Pathway enrichment analysis showed significant alterations in the innate immune system pathways, including complement, coagulation, and neutrophil degranulation, along with disrupted linoleic acid and cholesterol metabolism. Additionally, certain key metabolites and proteins were altered in aCKD patients, such as glutathione peroxidase 3, carnitine, homocitrulline, 3-methylhistidine, and several amino acids and derivatives. Conclusions: Our findings reveal significant dysregulation of the serum metabolome and proteome in aCKD, particularly in those pathways associated with endothelial dysfunction and CVD. These results suggest that CVD prevention in CKD may benefit from a multifaceted approach, including dietary interventions such as the Mediterranean diet.
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    Differential impact of optogenetic stimulation of direct and indirect pathways from dorsolateral and dorsomedial striatum on motor symptoms in Huntington’s disease mice
    (Elsevier, 2025-01) Conde-Berriozabal, Sara; Masana Nadal, Mercè; Sitjà Roqueta, Laia; García García, Esther; García Gilabert, Lia; Sancho Balsells, Anna; Fernández, Sara (Fernández García); Rodríguez Urgellés, Ened; Giralt Torroella, Albert; Castañé, Anna; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959-
    The alterations in the basal ganglia circuitry are core pathological hallmark in Huntington's Disease (HD) and traditionally linked to its sever motor symptoms. Recently it was shown that optogenetic stimulation of cortical afferences to the striatum is able to reverse motor symptoms in HD mice. However, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor phenotype is still not clear. Here, we aim to uncover the contributions of these striatal subcircuits to motor control in wild type (WT) and HD mice by using the symptomatic R6/1 mice. We systematically evaluated locomotion, exploratory behavior, and motor learning effects of the selective optogenetic stimulation of D1 or A2A expressing neurons (direct and indirect pathway, respectively), in DLS or DMS. Bilateral optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS resulted in subtle locomotor enhancements, while unaltering exploratory behavior. Additionally, bilateral stimulation of the indirect pathway from the DLS improved performance in the accelerated rotarod task, suggesting a role in motor learning. In contrast, in HD mice, stimulation of these pathways did not modulate any of these behaviors. Overall, this study highlights that selective stimulation of direct and indirect pathways from DLS and DMS have subtle impact in locomotion, exploratory activity or motor learning. The lack of responses in HD mice also suggests that strategies involving cortico-striatal circuits rather than striatal output circuits might be a better strategy for managing motor symptoms in movement disorders.
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    Brain–gut photobiomodulation restores cognitive alterations in chronically stressed mice through the regulation of Sirt1 and neuroinflammation
    (Elsevier , 2024-06-01) Sancho Balsells, Anna; Borràs Pernas, Sara; Flotta, Francesca; Chen, Wanqi; Toro, Daniel del; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959- ; Blivet, Guillaume; Touchon, Jacques; Xifró i Collsamata, Xavier; Giralt Torroella, Albert
    Background: Chronic stress is an important risk factor for the development of major depressive disorder (MDD). Recent studies have shown microbiome dysbiosis as one of the pathogenic mechanisms associated with MDD. Thus, it is important to find novel non-pharmacological therapeutic strategies that can modulate gut microbiota and brain activity. One such strategy is photobiomodulation (PBM), which involves the non-invasive use of light. Objective/hypothesis: Brain-gut PBM could have a synergistic beneficial effect on the alterations induced by chronic stress. Methods: We employed the chronic unpredictable mild stress (CUMS) protocol to induce a depressive-like state in mice. Subsequently, we administered brain-gut PBM for 6 min per day over a period of 3 weeks. Following PBM treatment, we examined behavioral, structural, molecular, and cellular alterations induced by CUMS. Results: We observed that the CUMS protocol induces profound behavioral alterations and an increase of sirtuin1 (Sirt1) levels in the hippocampus. We then combined the stress protocol with PBM and found that tissue-combined PBM was able to rescue cognitive alterations induced by CUMS. This rescue was accompanied by a restoration of hippocampal Sirt1 levels, prevention of spine density loss in the CA1 of the hippocampus, and the modulation of the gut microbiome. PBM was also effective in reducing neuroinflammation and modulating the morphology of Iba1-positive microglia. Limitations: The molecular mechanisms behind the beneficial effects of tissue-combined PBM are not fully understood. Conclusions: Our results suggest that non-invasive photobiomodulation of both the brain and the gut microbiome could be beneficial in the context of stress-induced MDD.
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    Effects of dietary cis/trans unsaturated and saturated fatty acids on the glucose metabolites and enzymes of rats.
    (Cambridge University Press (CUP), 2006-01-24) Bernal, Claudio Adrian; Rovira, Jordi; Colandré, María E.; Cussó, Roser; Cadefau Surroca, Joan Aureli
    The aim of the present study was to examine whether the level of dietary cis fatty acid (cFA), or the isomers (trans or cis) and/or the saturation of the fatty acids at high dietary fat levels altered the intracellular glucose metabolites and certain regulatory enzyme activities in the skeletal muscle and liver of rats. The animals were fed for 30 d on either a recommended control diet (7 % cFA, w/w) or a high-fat diet (20 % fatty acids, w/w). The high-fat diet was enriched with either cFA, trans fatty acid (tFA), a moderate proportion of saturated fatty acid (MSFA), or a high proportion of saturated fatty acid (HSFA). The most striking findings were observed in the gastrocnemius muscle with a HSFA diet. There was a significant increase in glucose-6-phosphate (306 %), glucose-1-phosphate (245 %), fructose-6-phosphate (400 %), fructose-1,6-bisphosphate (86 %), glyceraldehyde-3-phosphate (38 %), pyruvate (341 %), lactate (325 %), citrate (79 %) and the bisphosphorylated sugars as compared with the cFA diet. These changes were paralleled by an increase in muscle triacylglycerol content (49 %) and a decrease in glucose (39 %). In addition, the amount of cFA and the other types of fatty acid (i.e. tFA and MSFA) led to no great differences in glucose metabolism as compared with the respective control group. These data support the hypothesis that glucose changes induced by a HSFA diet are a multifaceted abnormality. Glucose and lactate transport and intracellular glucose metabolism could be the key biochemical defects involved in this detrimental effect on glucose metabolism.
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    Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth
    (Elsevier, 2025-04-14) Guerrero, Mario; Proaño Pérez, Elizabeth; Serrano Candelas, Eva, 1982- ; García Valverde, Alfonso; Carrillo Rodríguez, Berenice; Rosell, Jordi; Serrano, César; Martín Andorrà, Margarita
    Gastrointestinal stromal tumors (GISTs) comprise about 80% of mesenchymal neoplasms in the gastrointestinal tract. Although imatinib mesylate is the preferred treatment, the development of drug resistance highlights the need for novel therapeutic strategies. Recently, we have identified the microphthalmia-associated transcription factor (MITF) as a critical player in pro-survival signaling and tumor growth. This study investigates the effects of MITF inhibition using ML329, an MITF pathway inhibitor, on GIST cell viability in vitro and in NMRI-nu/nu mouse xenograft models. ML329 suppresses growth in imatinib-sensitive (GIST-T1) and -resistant (GIST 430/654) cell lines, impairs MITF targets such as BCL2 and CDK2, and induces S-G2/M cell-cycle arrest. In vivo, ML329 is well tolerated and significantly reduces tumor growth in established imatinib-sensitive and -resistant GIST models. These findings underscore the importance of MITF in GIST growth and support its inhibition as a promising therapeutic approach.
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    Liver X receptors and inflammatory-induced C/EBPβ selectively cooperate to control CD38 transcription
    (Karger, 2024-12-19) Glaría Percaz, Estibaliz; Rodríguez Martínez, Pol; Font Díaz, Joan; Rosa, Juan Vladimir de la; Castrillo, Antonio; Crawshaw, Dylan J.; Vidal Taboada, José Manuel; Saura Martí, Josep; Matalonga, Jonathan; Nunes Chini, Eduardo; Caelles Franch, Carme; Valledor Fernández, Annabel
    Introduction: Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages. Methods: Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies. Results: Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ. Conclusion: This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.
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    A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity
    (Nature Publishing Group, 2024-02-05) Campos Mata, Leire de; Trinité, Benjamin; Modrego Guillén, Andrea; Tejedor Vaquero, Sonia; Pradenas Saavedra, Edwards; Pons Grífols, Anna; Rodrigo Melero, Natalia; Carlero, Diego; Marfil, Silvia; Santiago, César; Raïch Regué, Dàlia; Bueno Carrasco, María Teresa; Tarrés Freixas, Ferran; Abancó, Ferran; Urrea, Victor; Izquierdo Useros, Nuria; Riveira Muñoz, Eva; Ballana, Ester; Pérez Maillo, Mónica; Vergara Alert, Júlia; Segalés, Joaquim; Carolis, Carlo; Arranz, Rocío; Blanco, Julià; Magri, Giuliana
    Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from a COVID-19 convalescent individual infected during the first pandemic wave. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA+ memory B cell, with a broad neutralizing activity against former and new SARS-CoV-2 variants, including XBB.1.16 and BA.2.86 Omicron subvariants. Consistently, 17T2 demonstrates in vivo prophylactic and therapeutic activity against Omicron BA.1.1 infection in K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that 17T2 binds the BA.1 spike with the RBD in "up" position and blocks the receptor binding motif, as other structurally similar antibodies do, including S2E12. Yet, unlike S2E12, 17T2 retains its neutralizing activity against all variants tested, probably due to a larger RBD contact area. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 as a potential candidate for future clinical interventions.
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    A multi-site study on sex differences in cortical thickness in non-demented Parkinson’s disease
    (Springer Nature, 2024-12-01) Oltra González, Javier; Segura i Fàbregas, Bàrbara; Strafella, Antonio P.; Eimeren, Thilo van; Díez Cirarda, María; Ibarretxe Bilbao, Naroa; Monté Rubio, Gemma C.; Ojeda, Natalia; Peña Lasa, Javier; Eggers, Carsten; Lucas Jiménez, Olaia; Ruppert, Marina C.; Sala Llonch, Roser; Theis, Hendrik; Uribe, Carme; Junqué i Plaja, Carme, 1955-; Factors sexuals en les malalties
    Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson’s disease (PD). However, though sex differences in cortical gray matter measures in early drugnaïvepatientshavebeendescribed,littleisknownaboutdifferencesincorticalthickness(CTh)as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58±8.44 years old; mean disease duration 6.42±5.11 years) and 86 healthy controls (50% males; mean age 65.49±9.33years old) with available T1-weighted 3T MRI datafrom four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showedthinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), andonelimbicregion(right posterior cingulate).In PDmales,lowerCThvaluesinnine outoftenregionswereassociatedwithlongerdiseasedurationandolderage,whereasinPDfemales, lower CThwasassociatedwith older agebut with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data
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    Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice
    (MDPI, 2024-03-27) Portolés, Irene; Ribera, Jordi; Fernández Galán, Esther; Lecue Costas, Elena; Casals Mercadal, Gregori; Melgar Lesmes, Pedro; Fernández Varo, Guillermo; Boix i Ferrero, Loreto; Sanduzzi Zamparelli, Marco; Aishwarya, Veenu; Reig, María; Jiménez Povedano, Wladimiro; Morales Ruiz, Manuel
    RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology, and pathology. Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. AUM Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with AUM Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. In conclusion, Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients, and plays a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.
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    RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
    (Oxford University Press, 2024-10-14) Campoy Campos, Genís; Solana Balaguer, Júlia; Guisado Corcoll, Anna; Chicote González, Almudena; García Segura, Pol; Pérez Sisqués, Leticia; Gabriel Torres, Adrián; Canal de la Iglesia, Mercè; Molina Porcel, Laura; Fernández Irigoyen, Joaquín; Santamaría, Enrique; Ribas de Pouplana, Lluís; Alberch i Vié, Jordi, 1959-; Marti Puig, Eulalia; Giralt Torroella, Albert; Pérez Navarro, Esther; Malagelada Grau, Cristina
    RTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer’s disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC), which ligates the excised exons of intron-containing tRNAs and the mRNA exons of the transcription factor XBP1 during the unfolded protein response (UPR). We also found that RTP801 modulates the mRNA ligase activity of the complex in vitro since RTP801 knockdown promoted XBP1 splicing and the expression of its transcriptional target, SEC24D. Conversely, RTP801 overexpression inhibited the splicing of XBP1. Similarly, in human AD postmortem hippocampal samples, where RTP801 is upregulated, we found that XBP1 splicing was dramatically decreased. In the 5xFAD mouse model of AD, silencing RTP801 expression in hippocampal neurons promoted Xbp1 splicing and prevented the accumulation of intron-containing pre-tRNAs. Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach.
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    Preserved VPS13A distribution and expression in Huntington’s disease: Divergent mechanisms of action for similar movement disorders?
    (Frontiers Media, 2024-06-05) García García, Esther; Carreras Caballé, Maria; Coll Manzano, Albert; Ramón Lainez, Alba; Besa Selva, Gisela; Pérez Navarro, Esther; Malagelada Grau, Cristina; Alberch i Vié, Jordi, 1959- ; Masana Nadal, Mercè; Rodríguez Allué, Manuel José
    VPS13A disease and Huntington’s disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.
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    Palmitoylcarnitine impairs immunity in decompensated cirrhosis
    (Elsevier, 2024-08-22) Wei Zhang, Ingrid; Sánchez Rodríguez, María Belén; López Vicario, Cristina; Casulleras, Mireia; Duran Güell, Marta; Flores Costa, Roger; Aguilar, Ferran; Rothe, Michael; Segalés, Paula; García Ruiz, Carmen; Fernández Checa Torres, José Carlos; Trebicka, Jonel; Arroyo, Vicente; Clària i Enrich, Joan
    Background & aims: In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells. Methods: Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis. Results: Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, p = 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene HMOX1, and increased CXCL8 expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of HMOX1. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced CXCL8 expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis. Conclusions: Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis. Impact and implications: Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings underline the importance of immunometabolism as a treatment target in patients with acute decompensation of cirrhosis and ACLF.
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    Liver X Receptors Inhibit Macrophage Proliferation through Downregulation of Cyclins D1 and B1 and Cyclin-Dependent Kinases 2 and 4
    (American Association of Immunologists, 2011-04-15) Pascual García, Mónica; Carbó, José M.; León Moreno, Theresa Elizabeth; Matalonga, Jonathan; Out, Ruud; Van Berkel, Theo; Sarrias, Maria Rosa; Lozano, Francisco; Celada Cotarelo, Antonio; Valledor Fernández, Annabel
    Macrophages serve essential functions as regulators of immunity and homeostasis, and their proliferation contributes to pathogenesis of certain disorders. In this report, we show that induction of macrophage proliferation by the growth factor M-CSF is negatively modulated by agonists that activate the nuclear receptor liver X receptor (LXR), both in vitro and in vivo. Both isoforms LXR α and β are involved in the antiproliferative actions of LXR ligands in macrophages. In contrast, M-CSF does not exert negative effects on LXR-mediated gene expression. Treatment with LXR agonists results in the accumulation of macrophages in the G0/G1 phase of the cell cycle without affecting ERK-1/2 phosphorylation. The use of small interfering RNA or genetically modified mice revealed that, in contrast to other cellular models, functional expression of either the cyclin-dependent kinase inhibitor p27KIP1 or the cholesterol transporters ATP-binding cassette A1 or ATP-binding cassette G1 was not required for the antiproliferative effects of LXR agonists in macrophages. Western blot analysis revealed that protein expression of key molecules that regulate progression through the cell cycle, such as cyclins D1 and B1 and cyclin-dependent kinases 2 and 4, was downregulated upon LXR activation. These observations suggest a role for LXR agonists in limiting macrophage proliferative responses associated to pathogenic disorders.
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    Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-gamma-Induced Inflammatory Responses and LXR-Dependent Gene Expression
    (American Association of Immunologists, 2013-06-15) Pascual Garcia, Monica; Rué Cabré, Laura; León Moreno, Theresa Elizabeth; Julve, Josep; Carbó, José M.; Matalonga, Jonathan; Auer, Herbert; Celada Cotarelo, Antonio; Escola-Gil, Joan Carles; Steffensen, Knut R.; Pérez Navarro, Esther; Valledor Fernandez, Annabel
    Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ. Transcriptional profiling studies demonstrate that ∼38% of the IFN-γ–induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-γ–induced genes in primary microglia and in a model of IFN-γ–induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets. Treatment with IFN-γ inhibited, in a STAT1-dependent manner, the LXR-dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ. The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1-dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/STAT1 and LXRs with implications both in the control of IFN-γ–mediated immune responses and in the regulation of lipid metabolism.