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Hypoglycosylation of Piezo1 and Cavα2δ subunit: relevance for neuronal excitability and neurological disorders associated to Phosphomannomutase 2 deficiency (PMM2-CDG)
No full textEls defectes congènits de la glicosilació (CDG) són una família de malalties causades per mutacions en gens involucrats en les vies de la glicosilació. La PMM2-CDG, associada a mutacions en la fosfomanomutasa 2 (PMM2), es el subtipus més comú de CDG i cursa amb alteracions neurològiques severes com els stroke-like episodes (SLEs). Malgrat els mecanismes patològics són desconeguts, s’ha descrit que la hipoglicosilació del canal iònic CaV2.1 indueix un guany de funció que podria contribuir a aquestes manifestacions neurològiques. Apart, els traumatismes cranials s’han identificat com un potencial desencadenant dels SLEs. En aquesta tesi descrivim que la hipoglicosilació de Piezo1, expressat heteròlogament en cèl·lules HEK293, augmenta la sensibilitat mecànica del canal en resposta a pressió negativa i polsos uniaxials d’estirament sense alterar la cinètica d’inactivació. A més, el tractament de neurones de ratolí en cultiu primari amb els inhibidors de la glicosilación swainsonine o kifunensine augmenta els nivells de Piezo1 al soma sense alterar el seu patró de localització sinàptica. Aquests tractaments també incrementen l’influx de calci en resposta a Yoda1 o polsos uniaxials d’estirament. Finalment, mostrem com la disrupció de l’expressió de la PMM2 redueix la glicosilació i el tràfic a membrana de la subunitat CaVα2δ en cèl·lules HEK293 mentre que en C. elegans augmenta la sensibilitat a aldicarb, indicatiu d’un increment en la neurotransmissió a la sinapsi neuromuscular. En conjunt, aquests resultats suggereixen que la hipoglicosilació de Piezo1 i el complex CaV2.1/α2δ indueixen un guany de funció que podria contribuir en les manifestacions neurològiques observades en els pacients PMM2-CDG en afavorir l’excitabilitat neuronal.The congenital disorders of glycosylation (CDGs) are a disease family caused by mutations in genes involved in the glycosylation pathways. PMM2-CDG, associated with mutations in the phosphomannomutase 2 (PMM2) gene, is the most common CDG subtype and presents with severe neurological alterations such as stroke-like episodes (SLEs). Although the pathomechanisms are not fully understood, hypoglycosylation of CaV2.1 has been shown to induce a gain-of-function in the channel that may contribute to the above-mentioned neurological symptoms. Additionally, head trauma has been recently identified as a potential trigger for SLEs. Here we report that hypoglycosylation of Piezo1 heterologously expressed in HEK293 cells increases its mechanosensitivity in response to negative pressure and 40% uniaxial stretch pulses without affecting the inactivation kinetics. Additionally, the treatment of murine cortical neurons in primary culture with the glycosylation inhibitors swainsonine or kifunensine increases Piezo1 levels at the soma without altering its synaptic localization pattern. These treatments also increase Ca2+ responses upon Yoda1 stimulation and 40% uniaxial stretch pulses. Also, we show that disruption of PMM2 expression impairs CaVα2δ glycosylation and membrane trafficking in HEK293 cells while also increases aldicarb sensitivity in C. elegans, indicative of an enhanced neurotransmission at the worm neuromuscular junction. Together, our results suggest that the hypoglycosylation-driven gain-of-function effect on Piezo1 and the CaV2.1/α2δ channel complex may contribute to the neurological manifestations observed in PMM2-CDG patients by favoring neuronal excitability.Programa de Doctorat en Biomedicin
Netflix guanya entre les plataformes, guanya amb el màrqueting i amb la ignorància col·lectiva
No full textElucidating the dynamics of the 3D GPCRome
No full textG Protein-Coupled Receptors (GPCRs) are a diverse protein family integral to a wide range of physiological processes. Although their three-dimensional structures have been extensively characterised through experimental methods, these approaches provide only static snapshots of these inherently flexible and dynamic proteins. In this thesis, we have generated two extensive datasets of Molecular Dynamics (MD) simulations of GPCRs, including GPCR-transducer protein complexes. Employing these datasets we explored various dynamic features of GPCRs, such as conformational equilibrium, the formation of pockets and tunnels by membrane lipids and the role played by non-covalent interactions in transducer selectivity. Additionally, we have developed interactive online tools within the GPCRmd web server (www.gpcrmd.org) to make our results replicable and accessible to the broader scientific community. These unprecedented datasets and insights shed light on critical aspects of GPCR dynamic functionality, provide new tools for MD simulation analysis and open new avenues for future research in this field.Els Receptors acoblats a proteïna G (GPCRs) estan implicats en una gran varietat de processos biològics. Malgrat les seves estructures tri-dimensionals han estat estudiades en detall, aquestes proveeixen només una imatge estàtica d’unes proteïnes inherentment dinàmiques i flexibles. En aquesta tesi, hem creat dos datasets de simulacions Dinàmiques Moleculars (MD) de GPCRs, incloent-hi complexos GPCRs-transductor. Fent ús d'aquests datasets, hem investigat diversos aspectes dinàmics de les GPCR, com ara l’equilibri conformacional, la formació de llocs al·lostèrics i túnels pels lípids de membrana, i el rol de les interaccions no covalents en la selectivitat de transductors. A més, hem desenvolupat un conjunt d'eines interactives on-line al nostre servidor web GPCRmd (www.gpcrmd.org) per fer els nostres resultats reproduïbles i accessibles a la comunitat científica. En conjunt, aquests datasets i descobriments sense precedent revelen aspectes crítics sobre la funcionalitat de les GPCR, proveeixen noves eines per l'anàlisi de simulacions i obren noves vies d'investigació en aquest camp.Programa de Doctorat en Biomedicin
Trade and urbanization: evidence from Hungary?
No full textI study how trade affects urbanization and real income. To this end, I exploit large-scale exogenous changes in trade stemming from the redrawing of Hungary's borders after the First World War. I show that urbanization in counties near the new border decreased significantly relative to counties farther away. I rationalize this reduced-form finding in a spatial model in which benefits from trading drive agglomeration around locations where trading activity takes place. Structurally estimating the model, I find a 15.55 percent decrease in Hungarian residents' average real income after the redrawing of borders, with the largest losses concentrated in border regions
La protección de la capacidad contributiva en el Derecho de la Unión Europea
No full textEn este trabajo se analiza en qué medida el Derecho de la Unión Europea permite y asegura la protección de la capacidad contributiva de las personas físicas en un contexto transfronterizo. Por ello, se estudia, en primer lugar, el significado y el valor jurídico del principio de capacidad contributiva, observando la existencia de diferencias y similitudes en la concepción y concretización de este principio entre los Estados miembros, y, en segundo lugar, se examina la jurisprudencia del Tribunal de Justicia de la Unión Europea sobre dos elementos centrales en la consideración de la capacidad contributiva de las personas físicas: los gastos relacionados con la actividad y los gastos relacionados con sus circunstancias personales y familiares
Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior
No full textObjectives: Overconsumption of palatable food and energy accumulation are evolutionary mechanisms of survival when food is scarce. These innate mechanisms becom detrimental in obesogenic environment promoting obesity and related comorbidities, including mood disorders. This study aims at elucidating the role of the endocannabinoid system in energy accumulation and hedonic feeding. Methods: We applied a genetic strategy to reconstitute cannabinoid type-1 receptor (CB1) expression at functional levels specifically in CaMKII+ neurons (CaMKII-CB1-RS) and adipocytes (Ati-CB1-RS), respectively, in a CB1 deficient background. Results: Rescued CB1 expression in CaMKII+ neurons, but not in adipocytes, promotes feeding behavior, leading to fasting-induced hyperphagia, increased motivation, and impulsivity to palatable food seeking. In a diet-induced obesity model, CB1 re-expression in CaMKII+ neurons, but not in adipocytes, compared to complete CB1 deficiency, was sufficient to largely restore weight gain, food intake without any effect on glucose intolerance associated with high-fat diet consumption. In a model of glucocorticoid-mediated metabolic syndrome, CaMKII-CB1-RS mice showed all metabolic alterations linked to the human metabolic syndrome except of glucose intolerance. In a binge-eating model mimicking human pathological feeding, CaMKII-CB1-RS mice showed increased seeking and compulsive behavior to palatable food, suggesting crucial roles in foraging and an enhanced susceptibility to addictive-like eating behaviors. Importantly, other contingent behaviors, including increased cognitive flexibility and reduced anxiety-like behaviors, but not depressive-like behaviors, were also observed. Conclusions: CB1 in CaMKII+ neurons is instrumental in feeding behavior and energy storage under physiological conditions. The exposure to risk factors (hypercaloric diet, glucocorticoid dysregulation) leads to obesity, metabolic syndrome, binge-eating and food addiction.This work was supported by CRC1193 “Neurobiology of resilience” to B.L.; EU-FP7 REPROBESITY (HEALTHF2- 2008-223713 to B.L.); Spanish “Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (AEI)” (PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033, RD21/0009/0019 and PDI2023-1511680B-C21), the Spanish “Instituto de Salud Carlos III, RETICS-RTA” (#RD12/0028/0023), the “Generalitat de Catalunya, AGAUR” (#2017 SGR-669), “ICREA-Acadèmia” (#2015) and the Spanish “Ministerio de Sanidad, Servicios Sociales e Igualdad”, “Plan Nacional Sobre Drogas of the Spanish Ministry of Health” (#PNSD-2017I068) to R.M., "la Caixa Health" LCR/PR/HR22/5240017 to R.M. and E.M-G., “Plan Nacional Sobre Drogas of the Spanish Ministry of Health” (#PNSD-2019I006, #PNSD-2023I040) and Spanish “Ministerio de Ciencia e Innovación” (ERA-NET) PCI2021-122073-2A to E.M-G
Piular or tuitejar? a study of social media loanwords in catalan
No full textTreball de fi de màster en Lingüística Teòrica i AplicadaDirectores: : Dra. Gemma Boleda Torrent i Dra. Iria de Dios FloresGlobalisation has allowed increased contact between societies and cultures. The evolution of societies and the creation of new technologies make coining new terms an inevitable task for language users. This study aims to investigate the processes of integrating foreign words, especially verbs, into the Catalan language in a social media setting, with an informal register. We create a list of words to study and collect data from Twitter/X. We disambiguate the contexts in which the words relate to social media by prompting large language models, with 0.9 accuracy. Our findings show that using native words is more common than adapting foreign roots. This behaviour is not shared with other findings in the context of newspapers and magazine texts, and we hypothesise that the register may be the reason. We also find both
inflection and light verb constructions used to create new verbal forms
The influence of socio-economic status on the fulfilment of Saint-Gallen recommendations for early-stage breast cancer
No full textSocio-economic status (SES) is related to breast cancer diagnosis and prognosis. We study if SES is related to the adequacy of the treatment according to Saint Gallen consensus in Spanish women with incident breast cancer. Breast cancer cohort was assembled from incident cases from MCC-Spain and prospective followed-up afterwards. Participants were then classified according to the Saint-Gallen consensus in three categories (In Saint-Gallen, who received therapy accorded by Saint Gallen; Over Saint-Gallen, who received some additional therapy; or Under Saint-Gallen, who did not receive the complete therapy). Association between SES and Saint-Gallen fulfilment was analyzed using multinomial logistic regression, adjusting for clinicopathological and patient-related variables. 1115 patients in stages I and II were included. Women with university education were 58% more likely to receive over Saint-Gallen therapies (RRR = 1.68; 95%CI 0.84-3.33). In the simplified SES score, women with higher SES were over Saint-Gallen 52% more than those with lower SES (RRR = 1.52; 95%CI 0.88-2.64). Women with higher SES more often received over Saint-Gallen therapies. Further analyses are needed to understand the influence of these differences on the overall survival as well as its potential unwanted side effects
Adolescència i salut mental: de la representació mediàtica a la prevenció de l’estigma a les aules = Adolescence and mental health: from their representation in the media to the prevention of stigma in classrooms
No full textEl nombre d’adolescents amb trastorns de salut mental i d’ingressos hospitalaris per aquesta causa ha incrementat significativament els darrers anys, i Espanya se situa entre els països europeus amb el nombre més elevat de diagnòstics. Gran part de la investigació realitzada fins ara s’ha centrat en els efectes del discurs dels mitjans de comunicació sobre la salut mental dels menors d’edat; no obstant això, són escassos
els estudis sobre la representació del benestar mental dels adolescents en aquests mitjans. Aquest treball aprofundeix, mitjançant una anàlisi de la literatura existent, en la imatge de la salut mental adolescent en la ficció audiovisual, els mitjans informatius i les xarxes socials. L’anàlisi també aprofundeix en la importància de la perspectiva de gènere en aquesta representació, i reflexiona sobre la necessitat de treballar l’educació mediàtica, amb l’aportació d’eines per abordar la prevenció de l’estigma a les aules.The number of adolescents with mental health disorders and admissions to hospitals for this reason has increased significantly in recent years, placing Spain among the European countries with the highest number of diagnoses. Most of the research carried out so far has focused on the effects of the
media discourse regarding the mental health of minors; however, there have been few studies on the representation in the media of the mental health of adolescents. This work examines, through an analysis of the existing literature, the image of adolescent mental health in audiovisual fiction, news media and social media.
The analysis also studies the importance of the gender perspective in this representation and reflects on the need to work on media literacy, offering tools to address the prevention of stigma in the classroom.Aquest estudi s’ha dut a terme en el marc del Projecte nacional d’R+D+I “Adolescentes receptores y creadores de contenido sobre salud mental en redes sociales. Discurso, incidencia y alfabetización digital sobre trastornos psicológicos y su estigma. (SMARS)”, (ref. PID2022-141454OB-I00), finançat pel Ministeri de Ciència, Innovació i Universitats d’Espanya (2023-2026)
Juventud, migraciones y convivencia : cuatro estudios de caso en el Barcelonés (2000-2024)
No full textEsta tesis doctoral analiza la cuestión de la compleja interrelación de los espacios y la acogida de los jóvenes migrantes y sus familias, así como los efectos que tienen en las siguientes generaciones. Se pregunta por el papel que juegan las relaciones en esos espacios/territorios y por cómo los mecanismos de identidad/alteridad/discriminación/estigma acaban constituyendo elementos clave de los conflictos, violencias y racismos actuales. La investigación parte de 4 estudios de caso, realizados en diferentes periodos, que no sólo representan 4 contextos espaciales sino temporales en relación con la historia de las migraciones de personas jóvenes en el Barcelonés (2000-2024). La metodología utilizada combina la etnografía, estudios de caso y procesos participativos a partir de la colaboración en proyectos de intervención social en diferentes territorios y a nivel transnacional. Los resultados explican la evolución del proceso a lo largo del tiempo y la incidencia e implicación que han tenido las políticas públicas, los mecanismos comunitarios y la construcción de discursos colectivos que se han posicionado de forma más o menos clara con relación a la defensa de los derechos humanos y sus mecanismos de protección. Se trata de un recorrido que problematiza el fenómeno y a la vez permite vislumbrar las problemáticas de inclusión/exclusión y sus repercusiones para la convivencia y la cohesión social.Programa de Doctorat en Comunicaci