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Changes in cardiovascular health at midlife and subsequent cardiovascular outcomes in individuals with diabetes
No full textBackground: Whether improvements in cardiovascular health (CVH) in midlife mitigate cardiovascular disease (CVD) risk in patients with diabetes remains underexplored. Objectives: The aim of the study was to examine the relationships between changes in CVH during midlife and subsequent risks of CVD events and all-cause mortality among individuals with and without diabetes. Methods: The study utilized data from the Atherosclerosis Risk in Communities Study. CVH data were collected during visits 1 and 3 and the median follow-up was 23 years. CVH was based on ideal Life's Simple 7 metrics and categorized as low (0-2 metrics), moderate (3 or 4 metrics), and favorable CVH (5-7 metrics). Cox proportional hazards regression models were used to determine the association between changes in CVH and CVD outcomes. Results: Among the final sample (N = 8,741), 806 had diabetes (9.2%). Of those with diabetes, 62.3% had low CVH at both visits, 12.0% maintained moderate CVH, 15.0% showed improvement, and 10.3% experienced a decline in CVH. Only 0.4% maintained favorable CVH. Those with improved CVH had lower CVD event risks (HR: 0.69; 95% CI: 0.50-0.93), as did those who maintained moderate CVH (HR: 0.68; 95% CI: 0.50-0.94) or shifted from moderate to low CVH (HR: 0.60; 95% CI: 0.41-0.88). Similar patterns were observed for all-cause mortality. In comparison to participants without diabetes who maintained a favorable CVH trajectory at midlife, those with diabetes consistently displayed higher risks of CVD events and mortality, regardless of their CVH trajectory. Conclusions: For patients with diabetes, achieving or maintaining ideal CVH levels at midlife may help improve outcome; however, CVD risk is not completely mitigated by favorable CVH trajectories
Instrumentos de rendición de cuentas ante la desinformación: impacto de las plataformas de fact-checking como herramientas de accountability y propuesta curricular
No full textDiagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability
No full textRecently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (MOP-11-51-31; RFN 152985, 159815 and 162303), Canadian Consortium of Neurodegeneration and Aging (MOP-11-51-31-team 1), the Alzheimer's Association (NIRG-12-92090 and NIRP-12-259245), Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec-Santé (Chercheur Boursier, 2020-VICO-279314) and the Colin J. Adair Charitable Foundation. Research reported in this publication from the HABS study was supported by the National Institute on Aging of the National Institutes of Health under award numbers R01AG054073, R01AG058533, P41EB015922 and U19AG078109. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.T. is funded by the Colin J. Adair Charitable Foundation scholarship and the McGill Faculty of Medicine bursary award. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (nos. 2022-01018 and 2019-02397), the European Union's Horizon Europe research and innovation program under grant agreement no. 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation, USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre and the UK Dementia Research Institute at UCL (UKDRI-1003). The BioFINDER-2 study was supported by the Alzheimer's Association (SG-23-1061717), Swedish Research Council (2022-00775), ERA PerMed (ERAPERMED2021-184), the Knut and Alice Wallenberg foundation (2017-0383), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's disease) at Lund University, the Swedish Alzheimer Foundation (AF-980907), the Swedish Brain Foundation (FO2021-0293), the Parkinson foundation of Sweden (1412/22), the Cure Alzheimer's fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2022-1259) and the Swedish federal government under the ALF agreement (2022-Projekt0080). The precursor of 18F-flutemetamol was sponsored by GE Healthcare. The Mayo Clinic Study of Aging is supported by the National Institutes of Aging (U01 AG006786), the GHR foundation and the Mayo Medical Foundation for Education and Research, as well as NIA grants R37 AG011378 and R01 AG041851. M.S.-C. receives funding from the European Research Council under the European Union¿s Horizon 2020 research and innovation program (grant agreement no. 948677), project PI19/00155, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and from a fellowship from La Caixa Foundation (ID 100010434) and from the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 847648 (LCF/BQ/PR21/11840004). The SPIN cohort has received funding from CIBERNED; Instituto de Salud Carlos III; jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, 'Una manera de hacer Europa'; Generalitat de Catalunya; Fundació 'La Marató TV3' Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica; Global Brain Health Institute; Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas; Jérôme Lejeune Foundation
Regulation of tumor-infiltrating T lymphocytes by circadian molecular clocks
No full textCircadian rhythms are the natural 24-hour cycles governing physiological processes and play a critical role in regulating immune function. This thesis explores the intricate connections between circadian rhythms and the immune response in cancer, focusing on how disruptions in these rhythms may influence T cell efficacy against tumor cells. By integrating insights from chronobiology and immunology, the present work investigates the molecular mechanisms underlying circadian regulation of T cells and their possible implications for cancer progression and treatment. Experimental data highlight how circadian regulation can shape T cell anti-tumor function, potentially creating a more permissive environment for tumor growth. Furthermore, the thesis examines novel mechansims regulating T cell responses aimed at optimizing cancer immunotherapy. These findings underscore the importance of taking into account the circadian regulation of adaptive immune responses to improve current treatments of cancer and other diseases.Els ritmes circadians són cicles naturals de 24 hores que governen els processos fisiològics i juguen un paper crucial en la regulació del sistema immunitari. Aquesta tesi explora les complexes interaccions entre els ritmes circadians i la resposta immune contra el càncer, centrant-se en com les alteracions d’aquests ritmes poden influir en l’eficàcia de les cèl·lules T en la lluita contra les cèl·lules tumorals. Integrant coneixements de la cronobiologia i la immunologia, aquest treball investiga els mecanismes moleculars subjacents a la regulació circadiana de les cèl·lules T i les seves possibles implicacions en la progressió i el tractament del càncer. Els resultats obtinguts destaquen com la regulació circadiana pot modular la funció antitumoral de les cèl·lules T, creant un entorn potencialment més permissiu per al creixement tumoral. A més, la tesi examina nous mecanismes de regulació de les respostes de les cèl·lules T amb l'objectiu d'optimitzar la immunoteràpia contra el càncer. Aquests resultats posen en evidència la importància de considerar la regulació circadiana de les respostes immunitàries adaptatives per a millorar els tractaments actuals del càncer i altres malalties.Los ritmos circadianos son ciclos naturales de 24 horas que gobiernan los procesos fisiológicos y juegan un papel crucial en la regulación del sistema inmunitario. Esta tesis explora las complejas interacciones entre los ritmos circadianos y la respuesta inmune contra el cáncer, centrándose en cómo las alteraciones de estos ritmos pueden influir en la eficacia de las células T en la lucha contra las células tumorales. Integrando conocimientos de la cronobiología y la inmunología, este trabajo investiga los mecanismos moleculares subyacentes a la regulación circadiana de las células T y sus posibles implicaciones en la progresión y el tratamiento del cáncer. Los resultados obtenidos destacan cómo la regulación circadiana puede modular la función antitumoral de las células T, creando un entorno potencialmente más permisivo para el crecimiento tumoral. Además, la tesis examina nuevos mecanismos de regulación de las respuestas de los linfocitos T con el objetivo de optimizar la inmunoterapia contra el cáncer. Estos resultados ponen en evidencia la importancia considerar la regulación circadiana de las respuestas inmunitarias adaptativas para mejorar los tratamientos actuales del cáncer y otras enfermedadesPrograma de Doctorat en Biomedicin
A new dataset on legislative decision-making in the European Union: the DEU III dataset
No full textThis paper introduces the updated version of our dataset, which is the third iteration of the Decision-making in the European Union (DEU-III) dataset. We outline the DEU project before describing the dataset in detail, including the case-selection criteria, and the definitions and operationalisations of the main constructs. The paper discusses the integration of the dataset with other variables that are used in many of the contributions to this special issue and other studies. Finally, we describe validity and reliability test of the DEU-III dataset as well as some avenues for its future use by scholars.This work was supported by the Spanish Ministry of Economy and Competitiveness under Grant CSO2015-67213-C2-2-P; it was also supported by the Erasmus+ programme of the European Union under Grants 611941 - EPP- 1-2019-1-ES-EPP-JMO- CoE (Barcelona Center for European Studies) and 600488 - EPP- 1- 2019- 1- ES- EPPJMO- CHAIR (Jean Monnet Chair in European Governance)
Economic principles for the enforcement of abuse of dominance provisions
No full textThe European Commission (EC) has recently announced its intention to issue Guidelines on exclusionary abuses. In this paper, we explain how economics can and should be used to inform a sound and effects-based approach in the enforcement of Article 102 TFEU. In particular, the EC should be guided only by a consumer welfare standard; exclusive dealing and exclusivity rebates should be subject to a (rebuttable) presumption of harm; price-cost tests are meaningful only for predation and other practices that do not reference rivals; essentiality of the input should not be a requirement for vertical foreclosure cases of any type, but such cases should be limited only to dominant firms that satisfy certain criteria
La protección de los derechos políticos frente a las funciones disciplinarias de las autoridades administrativas: subsidiariedad y deferencia en el Sistema Interamericano de Derechos Humanos
No full textEste artículo analiza una de las tensiones más importantes entre la protección de los derechos políticos -tanto de los funcionarios públicos elegidos popularmente como de sus electores- y las funciones disciplinarias de algunas autoridades administrativas. Esa tensión se profundiza en la medida en que las normas constitucionales nacionales y los tratados internacionales también protegen esas funciones de las autoridades disciplinarias con el fin de que estas persigan y sancionen la corrupción. El objetivo es preservar los recursos públicos que se destinan, entre otros fines, a la satisfacción de los Derechos Económicos, Sociales, Culturales y Ambientales. La investigación propone que, en el ámbito del Sistema Interamericano de Protección de los Derechos Humanos, esa tensión se puede superar mediante una fórmula de mutua deferencia que puede ser aplicada en todos los Estados. La deferencia debe existir de parte de la Corte Interamericana de Derechos Humanos con los Estados y de parte de las autoridades disciplinarias internas con los estándares establecidos por el tribunal interamericano. El artículo también señala las condiciones necesarias para que ocurra la mutua deferencia y advierte sobre los peligros de que la Corte Interamericana mantenga una interpretación textualista y austera del artículo 23 de la Convención Americana sobre Derechos Humanos.This article analyzes one of the most important tensions between the protection of political rights – of both popularly elected officials and their constituents - and the disciplinary functions of some administrative authorities. This tension is deepened insofar as national constitutional norms and international treaties also protect the functions of disciplinary authorities with a view to enabling the prosecution and punishment of corruption. The objective is to preserve public resources which necessary, among other purposes, to the satisfaction of Economic, Social, Cultural and Environmental Rights. The research proposes that, within the framework of the Inter-American System for the Protection of Human Rights, this tension can be overcome through a formula of mutual deference that can be applied in all States. The deference must exist on behalf of the Inter-American Court of Human Rights in what concerns the States and on the part of the internal disciplinary authorities in what concerns the standards established by the Inter-American Court. The article also indicates the necessary conditions for mutual deference to occur and warns about the dangers of the Inter-American Court maintaining a textual and austere interpretation of Article 23 of the American Convention on Human Rights
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
The Role of Circadian Clock Integrity in Cellular Adaptation to Stress
No full textLes cèl·lules conviuen amb contínues pertorbacions ambientals que comprometen la seva viabilitat, anomenades condicions d’estrès ambientals. Aquesta tesi explora la interacció entre els ritmes circadiaris i les respostes a l'estrès en cèl·lules de mamífer. Mitjançant un cribratge genòmic fent servir el sistema CRISPR/Cas9, hem identificat diferents components circadiaris essencials per a la supervivència cel·lular sota diversos estressos ambientals. A més, hem caracteritzat la regulació exercida pel rellotge circadiari sobre el procés d'adaptació cel·lular a nivell transcripcional. Hem descobert que la proteïna quinasa activada per estrès (SAPK) p38α actua com a connexió entre la senyalització cel·lular durant estrès i el rellotge circadiari, fosforilant directament components centrals del rellotge. Hem estudiat com els mutants no fosforilables i fosfomimètics per p38α d'aquests components del rellotge regulen la capacitat transcripcional del rellotge molecular. En conjunt, aquesta tesi aporta noves perspectives sobre com p38α pot regular el rellotge circadiari en situacions d’estrès cel·lular, mantenint la funció circadiària intacta per obtenir respostes adaptatives més robustes contra canvis ambientals, optimitzant així la supervivència cel·lular.Cells deal with continuous environmental perturbations that compromise cell fitness. This thesis explores the critical interplay between circadian rhythms and stress responses in mammalian cells. Through a genome-wide CRISPR/Cas9 screen, we identified different core circadian components as essential for cellular survival under different environmental stresses. Furthermore, we characterized the regulation exerted by the circadian clock to the cellular adaptation process at the transcriptional level. We discovered that p38α stress-activated protein kinase (SAPK) acts as a molecular bridge between stress signaling and circadian regulation by directly phosphorylating core clock components. We studied how p38α-unphosphorylatable and phosphomimetics mutants of these clock components regulate circadian-dependent transcription. Overall, this thesis provides new insights in how p38α SAPK can regulate the circadian clock during stress, enabling cells to leverage intact circadian function for more robust adaptive responses against diverse stressors, thereby optimizing cellular survival.Universitat Pompeu Fabra. Doctorat en Biomedicin
Prognostic value of PARP1 and PARP2 copy number alterations in prostate cancer
No full textPARP1/2 have overlapping yet nonredundant biological functions in DNA repair and androgen receptor-transcriptional regulation. Studies on PARP alterations in human tumors have yielded conflicting results. In prostate cancer (PCa), PARP1/2 protein overexpression has been related to androgen deprivation therapy resistance, biochemical recurrence, and progression to metastases. PARP inhibitors have been approved for treating metastatic castration-resistant PCa with homologous recombination repair gene mutations. However, the significance of PARP1/2 genomic alterations is not fully studied. We aimed to analyze PARP1/2 alterations in PCa, assess their value as prognostic markers, and explore their relevance for potential therapeutic stratification. PARP1/2 copy number status was evaluated in 121 PCa primary tumors using real-time PCR. In 29 of them, a regional pelvic lymph node involvement was also analyzed. BRCA1/2 somatic mutations were analyzed in 24 PCa cases. Relationship with clinicopathological features, progression to metastases, and prostate-specific antigen recurrence was assessed. PARP1 loss and PARP2 gain were detected in 34.7% and 32.2% of primary tumors, respectively, with a high frequency of co-occurrence (P < .001). Both alterations were statistically associated with locally advanced disease at the time of diagnosis (P = .036; P = .006), metastatic dissemination (P = .014; P = .003), and other aggressive clinicopathological characteristics (such as the presence of Gleason pattern 5, high-grade, and high-stage). Cases with exclusive PARP2 gain had the shortest time to prostate-specific antigen recurrence, whereas double wt patients displayed the best outcome (P = .007). In 29 paired primary tumors and regional pelvic lymph node involvement, PARP1 loss showed strong concordance (P = .001), whereas PARP2 gain did not (P = .411). In conclusion, loss of PARP1 and gain of PARP2 show strong co-occurrence and are associated with clinicopathological characteristics of aggressiveness. PARP2 alterations appear to have a particularly significant impact on disease prognosis. Furthermore, these data suggest that the analysis of PARP1/2 copy number status could be useful in predicting PCa outcomes. Its role in therapy warrants further evaluation.The study has been funded with the “BecaLeonardo de la Peña 2022” through the Foundation for Research in Urology of the Spanish Association of Urology, and the FIS/ISC III/FEDER PI22/00171 from the Spanish Ministry of Health. Yélamos lab is funded by grant PID2023-146049OB-I00 from Agencia Estatal de Investigación of Spanish Ministry of Science, Innovation and Universities (MICIU/AEI /10.13039/501100011033 and FEDER, UE)