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Synchrotron-based X-ray 3D phase contrast imaging and analysis of transmural myocardial tissue from heart failure patients
No full textSynchrotron-based X-ray phase contrast imaging (X-PCI) is a non-destructive imaging modality that can provide high resolution three-dimensional (3D) visualisation of transmural myocardial tissue, collagen matrix reconstruction, and quantification of myocyte aggregate orientation (‘myomapping’). We aimed to use X-PCI to analyse microstructural features in transmural myocardial samples from patients with advanced heart failure. Six patients were included: two receiving a left ventricular assist device (LVAD) for ischaemic (ICM) and dilated cardiomyopathy (DCM), and four undergoing heart transplantation (HTx), two for the ICM, one for DCM and one for toxic cardiomyopathy. Samples were obtained by left ventricular (LV) apical coring (LVAD group) or from the LV free wall of the explanted hearts (HTx group) and imaged by X-PCI using a multi-scale setup (maximal resolution at 0.65 µm pixel size). The 3D image datasets were analysed via two-dimensional orthogonal cuts in different layers. Visualisation and quantification of the myocyte aggregates orientation showed a disruption in epicardial-to-endocardial transition in DCM, whereas the collagen matrix reconstruction identified characteristic fibrosis patterns amongst different HF aetiologies. In conclusion, X-PCI is a 3D imaging method that can extend the amount of information available from ex-vivo tissue analysis and, as an addition to multimodal imaging protocols, potentially improve disease phenotyping
Prediction hubs are context-informed frequent tokens in LLMs
No full textHubness, the tendency for a few points to be among the nearest neighbours of a disproportionate number of other points, commonly arises when applying standard distance measures to high-dimensional data, often negatively impacting distance-based analysis. As autoregressive large language models (LLMs) operate on high-dimensional representations, we ask whether they are also affected by hubness. We first prove that the only large-scale representation comparison operation performed by LLMs, namely that between context and unembedding vectors to determine continuation probabilities, is not characterized by the concentration of distances phenomenon that typically causes the appearance of nuisance hubness. We then empirically show that this comparison still leads to a high degree of hubness, but the hubs in this case do not constitute a disturbance. They are rather the result of context-modulated frequent tokens often appearing in the pool of likely candidates for next token prediction. However, when other distances are used to compare LLM representations, we do not have the same theoretical guarantees, and, indeed, we see nuisance hubs appear. There are two main takeaways. First, hubness, while omnipresent in high-dimensional spaces, is not a negative property that needs to be mitigated when LLMs are being used for next token prediction. Second, when comparing representations from LLMs using Euclidean or cosine distance, there is a high risk of nuisance hubs and practitioners should use mitigation techniques if relevant.We thank Santiago Acevedo, Luca Moschella, the members of the COLT group at Universitat Pompeu Fabra and the ARR reviewers for feedback and advice. Beatrix M. G. Nielsen was supported by the Danish Pioneer Centre for AI, DNRF grant number P1. Iuri Macocco and Marco Baroni received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 101019291) and from the Catalan government (AGAUR grant SGR 2021 00470). This paper reflects the authors’ view only, and the funding agencies are not responsible for any use that may be made of the information it contains
Control del territorio, medidas represivas y urbicidios en la Corona de Aragón a raíz de la guerra de Sucesión de España (1705-1715)
No full textEste trabajo tiene como objetivo estudiar los mecanismos represivos aplicados en la Corona de Aragón a raíz de la guerra de Sucesión de España, las estrategias político-militares borbónicas utilizadas para someter y asimilar políticamente a su población, así como detectar posibles casos de urbicidio y la razón política y pragmática que los impulsó. Veremos las peculiaridades de este proceso de dominación, las motivaciones que lo precipitaron y si este fue un caso singular o, por el contrario, se puede enmarcar dentro de unas dinámicas represivas que, paralelamente, padecieron otros territorios europeos.This work aims to study the repressive mechanisms applied in the Crown of Aragon following the War of the Spanish Succession, the Bourbon political-military strategies used to subdue and politically assimilate its population, as well as detect possible cases of urbicide and the political and pragmatic reason that drove them. We will see the peculiarities of this process of domination, the motivations that precipitated it and whether this was a singular case or, on the contrary, it can be framed within repressive dynamics that, in parallel, other European territories suffered.Programa de Doctorat en Històri
An EU reponse to authoritarian conflict management in the Middle East? Navigating the rehabilitation-reconstruction-return cycle in Syria
No full textA Model of mammary microvasculature: evaluating hormone responsiveness and luminal-like tumor integration
No full textThis thesis aims to fill gaps in the research on breast microvasculature by creating a perfusable microvasculature system within a microfluidic platform. For the first time, we co-cultured primary breast endothelial cells and fibroblasts to establish mammary-specific microvessels. Using this system, the two main aims are to explore dose-dependent responses of breast microvasculature to sex hormones and integrate luminal-like breast cancer. To achieve the first objective, we simulate different phases of the menstrual cycle by combining varying concentrations of estrogen and progesterone. The evaluation encompasses vascular remodeling, barrier function, and the release of angiogenic factors within the mammary microvasculature. Tissue specificity is ensured by comparing the breast-specific microvasculature with an alternative model using endothelial cells from a different source and breast fibroblasts. In the second aim, a mammary epithelial layer is integrated, mimicking a lactiferous duct. This setup enables us to investigate the barrier properties of the mammary duct, including the influence of hormonal fluctuations and the effects of tamoxifen. Ultimately, luminal-like breast cancer is incorporated into the system alongside the epithelial mammary layer, simulating ductal carcinoma. This addition contributes to a distinctive 3D model and enhances our comprehension of drug delivery dynamics.Esta tesis tiene como objetivo la investigación sobre la microvasculatura mamaria mediante la creación de un sistema de microvasculatura perfusable utilizando una plataforma microfluídica. Por primera vez, co-cultivamos células endoteliales mamarias primarias y fibroblastos para establecer microvasos específicos de la glándula mamaria. Utilizando este sistema, los dos objetivos principales son explorar las respuestas a diferentes dosis de hormones sexuales la microvasculatura mamaria e integrar un cáncer de mama luminal. Para alcanzar el primer objetivo, simulamos diferentes fases del ciclo menstrual combinando concentraciones variables de estrógeno y progesterona. La evaluación abarca la remodelación vascular, la función de barrera y la liberación de factores angiogénicos dentro de la microvasculatura mamaria. Al comparar la microvasculatura de nuestro sistema con un modelo alternativo de células endoteliales de vena umbilical humana (HUVEC) y fibroblastos de mama, observamos que los efectos hormonales son específicos de la microvasculatura mamaria. En el segundo objetivo, se integra un layer epitelial mamario, imitando un conducto lactífero. Esta configuración nos permite investigar las propiedades de barrera del conducto mamario, incluyendo la influencia de las fluctuaciones hormonales y los efectos del tamoxifeno. Finalmente, se introduce un cáncer de mama luminal en el sistema junto a el layer epitelial mamario, simulando un carcinoma ductal. Esta adición contribuye a un modelo 3D distintivo y mejora nuestra comprensión de la dinámica de la entrega de fármacos.Programa de Doctorat en Biomedicin
La presunción de indefinición del contrato de trabajo temporal por no respetarse su forma escrita
No full textEl presente estudio tiene por objeto analizar el artículo 8.2 del Estatuto de los Trabajadores que presume por tiempo indefinido y a jornada completa al contrato de trabajo temporal que no observe la exigencia de forma escrita a no ser que el empresario pruebe su naturaleza temporal o el carácter a tiempo parcial de los servicios. Se trata ésta de una previsión normativa con una larga tradición histórica, pero de difíciles contornos. Sin embargo, tras analizar su régimen jurídico se concluye que no estamos ante una presunción sino más bien ante una ficción legal porque de la inobservancia de la forma escrita en un contrato de trabajo temporal no se deduce ni se desprende que el mismo fuera indefinido. Y si el fin de la norma es controlar el uso adecuado y no fraudulento de la contratación temporal, resulta criticable que se permita a la empresa probar la naturaleza temporal del contrato
Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers
No full textThe mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.This project was funded by PID2021-123300NB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE to F.S and M.C.; 2021SGR00293 from the Agency for the Management of University and Research Grants (Generalitat de Catalunya) to M.C.; PID2021-122551OB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE to I.F.; and FPU20/01473 from the Spanish Ministerio de Universidades to P.L.G. We thank R. Guigó for financial support to M.R.R. and R.N. through grant PID2021-128956NB-I00 funded by MCIN/AEI/10.13039/501100011033/FEDER, UE. M.R.R. and R.N. acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S and MCIN/AEI/10.13039/501100011033) and the Generalitat de Catalunya through the CERCA program
The associations of childhood adversities and mental disorders with suicidal thoughts and behaviors - Results from the World Mental Health International College Student Initiative
No full textObjective: To investigate the associations of demographic variables, childhood adversities (CAs), and mental disorders (MDx) with onset, transition, and persistence of suicidal thoughts and behaviors (STB) among first-year university students. Method: Poisson regression models within a discrete-time survival framework were constructed using web-based self-report survey data from 72,288 incoming university students across 18 countries (response rate=20.9%; median age=19 years, 57.9% female, 1.4% transgender, 21.0% non-heterosexual). These models examined the associations of four demographic variables, five CAs, and eight MDx with STB outcomes. Results: Lifetime prevalence of suicidal ideation, plans, and attempts was 47.0%, 26.0%, and 9.6%, respectively; 12-month estimates were 30.6%, 14.0%, and 2.3%. In unadjusted analyses, associations were strongest between lifetime onset of suicidal ideation and CAs (RR range 4.4-7.0), particularly parental psychopathology (relative risk [RR]=7.0 [95% CI 6.5-7.7]), followed by MDx (RR range 1.3-3.0). Of the demographic subgroups, transgender students had highest risk of STB (lifetime ideation onset RR=2.4 [2.3-2.6]; ideation-to-attempt transition RR=1.5 [1.3-1.8]). In fully adjusted models, strongest predictors of lifetime ideation onset were emotional abuse (RR=2.1 [1.9-2.2]), major depressive disorder (RR=2.0 [1.9-2.1]), and bipolar disorder (RR=1.8 [1.6-2.0]). Ideation-to-attempt transition remained most strongly associated with panic disorder (RR=1.5 [1.3-1.7]), bipolar disorder (RR=1.4 [1.2-1.7]), and sexual abuse (RR=1.4 [1.2-1.7]). Most predictors were significantly but weakly associated with persistence of ideation and plan, while only physical abuse remained associated with repeated suicide attempts (RR=1.3 [1.0-1.8]). Conclusion: CAs and MDx are strong predictors of both onset of and transition within the STB spectrum, underscoring the importance of implementing early-life prevention interventions
El debate sobre la gestación subrogada en el contexto español: entre la prohibición y la realidad social
No full textTreball de Fi de Grau en Dret. Curs 2024-2025Tutor: Ángel Serrano de NicolásDe acuerdo con el artículo 10 de la Ley 14/2006, la gestación subrogada está expresamente prohibida en España. Sin embargo, su creciente presencia a nivel internacional y la realidad de muchas familias que recurren a esta técnica en el extranjero han intensificado el debate jurídico, ético y social en España. Este trabajo analiza el marco legal vigente, así como las implicaciones que ello conlleva en términos de filiación, derechos del menor, reconocimiento registral y protección de los derechos de la madre gestante. Asimismo, se analiza la jurisprudencia más relevante del Tribunal Supremo y las principales leyes e instrucciones de la DGRN (actualmente, DGSJFP) que regulan esta materia, llegando a la conclusión de que existe una grave discrepancia entre la normativa y su aplicación práctica. A través de las sentencias más relevantes del Tribunal Supremo vemos como éste ha endurecido progresivamente su postura, siempre manifestando una clara oposición hacia esta práctica y reafirmando su nulidad e ilegalidad en nuestro ordenamiento jurídico. Finalmente, cabe destacar la nueva instrucción de la DGSJFP, la cual endurece los criterios para inscribir las filiaciones por gestación subrogada en el extranjero que venían estableciendo sus predecesoras, las cuales ha derogado.According to article 10 of Law 14/2006, surrogacy is expressly prohibited in Spain. However, its growing international presence and the reality of many families who resort to this technique abroad have intensified the legal, ethical and social debate in Spain. This paper analyses the current legal framework, as well as the implications that this entails in terms of filiation, the rights of the minor, registry recognition and protection of the rights of the gestational mother. It also analyses the most relevant case law of the Supreme Court and the main laws and instructions of the DGRN (currently, DGSJFP) that regulate this matter, reaching the conclusion that there is a serious discrepancy between the regulations and their practical application. Through the most relevant rulings of the Supreme Court, we can see how it has progressively hardened its position, always expressing clear opposition to this practice and reaffirming its nullity and illegality in our legal system. Finally, it is worth mentioning the new instruction of the DGSJFP, which tightens the criteria for registering surrogacy filiations abroad that had been established by its predecessors, which it has repealed