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Workflow management applications for comparative omics
No full textEl crecimiento explosivo de los datos biológicos exige soluciones computacionales que sean escalables, reproducibles y robustas. Los sistemas de gestión de flujos de trabajo (workflows), especialmente cuando se combinan con la contenedorización, abordan estos desafíos al automatizar, paralelizar y estandarizar análisis bioinformáticos complejos. En esta tesis exploro las aplicaciones de dichos sistemas en la ómica comparativa, con un enfoque en el desarrollo e implementación de canalizaciones (pipelines) reutilizables dentro de la comunidad nf-core. A través del estudio piloto TANGO1, que investigó la región transmembrana de la proteína TANGO1, se identificaron y abordaron varias necesidades computacionales críticas mediante soluciones personalizadas de flujos de trabajo. Estas incluyen REPORTHO y MULTIPLESEQUENCEALIGN para la recuperación y alineamiento de ortólogos, PARALOGS para el análisis filogenético de familias génicas, y STIMULUS para la selección de modelos en aprendizaje automático. En conjunto, estos proyectos ilustran cómo los gestores de flujos de trabajo potencian la investigación biológica al mejorar la reproducibilidad, la eficiencia y la integración de datos en diversas aplicaciones ómicas.The explosive growth of biological data demands computational solutions that are scalable, reproducible, and robust. Workflow management systems, especially when combined with containerization, address these challenges by automating, parallelizing, and standardizing complex bioinformatics analyses. In this thesis I explore the applications of such systems in comparative omics, with a focus on the development and implementation of reusable pipelines within the nf-core community. Through the TANGO1 pilot study, which investigated the transmembrane region of the TANGO1 protein, several critical computational needs were identified and addressed via custom workflow solutions. These include REPORTHO and MULTIPLESEQUENCEALIGN for ortholog retrieval and alignment, PARALOGS for phylogenetic analysis of gene families, and STIMULUS for model selection in machine learning. Together, these projects illustrate how workflow managers empower biological research by enhancing reproducibility, efficiency, and data integration across diverse omics applications.Universitat Pompeu Fabra. Doctorat en Biomedicin
FoldX force field revisited, an improved version
No full textMotivation: The FoldX force field was originally validated with a database of 1000 mutants at a time when there were few high-resolution structures. Here, we have manually curated a database of 5556 mutants affecting protein stability, resulting in 2484 highly confident mutations denominated FoldX stability dataset (FSD), represented in non-redundant X-ray structures with <2.5 Å resolution, not involving duplicates, metals, or prosthetic groups. Using this database, we have created a new version of the FoldX force field by introducing pi stacking, pH dependency for all charged residues, improving aromatic-aromatic interactions, modifying the Ncap contribution and α-helix dipole, recalibrating the side-chain entropy of methionine, adjusting the H-bond parameters, and modifying the solvation contribution of tryptophan and others. Results: These changes have led to significant improvements for the prediction of specific mutants involving the above residues/interactions and a statistically significant increase of FoldX predictions, as well as for the majority of the 20 aa. Removing all training sets data from FSD [Validation FoldX Stability Dataset (VFSD) dataset] resulted in improved predictions from R = 0.693 (RMSE = 1.277 kcal/mol) to R = 0.706 (RMSE = 1.252 kcal/mol) when compared with the previously released version. FoldX achieves 95% accuracy considering an error of ±0.85 kcal/mol in prediction and an area under the curve = 0.78 for the VFSD, predicting the sign of the energy change upon mutation. Availability and implementation: FoldX versions 4.1 and 5.1 are freely available for academics at https://foldxsuite.crg.eu/
Semantic consistency in RAG: evaluating modern encoder-only models on active and passive voice in english and russian
No full textTreball de fi de màster en Lingüística Teòrica i Aplicada. Directora: Dra. Núria BelRetrieval-Augmented Generation (RAG) systems depend on dense embeddings to retrieve relevant context for open-domain question answering. A critical requirement for these embeddings is semantic consistency – the ability to remain stable across meaning-preserving variation. This study examines how modern encoder-only models handle active/passive voice alternations in English and Russian. Using a bilingual dataset of 500 factual question pairs, we evaluate semantic consistency (Overlap@K) and retrieval quality (MRR, Recall@K) in raw and fine-tuned versions of EuroBERT and RuModernBERT. Findings show that representations of raw encoders are only partially semantic: they are sensitive to word order, morphology, and query length. Consistency was significantly higher in English, indicating that morphologically rich languages like Russian are more challenging. EuroBERT performed poorly on Russian due to limited training exposure and subword fragmentation.
RuModernBERT performed better on Russian passives, likely reflecting its training data. Contrastive fine-tuning substantially improved performance, though not all fine-tuned models benefited equally – EuroBERT_FT and LaBSE showed limitations tied to tokenization and training objectives
Worlds apart: The impact of (in)congruence on electoral behaviour: When voters and parties do not align
No full textThis thesis provides a comprehensive analysis of the impact of ideological incongruence between voters and political parties on electoral behaviour in European democracies. It introduces a novel approach to measuring the ideological distances within party systems, demonstrating that greater incongruence leads to higher voter abstention rates. The research further investigates how information on ideological proximity affects voters' participation and the congruence of their voting choices, revealing that while informed voters are more likely to participate, their specific voting decisions remain unaffected. Additionally, the study examines the consequences of voters' perceived detachment from political parties, showing that a lack of ideologically proximate parties significantly reduces electoral participation. These findings highlight the importance of ideological alignment for democratic engagement and suggest that improving voter-party congruence could mitigate voter disengagement and abstention, thereby improving the quality of political representation and the robustness of electoral democracies.Aquesta tesi doctoral proporciona una anàlisi completa de l'impacte de la incongruència ideològica entre els votants i els partits polítics en el comportament electoral a les democràcies europees. Introdueix un nou enfocament per mesurar les distàncies ideològiques en un sistema de partits, i demostra que una major incongruència ideològica condueix a taxes més altes d'abstenció electoral. La recerca investiga, a més, com donar informació als votants sobre la proximitat ideològica afecta la seva participació electoral i la congruència de les seves opcions de vot, mostrant que, tot i que els votants informats tenen més probabilitats de participar, les seves decisions específiques de vot no es veuen afectades. A més, l'estudi examina les conseqüències de la percepció de desvinculació dels votants amb els partits polítics, concloent que la manca de partits ideològicament propers redueix significativament la participació electoral. Les troballes de la tesi doctoral posen de manifest la importància de l'alineació ideològica per al compromís democràtic i suggereixen que la millora de la congruència entre votants i partits podria mitigar la desvinculació i l'abstenció dels votants, millorant en última instància la qualitat de la representació política i la robustesa de les democràcies electorals.Programa de Doctorat en Ciències Polítiques i Social
Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing
No full textWhile altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including patient-customised treatments for rare diseases, but AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that deep indel mutagenesis (DIM) -which can be made experimentally at very low cost - provides an efficient strategy to chart the regulatory landscape of human exons and rapidly identify candidate splicing-modulating oligonucleotides. DIM reveals autonomous effects of insertions, while systematic deletion scans delineate the checkerboard architecture of sequential enhancers and silencers in a model alternative exon. The results also suggest a mechanism for repression of transmembrane domain-encoding exons and for the generation of microexons. Leveraging deep learning tools, we provide a resource, DANGO, that predicts the splicing regulatory landscape of all human exons and can help to identify effective splicing-modulating antisense oligonucleotides.This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreements 670146 and 883742) and from the European Union's Horizon Europe under the grant agreement No 101071936. We also acknowledge support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme. We are grateful to the CRG Core Technologies Programme for their support and assistance in this work. We received funding from the Spanish State Research Agency (PID2020-114630GB-I00/AEI/10.13039/501100011033), LCF/PR/HR21/52410004, EMBL Partnership, the Bettencourt Schueller Foundation, the AXA Research Fund, and Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322). GQ was supported by PRE2022-102744, financed by MCIN/AEI/10.13039/501100011033 and FSE + . J.C. is funded by the BBSRC DTP (Bio-technology and Biological Sciences Research Council, Biosciences Doctoral Training Programme, Cambridge, UK. The Genotype-Tissue Expression (GTEx) data used for the analyses described in this manu-script were obtained from the GTEx Portal on May 8, 2018 and dbGaP accession number phs000424.v7.p2 on May 8, 2018. The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Funded by the European Union. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them
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No full textLa obligación de prevenir violaciones de derechos humanos frente a daños ambientales (climáticos) transfronterizos en el medio ambiente marino
No full textTreball de Fi de Màster: Màster Avançat en Ciències Jurídiques. Curs 2024-2025Tutor: Ángel J. Rodrigo HernándezEl presente trabajo examina la obligación de los Estados de prevenir violaciones de derechos humanos ocasionadas por daños ambientales transfronterizos en el medio ambiente marino, particularmente en el contexto del cambio climático. Partiendo del reconocimiento jurídico del nexo océano -clima y su impacto sobre diversos derechos humanos, se argumenta que los Estados pueden incurrir en responsabilidad internacional por omisión frente a los efectos extraterritoriales de sus emisiones de gases de efecto invernadero. En ese sentido, se plantea una concepción ampliada de la jurisdicción extraterritorial que permita responder adecuadamente a las particularidades del daño ambiental climático. Se sostiene que los Estados tienen la obligación de actuar con debida diligencia para prevenir tales violaciones, incluso más allá de sus fronteras, siempre que tengan control efectivo sobre la fuente del daño. El análisis de dicha obligación comprende su fundamento normativo; naturaleza jurídica; contenido normativo; supuesto de hecho y limitaciones. Se propone un marco interpretativo que permita avanzar en la justiciabilidad de las afectaciones climáticas a los derechos humanos en contextos marinos transfronterizos.This paper examines the obligation of States to prevent human rights violations caused by transboundary environmental damage to the marine environment, particularly in the context of climate change. Based on the legal recognition of the ocean -climate nexus and its impact on various human rights, it argues that States may incur international responsibility for omission in relation to the extraterritorial effects of their greenhouse gas emissions. In this regard, an expanded conception of extraterritorial jurisdiction is proposed that allows for an adequate response to the particularities of climate -related environmental damage. It is argued that States have an obligation to act with due diligence to prevent such violations, even beyond their borders, provided that they have effective control over the source of the damage. The analysis of this obligation includes its normative basis; legal nature; normative content; factual assumption; and limitations. An interpretative framework is proposed to advance the justiciability of climate -related human rights impacts in transboundary marine contexts
Acral melanoma in the Caucasian population: A comprehensive cohort study on epidemiological, clinicopathological, and prognostic features
No full textArticle disponible en castellà: http://hdl.handle.net/10230/71245Background: Acral melanoma is associated with poor prognosis. Studying the characteristics and prognosis of Caucasian patients is crucial to understand the distinct features of this tumor. Objectives: To analyze the epidemiological, clinicopathological, and prognostic features of acral melanoma in Caucasian patients. Methods: We conducted a retrospective, multicenter, cohort study of acral melanoma from a database across 20 hospitals from South Europe from January 2000 to December 2019. Results: A total of 733 acral melanomas were identified (median age, 67.5 years; 95.2%, Caucasians; 77.5% of which were located on the feet). Overall, 77.5% of cases were invasive melanomas. Foot melanomas had a higher proportion of invasive cases (80.8% vs 69.8%; p=0.003), stages III and IV at diagnosis (24.8% vs 11.7%; p<0.001), thicker Breslow depth (2.8mm vs 2.0mm; p=0.021) and a higher rate of positive sentinel lymph node biopsy (SLNB) (30.7% vs 15.7%; p=0.012). Thicker Breslow depth and later age of onset were risk factors for melanoma-specific survival. Thicker Breslow depth and ulceration were independent prognostic factors of relapse-free survival. Melanoma location and histopathological subtype were not associated with worse prognosis. Recurrences were a common finding (27.7%), with distant metastases appearing earlier than locoregional recurrences (1.32 years [IQR, 1.12-1.87] vs 2.14 years [IQR, 1.68-2.70]; p=0.015). Conclusion: This study, the largest in a predominantly Caucasian population, underscores the unfavorable outcomes of acral melanoma. Foot melanomas exhibited delayed detection, increased invasiveness, thicker Breslow depth, increased SLNB involvement, and higher AJCC stages. The high recurrence rate and early distant metastases emphasize the critical role of intensive follow-up and routine imaging modalities to detect asymptomatic relapses.Melanoma research at Hospital Universitari Arnau de Vilanova of Lleida was supported by grants from ISCIII/FEDER “Una manera de hacer Europa” (PI18/00573 & PI21/00294 to R.M. Marti), CIBERONC-CB16/12/00231, and Generalitat de Catalunya (2021/SGR0093). The research at the Melanoma group in Hospital Clinic Barcelona is supported by the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; AGAUR 2017_SGR_1134 and CERCA Programme by Generalitat de Catalunya, Spain; a Research Grant from “Fundación Científica de la Asociación Española Contra el Cáncer” GCB15152978SOEN, Spain; European Commission under the sixth Framework Programme, Contract No. LSHC-CT-2006-018702 (GenoMEL), by the European Commission under the seventh Framework Programme, Diagnoptics; the European Commision under the HORIZON2020 Framework Programme, iTobos and Qualitop; and European Commission under the Horizon Europe Programme, HORIZON-MISS-2021-CANCER-02, MELCAYA (reference 101096667). This research was in part supported by grants from Fondo de Investigaciones Sanitarias P.I. 18/00419 and 22/01467 Spain. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. J. Angel-Baldo held a predoctoral fellowship from IRBLleida/Diputació de Lleida
The European Union as a hyper-complex system. Tackling expertise and legitimacy: toward a competent democracy
No full textThis thesis explores the democratic legitimacy of the European Union, focusing on how it can be reformed to address the challenges posed by its hyper-complex structure. The work examines the tension between the growing reliance on expert knowledge in EU governance and the need to maintain democratic principles. By analysing the concepts of political legitimacy, the democratic deficit, and the role of expertise, the thesis investigates whether a model of "competent democracy" can reconcile these conflicting demands. The study suggests that a balance between technical competence and democratic representation is essential for the EU’ s legitimacy. A theoretical model is proposed, advocating for professionalised politics, where elected representatives are sufficiently trained to navigate complex governance issues while avoiding the pitfalls of technocracy.Esta tesis explora la legitimidad democrática de la Unión Europea, centrándose en cómo puede reformarse para enfrentar los desafíos que plantea su estructura hipercompleja. El trabajo examina la tensión entre la creciente dependencia del conocimiento experto en la gobernanza de la UE y la necesidad de mantener los principios democráticos. A través del análisis de los conceptos de legitimidad política, déficit democrático y el papel de los expertos, la tesis investiga si un modelo de "democracia competente" puede reconciliar estas demandas conflictivas. El estudio sugiere que un equilibrio entre la competencia técnica y la representación democrática es esencial para la legitimidad de la UE. Se propone un modelo teórico que aboga por una profesionalización de la política, donde los representantes elegidos estén suficientemente capacitados para manejar problemas complejos sin caer en la tecnocracia.Programa de Doctorat en Dre