43569 research outputs found
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The excess of carriers in rare disorders suggests a nonpathogenic effect for most variants of uncertain significance
No full textFunctional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect
Diverse real-life outcomes after intensive risk-adapted therapy for 1034 AML patients from the CETLAM Group
No full textGiven the heterogeneity of acute myeloid leukemia patients, it is necessary to identify patients considered fit for intensive therapy but who will perform poorly, and in whom alternative approaches deserve investigation. We analyzed 1034 fit adults ≤70 years intensively treated between 2012 and 2022 in the CETLAM group. Young adults ( ≤ 60 years) presented higher remission rates and improved survival than older adults above that age (CR 79% vs. 73%; p = 0.03 and 4-yr OS 53% vs. 33%; p < 0.001). Remission and survival outcomes varied among different genetic subsets. An especially adverse genetic group included complex, monosomal karyotype, TP53 alterations (deleted/mutated), and MECOMr. Transplant feasibility in this very adverse risk group was low, and OS and EFS at 4 years were 14% and 12%, in contrast to 70% and 57% in the favorable group and 38% and 32% in all other patients. We integrated clinical and genetic data into the Intensive Chemotherapy Score for AML (ICSA) with 6-risk categories with significantly different remission rates and OS, validated in another cohort of 581 AML patients from a previous CETLAM protocol. In summary, we identified groups of fit patients that benefit differently from an intensive approach which may be helpful in future treatment decisions
A High-performance computational framework for multiscale and multiphysics modelling of the intervertebral disc
No full textThis thesis develops a multiscale and multiphysics model of the intervertebral disc (IVD); it focuses on three main axes regarding:
Mechanical response: It introduces a compatible porohyperelastic framework capable of capturing the mechanics underlying the physiological functioning of the IVD. Validation confirms the framework's accuracy in simulating the IVD's poromechanical response.
Nutrient environment: It simulates cellular metabolic activity, integrating the effects of the deformable domain by including diffusive and advective terms.
Cellular response: It models indirect mechanotransduction response using parallel networks, predicting the mRNA expression of different structural proteins and proteases depending on the level of inflammation of the IVD cells. This results in 3D maps of cellular activity throughout the Nucleus Pulposus (NP).
The coupled models are integrated into the multiphysics Finite element-based code Alya, adapting and optimising the simulation for High-Performance Computing frameworks, reducing computational times, and allowing future studies of virtual populations.Esta tesis desarrolla un modelo multiescala y multifísica del disco intervertebral (IVD) centrada en tres ejes principales:
Respuesta mecánica: Desarrolla un marco porohiperelástico compatible, capaz de capturar la mecánica subyacente al funcionamiento fisiológico del IVD. La validación confirma la precisión del marco al simular la respuesta del IVD.
Entorno nutritivo: Se simula la actividad metabólica celular, integrando de manera innovadora los efectos de un dominio deformable con términos difusivos y advectivos.
Respuesta celular. Se modela respuesta la mecanotransducción indirecta mediante redes paralelas. prediendo la expresión de mRNA de diferentes proteínas estructurales y proteasas, en función del nivel de inflamación de las células del IVD dando lugar a la obtención de un mapa espacio-temporal de la actividad celular en todo el NP.
Todo ello se integra en el código multifísico Alya, adaptando y optimizando la simulación para HPC reduciendo los tiempos de computación y permitiendo futuros estudios de poblaciones virtuales.Programa de Doctorat en Tecnologies de la Informació i les Comunicacion
The molecular mechanism of spindle pole focusing: NuMA as a dynein adaptor and microtubule minus end regulator
No full textThis project investigates the molecular mechanisms underlying chromosome segregation during eukaryotic cell division. Specifically, it explores the role of the motor protein cytoplasmic dynein 1 in maintaining metaphase spindle integrity by clustering microtubule minus ends into focused poles. We conducted in vitro assays using purified proteins and total internal reflection fluorescence (TIRF) microscopy to show that the nuclear mitotic apparatus (NuMA) protein acts as a dynein adaptor. NuMA triggers dynein's processive motility, supported by the cofactors dynactin and lissencephaly 1 (Lis1). In addition, NuMA selectively arrests the growth of microtubule minus ends, binding preferentially to those not capped by the microtubule nucleator γ-tubulin ring complex (γTURC). It can also bind to new minus ends freshly generated by laser ablation. Finally, we showed that the dynein/dynactin/NuMA complex can transport microtubule minus ends. These findings clarify the interplay of dynein, dynactin, NuMA, and Lis1 in organizing spindle poles during cell division.Este proyecto investiga los mecanismos moleculares detrás de la segregación cromosómica en la división celular eucariota, enfocándose en la proteína motora dineína citoplasmática 1 y su rol en mantener la integridad del huso mitótico en metafase. Mediante ensayos in vitro con proteínas purificadas y microscopía de reflexión interna total de fluorescencia (TIRF), demostramos que la proteína del aparato mitótico nuclear (NuMA) actúa como adaptador de la dineína, activando su motilidad procesiva junto a los cofactores dinactina y lissencefalina 1 (Lis1). Además, NuMA detiene selectivamente el crecimiento de los extremos negativos de microtúbulos, prefiriendo aquellos no cubiertos por el nucleador de microtúbulos complejo anular de γ-tubulina (γTURC). También se puede unir a los extremos negativos recién generados por ablación láser. Finalmente, mostramos que el complejo dineína/dinactina/NuMA transporta extremos negativos. Estos hallazgos aclaran la interacción de dineína, dinactina, NuMA y Lis1 en la organización de los polos en la mitosis.Programa de Doctorat en Biomedicin
Understanding and targeting mitochondria to counteract cellular senescene: elucidation of novel senotherapies
No full textThe pathologic role of senescent cells is well established in a variety of diseases. Despite the ample evidence that mitochondria play a central role in cellular senescence, the understanding of the adaptations in the mitochondria of senescent cells is rather superficial. In this work, we have characterized that senescent cells display a substantial increase in mitochondrial mass and mtDNA copies, coupled to reduced mitochondrial membrane potential, increased ROS levels and hyperfusion. Comparative proteomic analyses showed significant changes in the composition and quantity of mitochondrial proteins, in particular, increased levels of proteins related to fatty acid β-oxidation and ATP synthesis. Our results demonstrate the involvement of the mtdsRNA/MAVS/MFN1 axis as an important source of the inflammatory phenotype of senescent cells. Inhibition of mitochondrial RNA polymerase, dsRNA sensors, MAVS or MFN1 result in SASP reduction. Our study further identified PPIF/CypD as a promising senolytic target through CRISPR/Cas9-based screening, whose inhibition has shown efficiency in eliminating senescent cells. Altogether, these findings identify potential senescence mitochondrial vulnerabilities and open new avenues for treating senescence-associated disorders.El papel patológico de las células senescentes está bien establecido en una variedad de enfermedades. A pesar de la amplia evidencia sobre el papel central que las mitocondrias desempeñan en la senescencia celular, la comprensión de las adaptaciones en las mitocondrias de las células senescentes es bastante superficial. En este trabajo hemos caracterizado que las células senescentes muestran un aumento sustancial en la masa mitocondrial y copias de ADN mitocondrial, junto con un potencial de membrana mitocondrial reducido, niveles aumentados de ROS e hiperfusión. Los análisis proteómicos mostraron cambios significativos en la composición y cantidad de proteínas mitocondriales, en particular, mayores niveles de proteínas relacionadas con la β-oxidación de ácidos grasos y la síntesis de ATP. Nuestros resultados demuestran la participación del eje mtRNA bicatenario(bc)/MAVS/MFN1 como una fuente importante del fenotipo inflamatorio de las células senescentes. La inhibición de la ARN polimerasa mitocondrial, los sensores de RNAbc, MAVS o MFN1 todos resultan en una reducción del SASP. Nuestro estudio identificó además PPIF/CypD como un objetivo senolítico prometedor a través de la detección basada en CRISPR/Cas9, cuya inhibición ha demostrado eficiencia en la eliminación de células senescentes. En conjunto, estos hallazgos identifican posibles vulnerabilidades mitocondriales en células senescentes y abren nuevas vías para el tratamiento de los trastornos asociados a la senescencia.Programa de Doctorat en Biomedicin
Assessing the Impact of Barcelona’s Superblocks on Housing Rental and Sale Prices
No full textTreball fi de màster de: Master in Intelligent Interactive SystemsSupervisor: Tomas Andrade WeberAcademic tutor: Vicenç Gómez CerdàThe Barcelona Superblock Programme is designed to improve environmental quality and public health by giving back private vehicle space to pedestrians, carrying out street pedestrianisation and the creation of green areas. This thesis studies how these interventions affect housing prices, focusing on the cases of the Poblenou and Sant Antoni Superblocks. We use a Difference-in-Differences design with Two-Way Fixed Effects to estimate changes in both rental and sale prices after the implementation of Superblocks (SBs). The design combines matched control groups with multiple model variants, and robustness is evaluated through placebo tests. Combining two data sources; Idealista, an online private real estate listing platform, and Gencat, the official database of actual transactions, we are able to assess the differences between these two sources and further contextualise the impact of the SBs. Results from Idealista show robust increases in both rental and sale prices in Poblenou, while in Sant Antoni, we do not find robust evidence of an impact on rental prices. Gencat-based estimates are generally more sensitive to model choice and sample limitations. Understanding the impact of urban interventions on housing prices is necessary. If Superblocks raise local prices, they may lead to unintended consequences like population displacement or a reduction in affordability. At the same time, price increases can reflect improved neighbourhood quality. This study not only quantifies those effects but also provides a framework for evaluating urban policy impacts on housing markets
Prisión permanente revisable: la vulneración constitucional avalada
No full textTreball de Fi de Grau en Dret. Curs 2024-2025Tutor: Jesús Becerra BriceñoLa creciente inquietud de la sociedad ante delitos de especial gravedad supuso la consideración de una respuesta punitiva más severa. En este contexto, se aprobó la Ley Orgánica 1/2015 que introdujo la prisión permanente revisable en nuestro ordenamiento jurídico reservada para delitos de excepcional gravedad y con el objetivo de reforzar la seguridad ciudadana y la confianza en el sistema judicial. Sin embargo, su introducción ha suscitado un intenso debate jurídico y doctrinal, enfrentando posiciones sobre su compatibilidad con los principios constitucionales y con los Derechos fundamentales. Mientras que sus defensores argumentan que es un mecanismo necesario para castigar los crímenes más atroces y proteger a la sociedad, sus opositores sostienen que constituye una forma encubierta de cadena perpetua, incompatible con el artículo 15 de la Constitución Española, que prohíbe penas inhumanas o degradantes, así como con el artículo 25.2, que establece la reinserción social como fin primordial de las penas. Asimismo, se ha cuestionado su adecuación a los principios de proporcionalidad y dignidad humana consagrados también en nuestra Carta Magna, de igual modo que su eficacia real en la reducción de la criminalidad y la reincidencia
The UN’s sustainable development goals 3 and 5 in the United States of America: access to culturally competent healthcare for Arab Muslim women in the US: an intersectional approach
No full textTreball guanyador del segon premi del 2025 en Benestar Planetari convocat conjuntament per la UPF, la UPF-BSM i la càtedra UNESCO de Cicle de Vida i Canvi Climàtic ESCI-UPF, al millors treballs de fi de grau (TFG) sobre temes de Benestar Planetari.Bachelor's degree in Global Studies. Curs 2024-2025Tutor: Antoni Luna GarciaThis dissertation investigates the barriers to accessing quality, culturally competent healthcare for Arab Muslim women in the United States. Positioned at the intersection of ethnicity, religion, and gender, these women face unique challenges shaped by both internal factors, such as cultural and religious norms, modesty concerns, and familial roles, and external factors, including Islamophobia, discrimination, sexism, and systemic gaps in healthcare provision. The United States is a pluralistic nation where various cultures coexist; however, disparities persist among them. The increasing Muslim population in the United States necessitates a nuanced understanding of their healthcare needs, particularly among subgroups like Arab Muslim women facing unique challenges. They remain underrepresented in health research and invisible in national data sets. Employing intersectionality and cultural competence frameworks, the study analyzes how overlapping systems of oppression exacerbate health disparities for this demographic. The work is situated within the framework of the United Nations Sustainable Development Goals (SDGs), focusing on SDG 3 (Good Health and Well-being) and SDG 5 (Gender Equality), and critically evaluates the United States' progress in meeting these goals. Through a review of literature, analysis of policy, and incorporation of expert insights, the research reveals significant shortcomings in the U.S. healthcare system and highlights the urgent need for culturally sensitive and gendered interventions. Questions of health are inseparable from questions of culture and gender when it comes to successfully implementing the right policies; hence, it is imperative to evaluate them together within the framework of the United Nations’ Sustainable Development Goals and its principle of “Leave No One Behind”. Addressing the specific needs of Arab Muslim women is essential for promoting genuine health and gender equity and ensuring that, indeed, no one is left behind in the quest for universal access to quality healthcare
Preschoolers mark focus types through multimodal prominence: further evidence for the precursor role of gestures
No full textThe present cross-sectional study assessed the role of multimodal cues in marking focus types during early childhood, focusing on prosodic prominence, gesture presence, and gestural prominence. A total of 116 Catalan-speaking three-, four- and five-year-olds participated in a semi-controlled interactive task eliciting words in three focus conditions: information, contrastive, and corrective. The data were coded manually using holistic assessments for all three measures. The results indicated, first, that children’s prosodic and gestural behavior was key in marking corrective focus. A significant tendency to use more gestures and increase both prosodic and gestural prominence was found in the corrective focus condition across the three age groups. Second, a developmental difference emerged in the acquisition of contrastive focus. Three-year-olds relied solely on gesture presence to encode contrastive focus, being unable to differentiate it prosodically from information focus. In turn, four- and five-year-olds used both gestures and prosody, with contrastive focus not only receiving more gestures than information focus but also increased prosodic prominence. This finding shows that gesture presence is a precursor to prosodic prominence in marking contrastive focus in Catalan, thus supporting the idea that gesture production can bootstrap the expression of focus type distinctions.This research was funded by grant PID2020-115385GA-I00, financed by MCIN/AEI/10.13039/501100011033 and by the European Regional Development Fund (ERDF), by the European Union. It was also supported by the grant AGAUR-FI Joan Oró 2025FI_B 00342, funded by the Agency for Management of University and Research Grants (Generalitat de Catalunya) together with the European Social Fund (ESF), by the European Union. The APC was funded by grants PID2021-123823NB-I00 and PID2020-115385GA-I00, financed by MCIN/AEI/10.13039/501100011033 and by the European Regional Development Fund (ERDF), by the European Union
The UN sustainable development goal 2.1 in the Socialist Republic of Vietnam: an assessment of urban food (in)security in Ho Chi Minh city
No full textBachelor's degree in Global Studies. Curs 2024-2025Tutor: Xavier Ortells-NicolauThe following research aims to analyse the situation regarding food (in)security within the framework of the United Nations Sustainable Development Goal 2 “Zero Hunger” and its corresponding target 2.1 in Ho Chi Minh City (Socialist Republic of Vietnam). The mixed-methods strategy that allows the mixture of quantitative and qualitative data not only provides a more accurate depiction of the matter, but also permits the combination of indicators, indexes and other numerical tools of investigation with qualitative review of the political discourse. Careful research is conducted in order to determine the current scenario globally, regionally, nationally and locally, as well as its evolution over the last years. In addition to the academic bibliography, the impact of governmental policies and the role of civil society, including food charity organisations, in guaranteeing food supplies is assessed at a local level. Major priority is given to those suffering from urban poverty, who are the most exposed to be left behind and experience with higher acuity the drawbacks of growth. The results determine whether the Vietnamese metropolis is performing in the right direction to achieve sustainable development and give place to conclude proposing a set of measures to improve its performance and commitment to Agenda 2030