Investigación de la distribución de los alelos HLA en poblaciones sanas y enfermas mediante la aplicación de nuevas metodologías de secuenciación

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Inmunología, Oftalmología y ORL, leída el 09/03/2021Increasing our knowledge of the HLA system, including both the complete sequence description and the assessment of its diversity at the worldwide human population-level, is of great importance for elucidating the molecular functional mechanisms of the immune system and its regulation in health and disease. Furthermore, assessment of HLA allelic and haplotypic diversity of each human population is essential in the clinical histocompatibility and transplantation setting as well as in the pharmacogenetics, immunotherapy and anthropology fields. Nevertheless, the inherent vast polymorphism and high complexity presented by the HLA system have been an important challenge for its unambiguous and in-depth (high-resolution) characterization by previously available legacy molecular HLA genotyping methods (e.g. SSP, SSO and even SBT). Recent application of novel next-generation sequencing (NGS) technology for high-resolution molecular HLA genotyping has enabled to obtain, at a high-throughput mode and larger scale, full-length and/or extended sequences and genotypes of all major HLA genes, thus overcoming most of these previous limitations. Objectives: I) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a first representative cohort of the Spanish population that could also serve as a healthy control reference group. Respective statistical analyses were performed for this immunogenetic population data. II) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a respective cohort of multiple sclerosis (MS) patients in the Spanish population (recruited at the Department of Neurology, Hospital Clínic, Barcelona, Catalonia, Spain). A first case-control study was carried out to examine HLA-disease associations with MS in these Spanish population cohorts as well as to attempt a fine-mapping of these allele and haplotype associations by full gene resolution level via NGS. In addition, a second analysis exercise (i.e. test case) of this case-control study was carried out using an alternative healthy control group dataset, exclusively from the Spanish northeastern region of Catalonia in this second case, to evaluate possible differences in the findings of HLA-disease association with MS due to plausible regional HLA genetic variation within mainland Spain (i.e. as a statistical way to try controlling for any possible existing population stratification)...El estudio del sistema HLA, incluyendo la descripción completa de su secuencia y de la diversidad de este complejo HLA a nivel poblacional, es de gran importancia de cara a poder entender los mecanismos moleculares y funciones del sistema inmune así como su regulación en individuos sanos y enfermos. Además, la caracterización exhaustiva de la diversidad de alelos y haplotipos HLA de cada población humana es esencial en el campo de la inmunología de trasplante e histocompatibilidad al igual que en las áreas de farmacogenética e inmunoterapia. El inmenso polimorfismo y gran complejidad que presenta el sistema HLA han sido hasta ahora importantes barreras de cara a poder caracterizarlo en gran detalle (por alta resolución) y sin ambigüedades mediante métodos de genotipaje HLA tradicionales disponibles (como son SSP, SSO o incluso SBT). La reciente aplicación de la novedosa tecnología de secuenciación masiva NGS para el genotipaje molecular HLA por alta resolución ha posibilitado obtener secuencias completas o mucho más extendidas para genotipos de los principales genes de HLA, superándose así estas previas limitaciones. Objetivos: I) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una primera cohorte representativa de la población española que, igualmente, constituirá una población control de referencia para estudios de asociación de HLA y enfermedades. También, respectivos análisis estadísticos se realizaron para estos resultados de genotipaje HLA. II) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una correspondiente cohorte de pacientes con esclerosis múltiple (EM) de la población española (reclutados y procedentes del Departamento de Neurología del Hospital Clínic (Barcelona, Cataluña)). Un primer estudio de asociación HLA tomando casos (pacientes EM) frente a controles sanos se llevó a cabo para examinar la asociación de genes HLA y la enfermedad de EM en estas cohortes de población española antes mencionadas. Así se buscaba realizar un mapeo fino de las respectivas asociaciones alélicas y haplotípicas de HLA mediante la gran resolución alélica proporcionada por esta metodología de secuenciación masiva. De modo adicional, y como un segundo ejercicio de análisis en este estudio de asociación HLA, se utilizó un grupo control sano alternativo al previo, que incluía individuos procedentes de la región de Cataluña (situada al noreste de España) exclusivamente en este caso, para evaluar así posibles diferencias dadas en la asociación de HLA con EM debido a la probable variación genética en HLA existente a nivel regional dentro del territorio de España...Fac. de MedicinaTRUEunpu

Optimization for Deep Learning Systems Applied to Computer Vision

149 p.Since the DL revolution and especially over the last years (2010-2022), DNNs have become an essentialpart of the CV field, and they are present in all its sub-fields (video-surveillance, industrialmanufacturing, autonomous driving, ...) and in almost every new state-of-the-art application that isdeveloped. However, DNNs are very complex and the architecture needs to be carefully selected andadapted in order to maximize its efficiency. In many cases, networks are not specifically designed for theconsidered use case, they are simply recycled from other applications and slightly adapted, without takinginto account the particularities of the use case or the interaction with the rest of the system components,which usually results in a performance drop.This research work aims at providing knowledge and tools for the optimization of systems based on DeepLearning applied to different real use cases within the field of Computer Vision, in order to maximizetheir effectiveness and efficiency

Horizontal Inequity in Access to Healthcare Services and Educational Level in Spain

The aim of this study is to measure horizontal equity in the use of healthcare services in Spain, proposing two methodological innovations. First by defending it as equality of access for equal need, irrespective of educational level, unlike the prevailing methodological approach to horizontal equity which relates it to income. Second, by estimating it by means of the slope index of the inequality of characteristics, analagous to the inequity index proposed by Kakwani, Wagstaff and van Doorslaer (1997; HIWV) but presenting some methodological advantages, the greater robustness of the data available on educational level than of those on income, and the possibility of isolating the net effect of the educational level on the use of healthcare by controlling for other variables. The methodology is designed in three parts: (1) estimation of the relationship between the educational level and the use of healthcare services by means of a model of the likelihood of demand for healthcare services, commonly used in the literature; (2) estimation of the relationship between educational level and health by approximating a production function of individuals' health according to their personal characteristics and other factors conditioning health; and (3) estimation of the slope index of inequality as a measure of horizontal inequity, using educational level instead of income as the criterion for ranking individuals. The data base used was a sample of 55,598 observations from the Survey of disabilities, handicaps and state of health of 1999, carried out in Spain. No significant statistical association was found between educational level and use of healthcare services. On the other hand, the relationship between educational level and health, with the three proxy variables used (perception of health, days of limitation and number of chronic illnesses) shows a positive correlation, i.e. an increase in educational level is associated with a greater probability of enjoying better health. Horizontal inequity, measured by the proposed slope index of inequality, gives a range of statistically significant values between 13.91% and 9.40%, depending on cases, i.e. the significant inverse relationship between state of health and educational level is not reflected proportionally in healthcare use, implying that, with greater need, the access of individuals with a lower educational level to public healthcare services is the same as for the rest. These results suggest that the educational level may be a variable to consider when characterizing the healthcare needs of a population in a defined geographical area, at least from the normative characterization of horizontal equity proposedEducation and health; Healthcare needs; Horizontal Inequity; Logistic regression ; Ordinal regression; Regional funding

La canonización de Raimundo de Peñafort en Quito. Un ritual barroco entre la exhibición y el ocultamiento (1603) [Estudios]

Tomando como caso de estudio los festejos en honor de la canonización de Raimundo de Peñafort en Quito, en 1603, el artículo ofrece una reflexión alrededor de la cultura barroca en Hispanoamérica desde el punto de vista de la soberanía. El texto muestra cómo las élites quiteñas se apropiaron de las festividades organizadas en Quito en honor al santo catalán. Los criollos utilizaron las celebraciones en honor a San Raimundo como una estrategia política para solicitar a la Corona que deroguen los castigos impuestos a la ciudad luego de la Rebelión de las Alcabalas (1593).Taking as a case study the festivities in honor of the canonization of Raimundo de Peñafort in Quito in 1603, this article offers a reflection on Baroque culture in Spanish America from the point of view of the Monarchy. The text shows how local elites appropriated festivities organized in honor of the Catalonian saint for their own uses. The authorities in Quito used the celebrations in honor of Saint Raimundo as a political strategy to petition the Crown to abolish the punishment imposed on the city after the “rebelión de las alcabalas” (1593)

Non-monotonic entanglement of physical EM field states in non-inertial frames

We develop a general technique to analyse the quantum effects of acceleration on realistic spatially-localised electromagnetic field states entangled in the polarization degree of freedom. We show that for this setting, quantum entanglement may build up as the acceleration increases, providing a clear signature of the quantum effects of relativistic acceleration.Comment: 5 pages, 3 figure

Chemical distribution of HII regions towards the Galactic anticentre

We study the physical and chemical properties of a sample of HII regions located at RG >11 kpc and present the radial distribution of abundances towards the Galaxy anticentre. We carried out optical spectroscopic observations of nine HII regions with the WHT. The sample was increased by searching the literature for optical observations of regions towards the Galactic anticentre, re-analysing them to obtain a single sample of 23 objects covering the Galactocentric radius from 11 kpc to 18 kpc to be processed in a homogeneous and consistent manner. Accurate electron densities and temperatures of several ionic species were derived in 13 HII regions. These physical parameters were applied to the spectra to determine direct total chemical abundances. For those regions without direct estimations of temperature, chemical abundances were derived by performing tailor-made photoionisation models and/or by using an empirical relation obtained from radio recombination and optical temperatures. We performed weighted least-squares fits to the distribution of the derived abundances along the Galactocentric distances to study the radial gradients of metallicity. The distributions O/H, N/H, S/H, and Ar/H towards the anticentre can be represented by decreasing linear radial gradients, while in the case of N/O abundances the radial distribution is better fitted with a two-zone model. The He/H radial gradient is presented here for the first time; we find a slope that is not significantly different from zero. The derived gradient for oxygen shows a clear decrease with distance with a slope of -0.053dex/kpc. Although a shallower slope at large Galactocentric distances is suggested by our data, the flattening of the distribution cannot be confirmed and more objects towards the anticentre need to be studied in order to establish the true form of the metallicity gradient.Comment: Accepted for publication in Section 5. Galactic structure, stellar clusters and populations of Astronomy and Astrophysics. The official date of acceptance is 13/09/2016. 19 pages, 15 figures and 10 table

Entanglement of arbitrary spin fields in noninertial frames

We generalize the study of fermionic and bosonic entanglement in noninertial frames to fields of arbitrary spin and beyond the single-mode approximation. After the general analysis we particularize for two interesting cases: entanglement between an inertial and an accelerated observer for massless fields of spin 1 (electromagnetic) and spin 3/2 (Rarita-Schwinger). We show that, in the limit of infinite acceleration, no significant differences appear between the different spin fields for the states considered. © 2011 American Physical Society.s. E. M.-M. was supported by a CSIC Grant No. JAE-PREDOC2007 and by the Spanish MICINN Project No. FIS2008-05705/FIS and the QUITEMAD consortium.Peer Reviewe

La manipulación en los medios de comunicación: tratamiento informativo del 11M

Decenes Jornades de Foment de la Investigació de la FCHS (Any 2004-2005

Podoplanin in Inflammation and Cancer.

Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial–mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.post-print1279 K

Zirconia implant abutments : a review

Objectives: An increasing aesthetic demand within developed populations conducted to the fabrication of metalfree restorations and to a wide use of ceramic materials, due to its excellent characteristics of biocompatibility and aesthetics. With the incessant increase of commercial labels involved in this technological advance, a review is imposed on ceramic abutments, specifically on zirconia. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the terms ?Dental Abutments?, ?Dental Porcelain? and ?Zirconia?. The review was divided by subtopics: zirconia physical and mechanical properties, precision fit in the implant-abutment interface, zirconia abutments strength and, finally, bacterial adherence and tissues response. Several studies demonstrate that zirconia abutments offer good results at all the levels but relevant issues need further studies and evaluation. One of the most important is the clinical long term success of zirconia abutments on implants, given that in the literature there are no sufficient in vivo studies that prove it