Do compassionate firms outperform? The role of organizational learning

Purpose – Based on a new management paradigm rooted on care and compassion, this study explores the consequences of compassion at work on organizational learning and firm performance. Design/methodology/approach – Structural equation modeling (SEM) was employed to analyze the research model by using data from two different samples. Findings – Results confirm that compassion increases firm performance through organizational learning capability; however, compassion do not enhances directly firm performance. Research limitations/implications – The study findings indicate that when compassion is propagated among organizational members, organizations are better able to learn so they obtain a competitive advantage that is difficult to imitate and leads to higher firm performance. Originality/value – This study takes a step forward on literature by providing empirical evidence for a promising area of management research such is compassion in organizations

Investigating how children with autism differ from typically developed children: the acquisition of english ditransitive structures

This undergraduate dissertation presents a grammatical study investigating the acquisition of ditransitive structures by English native speakers. Concretely, it compares the production of two child groups: typically developed children (TD) and children diagnosed with Autistic Spectrum Disorder (ASD). The analysis deals with the acquisition of ditransitive structures in different aspects: age of acquisition, acquisition of the different types of ditransitive structures and the different verbs these children use in semantic terms. The results of this study reveal that ASD children acquire ditransitive structures much later than TD children. However, both TD and ASD children acquire double object constructions (DOC) before prepositional dative constructions (PDC). Another similarity is that both child groups tend to use verbs from the “giving” semantic group when producing ditransitive structures.Este trabajo de fin de grado ofrece una investigación sobre la adquisición de las estructuras ditransitivas por niños ingleses nativos. Concretamente, este estudio compara la producción de estas estructuras por niños de desarrollo típico con niños con autismo. El análisis aborda la adquisición de las estructuras ditransitivas desde varios enfoques: edad de adquisición, adquisición de los diferentes tipos de estructuras ditransitivas y los diferentes verbos usados por los participantes en términos semánticos. Los resultados de este estudio revelan que los niños con autismo adquieren las estructuras ditransitivas de manera tardía en comparación con los niños de desarrollo típico. Sin embargo, ambos grupos de niños adquieren antes las construcciones de doble objeto que las construcciones dativas con preposición. Otra similitud que comparten es el hecho de que ambos grupos tienden a usar verbos del grupo semántico del tipo “dar” cuando producen estructuras ditransitivas.Grado en Estudios Inglese

Análisis de la incidencia de los talleres de evaluación, programación y capacitación educativa (TEPCE), en el desarrollo de los proceso de enseñanza aprendizaje

Este trabajo trata sobre el análisis de la incidencia de los Talleres de Evaluación, Programación y Capacitación Educativa (TEPCE), en el desarrollo del proceso enseñanza aprendizaje que realiza el docente de sexto grado de la escuela Rural Mixta Muyuca del municipio de El Jícaro,departamento de Nueva Segovia, durante el primer semestre del año 2012. La investigación se corresponde con un estudio de caso, centrado en una microetnografía en el ámbito educativo. El método utilizado nos permitió diseñar instrumentos de recolección de la información donde no se considera la cuantificación o estadística. Entre estos tenemos la entrevista en profundidad, observación directa, grupo focal y análisis documental. En los resultados obtenidos después de realizar el análisis intensivo de la información,se encontró en términos generales que el docente de sexto grado no utiliza una diversidad de estrategias de enseñanza para obtener aprendizajes significativos con sus alumnos.Siempre utiliza las mismas estrategias tradicionales en las diferentes disciplinas

Beocio: selección de inscripciones y papiros

Grado en Filología Clásic

Mecanismos de extensión de la longevidad y envejecimiento saludable por sobre-expresión de citocromo b5 reductasa 3

Introduction. Aging is a natural time-dependent process characterized by the accumulation of damage in cellular structures that compromises cellular and tissue function leading ultimately to the death of the organism. Furthermore, aging is the most significant risk factor for chronic diseases including cancer, cardiovascular disease (CVDs) and neurodegeneration. Nine candidates have been proposed as the main features of aging. These candidates which have been regarded as "The Hallmarks of Aging" are: telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication. Given the great complexity of the changes that participate in the establishment of the aging phenotype, numerous theories have been proposed to explain its aetiology, but neither of them appears to be capable of fully explaining the origin of this process, and they often contradict each other. Among them, the Free Radical Theory of Aging proposes that oxidative stress and redox imbalance are factors directly related with aging. The general idea of this theory is to consider reactive oxygen species (ROS) and other reactive species, that are continuously generated in the organism, as the main cause of aging. Therefore, cellular aging is associated with chronic oxidative stress. ROS are products of normal cellular metabolism in mitochondrial respiration and can be also produced in defensive responses of cells against infectious agents, upon exposure to xenobiotics, cytokines, redox stress, and in a several of intracellular signaling pathways. Mitochondria are both the main source and a major target of ROS. Mitochondria are one of the most important organelles in aerobic organisms, as the sites where aerobic respiration takes place to produce the energy that is necessary to sustain most cellular processes. Mitochondria also participate in additional cellular processes of great relevance, including β-oxidation of fatty acids, calcium signaling, and apoptosis. However, ROS and free radicals are generated as by-products of mitochondrial metabolism that attack nucleic acids, proteins, and membrane phospholipids. Among phospholipids, those containing polyunsaturated fatty acids (PUFAs) are more susceptible to oxidation by free radicals, leading to lipid peroxidation that causes a loss of membrane fluidity and impairs many cell functions. Additionally, with age, mitochondrial enzymes, ATP production, and respiratory capacity decline and, at the same time, ROS and mitochondrial mutations increase, being these changes accompanied by alterations in morphology and abundance of these organelles. Mutations in mtDNA result in a loss of mitochondrial function and turnover. This leads to the autophagic digestion of defective mitochondria which, if not accompanied by efficient mitochondrial biogenesis, may lead to the consequent decrease in the synthesis of ATP and bioenergetic dysfunction. Mitochondria are generated by growth and division of pre-existing organelles. In addition, they are highly dynamic structures that undergo continuous changes in size, shape, number, and distribution, which is highly controlled by a balance between fusion and fission. Their dynamics is determined by mitochondrial turnover, biogenesis, and a balance between the frequency of fusion and fission events. These events are critical for the normal function of cells, allowing the replacement of old or damaged mitochondria which are continuously removed from the cell. All these mechanisms allow the maintenance and distribution of mtDNA, the quality control of the organelle, and the regulation of apoptosis. Imbalanced mitochondria dynamics contributes to the loss of mitochondrial homeostasis, leading to alterations in mitochondrial function, metabolism, and signaling. Progressive mitocondrial dysfunction is considered a hallmark of aging, and it has been involved in a wide range of pathological conditions whose incidence increases with aging, as neurodegenerative diseases, diabetes, CVDs, muscle atrophy and cancer, and it is also related with several processes of embryonic development. Mitochondria are eliminated when they are damaged or dysfunctional through a process regulated called mitophagy. Nutritional and genetic interventions are among the strategies currently followed by researchers to delay or even reverse the deleterious consequences of aging. Caloric restriction (CR) without malnutrition is the most effective nongenetic intervention that delays aging and increases lifespan in numerous organisms. Beneficial effects of CR on longevity are mainly due to an improvement in mitochondrial function. Furthermore, there is an important metabolic adaptation to CR, causing substantial changes in numerous signaling pathways that regulate growth, metabolism, repair of damage, oxidative stress, autophagy and inflammatory processes. Among these changes, CR increases the amount of monounsaturated fatty acids (MUFAs) in membranes while decreasing PUFAs without any observed changes in saturated fatty acids (SFA), which is in accordance with the Theory of Membranes in Aging that proposes that lifespan is inversely related to the level of unsaturation, particularly the level of n-3 PUFA, in membrane phospholipids. Moreover, CR modulates key molecules involved in the regulation of autophagy and increases NAD+ levels activating enzymatic activity of the sirtuins (SIRTs). Homeostasis of NAD+ is important for the maintenance of many functions and protection against aging and age-related diseases. NAD+ is a metabolic regulator and its efficacy has been reported in metabolic diseases such as insulin resistance, fatty liver or hypertension. The overexpression of enzymes capable of generating NAD+ from the oxidation of NADH, as NADH-cytochrome b5 reductase-3 (CYB5R3), is another strategy that is currently under evaluation. CYB5R3 is a flavoprotein that participates in the elongation and desaturation of fatty acids, which seems to be an excellent candidate as a novel effector for the regulation of metabolism, mainly at mitochondrial level. CYB5R3 plays an important role in the regulation of metabolic pathways associated with healthspan and aging through mechanisms that appear to be related with protection against oxidative stress, production of cellular NAD+ and alterations in fatty acids composition. Although CYB5R3 shows a constitutive basal expression in many tissues, its expression can be also induced in response to environmental stress and nutrient deprivation. Constitutive expression of the Cyb5r3 gene is controlled by SP1 transcription factor, which can be further upregulated through pathways involving forkhead box O3 (FOXO3a) and nuclear factor erythroid 2-related factor 2 (NFE2L2) transcription factors. Mice overexpressing this protein showed increased longevity and displayed greater protection against diseases associated with aging. At the metabolic level, CYB5R3 overexpression increases insulin sensitivity, decreases inflammation and oxidative stress, and protects mice against cancer induction. Therefore, this enzyme plays a fundamental role in the regulation of lipid metabolism that allows to increase lifespan, suggesting that strategies aimed at incrementing CYB5R3 expression and/or activity may constitute viable interventions to confer protection against metabolic pathologies and to improve healthspan. Dietary fats are essential components to generate energy. Fatty acids (FAs) can be categorized as saturated (SFAs), monounsaturated (MUFAs), or polyunsaturated (PUFAs) and most of them can be synthesized by the organisms excepting the socalled essential fatty acids that must be ingested through the diet. In addition, FAs are an important source of energy due to their ability to be efficiently stored as triglycerides (TGs). Several studies have reported the relationship between dietary fat and the risk of metabolic and CVDs, among other disorders. Diets rich in MUFAs and PUFAs have cardioprotective effects, while the relationship between SFA and the risk of coronary heart disease is still controversial. Fatty acids can undergo autoxidation reactions generating lipid peroxides that affect the properties of biological membranes. Additionally, the toxic products derived from peroxidation can damage proteins, DNA, and other biomolecules. Since lipids are prone to oxidation, which exerts negative effects in health, the use of antioxidants in foods has become extensive to prevent lipid oxidation. The liver and heart are closely related in health and in disease. Deregulated hepatic lipid metabolism and many metabolic diseases, such as diabetes and obesity, are ultimately detrimental to cardiac function. The liver is the main organ in the regulation of energy metabolism. It performs three essential functions: the metabolic processing of proteins, carbohydrates and lipids after their absorption in the intestine, the detoxification of toxic agents and substances, and the storage of energy in form of glycogen. In spite of some changes occurring during aging (see below), the liver ages fairly well. Although in normal conditions hepatocyte turnover rate is low, the liver shows a relatively high rate of regeneration. That is why this organ has been widely used as a model to study the effects of diets, CR and other anti-aging interventions. Aging-related changes in liver include a reduction of weight and volume, a decline in the rate of hepatic regeneration, increased size of hepatocytes, polyploid nuclei, decreased area of smooth endoplasmic reticulum, decreased clearance of free radicals, and a decrease in the number and function of mitochondria, resulting in a decline in the ATP production. Aging is also associated with redistribution of fat in the body characterized by increased fat deposition in non-adipose tissues, including liver. All these structural and functional alterations could contribute to the development of liver disease with age. The heart is the main organ of the circulatory system and one of the first organs to be formed during the embryonic development. The heart is a complex organ containing different cell types that contribute to the structural, biochemical, mechanical, and electrical properties of the organ. Among the cell types, cardiomyocytes, responsible for the contractile function of the myocardium, are well differentiated cells without regeneration capacity. The most drastic changes in heart function occurring with age are: left ventricular hypertrophy, alterations in the diastolic function, aortic valve calcification, arrhythmia and heart failure. These alterations are, at least in part, due to a decrease in the number of cardiomyocytes, as well to hypertrophy and fibrosis due to an increased collagen and alterations in the extracellular matrix. As postmitotic cells, cardiomyocytes are highly susceptible to age-related mitochondrial damage and ROS production which results in an overall enhancement in the rate of cardiomyocyte death with age. The progressive decline of cardiomyocyte mitochondrial function is considered the major mechanism underlying heart aging, in addition to the accumulation of cholesterol and fatty acids in tissues which lead to the production of inflammatory cytokines as well as ROS that further contribute to CVDs prevalence and mortality. Starting hypothesis and objectives. Previous studies developed in our group were focused on NADH-cytochrome b5 reductase-3 (Cyb5r3) as a new pro-longevity gene. Mice overexpressing CYB5R3 contain higher levels of polyunsaturated fatty acids in hepatic membranes, which resembles, at least partially, the effects of the consumption of a diet containing fish oil or the overexpression of the Fat-1 gene of C. elegans. Unsaturated fatty acids show high susceptibility to peroxidation. However, CYB5R3 transgenic mice exhibited a significant reduction in lipid peroxidation. The specific changes in FA composition that take place in mice overexpressing CYB5R3 may be the result of a metabolic reprogramming, and could be indicative of an improvement in mitochondrial function, leading to a lower generation of ROS and the prevention of the oxidative damage accumulation, which partially mimics the effects observed in animals subjected to CR. These mice showed increased insulin sensitivity and improved regulation of glucose homeostasis, less inflammation and decreased oxidative damage, and were protected against induced cancer. However, mice over- expressing CYB5R3 fed a standard diet ad libitum were fatter than wild-type controls, and preferentially use carbohydrate to meet their energy needs. This differs from studies with CR as antiaging intervention that showed an improvement in healthspan and lifespan due to the enhancement of β-oxidation as a preferential source of energy. Thus, CYB5R3 overexpression could contribute to extend lifespan in mice by mechanisms that may be independent of those described for CR. Since CYB5R3 increase has been reported in long-term CR intervention, it has been hypothesized that the beneficial effects of CR could be mediated, at least partially, by a such increase of CYB5R3. However, it has not yet been studied how the CYB5R3 overexpression affects mitochondrial processes that are relevant to determine the aging pattern, and how the alterations in fatty acid composition and CR can interact with the changes elicited by CYB5R3 overexpression in transgenic mice. The working hypothesis of this PhD is that mitochondrial efficiency is optimized in CYB5R3 transgenic mice, which leads to an improvement in energy production and better preservation of mitochondria during aging. For this reason, our main objective has been to study several mitochondrial function markers in liver and heart tissues of CYB5R3-overexpressing mice submitted to nutritional interventions (CR and alterations in fat composition of the diet) and aging. To this end, we have pursued the following 5 specific aims: 1. To study the physiological effects of CYB5R3 overexpression, dietary fats, CR and aging on body composition and biochemical profile. 2. To characterize the CYB5R3 overexpression in liver and heart in the three proposed interventions. 3. To determine the combined effect of CYB5R3 overexpression and CR on key markers of mitochondrial function. 4. To determine dietary conditions that maximize mitochondrial preservation in mice overexpressing CYB5R3. 5. To determine the effects of aging on the mitochondria parameters studied in the previously indicated aims in CYB5R3 overexpressing mice. The results of this PhD can help identify healthy lifestyles and nutritional patterns that can modulate healthy aging and extend longevity, as well as to identify new mitochondrial targets that allow the preservation of mitochondrial physiology and aid in the prevention of metabolic diseases associated with age.Introducción. El envejecimiento se define como el declive funcional dependiente del tiempo que se caracteriza por la acumulación de daños en las estructuras celulares, comprometiendo la función celular y tisular dando lugar, en último término, a la muerte del organismo. El envejecimiento es el principal factor de riesgo de las enfermedades crónicas incluyendo cáncer, enfermedades cardiovasculares (CVDs) y neurodegenerativas. Se han propuesto nueve causas principales por las que se produce el envejecimiento: las denominadas “marcas distintivas del envejecimiento”, que son las siguientes: acortamiento telomérico, inestabilidad genómica, modificaciones epigenéticas, pérdida de la proteostasis, disfunción mitocondrial, desregulación de la detección del estado nutricional, senescencia celular, alteración de la comunicación intercelular y perdida de células madre. Para tratar de explicar los cambios celulares que dan lugar el fenotipo del envejecimiento se han propuesto numerosas teorías, pero, debido a la complejidad de este proceso, ninguna de ellas puede explicar completamente el origen del envejecimiento. De estas teorías, la llamada Teoría de los Radicales Libres propone que el estrés oxidativo y el desajuste en el estado redox del organismo dan lugar al envejecimiento. Esta teoría considera que las especies reactivas de oxígeno (ROS) y otras especies reactivas (que están continuamente generándose en el organismo) son la principal causa del envejecimiento. Por lo tanto, el envejecimiento celular estaría provocado por un estrés oxidativo crónico. Las ROS son productos del metabolismo celular producidos por la respiración mitocondrial, respuesta defensiva de las células frente a agentes infecciosos, exposición a xenobióticos, respuesta a citoquinas y estrés redox. Además, actúan como moléculas de señalización celular. Las mitocondrias son la mayor fuente de ROS y las principales afectadas por el daño oxidativo que estas moléculas pueden llegar a causar. Además, son uno de los orgánulos más importantes en los organismos aeróbicos, que se encargan de la respiración celular y producen la energía necesaria para las funciones vitales de la célula. Las mitocondrias también participan en otros procesos celulares de gran importancia como la β-oxidación de ácidos grasos, homeostasis de calcio y apoptosis. Sin embargo, las ROS y los radicales libres son productos del metabolismo mitocondrial que, debido a su alta reactividad, interaccionan con los ácidos nucleicos, proteínas y fosfolípidos de membranas, dañando sus estructuras. Los fosfolípidos de membrana que contienen ácidos grasos poliinsaturados (PUFA) son los más susceptibles de ser oxidados por los radicales libres, dando lugar a la peroxidación lipídica, que altera las características de las membranas biológicas y afecta considerablemente a la función celular. Por otro lado, con el envejecimiento, las enzimas mitocondriales, la producción de ATP y la capacidad respiratoria de la célula disminuyen, a la vez que aumenta la producción de ROS. Los daños producidos en las mitocondrias dan lugar a mutaciones y alteraciones en la morfología y abundancia de estos orgánulos. Las mutaciones en el DNA mitocondrial (mtDNA) dan lugar a una pérdida de la función mitocondrial y a una desregulación de su recambio en la célula. El recambio mitocondrial se produce mediante la eliminación de mitocondrias dañadas por el proceso de autofagia, y la síntesis de nuevas mitocondrias a través de la biogénesis mitocondrial. Alteraciones en alguno de esos procesos dan lugar a una disminución de la síntesis de ATP y disfunción bioenergética. La biogénesis mitocondrial se produce por el crecimiento y división de mitocondrias preexistentes. Además, estos orgánulos son altamente dinámicos y están constantemente cambiando de forma, tamaño, número y distribución en la célula. Esta dinámica está controlada por un balance entre los procesos fusión y fisión mitocondrial, siendo estos eventos críticos para el correcto funcionamiento de las células que, a su vez, permiten el reemplazo de las mitocondrias viejas o dañadas. Todos esos mecanismos, además, participan en la distribución del DNA mitocondrial, en el mantenimiento del orgánulo en condiciones óptimas y en la regulación de la apoptosis. Un desajuste en la dinámica mitocondrial da lugar a la perdida de la homeostasis del orgánulo, provocando alteraciones en su funcionamiento, metabolismo y señalización. La disfunción mitocondrial progresiva está considerada una marca distintiva del envejecimiento e involucra una gran variedad de condiciones patológicas que aumentan con el envejecimiento como son las enfermedades neurodegenerativas, diabetes, CVDs, atrofia muscular y cáncer. También están implicadas en numerosos procesos del desarrollo embrionario. La eliminación mitocondrial por autofagia es un proceso altamente regulado llamado mitofagia. Con el fin de retrasar o revertir los efectos deletéreos del envejecimiento, numerosas intervenciones nutricionales y genéticas están siendo estudiadas. Entre ellas, la restricción calórica (CR) sin malnutrición es la intervención no genética más efectiva que retrasa el envejecimiento e incrementa la vida máxima en numerosos organismos. Los efectos beneficiosos de la CR sobre la longevidad se deben en gran parte a una mejora en la función mitocondrial. Además, la CR produce adaptaciones metabólicas muy importantes dando lugar a cambios en numerosas rutas de señalización que participan en el crecimiento, metabolismo, mecanismos de reparación de daños, estrés oxidativo, autofagia y procesos inflamatorios. Entre esos cambios, la CR aumenta el contenido de ácidos grasos monoinsaturados (MUFA), disminuye el contenido de PUFA y no provoca cambios en la cantidad de ácidos grasos saturados (SFA) en las membranas biológicas, lo que apoya la Teoría de las Membranas en el envejecimiento que establece que la longevidad máxima esta inversamente relacionada con el nivel de insaturación de las membranas biológicas, particularmente con los niveles de PUFA n-3. Por otro lado, la CR modula moléculas clave que participan en la regulación de la autofagia e incrementa los niveles de NAD+ resultando en la activación de enzimas como las sirtuinas. La homeostasis de NAD+ es importante para el mantenimiento de muchas funciones y protección frente al envejecimiento y de las enfermedades relacionadas con éste. El NAD+ es un regulador metabólico y su eficacia ha sido probada en enfermedades metabólicas como la resistencia a insulina, hígado graso o hipertensión. La sobreexpresión de enzimas capaces de generar NAD+, como la NADH citocromo b5 reductasa 3 (CYB5R3), es una estrategia que está siendo estudiada actualmente. La CYB5R3 es una flavoproteína que participa en la elongación y desaturación de ácidos grasos, lo que la hace una excelent

Between Women: Female Health Workers and the Struggle to Transform Diets in Rural Mexico, 1920-1960

This article explores food and foodways in Mexico through the analysis of nutrition discourses and the experience of a visiting nurse in the state of Guanajuato in the middle of the twentieth century. After the Mexican revolution there was an increased interest in changing the diet of the poor. The idea behind nutrition discourses was that a better diet would improve the health and productivity of workers, and eventually boost their earnings. Understandings of good nutrition were influenced by eugenics and the discourse of mestizaje, which materialized in welfare programs. Women played a key role as they were responsible for implementing these programs as well as the main target of them. The experience of a visiting nurse reveals gender and social class dynamics as well as negotiations needed to implement state programs. It also shows the limited success of state policy as it was unable to address the main problems: lack of resources and access to basic services. Eventually peasant and working-class diet changed as a result of increased processed food consumption, having a negative impact on the health of most Mexicans.This article explores food and foodways in Mexico through the analysis of nutrition discourses and the experience of a visiting nurse in the state of Guanajuato in the middle of the twentieth century. After the Mexican revolution there was an increased interest in changing the diet of the poor. The idea behind nutrition discourses was that a better diet would improve the health and productivity of workers, and eventually boost their earnings. Understandings of good nutrition were influenced by eugenics and the discourse of mestizaje, which materialized in welfare programs. Women played a key role as they were responsible for implementing these programs as well as the main target of them. The experience of a visiting nurse reveals gender and social class dynamics as well as negotiations needed to implement state programs. It also shows the limited success of state policy as it was unable to address the main problems: lack of resources and access to basic services. Eventually peasant and working-class diet changed as a result of increased processed food consumption, having a negative impact on the health of most Mexicans.El presente artículo explora los discursos y las practicas alimenticias entre 1920 y 1960 a través del análisis de las políticas y programas nutricionales en México. Tras la revolución mexicana incrementó el interés en torno a cómo mejorar la alimentación de las clases obreras y campesinas. Médicos y creadores de políticas públicas consideraron que una mejor dieta tendría un impacto positivo en la salud y productividad de los trabajadores, lo cual eventualmente se reflejaría en su salario. Se asumía que los trabajadores se ausentaban del espacio laboral debido a enfermedad o debilidad física, lo cual afectaba su productividad e ingresos. Los discursos de nutrición estuvieron influenciados por las teorías eugenésicas, así como por la ideología del mestizaje, lo cual se materializaba en los programas de bienestar social creados por el estado mexicano. Las mujeres tuvieron un papel central en dichos programas, ya que estuvieron a cargo de implementarlos y además fueron blanco principal de éstos. Las enfermeras visitadoras y los médicos trataron de introducir ideales y valores de clase media en la vida cotidiana de obreros y campesinos, sin abordar los problemas centrales: la falta de recursos y acceso a servicios básicos

Exploiting Oxidative Phosphorylation to Promote Stem and Immunoevasive Properties of Pancreatic Cancer Stem Cells

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 14-02-2020Esta tesis tiene embargado el acceso al texto completo hasta el 14-08-2021Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 9% and is expected to become the second most lethal tumor by the year 2030. These alarming statistics can be attributed to the high metastatic and chemoresistant capacity of this tumor, and the ineffectiveness of conventional therapies to provide long-term progression-free survival (> 5 years). The latter is believed to be due, in large part, to the existence of a “stem”-like subpopulation of cells within the tumor known as cancer stem cells (CSCs), which have inherent plasticity, have been experimentally shown to be the initiators of the primary tumor, are able to evade chemotherapy, remain quiescent and metastasize to distant organs. To better understand the biology and plasticity of pancreatic CSCs, with the ultimate goal of eliminating them, we have initiated studies to dissect these cells at the molecular level. Metabolic adaptation is believed to be one of the hallmarks of cancer cells. Interestingly, we published that against established dogma, pancreatic CSCs have a metabolism dependent on oxidative mitochondrial phosphorylation (OXPHOS) in contrast to non-CSCs, which depend on glycolytic metabolism (Warburg effect). Using this discovery to our advantage, we have developed a novel 2D in vitro system for long term enrichment of pancreatic CSCs that is amenable to drug screening and CSC-specific studies. Specifically, in the presence of galactose we can establish long-term 2D cultures of primary PDX-derived PDAC cultures enriched in PaCSCs. Compared to glucose, ATP yield from galactose is slower. Thus, due to ATP yield differences, non-PaCSCs cannot survive in galactose, while OXPHOS-dependent PaCSCs survive and become enriched. Moreover, under galactose condition, we show that primary PDAC cells are highly plastic, present an enrichment in CSC biomarkers and pluripotency-associated genes, enter into a slow-cycling/quiescent stage, increase mitochondrial networks and OXPHOS activity and are more invasiveness in vivo, the latter being due, in part, to the modulation of immune evasion markers, an aspect of PaCSCs biology that has been poorly studied to date. In summary, this novel cell culture system could be potentially used to screen for novel CSC-specific inhibitors as well as new compounds directed towards cancer cell metabolism, an area of research that is gaining considerable attention, and based on the correlation observed with immune evasion, may synergize with immunotherapeutic approaches for improved and long-lasting antitumor outcomesEl adenocarcinoma ductal de páncreas (PDAC), la cuarta causa principal de muerte por cáncer, tiene una tasa de supervivencia a 5 años de aproximadamente el 9% y se espera que se convierta en el segundo tumor más letal para el año 2030. Estas alarmantes estadísticas pueden atribuirse a la alta capacidad metastásica y quimiorresistencia de este tumor y la ineficacia de las terapias convencionales, las cuales no proporcionan una supervivencia a largo plazo (> 5 años). Se cree que esto último se debe a la existencia de una subpoblación de células "madre" dentro del tumor conocida como células madre de cáncer (CSCs), las cuales poseen una plasticidad intrínseca, son las iniciadoras del tumor primario, pueden evadir la quimioterapia, permanecer inactivas y metastatizar en órganos distales. Para comprender mejor la biología y la plasticidad de las CSC pancreáticas hemos iniciado estudios para diseccionar estas células a nivel molecular. Se cree que la adaptación metabólica es una de las características de las células tumorales. En 2015 publicamos que las CSC pancreáticas tienen un metabolismo basado en la fosforilación oxidativa (OXPHOS) en comparación con las no CSCs, que dependen de un metabolismo glucolítico (efecto Warburg). Utilizando como ventaja este descubrimiento, hemos desarrollado un novedoso sistema 2D in vitro basado en la utilización de galactosa como fuente de carbono para el enriquecimiento a largo plazo de CSC pancreáticas, lo que nos servirá para el estudio de nuevos fármacos y características específicas de las CSC. En comparación con el uso de glucosa, la obtención de ATP a partir de galactosa es más lento. Por lo tanto, las no PaCSC no pueden sobrevivir en presencia de galactosa como única fuente de carbono, mientras que las PaCSC dependientes de OXPHOS sobreviven y se enriquece su población. Además, en condiciones de galactosa, las células son altamente plásticas, presentan un enriquecimiento en biomarcadores CSC, son más quiescentes, aumentan las redes mitocondriales, la actividad OXPHOS y son más invasivas in vivo, esto último debido, en parte, a la modulación de los marcadores de evasión inmune, un aspecto de la biología de las PaCSCs que ha sido poco estudiado hasta la fecha. En resumen, este nuevo sistema podría usarse potencialmente para detectar nuevos inhibidores de CSC y compuestos dirigidos hacia el metabolismo y la inmuno-evasión de las células tumorales, un área de investigación que está recibiendo una considerable atención actualment

La lengua de los personajes. Caracterización lingüística en la obra de Eurípides a partir de los Heraclidas

The purpose of this thesis is to determine how Euripidean characters are characterised through their language with respect to one another. Heraclidae is taken as a starting point. The thesis is divided into five chapters with an abstract and concluding remarks in English, an index locorum and a list of figures. Chapter 1 deals with the much-discussed question of what characterisation implies and how it can be approached. Chapter 2 addresses the method, whose aim is to establish guidelines for approaching linguistic characterisation in a dramatic corpus. The potentially relevant features for the study of linguistic characterisation have been selected under the framework of Speech Act Theory, Conversation Analysis, and especially, Politeness Theory, thus forming the baselines of a threefold approach. Chapter 3 examines the socio-pragmatic factors pertaining to the use of forms of address with a focus on the forms of address at the right periphery, namely, at the end of the clause. The last two chapters are about two speech acts, namely approval and supplication. Chapter 4 examines the distribution of approval formulae, which can be considered as taxemic markers. Chapter 5 offers an analysis of how im/politeness strategies work with regard to the role played by the characters involved in a number of suppliant scenes