14,643 research outputs found

    Building body identities - exploring the world of female bodybuilders

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    This thesis explores how female bodybuilders seek to develop and maintain a viable sense of self despite being stigmatized by the gendered foundations of what Erving Goffman (1983) refers to as the 'interaction order'; the unavoidable presentational context in which identities are forged during the course of social life. Placed in the context of an overview of the historical treatment of women's bodies, and a concern with the development of bodybuilding as a specific form of body modification, the research draws upon a unique two year ethnographic study based in the South of England, complemented by interviews with twenty-six female bodybuilders, all of whom live in the U.K. By mapping these extraordinary women's lives, the research illuminates the pivotal spaces and essential lived experiences that make up the female bodybuilder. Whilst the women appear to be embarking on an 'empowering' radical body project for themselves, the consequences of their activity remains culturally ambivalent. This research exposes the 'Janus-faced' nature of female bodybuilding, exploring the ways in which the women negotiate, accommodate and resist pressures to engage in more orthodox and feminine activities and appearances

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms

    Identification of Hindbrain Neural Substrates for Motor Initiation in the hatchling Xenopus laevis Tadpole

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    Animal survival profoundly depends on the ability to detect stimuli in the environment, process them and respond accordingly. In this respect, motor responses to a sensory stimulation evolved into a variety of coordinated movements, which involve the control of brain centres over spinal locomotor circuits. The hatchling Xenopus tadpole, even in its embryonic stage, is able to detect external sensory information and to swim away if the stimulus is considered noxious. To do so, the tadpole relies on well-known ascending sensory pathway, which carries the sensory information to the brain. When the stimulus is strong enough, descending interneurons are activated, leading to the excitation of spinal CPG neurons, which causes the undulatory movement of swimming. However, the activation of descending interneurons that marks the initiation of motor response appears after a long delay from the sensory stimulation. Furthermore, the long-latency response is variable in time, as observed in the slow-summating excitation measured in descending interneurons. These two features, i.e. long-latency and variability, cannot be explained by the firing time and pattern of the ascending sensory pathway of the Xenopus tadpole. Therefore, a novel neuronal population has been proposed to lie in the hindbrain of the tadpole, and being able to 'hold' the sensory information, thus accounting for the long and variable delay of swim initiation. In this work, the role of the hindbrain in the maintenance of the long and variable response to trunk skin stimulation is investigated in the Xenopustadpole at developmental stage 37/38. A multifaceted approach has been used to unravel the neuronal mechanisms underlying the delayed motor response, including behavioural experiments, electrophysiology analysis of fictive swimming, hindbrain extracellular recordings and imaging experiments. Two novel neuronal populations have been identified in the tadpole's hindbrain, which exhibit activation patterns compatible with the role of delaying the excitation of the spinal locomotor circuit. Future work on cellular properties and synaptic connections of these newly discovered populations might shed light on the mechanism of descending control active at embryonic stage. Identifying supraspinal neuronal populations in an embryonic organism could aid in understanding mechanisms of descending motor control in more complex vertebrates

    Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico

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    La sepsis es una afección potencialmente mortal causada por una respuesta anormal del huésped a una infección, produciendo respuestas fisiológicas alteradas que dañan los propios tejidos del paciente y pueden provocar disfunción orgánica e incluso la muerte. Asimismo, algunos pacientes sépticos progresan a shock séptico, caracterizado por alteraciones circulatorias, celulares y metabólicas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunológico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresión, la alta complejidad de la fisiopatología de la sepsis requiere una mayor investigación para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citotóxicos en la sepsis, ya que actúan como patrones moleculares asociados a daño, que inducen estrés oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activación de la piroptosis, un mecanismo de muerte celular programada que produce inflamación mediante la expresión de IL-18, IL-1β and IL-1α. Sin embargo, a pesar de la evidencia de activación del inflamasoma en las células inmunes durante la sepsis, se desconoce si las histonas extracelulares son capaces de activar los inflamasomas endoteliales y sus consecuencias. En este trabajo destacamos el papel previamente desconocido de las histonas extracelulares, mediando la activación del inflamasoma NLRP3 y la piroptosis en las células endoteliales, contribuyendo a la disfunción endotelial y la desregulación de la respuesta inmune mediada por el endotelio. Asimismo, también demostramos cómo la acetilación de histonas disminuye la activación de la piroptosis. Además, demostramos que la piroptosis se produce en pacientes con shock séptico y los niveles de histonas circulantes se correlacionan con la expresión de citoquinas proinflamatorias y citoquinas piroptóticas, la liberación de factores de adhesión endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones clínicas. De manera similar, hemos analizado las respuestas inmunorelacionadas que ocurren durante las primeras etapas de la sepsis con el objetivo de proporcionar nuevos datos comparando las cantidades de citoquinas, inmunomoduladores y otros mediadores endoteliales en pacientes críticamente enfermos no sépticos, sépticos y de shock séptico. Nuestro enfoque ayudará a caracterizar rápidamente las respuestas inmunes alteradas en pacientes sépticos y de shock séptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilación del ADN en el control del sistema inmune séptico. Nuestros resultados demostraron el papel central de la metilación del ADN modulando la respuesta molecular en los pacientes de shock séptico y contribuyendo a la inmunosupresión, a través de la alteración de los patrones de metilación de los promotores de IL-10 y TREM-2.Sepsis is a life-threatening condition caused by an abnormal host response to an infection that produce altered physiological responses which damages own tissues of the patient and can result in organ dysfunction and in some cases death. Likewise, a subset of septic patients progresses to septic shock, characterized by substantial circulatory, cellular and metabolic abnormalities, which substantially increase the risk of mortality. Sepsis is characterized by a malfunction of the immune system and it can lead to an altered immune response and immunosuppression. Moreover, the high complexity of the pathophysiology of sepsis requires of further investigation to characterize the immune responses in sepsis and septic shock. Likewise, circulating extracellular histones have gained relevance as cytotoxic mediators in sepsis pathophysiology, since they act as damage-associated molecular patterns, which induce oxidative stress and activate NLRP3 inflammasome. Subsequently, inflammasome mediates pyroptosis activation, a programmed cell death mechanism that produces inflammation through the release of IL-18, IL-1β and IL-1α. However, despite inflammasome activation may occur in immune cells during sepsis, it is unknown if this process also takes place in endothelial cells and particularly whether extracellular histones are capable of activating endothelial inflammasomes and their consequences. In this work we highlight a previously unknown role for extracellular histones, that mediates the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how histone acetylation decreases pyroptosis activation. Furthermore, we show how pyroptosis occurs in septic shock patients and how circulating histone levels correlate with the expression of pro-inflammatory and pyroptotic cytokines, the release of endothelial adhesion factors and septic shock severity. We propose histone-mediated pyroptosis as a new target to develop clinical interventions. Similarly, we have analyzed the immune-related responses occurring during the early stages of sepsis with the aim of providing new data by comparing the amounts of cytokines, immune modulators and other endothelial mediators in critically-ill non-septic patients, septic and septic shock patients. Our approach will help to rapidly characterize the altered immune responses in septic and septic shock patients admitted in the Intensive Care Unit. Finally, we also analyzed the role of DNA methylation in the control of septic immune system. Our results demonstrated the central role of DNA methylation modulating the molecular response in septic shock patients and contributing to immunosuppression, through the alteration of DNA methylation patterns of IL-10 and TREM2 promoters

    Metabolic phenotyping of opioid and psychostimulant addiction: A novel approach for biomarker discovery and biochemical understanding of the disorder.

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    Despite the progress in characterising the pharmacological profile of drugs of abuse, their precise biochemical impact remains unclear. The metabolome reflects the multifaceted biochemical processes occurring within a biological system. This includes those encoded in the genome but also those arising from environmental/exogenous exposures and interactions between the two. Using metabolomics, the biochemical derangements associated with substance abuse can be determined as the individual transitions from recreational drug to chronic use (dependence). By understanding the biomolecular perturbations along this time course and how they vary across individuals, metabolomics can elucidate biochemical mechanisms of the addiction cycle (dependence/withdrawal/relapse) and predict prognosis (recovery/relapse). In this review, we summarise human and animal metabolomic studies in the field of opioid and psychostimulant addiction. We highlight the importance of metabolomics as a powerful approach for biomarker discovery and its potential to guide personalised pharmacotherapeutic strategies for addiction targeted towards the individual's metabolome

    Studies on the insecticidal mechanism of Bacillus thuringiensis Vip3A and Cry proteins

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    El control de plagas y patógenos ha tenido un efecto importante en la mejora del rendimiento de los sistemas agrícolas a nivel mundial. Diferentes tipos de insecticidas químicos se han usado extensivamente durante mucho tiempo para el control de plagas de insectos. Debido a la aparición de resistencias, problemas de contaminación de aguas y problemas de salud humana causados por dichos insecticidas de síntesis, la agricultura moderna necesita una estrategia de gestión integrada de plagas más saludable, respetuosa con el medio ambiente y sostenible. El uso de Bacillus thuringiensis (Bt) y sus proteínas insecticidas para el control de plagas es una de las estrategias biotecnológicas más importantes hasta la fecha. Además, los genes que codifican sus proteínas insecticidas han sido transferidos a plantas, las cuales están siendo utilizadas comercialmente, desde 1996 en gran parte del mundo para el control eficiente de numerosas plagas de insectos. En los últimos años, una nueva subclase de proteínas insecticidas secretables (Vip3) producida durante el crecimiento vegetativo de Bt se ha considerado para la aplicación combinada con las convencionalmente empleadas proteínas Cry, cuya aplicación se ve amenazada por la aparición de poblaciones de insectos resistentes. Las proteínas Vip3 no tienen homología de secuencia con las proteínas Cry y son tóxicas para insectos lepidópteros, sin embargo, su modo de acción todavía no se conoce completamente. En este proyecto de tesis, con el objetivo de mejorar su aplicación en el control biotecnológico de plagas y la comprensión del modo de acción de las proteínas Vip3, se estudiaron diversos aspectos de su actividad insecticida (espectro de acción, resistencia cruzada e interacción con otras proteínas), y se realizó un estudio de los residuos clave para el mantenimiento de la estructura tridimensional y la toxicidad de la proteína Vip3Af mediante mutagénesis dirigida. También analizamos la posible implicación de la unión a receptores en la aparición de resistencia utilizando una cepa resistente que había sido seleccionada con Vip3Aa. En primer lugar, se investigó la toxicidad de 10 toxinas Bt (Cry1Ab, Cry1Ac, Cry1Ah, Cry1Fa, Cry2Aa, Cry2b, Cry1Ie, Vip3Aa19, Vip3Aa16 y Vip3Ca) frente a Mythimna separata (plaga agrícola muy destructiva en Asia y Australia), así como su aplicación combinada mediante bioensayos llevados a cabo en laboratorio. Los resultados mostraron que la concentración letal media LC50 (Cry1Ac/Vip3Aa19/Vip3Ca 3061 veces) se obtuvo rápidamente después de 8 o 9 generaciones de selección en laboratorio. Sin embargo, no se obtuvo resistencia notable seleccionando con Cry1Ab o Cry1F en la misma población y durante el mismo número de generaciones. En un estudio realizado por otros investigadores, también se encontró una respuesta rápida similar a la selección de Vip3Aa en H. virescens, alcanzando un nivel de resistencia > 2300 veces mayor en la décima generación. Es importante hacer notar que esta rápida evolución de la selección en condiciones de laboratorio contrasta con los resultados obtenidos con las proteínas Cry1, tanto en nuestro trabajo como por otros autores: una la población de O. furnacalis adquirió un nivel de resistencia a Cry1Ab de alrededor de 100 veces sólo después de 35 generaciones de selección; de manera similar, una población de O. nubilalis desarrolló una resistencia de más de 3000 veces a Cry1F después de 35 generaciones de selección. Esta diferencia en respuesta a la selección, además de reflejar una frecuencia mucho mayor de alelos de resistencia para Vip3Aa, puede sugerir diferencias en los mecanismos de resistencia a las proteínas Vip3Aa y Cry1, lo cual queda en evidencia cuando se estudia la unión de Vip3A a BBMV de insectos resistentes El análisis de la unión de 125I-Vip3Aa a BBMV de larvas de M. separata tanto de insectos susceptibles y resistentes no reveló ninguna diferencia de unión, ya sea cualitativa o cuantitativa. Los resultados sugieren que la unión alterada a los receptores de la membrana del intestino medio no es el principal mecanismo de resistencia a la proteína Vip3Aa. Numerosos estudios han demostrado que la alteración de los receptores de membrana es un mecanismo evolutivo común que confiere altos niveles de resistencia a las proteínas Cry, pero nunca se ha establecido su relación con la resistencia a Vip3A. Las diferencias de unión cualitativas o c

    Living with dying children: the suffering of parents

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    Although the relief of suffering and emotional support are fundamental to children's palliative care, their empirical study has been limited. The research questions for this study address three areas: the lived experience of parents of dying children; how other people's responses shape the parents' lived experience; and the place of emotion and suffering in the parents' lived experience. Implementing a qualitative strategy, a collective case study was undertaken in a children's hospice in England, with fieldwork completed between March 2008 and September 2009. Data was collected with nine parents using a range of tools including a focus group, participant observation, documentary observation and individual interviews. Within-case and cross-case modified grounded theory analysis facilitated clarification of emerging themes whilst preserving individual parent voices. The findings show that parents of dying children had existential issues put at stake through the emotional experience of parenting a dying child; these included their identity, place in society, time, and relationships. Such losses could constitute suffering, but in addition they limited the parents' interaction with society so that over time both the 'quantity' and 'quality' of intersubjectivity reduced. The parents perceived that other people tended not to legitimate their lived experience. Emotion was an important influence in this process. The parents of dying children managed their emotions, particularly those of a negative nature, in everyday life and when using hospice services. As a result they expressed somewhat inauthentic accounts of their felt experience, reframed according to perceived feeling rules. This also reduced intersubjectivity and supported the delegitimation of the parental experience. In conclusion, delegitimation of the parental experience stems from feeling rules which are derived from day to day interactions and contemporary social policy. Suffering may be prevented if individual experience is legitimated through improved intersubjectivity. A key factor for this is effective communication through which observers engage with the felt emotion of the suffering individual
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