18,590 research outputs found

    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

    Strung pieces: on the aesthetics of television fiction series

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    As layered and long works, television fiction series have aesthetic properties that are built over time, bit by bit. This thesis develops a group of concepts that enable the study of these properties, It argues that a series is made of strung pieces, a system of related elements. The text begins by considering this sequential form within the fields of film and television. This opening chapter defines the object and methodology of research, arguing for a non-essentialist distinction between cinema and television and against the adequacy of textual and contextual analyses as approaches to the aesthetics of these shows. It proposes instead that these programmes should be described as televisual works that can be scrutinised through aesthetic analysis. The next chapters propose a sequence of interrelated concepts. The second chapter contends that series are composed of building blocks that can be either units into which series are divided or motifs that unify series and are dispersed across their pans. These blocks are patterned according to four kinds of relations or principles of composition. Repetition and variation are treated in tandem in the third chapter because of their close connection, given that variation emerges from established repetition. Exception and progression are also discussed together in the fourth chapter since they both require a long view of these serial works. The former, in order to be recognised as a deviation from the patterns of repetition and variation. The latter, In order to be understood in Its many dimensions as the series advances. Each of these concepts is further detailed with additional distinctions between types of units, motifs, repetitions, variations, and exceptions, using illustrative examples from numerous shows. In contrast, the section on progression uses a single series as case study, Carnivàle (2003-05), because this is the overarching principle that encompasses all the others. The conclusion considers the findings of the research and suggests avenues for their application

    A Cornish palimpsest : Peter Lanyon and the construction of a new landscape, 1938-1964

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    The thesis examines the emergence of Peter Lanyon as one of the few truly innovative British landscape painters this century. In the Introduction I discuss the problematic nature of landscape art and consider the significance of Lanyon's discovery that direct description and linear perspective can be replaced with allusive representational elements by fusing the emotional and imaginative life of the artist with the physical activity of painting. Chapter One concentrates on the period 1936-8 when Lanyon was taught by Borlase Smart, a key figure in the St Ives art colony between the wars. Chapter Two examines the influence of Adrian Stokes and the links between Lanyon's painting and the theories developed in books such as Colour and Form and The Quattro Cento. Chapter Three analyses the period 1940-45 when Lanyon was directly influenced by the constructivism of Nicholson, Hepworth and Gabo. I look closely at their approaches to abstraction and assess Lanyon's relative position to them. The importance of Neo-Romanticism and the status of St Ives as a perceived avant-garde community is also addressed. In Chapter Four I discuss how Lanyon resolved to achieve a new orientation in his art on his return from wartime service with the RAF by synthesising constructivism, and traditional landscape. The Generation and Surfacing Series demonstrate his preoccupation with a sense of place, a fascination with the relationships between the human body and landscape and his struggle to find a technique and style that was entirely his own. His sense of existential insideness is discussed in Chapter Five through an examination of the work derived from Portreath, St. Just and Porthleven - key places in Lanyon's psychological attachment to the landscape of West Penwith. In Chapter Six I examine Lanyon's attachment to myths and archetypal forms, tracing the influence of Bergson's vitalist philosophy as well as his use of Celtic and classical motifs. Chapter Seven is a discussion of the malaise evident in Lanyon's work by 1955 and the impact of American Abstract Expressionism at the Tate Gallery a year later. In the summer of 1959 Lanyon joined the Cornish Gliding Club and Chapter Eight looks at how this necessitated a dynamic, expanded conception of the landscape and a re-thinking of relations within the picture field. The ability to dissolve boundaries encouraged him to break down distinctions between painting and construction so that abstract sculptural elements were now assembled into independent works of art. Finally, Chapter Nine assesses Lanyon's overall position in relation to his early influences and to St Ives art as a whole, his response to new directions in art coming out of London and NewYork in the early 1960s and the importance of travel as a stimulus for further realignment in his artistic and topographical horizons. His pictorial inventiveness and vitality remained unabated at the time of his death and would undoubtedly have continued to be enriched by travel abroad and contact with new movements in modem art on both sides of the Atlanti

    Epistemologies of possibility: social movements, knowledge production and political transformation

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    Urgent global problems - whether military conflicts, economic insecurities, immigration controls or mass incarceration-not only call for new modes of political action but also demand new forms of knowledge. For if knowledge frameworks both shape the horizons of social intelligibility and chart t he realms of political possibility, then epistemological interventions constitute a crucial part of social change. Social movements play a key role in this work by engaging in dissident knowledge practices that open up space for political transformation. But what are the processes and conditions through which social movements generate new ways of knowing?'What is politically at stake in the various knowledge strategies that activists use to generate social change? Despite a growing literature on the role of epistemological dimensions of protest, social movement studies tend to neglect specific questions of epistemological change. Often treating knowledge as a resource or object rather than a power relation and a social practice, social movement scholars tend to focus on content rather than production, frames rather than practices, taxonomies rather than processes. Missing is a more dynamic account of the conditions, means and power relations through which transformative knowledge practices come to be constituted and deployed. Seeking to better understand processes of epistemological transformation, this thesis explores the relationship between social movements, knowledge production and political change. Starting from an assumption that knowledge not only represents the world, but also works to constitute it, this thesis examines the role of social movement knowledge practices in shaping the conditions of political possibility. Drawing from the context of grassroots queer, transgender and feminist organizing around issues of prisons and border controls in North America, the project explores how activists generate new forms of knowledge and forge new spaces of political possibility. Working through a series of concepts-transformation, resistance, experience, co-optation, solidarity and analogy - this thesis explores different ways of understanding processes of epistemological change with in social movement contexts. It considers processes that facilitate or enable epistemological change and those that limit or prohibit such change. Bringing together a range of theoretical perspectives, including feminist, queer, critical race and post-structuralist analyses, and drawing on interviews with grassroots activists, the thesis explores what is politically at stake in the different ways we conceptualise, imagine and engage in processes of epistemological change

    Making Sense of Ayahuasca Non-Sense: A critical study of UK groups consuming a psychoactive plant mixture and their struggle to find religious meaning

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    How we make sense of ourselves, and the cosmos is an ongoing concern, guided by the people we meet, environments we exist within, and plants we consume. Having spent over a year observing forty-nine participants within three UK-based ayahuasca churches, it is clear that the psychoactive 'brew' ayahuasca creates intense changes to how individuals think about themselves and the world they live in. At the heart of the ayahuasca experience are non-sensical hallucinations and visions, which often exist outside of perceptual understanding, leaving individuals feeling lost in an unknowable universe. As we will come to see, making sense of non-sensical ayahuasca experiences requires individuals to negotiate multiple 'common-sense' views of reality. Taking a view that mind is something that happens within life, this ethnographic study uses participant observation, interviews, conversations, personal diaries, and my experiences as an ayahuasca tourist to detail how making sense of reality is also an act of making oneself. In so doing, I argue that ayahuasca hallucinations and visions function as a source of ongoing mental innovation, facilitating preferred views of reality throughout these psychoactive churches. Critically, we will see how frequent ayahuasca consumption engenders in-depth beliefs in the supernatural, and in particular, devotion to the goddess Ayahuasca, who functions as the unchallengeable road to knowing oneself and reality. Acting as an otherworldly guide, the immaterial goddess Ayahuasca plays a key part in how individuals convert non-sensical experiences into sense, while providing practical advice for how to achieve salvation. Problematically though, positioning the universe and oneself as predominantly supernatural tends to erode beliefs in the physical world, leaving these churches with incoherent views of reality, and at the periphery of everyday social life. As such, church doctrines seem increasingly unable to cope with life outside of their groups, and thus, tactically stigmatise competing views of reality as sinful and individuals espousing such heresies as under the control of malevolent demonic beings. Not surprisingly, this binary belief in a good and evil cosmos is a powerful regulatory force dictating what reality is within these churches, and who church members can claim to be

    3D printed Microneedles for Transdermal Drug Delivery

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    3D printing is a revolutionary manufacturing and prototyping technology that has altered the outlooks of numerous industrial and scientific fields since its introduction. Recently, it has attracted attention for its potential as a manufacturing tool for transdermal microneedles for drug delivery. In the present thesis, the 3D printability of solid and hollow microneedles via photopolymerisation-based 3D printing was investigated, aiming at establishing robust manufacturing strategies for reproducible, mechanically strong and versatile microneedles. The developed microneedles were employed as drug delivery systems for the treatment of diabetes via insulin administration. Solid microneedles featuring different geometries were designed and 3D printed. It was demonstrated that the printing and post-printing parameters affected the printed quality, a finding that was employed to optimise the manufacturing strategy. Microneedle geometry was also found to have an impact on the piercing and fracture behaviour; however all microneedle designs were found to be mechanically safe upon application. The solid microneedles were subsequently coated with insulin-polymer films, using a 2D inkjet printing technology. The coating process achieved spatial control of the drug deposition, with quantitative accuracy. The microneedle geometry was shown to influence the morphology of the coating film, an effect that was pronounced during in the in vitro delivery studies of insulin to porcine skin. Furthermore, hollow microneedles were designed and 3D printed, featuring different heights. Two photopolymerisation-based technologies were studied, and their performance was compared. The key influential parameters of the printing outcome and microneedle quality were identified to be the printing angle and the size of the microneedle opening. The hollow microneedles were found to be effective in piercing porcine skin without structural damaging. The hollow microneedles were incorporated into complex patches with internal microfluidic structures for the provision and distribution of drug-containing solutions. The developed complex hollow microneedle patches were coupled with a microelectromechanical system to create a novel platform device for controlled, personalised transdermal drug delivery. Advanced imaging techniques revealed that the device achieved distribution of the liquid within porcine skin tissue without the creation of depots that would delay absorption. The device was evaluated for its efficacy to transdermally deliver a model dye and insulin in vitro. In vivo trials were also conducted using diabetic rodents, with the device achieving faster onset of insulin action and sustained glycemic control, in comparison to subcutaneous injections. Overall, the findings of the present research are anticipated to elucidate key problematic areas associated with the application of 3D printing for microneedle manufacturing and propose feasible solutions. The outermost goal of this work is to contribute to the advancement of knowledge in the field of 3D printed transdermal drug delivery systems, in order to bring them one step closer to their adoption in the clinical setting
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