63,115 research outputs found

    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

    South Yorkshire low carbon energy supply chains: insulation sector summary

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    South Yorkshire low carbon energy supply chains: hydrogen sector summary

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

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    La sepsis es una afecci贸n potencialmente mortal causada por una respuesta anormal del hu茅sped a una infecci贸n, produciendo respuestas fisiol贸gicas alteradas que da帽an los propios tejidos del paciente y pueden provocar disfunci贸n org谩nica e incluso la muerte. Asimismo, algunos pacientes s茅pticos progresan a shock s茅ptico, caracterizado por alteraciones circulatorias, celulares y metab贸licas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunol贸gico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresi贸n, la alta complejidad de la fisiopatolog铆a de la sepsis requiere una mayor investigaci贸n para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citot贸xicos en la sepsis, ya que act煤an como patrones moleculares asociados a da帽o, que inducen estr茅s oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activaci贸n de la piroptosis, un mecanismo de muerte celular programada que produce inflamaci贸n mediante la expresi贸n de IL-18, IL-1尾 and IL-1伪. Sin embargo, a pesar de la evidencia de activaci贸n del inflamasoma en las c茅lulas 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 activaci贸n del inflamasoma NLRP3 y la piroptosis en las c茅lulas endoteliales, contribuyendo a la disfunci贸n endotelial y la desregulaci贸n de la respuesta inmune mediada por el endotelio. Asimismo, tambi茅n demostramos c贸mo la acetilaci贸n de histonas disminuye la activaci贸n de la piroptosis. Adem谩s, demostramos que la piroptosis se produce en pacientes con shock s茅ptico y los niveles de histonas circulantes se correlacionan con la expresi贸n de citoquinas proinflamatorias y citoquinas piropt贸ticas, la liberaci贸n de factores de adhesi贸n endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones cl铆nicas. 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 cr铆ticamente enfermos no s茅pticos, s茅pticos y de shock s茅ptico. Nuestro enfoque ayudar谩 a caracterizar r谩pidamente las respuestas inmunes alteradas en pacientes s茅pticos y de shock s茅ptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilaci贸n del ADN en el control del sistema inmune s茅ptico. Nuestros resultados demostraron el papel central de la metilaci贸n del ADN modulando la respuesta molecular en los pacientes de shock s茅ptico y contribuyendo a la inmunosupresi贸n, a trav茅s de la alteraci贸n de los patrones de metilaci贸n 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-1尾 and IL-1伪. 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

    The company she keeps : The social and interpersonal construction of girls same sex friendships

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    This thesis begins a critical analysis of girls' 'private' interpersonal and social relations as they are enacted within two school settings. It is the study of these marginal subordinated worlds productivity of forms of femininity which provides the main narrative of this project. I seek to understand these processes of (best) friendship construction through a feminist multi-disciplinary frame, drawing upon cultural studies, psychoanalysis and accounts of gender politics. I argue that the investments girls bring to their homosocial alliances and boundary drawing narry a psychological compulsion which is complexly connected to their own experiences within the mother/daughter bond as well as reflecting positively an immense social debt to the permissions girls have to be nurturant and ; negatively their own reproduction of oppressive exclusionary practices. Best friendship in particular gives girls therefore, the experience of 'monogamy' continuous of maternal/daughter identification, reminiscent of their positioning inside monopolistic forms of heterosexuality. But these subcultures also represent a subversive discontinuity to the public dominance of boys/teachers/adults in schools and to the ideologies and practices of heterosociality and heterosexuality. By taking seriously their transmission of the values of friendship in their chosen form of notes and diaries for example, I was able to access the means whereby they were able to resist their surveillance and control by those in power over them. I conclude by arguing that it is through a recognition of the valency of these indivisiblly positive and negative aspects to girls cultures that Equal Opportunities practitioners must begin if they are serious about their ambitions. Methods have to be made which enable girls to transfer their 'private' solidarities into the 'public' realm, which unquestionably demands contesting with them the causes and consequences of their implication in the divisions which also contaminate their lives and weaken them

    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, Carniv脿le (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

    Reforming the United Nations

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    The thesis deals with the financial crisis that the United Nations faced starting in 1985 when the US Congress decided to withhold a significant part of the US contribution to the UN regular budget in order to force a greater say for the major contributors on budgetary issues, budgetary restraint and greater efficiency. The UN responded by the adoption of resolution 41/213 of 19 December 1986 that was based on the recommendations of a Group of High-level Intergovernmental Experts ("G-18") set up a year earlier. A new system was introduced regarding the formulation of the regular budget of the United Nations Organisation and a broader process of reform was initiated including a restructuring of the Secretariat and of the intergovernmental machinery in the economic and social fields. After an introductory chapter (Chapter I), the thesis examines the UN problems at the budgetary/financial and administrative/structural levels, the solutions proposed from within and without the United Nations established framework and the actual attempts at reform (Chapters II and ifi). The realisation that the implementation of reforms is rather disjointed and often unsuccessful (e.g. the failure to restructure the intergovernmental machi.neiy) prompts a search for the deeper causes of the UN problems at the political level and the attitudes of the main actors, namely the USA, the USSR, some up-and-coming states, notably Japan, the Third World states and, finally, of the UN Secretary-General and the Secretariat (Chapter 1V). Although the financial crisis may have subsided since 1988 and the USA seem committed to paying up their dues, the deeper UN crisis of identity has not been resolved and is expected to resurface if no bold steps are taken. In that direction, some possible alternative courses for the UN in the future are discussed drawing upon theory and practice (Chapte

    Recent Hong Kong cinema and the generic role of film noir in relation to the politics of identity and difference

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    This thesis identifies a connection in Hong Kong cinema with classical Hollywood film noir and examines what it will call a 'reinvestment' in film noir in recent films. It will show that this reinvestment is a discursive strategy that both engages the spectator-subject in the cinematic practice and disengages him or her from the hegemony of the discourse by decentring the narrative. The thesis argues that a cinematic practice has occurred in the recent reinvestment of film noir in Hong Kong, which restages the intertextual relay of the historical genre that gives rise to an expectation of ideas about social instability. The noir vision that is seen as related to the fixed categories of film narratives, characterizations and visual styles is reassessed in the course of the thesis using Derridian theory. The focus of analysis is the way in which the constitution of meanings is dependent on generic characteristics that are different. Key to the phenomenon is a film strategy that destabilizes, differs and defers the interpretation of crises-personal, social, political and/or cultural-by soliciting self-conscious re-reading of suffering, evil, fate, chance and fortune. It will be argued that such a strategy evokes the genre expectation as the film invokes a network of ideas regarding a world perceived by the audience in association with the noirish moods of claustrophobia, paranoia, despair and nihilism. The noir vision is thus mutated and transformed when the film device differs and defers the conception of the crises as tragic in nature by exposing the workings of the genre amalgamation and the ideological function of the cinematic discourse. Thus, noirishness becomes both an affect and an agent that contrives a self-reflexive re-reading of the tragic vision and of the conventional comprehension of reality within the discursive practice. The film strategy, as an agent that problematizes the film form and narrative, gives rise to what I call a politics of difference, which may also be understood as the Lyotardian 'language game' or a practice of 'pastiche' in Jameson's terminology. Under the influence of the film strategy, the spectator is enabled to negotiate his or her understanding of recent Hong Kong cinema diegetically and extra-diegetically by traversing different positions of cinematic identification. When the practice of genre amalgamation adopts the visual impact of the noirish film form, the film turns itself into a playing field of 'fatal' misrecognition or a site of question. Through cinematic identification and alienation from the identification, the spectator-subject is enabled to experience the misrecognition as the film slowly foregrounds the way in which the viewer's presence is implicated in the narrative. This thesis demonstrates that certain contemporary Hong Kong films introduce this selfconscious mode of explication and interpretation, which solicits the spectator to negotiate his or her subject-position in the course of viewing. The notions of identity and subjectivity under scrutiny will thus be reread. With reference to The Private Eye Blue, Swordsman II, City a/Glass and Happy Together, the thesis shall explore the ways in which the Hong Kong films enable and facilitate a negotiation of cultural identity

    Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

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    Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases

    Towards the development of care management in community care for elderly people in Korea

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    This study is concerned with the feasibility of several forms of care management in the development of community care for elderly people in Korea. Chapter one introduces the background of community care in Korea in the light of demographic, socio-economic, and political realities. This chapter reviews the changing Korean society as a barometer to understand the scope, size, and speed of social needs, especially community care for elderly people, over the last few decades. Chapter two explores various definitions, concepts, and theories of community, community care, and care management by building upon trends previously established in the research. This helps to identify the different models of care management and the pre-conditions necessary for the application of different models in Korea. Chapter three explores what factors have affected the development of community care, and what community dare has achieved for elderly people in the UK. Especially, care management in community care for elderly people in the UK is examined in detail. Chapter four details the findings of field research on community care for elderly people in Korea. This covers the needs of elderly people and their carers, and the social worker's tasks and available resources. The potential for the use of care management based on the findings of field research is assessed. Chapter five investigates whether the UK models of care management are suitable for Korean society, which interventions are useful for developing care management, and the strategies, and principles involved
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