43,246 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

    Balancing the urban stomach: public health, food selling and consumption in London, c. 1558-1640

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    Until recently, public health histories have been predominantly shaped by medical and scientific perspectives, to the neglect of their wider social, economic and political contexts. These medically-minded studies have tended to present broad, sweeping narratives of health policy's explicit successes or failures, often focusing on extraordinary periods of epidemic disease viewed from a national context. This approach is problematic, particularly in studies of public health practice prior to 1800. Before the rise of modern scientific medicine, public health policies were more often influenced by shared social, cultural, economic and religious values which favoured maintaining hierarchy, stability and concern for 'the common good'. These values have frequently been overlooked by modern researchers. This has yielded pessimistic assessments of contemporary sanitation, implying that local authorities did not care about or prioritise the health of populations. Overly medicalised perspectives have further restricted historians' investigation and use of source material, their interpretation of multifaceted and sometimes contested cultural practices such as fasting, and their examination of habitual - and not just extraordinary - health actions. These perspectives have encouraged a focus on reactive - rather than preventative - measures. This thesis contributes to a growing body of research that expands our restrictive understandings of pre-modern public health. It focuses on how public health practices were regulated, monitored and expanded in later Tudor and early Stuart London, with a particular focus on consumption and food-selling. Acknowledging the fundamental public health value of maintaining urban foodways, it investigates how contemporaries sought to manage consumption, food production waste, and vending practices in the early modern City's wards and parishes. It delineates the practical and political distinctions between food and medicine, broadly investigates the activities, reputations of and correlations between London's guild and itinerant food vendors and licensed and irregular medical practitioners, traces the directions in which different kinds of public health policy filtered up or down, and explores how policies were enacted at a national and local level. Finally, it compares and contrasts habitual and extraordinary public health regulations, with a particular focus on how perceptions of and actual food shortages, paired with the omnipresent threat of disease, impacted broader aspects of civic life

    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 labour supply and retirement of older workers: an empirical analysis

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    This thesis examines the labour supply of older workers, their movement into retirement, and any movement out of retirement and back into work. In particular the labour force participation, labour supply and wage elasticity and other income elasticity of work hours are estimated for older workers and compared to younger workers. The thesis goes on to look at the movement into retirement for older workers as a whole by examining cohorts by gender, wave and age. The thesis also presents a descriptive and quantitative 鈥 examination of the changes in income and happiness that occur as an individual retires. Finally the thesis examines the reasons why an individual may return to work from v . retirement. The results of the findings suggest: that younger workers are significantly more responsive to wage and household income changes than older worker

    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

    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

    The Caribbean Syzygy: a study of the novels of Edgar Mittelholzer and Wilson Harris

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    The problem of racial inheritance - the "search for identity" - is a recurring theme in the criticism of Caribbean literature. It is a pre-occupation with Caribbean writers, affecting both subject matter and literary quality, as FM. Birbalsingh, for example, has shown with reference to the novels of John Hearne and E,R. Braithwaite (Caribbean quarterly Vols. 14, December 1968 and 16, March 1970). This study of the work of Edgar Mittelholzer and Wilson Harris will attempt to show that there are important areas still to be explored relating Caribbean literature to its complex racial and cultural background. Both Mittelholzer and Harris deserve close, critical study in their own right; but a parallel examination reveals similarities and differences which bring into sharper focus wider concerns of Caribbean literature. The two important directions of West Indian writing are more clearly seen: the one, pioneered by Mittelholzer, in which the writer looks outward towards a "parent" culture, and the other looking inward, seeking in its own, complex inheritance the raw material for new and original growth. Mittelholzer and Harris are both Guyanese of mixed racial stock, both deeply concerned with the psychological effects of this mixture, and both writers have a profound awareness of the Guyanese historical and cultural heritage. They also share a deep feeling for the Guyenese landscape which appears in their work as a brooding presence affecting radically -the lives of those who live within i-t. Mittelholzer's attitude to his mixed racial and cultural origins, however, produces in his work a schizophrenic Imbalance while Harris, by accepting racial and cultural complexity as a starting-point, initiates a uniquely creative and experimental art. Mittelholzer, in his approach to history, human character eM landscape, remains a vi "coastal" writer never really concerned (as Harris is) with. the deeper significance of the "Interior" and all that this implies, both in a geographical and psychological sense. The fact that Mittelbolzer's work reflects a psychological imbalance induced by a pre-occupation with racial identity has been demonstrated by Denis Williams in the 1968 Mittelholzer Lectures, and by Joyce Sparer in a series of articles in the Guyana Graphic. Mittelholzer's awareness of this imbalance, however, and his attempt to come to terms with it in his art remain to be examined and documented, as does Harris's attempt to create am "associative" art aimed at healing the breach in the individual consciousness of Caribbean Man. The aim of this study is to demonstrate that Mitteholzer and. Harris, although antithetical in impact and style (each representing an approach to fiction directly opposed to the other) are, in fact, the opposite elements of a dichotomy. Their work illustrates the negative and positive aspects of the racial and cultural schizophrenia of the Caribbean, for both writers in their different ways are preoccupied with (and therefore have embodied in their work) the juxtaposition and, contrasting of apparently irreconcilable emotional and intellectual qualities - the Caribbean Syzygy

    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

    Gendered spaces in contemporary Irish poetry

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    The thrust of this thesis is summarized by the following questions: How does contemporary Irish poetry migrate from traditional conceptions of identity drawn on by the cultural nationalism of the Irish Literary Revival, and what effects does this have on understanding gendered and national identity formation? Chapters are on the following: Seamus Heaney, Tom Paulin, Paul Muldoon, MedbhMcGuckian, Eavan Boland and Sara Berkeley. These poets are chosen for discussion since their work most effectively engages with the relationship between woman and nation, the representation of gendered national identity, and the importance of feminist and post-colonial theorization. Focusing on poetry worth and South of the border from the last fifteen years, the thesis asks how a younger generation of poets provide a response to nationality which is significantly different from their predecessors. The thesis is composed of three parts: the first understand how the male poets depart from conventional conceptions of the nation with reference to post-colonial theorization; the second explores how feminist theorization informs readings of how the female poets respond to the nation; the final part investigates migration in the poetry and problematizes this in terms of post-nationalism. Discussing the issue of deterritorialization in Irish poetry, the thesis notice how as the poets attempt to take flight from the mythologies of nationhood, they undermine the monoliths of gendered and national identity inscribed within Irish political discourse, which is typified at a representative level by the figure of Mother Ireland or Cathleen Ni Houlihan. Investigating the ways in which gender and nation, and the body and space are reinscribed by the poets, the thesis argues that their poetry challenges authentic conceptions of Irish identity and the nation-state, so as to loosen the legacy of a colonial and nationalist inheritance

    Botanical Journeys and China's Colonial Frontiers: 1840-1940

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    Over recent years, a body of scholarship has emerged on the topic of European and American travel writing in China. This thesis contributes to this growing field by examining four writers who travelled in China and worked as plant collectors and botanists. Largely forgotten today, these writers were influential and successful in their own day. Despite differences in geographical location and historical period, there are a number of common links that make a comparison of these travel writings productive. As travellers seeking botanical rarity and novelty, these writers explored regions of China unknown in the West, which over a period of one hundred years expanded outwards from the fringes of the treaty port areas to more remote regions of China's southwest. These writers, therefore, were on the frontiers of Western knowledge of China, and an examination of their writing provides important insights into the ways in which racial, geographical, and ecological differences were articulated and understood in the context of colonial and scientific exploration. While discussing how such differences have imperial significance, this study will also call attention to the instability of colonialist discourse in the context of China. Rather than focus exclusively on questions of imperialism, this study will show how representations of China's periphery regions also speak to metropolitan literary and cultural concerns, and a close reading of these travel writings shows that China offered powerful imaginary landscapes for home audiences. This project is organised chronologically and the chapters are divided according to the authors, with the exception of the first chapter where I introduce the historical and theoretical framework of the study and the final concluding chapter where I consider the significance of this study in the context of modern China
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