22,406 research outputs found

    Mapping Super-Relaxed States of Myosin Heads in Sarcomeres using Oblique Angle Fluorescent Microscopy

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    We have utilised modern methods of super-resolution fluorescent microscopy to spatially map fluorescently labelled ATP molecules in relaxed rabbit psoas skeletal muscles. For our imaging process, we have labelled ATP molecules with Rhodamine and Z-lines with Alexa488. Data from imaging these fluorophores have been collected using oblique angle fluorescent microscopy and further analysed to map super relaxed states (SRX) of myosin heads on the thick filament. Our experiments have concluded that most SRX of myosin heads were found in the C-zone of the thick filament, while other zones of thick filament had smaller populations of SRX. Further introduction of mavacamten (MAVA) to our imaging system has revealed an increase in SRX in both D and P zones, while the C zone population of SRX had remained constant. Further experiments must be conducted to establish a clear pattern and further proof our findings

    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

    The Role of English and Welsh INGOs: A Field Theory-Based Exploration of the Sector

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    This thesis takes a field theory-based approach to exploring the role of English and Welsh international non-governmental organisations (INGOs), using the lens of income source form. First, the thesis presents new income source data drawn from 933 Annual Accounts published by 316 INGOs over three years (2015-2018). The research then draws on qualitative data from 90 Leaders' letters include within the Annual Reports published by 39 INGOS, as well as supplementary quantitative and qualitative data, to explore the ways in which INGOs represent their role. Analysis of this income source data demonstrates that government funding is less important to most INGOs than has previously been assumed, while income from individuals is more important than has been recognised in the extant development studies literature. Funding from other organisations within the voluntary sector is the third most important source of income for these INGOs, while income from fees and trading is substantially less important than the other income source forms. Using this income source data in concert with other quantitative data on INGO characteristics as well as qualitative data drawn from the Leaders' letters, I then show that the English and Welsh INGO sector is a heterogenous space, divided into multiple fields. The set of fields identified by this thesis is arranged primarily around income source form, which is also associated with size, religious affiliation, and activities of focus and ways of working. As Bourdieusian field theory suggests, within these fields individual INGOs are engaged in an ongoing struggle for position: competing to demonstrate their maximal possession of the symbolic capitals they perceive to be valued by (potential) donors to that field. Further analysis of these Leaders' letters, alongside additional Annual Reports and Accounts data, also reveals a dissonance in the way in which INGOs describe their relationship with local partners in these different communication types. While these Leaders' letters and narrative reports tell stories of collaborative associations with locally-based partners, this obscures the nature of these relationships as competitive and hierarchical. The thesis draws on the above findings to reflect on the role of INGOs as suggested in the extant literature. This discussion highlights how the various potential INGO fields identified are associated with differing theoretical roles for INGOs. Finally, the thesis considers how INGO role representations continue to contribute to unequal power relations between INGOs and their partners

    A productive response to legacy system petrification

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    Requirements change. The requirements of a legacy information system change, often in unanticipated ways, and at a more rapid pace than the rate at which the information system itself can be evolved to support them. The capabilities of a legacy system progressively fall further and further behind their evolving requirements, in a degrading process termed petrification. As systems petrify, they deliver diminishing business value, hamper business effectiveness, and drain organisational resources. To address legacy systems, the first challenge is to understand how to shed their resistance to tracking requirements change. The second challenge is to ensure that a newly adaptable system never again petrifies into a change resistant legacy system. This thesis addresses both challenges. The approach outlined herein is underpinned by an agile migration process - termed Productive Migration - that homes in upon the specific causes of petrification within each particular legacy system and provides guidance upon how to address them. That guidance comes in part from a personalised catalogue of petrifying patterns, which capture recurring themes underlying petrification. These steer us to the problems actually present in a given legacy system, and lead us to suitable antidote productive patterns via which we can deal with those problems one by one. To prevent newly adaptable systems from again degrading into legacy systems, we appeal to a follow-on process, termed Productive Evolution, which embraces and keeps pace with change rather than resisting and falling behind it. Productive Evolution teaches us to be vigilant against signs of system petrification and helps us to nip them in the bud. The aim is to nurture systems that remain supportive of the business, that are adaptable in step with ongoing requirements change, and that continue to retain their value as significant business assets

    The mechanisms of antibody generation in the llama

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    The llama is able to generate a unique class of antibody. The heavy chain immunoglobulins consist only of two heavy chain polypeptides and bind antigen specifically through single protein domains. Although the mechanisms by which such an antibody interacts with antigen has been studied at some length the manner in which the heavy chain antibody is generated within the llama is unknown. In this study a number of components of the llama immune system have been characterised. The isolation of genes encoding the variable domain of the heavy chain antibody indicates that specific genetic elements within the llama genome are responsible for the generation of the heavy chain antibody. The discovery of constant region genes that encode the heavy chain antibody provides an explanation for the absence of a major immunoglobulin domain from the final, secreted gene product. The lack of this domain within the expressed antibody is believed to be the result of a single nucleotide splice site mutation. In order to investigate the process of llama antibody generation further additional components of the llama immune system, the recombination activating genes (rag) were isolated. One such llama rag gene (rag-i) was cloned, expressed and utilised in an in vitro assay system to investigate recombination events taking place during antibody generation. This assay involved the use of specific signal sequences derived from variable domain gene sequence data and represents, to our knowledge, the first examination of non-murine RAG activity. Through the use of this system distinct differences between llama and mouse recombination signal sequences (RSSs) were uncovered. These differences, located within a specific region of the RSS known as the coding flank, may play an important role in llama antibody generation. These results have led to the proposal of a number of models for the mechanisms involved in llama antibody generation

    Interactive Sonic Environments: Sonic artwork via gameplay experience

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    The purpose of this study is to investigate the use of video-game technology in the design and implementation of interactive sonic centric artworks, the purpose of which is to create and contribute to the discourse and understanding of its effectiveness in electro-acoustic composition highlighting the creative process. Key research questions include: How can the language of electro-acoustic music be placed in a new framework derived from videogame aesthetics and technology? What new creative processes need to be considered when using this medium? Moreover, what aspects of 'play' should be considered when designing the systems? The findings of this study assert that composers and sonic art practitioners need little or no coding knowledge to create exciting applications and the myriad of options available to the composer when using video-game technology is limited only by imagination. Through a cyclic process of planning, building, testing and playing these applications the project revealed advantages and unique sonic opportunities in comparison to other sonic art installations. A portfolio of selected original compositions, both fixed and open are presented by the author to complement this study. The commentary serves to place the work in context with other practitioners in the field and to provide compositional approaches that have been taken

    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

    In search of 'The people of La Manche': A comparative study of funerary practices in the Transmanche region during the late Neolithic and Early Bronze Age (250BC-1500BC)

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    This research project sets out to discover whether archaeological evidence dating between 2500 BC - 1500 BC from supposed funerary contexts in Kent, flanders and north-eastern Transmanche France is sufficient to make valid comparisons between social and cultural structures on either side of the short-sea Channel region. Evidence from the beginning of the period primarily comes in the form of the widespread Beaker phenomenon. Chapter 5 shows that this class of data is abundant in Kent but quite sparse in the Continental zones - most probably because it has not survived well. This problem also affects the human depositional evidence catalogued in Chapter 6, particularly in Fanders but also in north-eastern Transmanche France. This constricts comparative analysis, however, the abundant data from Kent means that general trends are still discernible. The quality and volume of data relating to the distribution, location, morphology and use of circular monuments in all three zones is far better - as demonstrated in Chapter 7 -mostly due to extensive aerial surveying over several decades. When the datasets are taken as a whole, it becomes possible to successfully apply various forms of comparative analyses. Most remarkably, this has revealed that some monuments apparently have encoded within them a sophisticated and potentially symbolically charged geometric shape. This, along with other less contentious evidence, demonstrates a level of conformity that strongly suggests a stratum of cultural homogeneity existed throughout the Transmanche region during the period 2500 BC - 1500 BC. The fact that such changes as are apparent seem to have developed simultaneously in each of the zones adds additional weight to the theory that contact throughout the Transmanche region was endemic. Even so, it may not have been continuous; there may actually have been times of relative isolation - the data is simply too course to eliminate such a possibility
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