10,958 research outputs found

    Epilepsy Mortality: Leading Causes of Death, Co-morbidities, Cardiovascular Risk and Prevention

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    a reuptake inhibitor selectively prevents seizure-induced sudden death in the DBA/1 mouse model of sudden unexpected ... Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by ..

    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 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

    The applied psychology of addictive orientations : studies in a 12-step treatment context.

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    The clinical data for the studies was collected at The PROMIS Recovery Centre, a Minnesota Model treatmentc entre for addictions,w hich encouragesth e membership and use of the 12 step Anonymous Fellowships, and is abstinence based. The area of addiction is contextualised in a review chapter which focuses on research relating to the phenomenon of cross addiction. A study examining the concept of "addictive orientations" in male and female addicts is described, which develops a study conductedb y StephensonM, aggi, Lefever, & Morojele (1995). This presents study found a four factor solution which appeared to be subdivisions of the previously found Hedonism and Nurturance factors. Self orientated nurturance (both food dimensions, shopping and caffeine), Other orientated nurturance (both compulsive helping dimensions and work), Sensation seeking hedonism (Drugs, prescription drugs, nicotine and marginally alcohol), and Power related hedonism (Both relationship dimensions, sex and gambling. This concept of "addictive orientations" is further explored in a non-clinical population, where again a four factor solution was found, very similar to that in the clinical population. This was thought to indicate that in terms of addictive orientation a pattern already exists in this non-clinical population and that consideration should be given to why this is the case. These orientations are examined in terms of gender differences. It is suggested that the differences between genders reflect power-related role relationships between the sexes. In order to further elaborate the significance and meaning behind these orientations, the next two chapters look at the contribution of personality variables and how addictive orientations relate to psychiatric symptomatology. Personality variables were differentially, and to a considerable extent predictably involved with the four factors for both males and females.Conscientiousness as positively associated with "Other orientated Nurturance" and negatively associated with "Sensation seeking hedonism" (particularly for men). Neuroticism had a particularly strong association with the "Self orientated Nurturance" factor in the female population. More than twice the symptomatology variance was explained by the factor scores for females than it was for males. The most important factorial predictors for psychiatric symptomatology were the "Power related hedonism" factor for males, and "Self oriented nurturance" for females. The results are discussed from theoretical and treatment perspectives

    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

    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

    Applications and practical considerations of polarisation structuring by a Fresnel cone

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    The polarisation property of light has been known about for hundreds of years. Often its use in technology has been limited to uniform states, however, more recently light with structured polarisation has gained interest. This is largely prompted by availability of spatial light modulators for generation, and increased computation speed to model complex focal fields. My PhD research has extended upon work carried out during a master’s project where we investigated the use of a solid glass cone (so-called Fresnel cone) for generating vector vortex beams. The aim of this thesis is to report on the potential use of a Fresnel cone in microscopy and polarimetry applications, and practical implications discovered. Expanding on the previous work, enhanced fidelity polarisation states are measured and a newly developed Fresnel cone coupling technique is shown, allowing high-efficiency annular vector vortex beam generation. We demonstrate through simulations based on vector diffraction theory that azimuthally polarised light with OAM generated using a Fresnel cone can provide sub-diffraction limited focal spots, below those of more well-known radially polarised light. Practical implications were encountered, prompting investigation into the effects of phase aberrations on resulting focal spots, and experimental measurement of cone surface topology. We find the uniformity of the Fresnel cone shape and apex angle is crucial to the focussing properties. For polarimetry application, full details are provided for a single-shot full-Stokes polarimeter technique and proof-of-principle experiment, where broadband operation is demonstrated. I conclude by summarising the findings of my research and suggest potential future work in this area

    Scalable software and models for large-scale extracellular recordings

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    The brain represents information about the world through the electrical activity of populations of neurons. By placing an electrode near a neuron that is firing (spiking), it is possible to detect the resulting extracellular action potential (EAP) that is transmitted down an axon to other neurons. In this way, it is possible to monitor the communication of a group of neurons to uncover how they encode and transmit information. As the number of recorded neurons continues to increase, however, so do the data processing and analysis challenges. It is crucial that scalable software and analysis tools are developed and made available to the neuroscience community to keep up with the large amounts of data that are already being gathered. This thesis is composed of three pieces of work which I develop in order to better process and analyze large-scale extracellular recordings. My work spans all stages of extracellular analysis from the processing of raw electrical recordings to the development of statistical models to reveal underlying structure in neural population activity. In the first work, I focus on developing software to improve the comparison and adoption of different computational approaches for spike sorting. When analyzing neural recordings, most researchers are interested in the spiking activity of individual neurons, which must be extracted from the raw electrical traces through a process called spike sorting. Much development has been directed towards improving the performance and automation of spike sorting. This continuous development, while essential, has contributed to an over-saturation of new, incompatible tools that hinders rigorous benchmarking and complicates reproducible analysis. To address these limitations, I develop SpikeInterface, an open-source, Python framework designed to unify preexisting spike sorting technologies into a single toolkit and to facilitate straightforward benchmarking of different approaches. With this framework, I demonstrate that modern, automated spike sorters have low agreement when analyzing the same dataset, i.e. they find different numbers of neurons with different activity profiles; This result holds true for a variety of simulated and real datasets. Also, I demonstrate that utilizing a consensus-based approach to spike sorting, where the outputs of multiple spike sorters are combined, can dramatically reduce the number of falsely detected neurons. In the second work, I focus on developing an unsupervised machine learning approach for determining the source location of individually detected spikes that are recorded by high-density, microelectrode arrays. By localizing the source of individual spikes, my method is able to determine the approximate position of the recorded neuriii ons in relation to the microelectrode array. To allow my model to work with large-scale datasets, I utilize deep neural networks, a family of machine learning algorithms that can be trained to approximate complicated functions in a scalable fashion. I evaluate my method on both simulated and real extracellular datasets, demonstrating that it is more accurate than other commonly used methods. Also, I show that location estimates for individual spikes can be utilized to improve the efficiency and accuracy of spike sorting. After training, my method allows for localization of one million spikes in approximately 37 seconds on a TITAN X GPU, enabling real-time analysis of massive extracellular datasets. In my third and final presented work, I focus on developing an unsupervised machine learning model that can uncover patterns of activity from neural populations associated with a behaviour being performed. Specifically, I introduce Targeted Neural Dynamical Modelling (TNDM), a statistical model that jointly models the neural activity and any external behavioural variables. TNDM decomposes neural dynamics (i.e. temporal activity patterns) into behaviourally relevant and behaviourally irrelevant dynamics; the behaviourally relevant dynamics constitute all activity patterns required to generate the behaviour of interest while behaviourally irrelevant dynamics may be completely unrelated (e.g. other behavioural or brain states), or even related to behaviour execution (e.g. dynamics that are associated with behaviour generally but are not task specific). Again, I implement TNDM using a deep neural network to improve its scalability and expressivity. On synthetic data and on real recordings from the premotor (PMd) and primary motor cortex (M1) of a monkey performing a center-out reaching task, I show that TNDM is able to extract low-dimensional neural dynamics that are highly predictive of behaviour without sacrificing its fit to the neural data
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