1,000 research outputs found

    Investigation of the pathological mechanisms in canine degenerative myelopathy and the potential involvement of extracellular vesicles in disease progression

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    Canine degenerative myelopathy (DM) is a progressive and lethal adult-onset neurodegenerative disease with nonspecific clinical signs that can end in tetraplegia and respiratory dysfunction. It is frequently identified in German shepherd dogs (GSD) but has been described in other breeds. A definitive diagnosis is reached after histopathological examination of the spinal cord where axon degeneration and demyelination are characterised. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are thought to have a pathological role in the disease and genotyping of the Sod1 gene can be used with clinical signs and histology to diagnose DM. The genetics, clinical signs and histology of DM suggests it may be a good naturally occurring large animal model for some forms of the human motor neurone disease, amyotrophic lateral sclerosis (ALS). This study aimed to 1) establish if defective cellular clearance pathways play a role in the aggregation of SOD1 and 2) if these defects contribute to the secretion of SOD1 positive extracellular vesicles (EVs) that 3) can spread mutant protein in a prion-like manner. Finally, 4) was to validate these findings with spinal cord tissue from DM cases using proteomics and biochemistry. In vitro studies using a neuroblastoma derived cell line (SK-N-SH) were conducted to assess the effect of disrupting various cell clearance and toxicity pathways on wildtype (WT) and mutant SOD1 aggregation and EV production. The reducing agent dithiothreitol increased the propensity of WT- and DM-SOD1 to aggregate (p ≀ 0.01) but did not have a statistically significant impact on the production of SOD1 positive EVs from cells. The autophagy inhibitor chloroquine increased the percentage of cells with DM-SOD1 aggregates (p ≀ 0.01), but not WT-SOD1 aggregates. EV secretion was not statistically significantly affected by chloroquine treatment in cells with DM-SOD1, but there was a significant increase in the EV marker flotillin-1 from cells containing WT-SOD1 (p ≀ 0.01). The proteasome inhibitor MG312 significantly increased the number of cells with WT- and DM-SOD1 aggregates (p < 0.0001), but they were higher in DM-SOD1 transfected cells (p ≀ 0.05). Flotillin-1 showed a downward trend from treated cells however this was only statistically supported with EVs from WT-SOD1 containing cells (p ≀ 0.01). WT- and DM-SOD1 showed an upwards trend in the EV fraction, but only reached significance in EVs from the cells containing DM-SOD1 (p ≀ 0.01). Overall, disruption to the main protein processing pathways caused the induction of nontypical clearance pathways and some of these appear to be less effective in the presence of the DM associated Sod1 mutation. Further, mutant SOD1 may have an impact on the stabilisation of the cell membrane as indicated by changes to associated proteins and this could have subsequent effects on protein clearance, particularly at the level of the endosome pathway and EVs. Further studies indicated there is a potential for EVs to spread WT- and DM-SOD1 to other cells in culture which suggests EVs could be recruited in DM for the spread of mutant SOD1 to other cells and may contribute to the progression of DM throughout the thoracic spinal cord and to the cervical and lumbar regions. Biochemical and proteomics analysis of spinal cords from control and DM dogs suggested axon and myelin integrity was disrupted and astrocytes were activated at early stages of DM. Evidence suggested these changes were the consequence of altered cellular metabolism, intracellular structure and protein processing. The Sod1 mutation caused an apparent reduction in SOD1 enzyme activity further suggesting the mutation is a contributor to the pathogenesis and progression of DM. Changes to plasma membrane organisation were also highlighted in the ex vivo study and may indicate perturbations to protein and lipid turnover. Ultimately the findings presented in this thesis contribute to the understanding of DM pathogenesis and will aid the search for DM biomarkers to enable earlier diagnosis, monitor disease progression and identify treatment targets

    Searches for baryon number violation in neutrino experiments: a white paper

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    Baryon number conservation is not guaranteed by any fundamental symmetry within the standard model, and therefore has been a subject of experimental and theoretical scrutiny for decades. So far, no evidence for baryon number violation has been observed. Large underground detectors have long been used for both neutrino detection and searches for baryon number violating processes. The next generation of large neutrino detectors will seek to improve upon the limits set by past and current experiments and will cover a range of lifetimes predicted by several Grand Unified Theories. In this White Paper, we summarize theoretical motivations and experimental aspects of searches for baryon number violation in neutrino experiments

    Numerical scattering amplitudes with pySecDec

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    We present a major update of the program pySecDec, a toolbox for the evaluation of dimensionally regulated parameter integrals. The new version enables the evaluation of multi-loop integrals as well as amplitudes in a highly distributed and flexible way, optionally on GPUs. The program has been optimised and runs up to an order of magnitude faster than the previous release. A new integration procedure that utilises construction-free median Quasi-Monte Carlo rules is implemented. The median lattice rules can outperform our previous component-by-component rules by a factor of 5 and remove the limitation on the maximum number of sampling points. The expansion by regions procedures have been extended to support Feynman integrals with numerators, and functions for automatically determining when and how analytic regulators should be introduced are now available. The new features and performance are illustrated with several examples

    The Public Performance Of Sanctions In Insolvency Cases: The Dark, Humiliating, And Ridiculous Side Of The Law Of Debt In The Italian Experience. A Historical Overview Of Shaming Practices

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    This study provides a diachronic comparative overview of how the law of debt has been applied by certain institutions in Italy. Specifically, it offers historical and comparative insights into the public performance of sanctions for insolvency through shaming and customary practices in Roman Imperial Law, in the Middle Ages, and in later periods. The first part of the essay focuses on the Roman bonorum cessio culo nudo super lapidem and on the medieval customary institution called pietra della vergogna (stone of shame), which originates from the Roman model. The second part of the essay analyzes the social function of the zecca and the pittima Veneziana during the Republic of Venice, and of the practice of lu soldate a castighe (no translation is possible). The author uses a functionalist approach to apply some arguments and concepts from the current context to this historical analysis of ancient institutions that we would now consider ridiculous. The article shows that the customary norms that play a crucial regulatory role in online interactions today can also be applied to the public square in the past. One of these tools is shaming. As is the case in contemporary online settings, in the public square in historic periods, shaming practices were used to enforce the rules of civility in a given community. Such practices can be seen as virtuous when they are intended for use as a tool to pursue positive change in forces entrenched in the culture, and thus to address social wrongs considered outside the reach of the law, or to address human rights abuses

    An investigation into the environmental sustainability of the South African ornamental horticultural industry

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    The ornamental horticultural industry makes use of natural resources to grow plants and produce allied products to sell to consumers, landscapers, retail garden centres, hardware stores, supermarkets, and government, but at what cost to the environment? The aim of this work was to determine the current environmental awareness of growers and garden centre retailers within the ornamental horticultural industry in South Africa. Followed by an investigation into the current business practices that promote sustainable natural resource use and management as well as the obstacles and challenges that the industry faces with implementing legislation and recommendations of best practices. The study was conducted over an 18-month period and 41 growers and retail garden centres in eight of the provinces in South Africa (Appendix 10) participated in research. In each case, the study participant was asked to complete the questionnaire and where possible, a site visit was conducted and / or a semi-structured interview as well as participatory observations followed to give a comprehensive overview of the sustainability practices of the businesses. These results were then compared to international best practices and similar research conducted globally by the ornamental horticultural industry. A review of international best practices in the ornamental horticultural industry showed six environmental resources namely soil, water, fertilizers, pesticides, energy, and waste. This was seen to be common to most studies involved in the production, growth, maintenance and sales of plants and allied products. This information was used to compile a best management practice manual for South African ornamental horticulture with guidelines and practical examples for conserving and managing natural resource usage and reducing the environmental impacts of the industry. Much research has been done on the exploitation and degradation of resources due to urbanisation, industrial activities, and agricultural practices. The resources are essential to the ornamental horticultural industry but if exploited or misused, can have detrimental effects on the environmental productivity of the industry and ultimately the “Sustainable Development Goals” prescribed by the United Nations. The linking of the relevant sustainable development goals to the 9 key factors of the green economy strategized by the South African government will enable the ornamental horticultural industry to play a greater part in the green and circular economy by providing nature-based solutions to environmental problems that it is facing such as climate change and pollution.Environmental SciencesD. Phil. (Environmental Management

    Leading-colour two-loop QCD corrections for top-quark pair production in association with a jet at a lepton collider

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    In dieser Arbeit wird die Berechnung der farbfĂŒhrenden Zweischleifen-QCD-Korrekturen fĂŒr die Top-Quark-Paarproduktion mit einem zusĂ€tzlichen Jet an einem Lepton-Collider prĂ€sentiert. Das Matrixelement wird in Vektor- und Axial-Vektorströme zerlegt und die Ströme werden weiter in Dirac-Spinorstrukturen und Formfaktoren zerlegt. Die Formfaktoren werden mit Projektoren extrahiert. Die auftretenden Feynmanintegrale werden mittels IBP-IdentitĂ€ten und Dimensionsverschiebungstransformationen durch eine Basis quasi-finiter Masterintegrale in 6−2Ï” Dimensionen ausgedrĂŒckt. Die Mehrheit der Feynmanintegrale gehört zu einer Doppelbox-Integralfamilie. Die Berechnung der Masterintegrale erfolgt durch numerisches Lösen von Differentialgleichungen in kinematischen Invarianten. Asymptotische Reihenentwicklungen der Masterintegrale in der Top-Quarkmasse werden verwendet, um die Anfangsbedingungen fĂŒr die numerischen Lösungen der Differentialgleichungen zu bestimmen. Die fĂŒhrenden Terme dieser Entwicklung werden mit der Expansion-by-Regions-Methode berechnet. Höhere Reihenkoeffizienten werden durch die Anwendung einer Differentialgleichung auf einen Ansatz fĂŒr die Reihenentwicklung bestimmt. Die renormierten Formfaktoren und die farbfĂŒhrende Zweischleifenamplitude werden an einem Referenzphasenraumpunkt zu hoher PrĂ€zision numerisch ausgewertet. Die Resultate werden mit elektroschwachen Ward-IdentitĂ€ten und durch numerische Vergleiche der IR-SingularitĂ€ten mit der erwarteten SingularitĂ€tsstruktur ĂŒberprĂŒft.In this work, the calculation of the leading-colour two-loop QCD corrections for top-quark pair production with an additional jet at a lepton collider is presented. The matrix element is decomposed into vector and axial-vector currents and the currents are further decomposed into Dirac spinor structures and form factors. The form factors are extracted with projectors. The Feynman integrals are reduced to a quasi-finite basis in 6 − 2Ï” dimensions using IBP identities and dimension-shift transformations. The majority of master integrals belong to a double-box integral family. The master integrals are computed by numerically solving systems of differential equations in the kinematic invariants. Asymptotic expansions of the master integrals in the top-quark mass variable are used to calculate initial conditions for the numerical differential equation solutions. The leading terms of the expansion are obtained with the expansion by regions and the higher orders are calculated by solving a system of equations obtained from applying the differential equation onto an ansatz of the expansion. The renormalized form factors and the leading-colour two-loop amplitude are evaluated numerically to high precision at a benchmark phase space point. The results are cross-checked with electroweak Ward identities and by numerically comparing the IR singularities with the expected singularity structure

    Poetry and Industrialism in Liverpool, Sheffield, and Manchester, 1770-1842

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    This thesis seeks to view the effects of industrial development in the years 1770-1842 in the cities of Manchester, Liverpool, and Sheffield through the lens of their literary output. While the majority of critical responses to urban poetry in this period have centred around London, this project attempts, within these cities, to examine a distinct poetic register reflective of urbanism and local identity, with the focus removed from the capital. Taking into account the social and professional interconnectivity that existed between these three centres, as well as the commercial interests, local history, and political contexts of each site, this thesis offers a complex portrait of the literary worlds that were active, and in some cases significantly influential and commercially successful, within the transpennine region. In doing so, I will demonstrate that the industrialisation, social transformations, and urbanisation that impacted the north of England at this time were not a peripheral presence in what constitutes Romantic-era poetry, but rather central to it, participant in the wider trends that characterise it as a literary movement. Most importantly, this thesis will make a case for these neglected areas as sites of vital poetic innovation, examining an underutilised resource for the conception of the role of literature within this socially, politically, and economically tumultuous period

    Fictional Practices of Spirituality I: Interactive Media

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    "Fictional Practices of Spirituality" provides critical insight into the implementation of belief, mysticism, religion, and spirituality into worlds of fiction, be it interactive or non-interactive. This first volume focuses on interactive, virtual worlds - may that be the digital realms of video games and VR applications or the imaginary spaces of life action role-playing and soul-searching practices. It features analyses of spirituality as gameplay facilitator, sacred spaces and architecture in video game geography, religion in video games and spiritual acts and their dramaturgic function in video games, tabletop, or LARP, among other topics. The contributors offer a first-time ever comprehensive overview of play-rites as spiritual incentives and playful spirituality in various medial incarnations
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