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Abstract: Bulk high temperature superconductors (HTS) based on the rare-earth barium cuprates [(RE)BCO] have the potential to be applied in a variety of engineering and technological applications such as trapped field magnets, rotating electrical machines, magnetic bearings and flywheel energy storage systems. The key materials figure of merit for most practical applications of bulk superconductors is simply the product of the maximum current density that can be supported, which correlates directly with the maximum achievable trapped magnetic field, and the physical length scale over which the current flows. Unfortunately, however, bulk (RE)BCO superconductors exhibit relatively poor mechanical properties due to their inherent ceramic nature. Consequently, the performance of these materials as trapped field magnets is limited significantly by their tensile strength, rather than critical current and size, given that the relatively large Lorentz forces produced in the generation of large magnetic fields can lead to catastrophic mechanical failure. In the present work, we describe a simple, but effective and reliable reinforcement methodology to enhance the mechanical properties of (RE)BCO bulk superconductors by incorporating hybrid SiC fibres consisting of a tungsten core with SiC cladding within the bulk microstructure. An improvement in tensile strength by up to 40% has been achieved via this process and, significantly, without compromising the superconducting performance of the bulk material.
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Neo-sex chromosomes are found in many taxa, but the forces driving their emergence and spread are poorly understood. The female-specific neo-W chromosome of the African monarch (or queen) butterfly Danaus chrysippus presents an intriguing case study because it is restricted to a single 'contact zone' population, involves a putative colour patterning supergene, and co-occurs with infection by the male-killing endosymbiont Spiroplasma. We investigated the origin and evolution of this system using whole genome sequencing. We first identify the 'BC supergene', a broad region of suppressed recombination across nearly half a chromosome, which links two colour patterning loci. Association analysis suggests that the genes yellow and arrow in this region control the forewing colour pattern differences between D. chrysippus subspecies. We then show that the same chromosome has recently formed a neo-W that has spread through the contact zone within approximately 2,200 years. We also assembled the genome of the male-killing Spiroplasma, and find that it shows perfect genealogical congruence with the neo-W, suggesting that the neo-W has hitchhiked to high frequency as the male-killer has spread through the population. The complete absence of female crossing-over in the Lepidoptera causes whole-chromosome hitchhiking of a single neo-W haplotype, carrying a single allele of the BC supergene and dragging multiple non-synonymous mutations to high frequency. This has created a population of infected females that all carry the same recessive colour patterning allele, making the phenotypes of each successive generation highly dependent on uninfected male immigrants. Our findings show how hitchhiking can occur between the physically unlinked genomes of host and endosymbiont, with dramatic consequences.
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This thesis develops an account of the right of peoples to participate in global governance affecting them. It starts by exploring at a conceptual level the principle of self-determination in international law and its associated rights, showing that the law of self-determination has evolved in a remedial and relational way to address situations of the dominance of peoples by states. The thesis outlines the rise of international organizations and global governance and the accompanying shift of regulatory authority from the national to the global level, and demonstrates that the activities of international organizations can profoundly affect peoples' rights and interests. On this basis, it argues that a new remedy is required: a right of peoples to participate in global governance activities affecting them, with correlative obligations held by states and international organizations. The thesis explores the scope and limitations of the proposed right. The thesis shows that, doctrinally speaking, positive international law lends some, limited support to the existence of the proposed right, but that, ultimately, a right of peoples to participate in global governance is not (yet) part of positive international law. The thesis draws on empirical research regarding the practice of international organizations and states to assess the extent to which the proposed right constrains the behaviour of international organizations and states acting through them, creating an extensive map of practice. It explores a myriad of instances of mechanisms, policies, and practices adopted by international organizations enabling peoples to be heard in processes affecting them, suggesting that there is an emerging standard of conduct corresponding to the proposed right and obligations. It will suggest that this practice is in part motivated by a belief that the participation of peoples in matters concerning them enables international organizations to more effectively carry out their functions and fulfil their mandates.
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Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
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Extracellular ATP (eATP) is an important signalling molecule in animals but its importance is less understood in plants. Accumulation of eATP in plants occurs in response to biotic and abiotic stresses. eATP causes downstream responses such as increase in cytosolic free calcium ([Ca$^2+$]$_cyt$), reactive oxygen species (ROS), nitric oxide (NO) and phosphatidic acid (PA). The identification of $/it Arabidopsis thaliana$ AtDORN1 (Does Not Respond to Nucleotides) as the first higher plant purinoreceptor has confirmed eATP in plant signalling systems. AtDORN1 is a plasma membrane receptor kinase that appears to command the eATP-induced transient increase in [Ca$^2+$]$_cyt$ and directs the translational response to wounding. The identity of the plasma membrane Ca$^2+$-permeable channels involved in eATP-induced [Ca$^2+$]$_cyt$ increases remain unknown. Patch clamp electrophysiology has shown that a plasma membrane Ca$^2+$ influx conductance lies downstream of the AtRBOHC NADPH oxidase in the response to eATP. As $/it Arabidopsis thaliana$ ANNEXIN 1 (AtANN1) underpins ROS-activated plasma membrane Ca$^2+$ influx conductance, it has been considered here as operating downstream of AtDORN1 in the eATP-induced increase in [Ca$^2+$]$_cyt$. In this thesis, the role of AtANN1, AtANN2 and AtANN4 in eATP signalling was tested in %/it A. thaliana$. Using (apo)aequorin, AtANN1 and ANNEXIN 2 (AtANN2) have been found to be involved in the root’s [Ca$^2+$]$_cyt$ response to both eATP and eADP whereas ANNEXIN 4 (AtANN4) might be acting as a negative regulator of AtANN1 (Chapters 3 and 4). Application of Gd$^3+$ as a plasma membrane Ca$^2+$ channel blocker indicated the possibility of the release of Ca$^2+$ from intracellular stores (Chapters 3 and 4). AtANN1 is confirmed to be downstream of the AtDORN1 receptor and also possibly downstream of AtRBOH NADPH Oxidase based on [Ca$^2+$]$_cyt$ measurement and ROS assays (Chapter 3). Loss-of-function mutants of AtANN1, AtANN2 and AtANN4 altered the eATP-induced gene expression of $/it AtACS6$ but not $/it AtWRKY40$ demonstrating a possible link between eATP signalling and hormone responses in plants (Chapters 3 and 4). Unlike AtANN1 and AtANN4, fewer studies regarding the involvement of AtANN2 in salinity stress and biotic stress were reported. In Chapter 5, results suggest that AtANN2 might not be part of the components mediating salinity stress and biotic stress in plants.
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Funder: Medical Research Council (MRC): Confidence in Concept award to Newcastle University
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The structural health of critical infrastructure is difficult to assess and monitor with existing methods of evaluation which rely predominantly on visual inspection and/or the installation of sensors to measure the in-situ performance of structures. There are vast numbers of critical structures that need to be monitored and these are often located in diverse geographical locations which are difficult and costly to access. Recent advances in satellite technologies provide the opportunity for global coverage of assets and the measurement of displacement to sub-centimetre accuracy. Such measurements could supplement existing monitoring techniques and provide asset owners with additional insights which could inform operational and maintenance decisions. Most past research within the field of Interferometric Synthetic Aperture Radar (InSAR) monitoring using satellite radar imagery focusses on widespread measurement of land areas, although there have been some case studies using InSAR to assess movements of individual structures such as dams. However, there is limited published research into the use of these techniques for accurately monitoring the displacements of individual civil engineering structures over time and relating these measurements to structural performance. This research focusses on bridges as a specific example of critical infrastructure to establish whether remote satellite monitoring can be used to measure displacements at a resolution that is sufficiently accurate for use in monitoring of performance, and examines the relevance and limitations of satellite monitoring to civil engineering applications in general. In order to assess the millimetre-scale performance of InSAR, an initial evaluation was undertaken in controlled conditions on a purpose-built test bed fitted with satellite reflectors at the National Physical Laboratory in Teddington to validate InSAR displacement measurements against traditional terrestrial in-situ displacement measurements. Subsequently, traditional sensor and surveying measurements of displacements were compared with InSAR displacement measurements at key points of interest on Waterloo Bridge and the Hammersmith Flyover. A further case study on Tadcaster Bridge was undertaken to demonstrate the potential applicability of InSAR displacement measuring techniques for monitoring bridges at risk of scour failure. Scour is the most common form of bridge collapse around the world and to date no cost-effective and widely applicable method for providing advanced warning of impending failure due to scour has been developed. Methodologies for integrating digital, structural and signal processing models for the identification and mapping of InSAR measurement points on bridge structures from SAR imagery were developed, as well as methodologies for combining satellite data with traditional surveying methods. An important outcome of this research was that through comparison of independent measurements, InSAR measurements are of a scale that is applicable to bridge monitoring. Remote sensing can therefore reach global coverage, with unsupervised readings over an interval of days, and as such supplement traditional inspection regimes. However, this outcome must be presented with several limitations. Practical implications of applying InSAR to real bridges are discussed, including imaging effects and the suitability of monitoring different forms of bridge deformation. The key to successful implementation of InSAR monitoring of bridges lies in understanding the limitations and opportunities of InSAR, and making a clear case to satellite data providers on what specifications (resolution, frequency, processing assumptions) would unlock using such datasets for wider use in monitoring of infrastructure. InSAR can provide measurements and useful insights for bridge monitoring but it is limited to specific cases and, at this stage of technological development, it should be considered as a tool for specific bridges and failure mechanisms rather than a full bridge monitoring solution.
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At present, Drug-Induced Liver Injury (DILI) is the most frequent cause of acute liver injury, with an incidence ranging from 0.023-1.5‰ in developed countries. DILI can be separated into two different types. Whereas intrinsic DILI concerns predictable dose-dependent hepatoxicity, idiosyncratic DILI refers to unpredictable adverse drug reactions for which there is no existing pharmacological explanation. Many prescription and over-the-counter drugs causing DILI do so in an undiscovered and idiosyncratic pattern. It is the latter that causes DILI to be the most frequent cause of safety-related drug withdrawals. This causes delays in the availability of treatments and is responsible for 20% to 40% of liver transplants and hepatic failures. While several mechanisms might be responsible for idiosyncratic DILI, a broad industry-wide consensus was reached in 2016 on the importance of the liver bile salt export pump (BSEP) and the need to test for BSEP inhibition at an early stage of drug development. An assay for BSEP-mediated bile acid transport was established to study the biochemical mechanisms of inhibition of BSEP activity by organic compounds. The four selected compounds showed competitive inhibition of taurocholate transport in Lineweaver-Burk plots but also other types of inhibition in Eadie-Hofstee plots. These results indicate that these inhibitors might compete with taurocholate for binding in the substrate-binding pocket and possibly, that the inhibitors are transported by BSEP. Interestingly, this work shows a strong inhibitory effect of excess Mg2+ on the ability of BSEP to transport glycocholic acid; the transport of taurocholic acid was not inhibited by Mg2+. To get more insight in structure-function relationships in BSEP, a condense and accurate database of all known BSEP point mutations from published literature was compiled. This database shows a total of 264 known mutations associated with several pathogenic and non-pathogenic phenotypes. To date, there is still little known about the effects of many of these mutations on BSEP activity. Only 82 of the 264 mutations have currently been investigated for their impact on function and expression level of BSEP. 2D and 3D primary cultured hepatocytes were used to establish the effect of DILI-inducing drugs on the synthesis of bile acids and their distribution across the cell and the media. Multivariate analyses of the data demonstrate that drugs can change the bile acid composition in hepatocytes and their environment. This might occur by regulating bile acid synthesis pathways and/or by modulating the selectivity of BSEP itself. Interestingly, some of the detected changes in bile acid concentrations might be early indicators of cell stress and cell death. The experiments also suggest that drugs can cause a change in BSEP expression in the plasma membrane, through changes in the trafficking of protein to and from the plasma membrane. These changes could explain the existence of non-pathogenic BSEP inhibitors. These findings increase our understanding of the influence of compounds on bile acid production and BSEP distribution and their potential roles in idiosyncratic DILI.
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Ghanaian smallholders grow one quarter of the world's cocoa, but climate change, individual extreme weather events, such as droughts, as well as deforestation increasingly threaten cocoa production. Pertinent information could bolster adaptive capacity. However, in Ghana's cocoa sector, relevant agricultural information is not available to all farmers, which can exacerbate power asymmetries. This paper focuses on how (i) agricultural and drought-adaptive information and (ii) socio-economic characteristics shape a cocoa farmer's adaptive capacity. We conducted our study in the aftermath of 2015–16's prolonged El Niño-induced drought that negatively impacted the livelihoods of cocoa smallholders across Ghana. In 48 semi-structured interviews and 12 focus groups, we asked smallholders how they responded to the drought to decipher how adaptive capacity compares between farmers receiving four different sources of agricultural information, and of diverse socio-economic status. Overall, agricultural information improved cocoa farmers' adaptive capacity compared to those who received no formal agricultural information. Smallholders detailed adaptive techniques that would be accessible to, and thus replicable by, other poorly-resourced cocoa farmers. Shade tree management and income diversification were identified as pertinent adaptive actions. However, we identified a divergence between exposure to agricultural information and its transformation into substantive adaptive action. Additionally, informal information sharing between smallholders represents an underutilized resource by extension programmes. We found that adaptive capacity is also determined by socio-economic characteristics: particularly gender, and to a lesser extent formal education level, proximity to asphalt roads, and land tenure. Finally, we present evidence that framing adaptive techniques in relatable terms that resonate with farmers' immediate livelihood concerns could narrow the adaptation deficit prevalent in Ghana's cocoa sector.
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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multi-systemic autoimmune disorder with evidence of circulating pathogenic ANCA. There are two main antigenic targets: proteinase 3 (PR3) and myeloperoxidase (MPO). Previous genome-wide association studies (GWAS) have provided evidence that PR3-AAV and MPO-AAV are genetically distinct autoimmune syndromes, though only three loci specific to PR3-AAV and one to MPO-AAV have been identified to date. With the European Vasculitis Genetics Consortium, we conducted a larger GWAS, powered to discover additional risk loci in both PR3-AAV and MPO-AAV independently. A meta-analysis of two European cohorts was conducted, comprising 1,610 PR3-AAV cases, 870 MPO-AAV cases and 11,947 controls. For PTPN22 (rs6679677), a further replication cohort, previously genotyped using the Sequenom MassARRAY platform, and comprising 1,122 PR3-AAV and 347 MPO-AAV cases and 1,531 controls was included in the combined analysis. This is the largest genome-wide association study of AAV to date and we have identified a total of 12 AAV susceptibility loci. Previously genome-wide significant loci were confirmed, including HLA class II, SERPINA1, PRTN3 and PTPN22. Seven new genome-wide significant loci were identified: three associated with PR3-AAV (BCL2L11-MIR4435-2HG, EBF3-MGMT, IGHV1-69), two with MPO-AAV (BACH2, ANKRD11-SPG7) and two shared by both (CTLA-4 and DGUOK-TET3). Further analyses based on common variants suggested that a substantial component of the genetic architecture was shared between PR3-AAV and MPO-AAV, similar to that observed between ulcerative colitis and Crohn’s disease. In addition, Mendelian randomisation analysis confirmed that a higher eosinophil count increased the risk of PR3-AAV but not MPO-AAV, and this effect might, in part, be modulated by MIR4435-2HG through prolongation of eosinophil survival. MIR4435-2HG encodes a long non-coding RNA that plays a critical role in the regulation of BCL2L11 transcription (a Bcl2 family member essential for controlling apoptosis) in myeloid cells and hence their lifespan. We have also identified a missense variant in IGHV1-69 (rs11845244) that leads to a loss in neutralising function of antibodies generated against the NEAT2 domain of Staphylococcus aureus. This therefore provides a plausible host genetic factor in determining the susceptibility to infectious disease and as a potential driver of PR3-AAV. Overall, this study provides key novel insights into disease biology for AAV and potential therapeutic targets.
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