Development of novel neurophysiological investigations for age-related muscle weakness

Ph. D. Thesis.No Abstract AvailableNIHR Newcastle Biomedical Research Centr

Targeting the clonal expansion of mitochondrial DNA mutations in ageing and disease

Ph. D. Thesis.The clonal expansion of mitochondrial DNA (mtDNA) mutations is believed to mediate the presentation and severity of clinical symptoms of a wide range of inherited and age-related diseases. The mechanisms of clonal expansion are not fully understood, however the ability of cells to maintain their normal function in lower levels of mtDNA mutational heteroplasmy highlights the importance of understanding clonal expansion in causing the progression of disease and might offer an avenue for potential therapeutic intervention. The origin and molecular nature of clonal expansion is explored in a range of mitochondrial myopathies in this thesis, using immunofluorescence techniques and single cell molecular studies. The data indicate that in skeletal muscle, clonal expansion originates in a perinuclear niche and spreads transversely throughout a muscle fibre, regardless of how the mtDNA mutation originally arose, and the size of deletion identified. The natural history of clonal expansion was explored in vivo using the heterozygous PolgA ‘mutator’ mouse model. A constant level of mtDNA mutations with increasing age was observed in these mice, but a progressive increase in mitochondrial respiratory chain dysfunction. These findings indicate that the mtDNA mutations were clonally expanding to higher heteroplasmy levels with ageing. The process of clonal expansion was manipulated by treatment with nicotinamide riboside (NR), in an attempt to increase mitochondrial biogenesis. NR supplementation resulted in increased mitochondrial protein mass, although not a consistent increase in mtDNA copy number. NR was able to attenuate age-associated respiratory chain complex IV dysfunction, however had no detectable effect on complex I. NR treatment had a complex effect on the mice, additionally showing an anti-inflammatory response on transcriptional analysis, and protection from age-associated weight gain. These effects are similar to those of a calorie restricted diet. NR supplementation it is unlikely to reverse the clonal expansion of mtDNA mutations and prevent mitochondrial disease but has shown evidence of slowing the process in colon. Mitochondrial disease is complex and heterogeneous, affecting a wide range of tissues in a variety of ways. Whilst NR supplementation has shown benefit, it is likely that a complex intervention would be required to better target the clonal expansion of mtDNA mutations.Wellcome Trus

Rights to dducation and employment for persons with disabilities in Nigeria : towards a human rights model of disability

PhD ThesisNigeria is a party to several international and regional instruments including the Convention on the Rights of Persons with Disabilities, and more recently the 2030 Agenda on Sustainable Development which guarantees explicitly the education and employment rights of persons with disabilities. These international instruments impose obligations on states including Nigeria in the implementation of education and employment for persons with disabilities. Therefore, this thesis evaluates Nigeria’s progress in achieving the (Sustainable Development Goals) SDGs by considering whether Nigeria is meeting its international obligations for persons with disabilities in education and employment. Applying the 4As (Adaptability, Acceptability, Availability, and Accessibility) and disability human rights frameworks, this thesis contends that although Nigeria has made some progress towards achieving the SDG goals 4 and 8, and has adopted some measures to protect and promote the education and employment rights of persons with disabilities, yet the country is still failing to meet its obligations to make education and employment acceptable, adaptable, available, and accessible to persons with disabilities. Moreover, Nigeria continues to promote the moral/medical approaches to disability rather than the human rights model of disability in its domestic framework and practices relevant to persons with disabilities in education and employment. For Nigeria to comply with its international obligations, it needs not only to move towards a human rights model of disability in its domestic laws, policies, and practices relevant to persons with disabilities in education and employment but also, shift towards protecting and promoting the rights of people with disabilities in these areas, by providing more financial resources and making procedural, institutional, substantive, and cultural changes. A shift towards a human rights model of disability by Nigeria will significantly improve the situation of persons with disabilities as well as ensure Nigeria’s progress in achieving inclusive quality education and full productive employment for persons with disabilities in line with the 2030 Agenda on Sustainable Development

Cybersecurity Regulation in the Financial Sector: Reflexive Risk Management in the UK, USA and Nigeria

Ph. D. ThesisThe consistent increase in the scale and forms of cyber threats, alongside the growth in use and global uptake of communications technologies, has made risk management a core function of 21st century service providers. This has necessitated the proactive mitigation of cyber threats and the integration of frameworks, policies and regulations that ensure the security of financial transactions. Exploring reflexivity as a mechanism for informing adaptive and resilient cybersecurity risk management practices, this thesis examines structures of coexistence between criminal justice and self-regulatory responses, multiple cycles of reflexive processes of self-examination, participation, communication, and revisions to influence future practices in ever evolving risk and policy landscapes. This thesis evaluates the review, identification, and control dimensions of cybersecurity risk management frameworks, analyses self-regulatory cybersecurity standards and specific cybersecurity legal frameworks applicable to financial institutions in the UK, US, and Nigeria, which can be implemented and/or remodelled to enhance the effectiveness of cybersecurity risk regulation. It observes that while effective cybersecurity risk regulation across the financial institutions is being hampered by factors such as cherry-picked laws, unclear mandates, and a lack of coordination between public and private stakeholders, strong implementation and enforcement structures may be facilitated by initiatives directed at networked governance and institutional arrangements involving a shared understanding of cyber threats and decision making processes. This thesis highlights the link between reflexivity and governance for learning in financial institutions, arguing that reflexivity will always not deliver learning, in the absence of good institutional structures of governance. Employing realist and constructivist risk theories and secondary analysis of qualitative data obtained from government and non government agencies to inform practices and steer regulatory policy decisions, this thesis identifies measures to enhance effective cybersecurity risk regulation in financial institutions and addresses possible challenges to reflexivity in cybersecurity risk regulation

Exploring the role of endoplasmic reticulum stress in skeletal dysplasia

Ph. D. ThesisThe term skeletal dysplasia comprises a range of diseases that lead to varying degrees of skeletal deformities, causing pain and reduction in quality of life. Whilst each disease is typically rare, together they are estimated to occur in up to 1 of 5000 people. The intracellular retention of secreted proteins has been identified as one common disease mechanism in several skeletal dysplasias, including pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Yet, the specific pathways that are involved may be mutation-, gene- or disease-specific, or subject to disease modifiers and thus require specific treatments. Several approaches to study skeletal dysplasia and the resulting endoplasmic reticulum stress in vitro, including the use of human induced pluripotent stem cells (hiPSCs), were evaluated. HT1080 fibrosarcoma cells overexpressing wild type and mutant p.D469del COMP were validated as an in vitro model system for PSACH before performing RNA sequencing and DNA methylation analysis. Additionally, several mutant COMP constructs were overexpressed in HT1080 cells to study a potential common mechanism of COMP-MED and PSACH. Whilst hiPSCs offer exciting opportunities for the in vitro study of skeletal diseases, high variation during differentiation protocols rendered them unsuitable for this study. DNA methylation analysis revealed an unexpectedly large number of differentially methylated CpG sites, whilst RNA sequencing of D469del COMP cells revealed an increase in inflammatory signalling, and a marked upregulation of MMP9 and GALNT18. Elevated MMP9 expression correlated with increased extracellular MMP9 activity. This was also found in cell lines overexpressing other disease-causing COMP proteins, but not in a cell model of MATN3-MED. The data presented in this thesis indicates that COMP mutations act via a common mechanism that is distinct from MED-causing mutations in MATN3. It also provides evidence that MMP9 could be a marker for COMP-caused stress in vitro and thus facilitate future drug screenings.MCDS therapy project, RUBICON networ

Room to roam and hotspots of conservation conflicts: Lions, livestock and people in the matrix

Ph. D. ThesisGlobally, large terrestrial carnivores have suffered precipitous declines in population and range. Today, they must persist in increasingly isolated natural habitat patches within a human-dominated landscape matrix. For the African lion (Panthera leo), approximately 44% of their remaining range lies outside of protected areas and retaliatory killing in response to the negative impacts of lions on communities is a key driver of lion declines in human-modified landscapes. In this thesis, I investigate the ecological and social aspects of human-lion interactions in order to understand the viability of the landscape matrix for supporting free-roaming lion populations. My literature review reveals that lion habitat preferences are varied and context-specific. While prey abundance and proximity to water are important drivers, lions adapt their habitat use in response to anthropogenic pressures. I demonstrate the use of two modelling techniques to develop maps of livestock depredation risk in the Ruaha landscape of Tanzania, showing that lion attacks follow predictable patterns in space based on features including distance to protected areas and rivers, and net primary productivity. I then examine the transferability of my approach as a simple, scalable method for predicting livestock depredation across three additional study sites. Finally, I trial the use of a novel experimental game to examine pastoralist decision-making in response to human-lion conflict. My findings suggest that non-lethal deterrents are the preferred mitigation strategy and that while incentive-based instruments can promote pro-conservation behaviour, these may be more effective when targeted at individuals rather than groups. This work contributes to our understanding of human-lion interactions and the resulting conservation conflicts. I highlight the complexity of the system and the broad range of methods and disciplines needed to understand it. To manage Africa’s changing landscapes effectively for roaming lions, future research should focus on habitat use outside of protected areas and develop collaborative approaches which lead to mutually beneficial results for both people and wildlife.National Geographi

Integrated topological representation of multi-scale utility resource networks

PhD ThesisThe growth of urban areas and their resource consumption presents a significant global challenge. Existing utility resource supply systems are unresponsive, unreliable and costly. There is a need to improve the configuration and management of the infrastructure networks that carry these resources from source to consumer and this is best performed through analysis of multi-scale, integrated digital representations. However, the real-world networks are represented across different datasets that are underpinned by different data standards, practices and assumptions, and are thus challenging to integrate. Existing integration methods focus predominantly on achieving maximum information retention through complex schema mappings and the development of new data standards, and there is strong emphasis on reconciling differences in geometries. However, network topology is of greatest importance for the analysis of utility networks and simulation of utility resource flows because it is a representation of functional connectivity, and the derivation of this topology does not require the preservation of full information detail. The most pressing challenge is asserting the connectivity between the datasets that each represent subnetworks of the entire end-to-end network system. This project presents an approach to integration that makes use of abstracted digital representations of electricity and water networks to infer inter-dataset network connectivity, exploring what can be achieved by exploiting commonalities between existing datasets and data standards to overcome their otherwise inhibiting disparities. The developed methods rely on the use of graph representations, heuristics and spatial inference, and the results are assessed using surveying techniques and statistical analysis of uncertainties. An algorithm developed for water networks was able to correctly infer a building connection that was absent from source datasets. The thesis concludes that several of the key use cases for integrated topological representation of utility networks are partially satisfied through the methods presented, but that some differences in data standardisation and best practice in the GIS and BIM domains prevent full automation. The common and unique identification of real-world objects, agreement on a shared concept vocabulary for the built environment, more accurate positioning of distribution assets, consistent use of (and improved best practice for) georeferencing of BIM models and a standardised numerical expression of data uncertainties are identified as points of development.Engineering and Physical Sciences Research Council Ordnance Surve

The Politics of Paradise: Aesthetic Fantasies of Otherwise within Tourist Economies in Northeast Brazil

PhD ThesisThis thesis asks how the concept of paradise offers an insight into the formation of political communities in tourist locations. I argue that ideas of paradise underpin the fantasies through which residents of Praia da Pipa, a paradisial beach town in northeast Brazil, cope with the changing demands of touristic economies as the town grows. Through their embodied engagements with paradisial space, I argue residents produce, reproduce, and challenge inequalities inherent to the developing tourist industry and persisting colonial social hierarchy through the political communities they form. Using ethnographic data, I explore the multiple and contrasting ways in which residents make sense of the world around them through the sense that life in Pipa should somehow be different and the way their engagements with the town both impart this expectation and challenge it, creating paradise as they do. To do this, I trace four interconnected modes of paradise as residents sense and enact it in the town to demonstrate the often-surprising ways in which its fantasies form the basis for possible social relations there. Firstly, I look at the way spatial conflicts engender governance through rendering the space one of consumption; secondly I explore the temporal framings through which residents craft their worlds through attachments to paradise; thirdly I consider how Edenic understandings underpin resistance; and finally I explore how the circulation of touristic capital in the form of mobility prompts chance connections and solidarities. Fantasies of paradise enable unexpected communities of sense within expected hierarchies of colonial power and capital, through which residents enact a critique of the limits of utopian promises of touristic development and its economies of dispossession. Overall, this interdisciplinary thesis contributes to understandings of the role of fantasies in the production of and challenges to touristic development and the political relations therein

Novel features in accelerometer-based gait analysis for long-term monitoring of Parkinson’s disease : a signature of gait.

PhD ThesisParkinson’s Disease (PD) is a neurodegenerative disease that can lead to restricted or slowed movement, gait impairments and increased risk of falling. Over recent decades, instrumented gait analysis (IGA) has contributed much to the understanding of gait impairments in PD. Due to the complexity of gait and high clinical interest a plethora of features have been suggested for gait analysis in the literature pertaining to several groups such as: traditional spatio-temporal (e.g. gait speed), frequency domain, etc. A subset of these traditional gait features has been proposed and validated in PD and older adults as a comprehensive model of gait comprising five factors: pace, rhythm, asymmetry, variability, and postural control. Analysis of gait may be grouped into the assessment of two types of variability, namely, within-subject variability which is needed for personal disease management and inter-subject variability which is useful in quantifying the overall impact of PD on gait. Advances in wearable technology have led to much smaller devices (e.g. accelerometers) being commercially available in conjunction with greatly increased battery lives to the degree that not only lab-based but also continuous recordings over 7 days (real-world) are possible. Wearable technology-based gait analysis is indeed emerging as a powerful tool to detect early disease and monitor progression. Data recorded as part of the ICICLE-GAIT 1 study provides acceleration data for over 100 people with PD and age-matched control subjects in both lab and realworld conditions. These datasets form the basis for the development of a new Phase plot methodology for gait analysis in PD. In this thesis I present a novel methodology for both assessing PD and tracking individual disease progression over multiple timescales. To accomplish this, I introduce a new feature domain, the Phase domain, based on a particular type of recurrence plot known as a Poincar´e plot. Poincar´e plots are sometimes referred to in the literature as return maps, self-similarity plots or Phase plots. Phase plots were being used in the early 1990s in ECG studies to produce self-similarity plots of beat-to-beat intervals. This technique proved to be reliable in detecting atrial fibrillation. The rare instances of its application to other fields are very limited and do not demonstrate any modification or development beyond that which has been used in ECG studies for decades. I develop methodology for application to gait analysis and, indeed, any cyclical biosignals. In this thesis I used the data from the ICICLE-GAIT study to demonstrate that with specific modifications and newly identified features (comprising the Phase domain), this novel Phase plot methodology is highly applicable to gait analysis within PD and provides a framework for: (i) identifying and characterising PD and (ii) individual disease tracking over the years following diagnosis. Throughout these analyses, traditional gait features serve as an established reference and benchmark. I employ statistical methods, such as non-linear mixed effects models and Statistical Parametric Mapping, to model PD progression and assess the clinical utility of Phase plots. I also used Discrete-Time Markov chain modelling, longitudinal analyses, and functional principal components analysis to demonstrate that Phase plots provide an objective, personalised, and clinically relevant signature of gait. In the case of PD patients (and controls to a lesser extent) four distinct Phase plot Types emerge and occur with high within-subject reproducibility, hence the signature interpretation. Many features within the Phase domain proved to be highly sensitive to the disease (people with PD versus controls). Using lab-based data, the Phase domain features outperformed traditional spatio-temporal features in classifying PD. Each domain of features performed similarly well in the prediction of MDS-UPDRS 2 (a useful proxy for PD progression). Specifically, part III of the UPDRS scale was used as this relates to motor function. In real-world conditions Phase plot features showed sensitivity to disease state and physical capability across multiple timescales e.g., daily fluctuations, and also across 18-month follow up time points. The Phase plot-based signature of gait is validated under lab-based conditions to reflect participants’ capacity for gait as well as under real-world conditions as a compact means of monitoring PD and walking performance through gait

Powered Wheelchair Users’ Experiences of Urban Mobility: Researching Access and Disablement through Mobile Methodologies and Digital Technologies

Ph. D. ThesisInaccessible environments and transportation exclude disabled people from full participation in society. Accessibility is affected by a wide range of socio-material factors, including the interaction between the environment and mobility devices. Yet to date, little research has investigated powered wheelchair users’ experiences of mobility, or how their knowledge might inform policymakers or service providers. In this thesis, I have worked with powered wheelchair users to document their experiences of mobility and explore how these might be conveyed to other people. An observational go-along method was used, travelling with thirteen participants as they captured their experiences using ‘JourneyCam’, a bespoke smartphone video and data collection tool. The data were used as prompts in semi-structured interviews following each journey. Two further participants were interviewed without first using JourneyCam. Finally, through a series of group workshops, nine participants explored how their collective experiences and knowledge might be used to create more accessible environments. Powered wheelchair users accumulate situated knowledge which they use to navigate disabling barriers, but this knowledge is gained through significant personal labour and experiences of psycho-emotional disablism. Participants highlighted a wide range of socio-material enablers and disablers to their mobility, including barriers associated with poorly implemented ‘accessibility’ features. However, their efforts to convey their knowledge to service providers were met with indifference, and funnelled through individualised complaints processes. In response participants sought more effective modes of engagement that might bring about systemic change, in line with their commitment to social model principles of confronting structural disablement. I conclude that not only could powered wheelchair users’ situated knowledge be a valuable resource for service providers and policymakers, but it is also a form of collective resistance to ableist societal practices. The social model of disability remains relevant for disabled people’s efforts to counter disablement, serving as an ‘oppositional device’ that fosters shared resistance.EPSR