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Harnessing fluorescence microscopy to elucidate the mechanisms of metabolic dysfunction-associated steatotic liver disease
No full textMetabolic dysfunction-associated steatotic liver disease is defined by hepatic lipid overload resulting in a metabolic shift and subsequent mitochondrial impairment. To facilitate the investigation of disease mechanisms and the identification of novel, translational therapeutic targets, it is essential to have an arsenal of effective models that recapitulate human disease. Here, a broad range of models is utilised to study steatotic liver disease, with a key focus on metabolic dysfunction. The models span from a hepatocyte cell line to mouse models to the establishment of a human tissue slice model. To quantify mitochondrial dysfunction across these systems, a range of microscopy techniques are employed. Fluorescence microscopy reveals lipid-induced mitochondrial fragmentation and membrane depolarisation in cellular and tissue contexts. Substantiating these findings, fluorescence lifetime imaging microscopy of autofluorescent metabolic cofactors detects shifts in hepatocyte metabolism without the need for exogenous dyes. We show that measuring fluorescence lifetime can capture features of metabolic change that standard histological methods used in diagnosis do not. A robust lifetime-based pipeline is developed and applied across in vitro, in vivo, and ex vivo models, culminating in the generation of a quantitative index of mitochondrial dysfunction capable of identifying disease-associated changes. Integrated into these experiments is the investigation of High Mobility Group Box 1 protein and its potential reparative effects in models of steatotic liver disease. Fully reduced forms of this protein show functional benefits in acute or lipid-damaged models, but limited effects in chronic disease suggest a need to refine dosing regimens or better account for cell-type-specific responses. Together, this work establishes a versatile platform for investigating mitochondrial dysfunction in steatotic liver disease and highlights the potential of fluorescence lifetime metabolic imaging to enhance current methods of histopathologic assessment in diagnosis
Developing ‘an eye for country’: the photographic in the production and transmission of geographical knowledge in the University of Oxford, 1906–1939
No full textThe proposition of thinking geographically and, thus, how to observe a landscape can be encapsulated in the phrase “an eye for country”. This thesis investigates how such a fundamental praxis of the discipline was transmitted both within a university and a secondary school context in the early twentieth century. Here, I concentrate on the specific relationship between photographic imagery and its role in the dissemination of geographical knowledge, an area that, hitherto, has not been foregrounded. However, photographic imagery was available in a variety of genres, including both lantern slides and pictorial view postcards. This research examines the content, audience(s) and intention of imagery within two university collections. The construction of two detailed catalogues of archival material from the Oxford School of Geography, presented in Appendices One and Two, revealed the wide ranging and eclectic sourcing of available imagery with which to construct and disseminate geographical knowledge. This archival material is composed, firstly, of glass lantern slides compiled and used by the School’s academics in their lectures from the inception of the Oxford School in 1899. The second archive emerges from the students’ regional descriptions of areas within the British Isles which derived from their personal interaction with the landscape and was a compulsory component of their diploma examinations from 1906 until 1939. By abstracting data from the catalogues, the impact of developments in photographic technology on the university student body, both as recipients of illustrated university lectures and as producers of their own geographical knowledge, is examined in this research. By engaging with the student body this research enlarges the institutional biography of a university department beyond the well-rehearsed canonical. By constructing mini-biographies of the Oxford student body, presented in Appendix Three, it became possible to investigate the careers of those students. That over two thirds of the cohort pursued teaching careers enables further understanding of the connections between the visual experiences of the university student and the onward transmission of geographical knowledge to a broader secondary school public. This thesis, thus, provides insights into a broader understanding of the everyday history of geography by investigating the spaces of both production and transmission of geographical knowledge with particular regard to the use of the photographic and the encouragement to observe geographically with an ‘eye for the country’
Modelling and investigating the circadian pattern in components of human pain circuitry
Full text linkHuman induced pluripotent stem cell (hiPSC)-derived models are useful tools for the study of pain that bridge the gap of fundamental interspecies differences in traditional animal models. However, currently available protocols for hiPSC-derived sensory neurons only generate certain clinically relevant subtypes of pain-detecting nociceptors in vitro, with notably a lack of neuropeptide secretion.
The present project has developed a novel hiPSC-based protocol for nociceptors that exhibit both baseline and chemically evoked secretion of calcitonin gene-related peptide (CGRP). Compared to benchmark protocols described in the literature, our method produced nociceptors with distinct pain-related phenotypes, including differential expression of subtype-specific markers (cMET and TRKA), co-expression of CGRP with somatostatin, and altered electrophysiological responsiveness to noxious heat.
The current project also confirmed the presence of an autonomous, oscillating molecular clock in sensory neurons differentiated in vitro, as an intrinsic feature of neuronal maturation. The molecular clock in nociceptors was associated with temporally dynamic gene transcription, protein abundance, translocation & phosphorylation, sodium channel dynamics, and firing activities.
Together, these findings established an integrated framework for generating functionally diverse nociceptors in vitro, with innate circadian molecular oscillations. The present study enables modelling of both physiological and pathological pain in human sensory ganglia, with close resemblance to ex vivo human nociceptors of electrophysiological, biochemical, and circadian properties
Simulating the avian quantum compass with radical pair spin dynamics
No full textThe mechanism underlying magnetic sensing in night migratory songbirds is believed to involve pairs of radicals, molecules containing a single unpaired electron, formed by photoexcitation of cryptochrome proteins in the avian retina. The overall quantum spin state of such radical pairs, and hence the concentration of subsequent reaction products, can be dependent on the direction of Earth strength external magnetic fields. While in vivo evidence for the so called Radical Pair Mechanism of magnetoreception is mostly circumstantial, the theory is well supported by photochemical experiments on purified cryptochrome proteins, which have been found in the avian retina and are known to form magnetically sensitive radical pairs in vitro. Reliable simulations of the underlying quantum spin dynamics face a number of challenges, but remain vital in guiding and interpreting experimental research.
Chapter 1 introduces the theoretical formalism of radical pair spin dynamics and provides an overview of the past experimental and computational findings that have given rise to a well-founded hypothesis for magnetoreception. The computational tools used to broach the viability of cryptochrome radical pair magnetoreceptors throughout the thesis are reviewed in Chapter 2.
The following chapters investigate aspects of a model radical pair based quantum compass. Several quantum mechanical and semiclassical techniques, most notably the Stochastic Schrödinger Equation approach, are utilised in Chapter 3 to obtain reliable estimates for the experimentally relevant half-field parameter, B1/2 under realistic experimental conditions. Chapter 4 goes on to explore the effects of weak radiofrequency fields on the performance of the quantum compass, and pushes the limits of the conventional spin dynamics model to highlight the disparity between experimental observations of radiofrequency disruption in migratory birds, and the current best understanding of the underlying spin dynamics.
Chapters 5 and 6 consider, respectively, the impact of isotopic substitution and the inclusion of dynamic internal magnetic interactions on the cryptochrome quantum compass, using advanced computational techniques to consider the most realistic spin systems possible, and avoiding the common pitfalls of simplified toy-model approaches. Finally, a more flexible approach is taken in Chapter 7 to decipher unexpected results from the first experimental reports of anisotropic magnetic field effects on cryptochrome proteins
Small-time asymptotics and the emergence of complex singularities for the KdV equation
No full textWhile real-valued solutions of the Korteweg–de Vries (KdV) equation have been studied extensively over the past 50 years, much less attention has been devoted to solution behaviour in the complex plane. Here we consider the analytic continuation of real solutions of KdV and investigate the role that complex-plane singularities play in earlytime solutions on the real line. We apply techniques of exponential asymptotics to derive the small-time behaviour for dispersive waves that propagate in one direction, and demonstrate how the amplitude, wavelength and speed of these waves depend on the strength and location of double-pole singularities of the initial condition in the complex plane. Using matched asymptotic expansions in the limit → 0+, we show how complex singularities of the timedependent solution of the KdV equation emerge from these double-pole singularities. Generically, their speed as they move from their initial position is of O(−2/3), while the direction in which these singularities propagate initially is dictated by a Painlevé II (PII) problem with decreasing tritronquée solutions. The well-known -soliton solutions of KdV correspond to rational solutions of PII with a finite number of singularities; otherwise, we postulate that infinitely many complex-plane singularities of KdV solutions are born at each double-pole singularity of the initial condition. We also provide asymptotic results for some non-generic cases in which singularities propagate more slowly than in the generic case. Our study makes progress towards the goal of providing a complete description of KdV solutions in the complex plane and, in turn, of relating this behaviour to the solution on the real line
'Tributarius' and terminological variation in the Anglo-Saxon diplomas of Worcester and Selsey
Full text linkThis thesis considers variations in the choice of terminology used to describe and quantify the landscape in Anglo-Saxon diplomas, with the aim of addressing whether these variations are due to temporal or geographic factors, and to what extent such factors are co-dependent. The twenty-three terms used for numerical land assessment form the basis of this investigation: their etymology is explored, together with analysis of concordance data from the 1,932 known diplomas, to assess the geographic and temporal range and relative frequency of their use alongside other words and phrases from the charters in which they occur, in order to discern textual parallels and diplomatic links between documents from different periods and scriptoria. From this, it is possible to observe trends in usage, which can then be considered against the social and political context of the production of the charters in question.Following this overview of textual and linguistic development, the main focus of this investigation is the uncommon Latin term tributarius, chosen due to its compact sample size (twenty-three extant examples) and number of analogous terms (mansus and cassatus being the most prevalent). The diplomas are discussed in detail, with close reading and comparison of their style and content. To aid this textual analysis, transcriptions, translations and critical commentary of the texts are provided. The overarching theme of the tributarius corpus is that of archival reuse and ‘improvement’ to suit the needs of later generations, particularly in cases of disputed ownership and alienation of ecclesiastical land.From this examination of the tributarius diplomas, it has become apparent that there are diplomatic links between the houses of Worcester and Selsey, from whose archives a significant proportion of the diplomas originate. As these houses were situated at such a geographic remove (in central Mercia and southern Sussex respectively), their diplomatic connection must involve factors other than proximity: ecclesiastical links, namely the involvement of St Wilfrid in the foundation of both houses; the ‘Mercian Supremacy’ of the long eighth century, which saw socio-political influence extend from the Midlands to the south coast; and the reuse of archival material, reviving a term which had fallen from prominence due to the increased centralisation of diploma production, but had been preserved in the archives of various ecclesiastical houses
Popular geopolitics
No full textPopular geopolitics explores the construction and circulation of geopolitical narratives and imaginaries in media and popular culture. It sits within critical geopolitics, which is an area of political geography that also has interdisciplinary influences spanning politics, international relations, and media studies. This entry traces the origins, evolution, and future of popular geopolitics through seven influential articles which have shaped the field and reflect its core theoretical and conceptual debates, from a traditional interest in representation to an awareness of the material and affective realms and the importance of studying audiences, production, and the circulation of geopolitics in the everyday. It identifies authors who have pushed popular geopolitical research in new directions and outlines their central contributions. Telling the story of popular geopolitics in this way, despite some unavoidable omissions, enables readers to understand key concepts, chart shifting approaches over time, and envision avenues for future research
Inverse probability weighted estimation of dynamic treatment regimen means in sequential multiple assignment randomised trials with missing data: a simulation study
Full text linkBackground: Dynamic treatment regimens (DTRs) guide personalised sequential treatment decisions for patients with a range of clinical or behavioural diseases. Sequential multiple assignment randomised trials (SMARTs) are designed to evaluate and optimise DTRs by randomising participants at multiple stages based on intermediate outcomes. To identify optimal DTRs in SMARTs, the mean outcome of each DTR is often estimated via inverse probability weighting (IPW), a statistical method that uses the inverse probability of treatment to address potential bias in the design. Like other randomised controlled trials, SMARTs are subject to missing data. Handling missing data in SMARTs is complicated by the sequential randomisation and dependence on intermediate outcomes. We evaluated the performance of complete case analysis (CCA) and multiple imputation (MI) for handling missing data when estimating the DTR mean outcomes using IPW in a two-stage SMART. Methods: We simulated 1000 datasets of 400 participants, based on a prototypical SMART design with two stages where only non-responders are re-randomised at stage 2. The estimands of interest were the four DTR means of a continuous outcome and were estimated using IPW. We defined four plausible missing data scenarios using missing data directed acyclic graphs (m-DAGs) and then assessed how each missing data method (CCA and MI) performed under different proportions of missingness (20%, 40%) and strengths of associations with missingness in stage 1 intermediate outcome, stage 2 treatment, and the final outcome. Results: Minimal bias was observed with MI when estimating the mean outcomes of the DTRs in most scenarios, except for when stage 1 intermediate outcome was missing dependent on baseline variables and stage 1 treatment. When data were missing dependent on other variables (for example, stage 2 treatment missing dependent on stage 1 intermediate outcome), CCA generally showed greater bias than MI when estimating the mean outcomes of the DTRs. Empirical standard errors were comparable across both missing data methods, with MI generally producing slightly lower values. Conclusion: We found that for a prototypical SMART design, MI generally showed close to zero bias and slightly lower standard errors compared to CCA when IPW was used to estimate the mean outcomes of DTRs in the settings explored
Level and determinants of district primary healthcare system technical efficiency in Ghana: two-stage stochastic frontier analysis
Full text linkBackground: Primary healthcare (PHC) is critical towards achieving Universal Health Coverage (UHC). In Ghana, PHC is organised at the district level and plays a key role in the country’s pursuit of UHC. However, many districts face challenges not only with limited resources but also with how effectively they are used. We examined how efficiently districts in Ghana use their health resources and what factors are associated with this efficiency. Methods: We used a two-step stochastic frontier analysis model using data from 181 districts. The output variable was a composite coverage index derived from eight PHC service indicators for 2021, primarily reflecting maternal and child health and infectious disease services. Input variables included district health expenditure for 2020/2021 and the number of health facilities and clinical staff in 2021. We then assessed the associations between efficiency scores generated by the model and health systems, socioeconomic and demographic factors, such as health facility type, insurance coverage, literacy level, Gini coefficient, poverty incidence, urbanisation and population density. Results: On average, districts operated at 87% efficiency, with scores ranging from 65% to 99%. Two factors were associated with the efficiency. First, districts with a higher proportion of PHC facilities tended to use resources more efficiently (coeff=0.151; 95% CI=0.041 to 0.261). Second, districts with greater income inequality were less efficient, measured by the Gini coefficient (coeff=−0.858; 95% CI=−1.146 to −0.252). Conclusion: Districts in Ghana have the potential to improve PHC outputs by about 13% on average by better use of existing resources and addressing determinants of efficiency. Findings suggest that districts with a higher proportion of PHC facilities and lower income inequality tend to be more efficient. These patterns highlight the value of strengthening PHC infrastructure and pursuing equity-focused policies as part of strategies to enhance efficiency in district health systems
Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy
Full text linkType 2 diabetes (T2D) precipitates diabetic cardiomyopathy (dbCM), a condition characterized by chronic inflammation, metabolic dysregulation and impaired cardiac performance. Here we show that the glucokinase activator AZD1656, originally developed for glycemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodeling in dbCM. In obese, hyperglycemic db/db mice with diastolic dysfunction, 6 weeks of AZD1656 treatment improved myocardial performance, reduced infarct size and enhanced post-ischaemic recovery. Integrated metabolic, functional and histological analyses revealed restoration of mitochondrial metabolism and attenuation of fibrosis. Mechanistically, AZD1656 remodeled the cardiac immune landscape by promoting infiltration of regulatory T cells. These findings demonstrate a link between cardiac inflammation and metabolic remodeling in dbCM and highlight that modulation of immune cells and metabolism can protect the diabetic heart. Targeting immunometabolic pathways may therefore offer a therapeutic strategy to alleviate cardiac dysfunction and reduce infarct vulnerability in T2D