VictorJuiz/thesis huggingface dataset:
Biophysical modeling of white matter in magnetic resonance imaging

Biophysical modeling can be combined with magnetic resonance imaging (MRI) to measure microstructural features of brain white matter (WM). Non-invasive measurements of WM microstructure is important whether we are trying to study pathology, monitor progression of disease or track drug efficacy. This DPhil project investigates the relationship between features of a biophysical model of WM and predicted/measured MRI signal properties.
An explicit multi-compartment model of WM is developed in Chapter 2. This model is based on the magnetic susceptibility of myelin and captures microstructural compartments in terms of their size, shape and physical properties. We use this model to examine the role of myelin content (g-ratio and axon density) by calculating microstructure-driven field perturbations and forward predicting the gradient echo (GRE) signal.
Chapter 3 focuses on myelin geometry and its relation to the GRE signal using the framework developed in Chapter 2. Current models of WM assume idealized packings of nested cylinders as axons. In reality, axons exist in varying geometries. We explore the role of geometry at the single axon and axon bundle level through simulation and by incorporating realism based on electron microscopy. We then apply this model to study demyelination (loss of healthy myelin, characteristic of many neurodegenerative diseases) by comparing simulation predictions with measurement collected from an animal model of demyelination. Overall, our results suggest that myelin geometry has a significant effect on the GRE signal and that estimates of microstructural features may be biased if myelin shape is not appropriately considered.
Chapter 4 extends the models developed in Chapters 2-3 to examine WM microstructure and its relation to the balanced steady state free precession (bSSFP) signal. We focus especially on asymmetries in the bSSFP profile and explore how these attributes could provide useful biomarkers for tissue health. We fit our biophysical model of WM to bSSFP measurements to quantify features specific myelin content. Our results demonstrate promise for the extraction of clinically relevant features of WM from in vivo bSSFP data as well as challenges in the current method.

Advisor: Foxley, E
Miller, K
Genotype and phenotype relationships in neurodevelopmental disorders

NeuroDevelopmental Disorders (NDDs) are a group of heterogeneous neuropsychiatric conditions, encompassing Developmental Delay (DD), Intellectual Disability (ID), Autism Spectrum Disorder (ASD) and Gilles de la Tourette Syndrome (GTS). NDDs often involve a life-long need of supportive services and represent a major economic and societal burden in Europe and the United States. Hitherto, no safe and effective treatment strategies are available, underpinning the urgency of deciphering their elusive aetiology.
NDDs have a strong genetic component. Accordingly, the mechanistic understanding of disease involves (1) the description of mutational landscapes, (2) the molecular and cellular of characterisation of genetic variants and (3) their integration at circuit and system levels. In this thesis, we tackled these theoretical underpinnings to provide insights into the genetics of NDDs and the onset of associated clinical abnormalities.
Firstly, aiming to shape the genetic architecture of GTS, a condition characterised by the presence of motor and vocal tics, we undertook a whole-genome CNV study of a cohort of Danish GTS cases and healthy controls. Using statistical and functional genomics approaches, we proposed novel potential candidate genes and implicated the disruption of early neurodevelopmental and late synaptic processes in the aetiology of GTS.
Secondly, to elucidate the vast phenotypic heterogeneity of NDDs, we conducted a systematic investigation of genotype and phenotype relationships in DD, ID and ASD. Taking advantage of extensive phenotypic and genetic data available for DD/ID and ASD patients, we grouped individuals based on their functional rare CNV and gene disruptions but did not to identify distinguishing clinical archetypes. Instead, we showed converging molecular perturbations underlie the onset of globally more similar clinical presentations and investigated the role of common variants in modulating their expressivity.
Lastly, we established the relevance of mouse models in the study of human disease. By applying comprehensive genomics approaches to over 1,000 mouse neuroanatomical knockouts, we implicated early neurodevelopmental and adult synaptic processes in the aetiology of ID and brain malformations. Furthermore, we showed that functionally converging genetic disturbances translate at the phenotypic level and proposed novel candidate ID genes.

Advisor: Webber, C
Davies, K
Entrepreneurship, job search and occupational choice in developing countries

This thesis is about entrepreneurship within the context of occupational choice in a frictional labour market. It unites two perspectives on entrepreneurship: the perspective of the entrepreneur as a firm, and the perspective of the entrepreneur as a self-employed worker. My emphasis is on developing countries, where a large share of the workforce are self-employed entrepreneurs. I combine theory with empirical applications using labour-force panel data from Mexico, Colombia and Ghana. The thesis consists of four chapters.
The model in Chapter 1 provides a theoretical framework to capture the nexus of occupational and firm size choices of entrepreneurs. In the model, these two choices are non-separable. Entrepreneurs face a trade-off: they could either make the most of their entrepreneurial potential, or run a smaller firm while waiting to take the next attractive job opportunity. Better opportunities in wage employment increase incentives to keep firms small.
Chapter 2 tests this model. To obtain variation in alternative employment opportunities for entrepreneurs, I exploit trade-induced changes to wage employment across local labour markets in Mexico. Using a large dataset built from several sources, I find evidence that is consistent with the theoretical predictions. I use guidance from theory, supplementary evidence, and an event study design to distinguish the occupational choice mechanism from competing channels.
Chapter 3 develops an empirical model where the observed allocation of individuals to occupations is a product of both the attractiveness and the availability of job opportunities. This type of selection mechanism is central to each of the other chapters in this thesis. The chapter is concerned with the identification of such a model that combines comparative advantage and search frictions. I estimate the model on panel data from urban Colombia and find evidence for both search frictions and selection on comparative advantage.
Finally, Chapter 4 builds and estimates a structural life-cycle model of sectoral choice between self-employment and wage-employment, costly job search, and capital accumulation in Ghana. We incorporate two central types of market frictions: credit constraints for entrepreneurs, and search frictions in the wage labour market. This provides a unified framework to think about career paths in developing countries. We link the estimated structural model to recent experimental literature in development economics, and use simulated experiments to interpret the mechanisms behind behavioural responses to labour market shocks.

Advisor: Quinn, S
Stevens, M
Proteomic profiling of metastatic matrisome reveals citrullination as a marker of colorectal liver metastasis

Colorectal cancer is one of the most frequently occurring malignancies and a major cause of cancer death. Distant metastases in this disease most commonly develop in the liver and are often untreatable. Here, we use proteomics to characterise, qualitatively and quantitatively, extracellular matrix (ECM) from colorectal cancer liver metastases. We show that citrullination of the ECM by cancer cell derived peptidyl arginine deiminase 4 (PAD4) is important for the growth of liver metastases. Citrullination of proteins, a posttranslational conversion of arginine residues to citrulline, is well recognised in rheumatoid arthritis, but largely undocumented in cancer. PAD4, a key enzyme responsible for catalysing citrullination, is produced by metastatic colorectal cancer cells and found at higher levels in human liver metastases than in normal liver. Functional significance for citrullination in metastatic growth was evident in murine models where inhibition of citrullination, either globally by pharmacologic inhibition of PADs or specifically in colorectal cancer cells by PAD4 knockdown reduced liver metastatic burden by 3- to 4-fold (P < 0.05). Additionally, citrullination of key extracellular matrix (ECM) component collagen type I in vitro led to greater adhesion and 25-30% decreased migration of colorectal cancer cells (P < 0.05) along with increased expression of characteristic epithelial markers, indicating a role for citrullination in promoting mesenchymal-to-epithelial transition (MET). Overall, our study revealed PAD4- dependent citrullination of the ECM altering mesenchymal-epithelial plasticity in colorectal cancer cells and the progression of liver metastasis. These data indicate that inhibition of citrullination could be exploited to potentially prevent the development of liver metastases in colorectal cancer.

Advisor: Muschel, R
The construction of professional identities in medical writing and fiction, c. 1830s-1910s

This thesis examines the representation of medical practitioners between the 1830s and 1910s in Britain and its Empire, drawing on the medical press and fiction. Moving away from the notion that practitioners’ identities were determined chiefly by their qualification or professional appointment, it considers how they were constructed in relation to different axes of identity: age, gender, race, and the spaces of practice.
Each chapter concentrates on a different figure or professional identity. I begin by looking at the struggling young medical man, before examining metropolitan practitioners (from elite consultants to slum doctors), and the hard-working country general practitioner. I then consider how gender and professional identities intersected in the figure of the medical woman. The last chapter examines practitioners of colonial medicine in British India.
This thesis considers a range of medical journals, from well-known titles such as the Lancet and British Medical Journal, to overlooked periodicals including the Medical Mirror, Midland Medical Miscellany, and Indian Medical Record. It also examines fiction by medical authors such as Arthur Conan Doyle and W. Somerset Maugham, and lesser-known figures including Margaret Todd and Henry Martineau Greenhow. I read these texts alongside other contemporary writing (from advice guides for medical men to fiction by lay authors) to scrutinise how ideas about practice were shaped in the medical and cultural imagination.
My research demonstrates not only how medical journals fashioned networks among disparate groups of practitioners but also how they facilitated professional rivalries. I reveal the democratising tendency of print culture, highlighting how it enabled a range of medical men and women to write about practice. Ultimately, the thesis develops our understanding of medical history and literary studies by uncovering how the profession engaged with textual practices in the formation of medical identities.

Keywords: medicine
Victorian
literature
periodicals
Advisor: Shuttleworth, S
Alberti, S
Transcriptomic approach to understanding and characterising disease pathogenesis in sarcoidosis

Sarcoidosis is a multisystem immunological disorder, centred on the dysregulation of T cell activity, macrophage activation and granuloma formation. Most pulmonary sarcoidosis patients have a good prognosis, but up to 20% can go on to develop lung fibrosis. Previous research in sarcoidosis has generally focused on sarcoidosis as a single disease entity, whereas this thesis has focused on the importance of phenotypical characterisation, in particular active fibrotic pulmonary disease, and the standardisation of measuring disease activity.
I first developed a scoring system to measure disease activity based on typical findings on high resolution CT scanning (CTAS). I then identified a set of readily available blood markers and a chest radiographic score as a surrogate for the CT activity score, which enables the physician to easily assess the level of disease activity in the clinic setting (SCAS).
Using a transcriptomic approach, I used the activity score to identify the immunological pathways and individual genes correlating directly with increasing activity, both at the site of disease and in the periphery. Enrichment of immune response and defense response gene sets, particularly in BAL cell samples, were observed as disease activity increased, with CCR2, TREM2, and CCL18 featuring as prominent genes involved in the propagation of activity. CXCL9 and CXCL10 were identified as peripheral markers of active disease reflecting the activity in various compartments. In addition, after phenotyping patients with active disease into those with and without fibrosis, differential gene expression showed enrichment of immune related gene sets in the fibrotic cohort, and highlighted the roles of several significantly upregulated genes including CCL19, CCR7, CXCR3, CCR2, ADAMDEC1 and MMP12 in the pathogenesis of fibrotic sarcoidosis. Finally, enrichment of an IPF signature derived from differential expression to sarcoidosis, was observed in the fibrotic sarcoidosis cohort. This information may lend itself to further therapeutic treatments options already used in other fibrotic lung conditions in this interesting and understudied phenotype.

Keywords: Sarcoidosis
Advisor: Ho, L
Domesticating Winckelmann: His critical legacy in Italian art scholarship, 1755-1834

This thesis explores the reception of Johann Joachim Winckelmann in Italian art scholarship, 1755-1834. Winckelmann posed a problem: he was a presence in Italy that could not be ignored, yet the views he expounded were Italophobic and contentious to an Italian readership. In light of this dilemma, the research question asked is how did Italian art scholarship respond to Winckelmann in this period and why did it respond in that way.
The core argument advanced is that there were two opposing reactions to Winckelmann, both of which were motivated by nationalism. On the one hand, Italian art scholars presented Winckelmann, his works, and his views as less attractive to an Italian readership than they would otherwise have appeared and, on the other hand, they presented him as more attractive. Through these reactions – termed foreignization and domestication respectively – art scholarship either defended against and ostracized Winckelmann or, when presented as less offensive, welcomed and embraced him amongst Italians. Thus this thesis argues that both reactions demonstrate a nationalistic attempt to portray Winckelmann in the manner most auspicious to the yet-to-be-united peninsula.
In order to explore this response to the German scholar, the thesis centres on three media: translations, art literature, and artistic journalism. Both foreignization and domestication are evident throughout the sources analysed, yet there is a predominance of domestication, achieved through a variety of methods.
This investigation adds to existing literature by examining the previously overlooked dilemma that Winckelmann posed. Moreover, employing the original conceptual framework of foreignization and domestication allows for a re-evaluation of how the art scholarship of the period engaged with the German scholar. Finally, demonstrating the infiltration of nationalistic sentiment in this period, even extending to Italian art scholarship, this thesis is the first to posit that nationalism played a significant role in Winckelmann’s critical legacy.

Keywords: Giambattista Gherardo D'Arco
Giovanni Battista Piranesi
Journals
Italy
Carlo Amoretti
Luigi Lanzi
Foreignization
Art History
Domestication
Nationalism
Translation
Carlo Fea
Winckelmann
Periodicals
Lawrence Venuti
Leopoldo Cicognara
Francesco Milizia
Advisor: Gardini, N
Ecclesial and world view characteristics of Catholic charismatic renewal groups in the United Kingdom

The Catholic Charismatic Renewal is one of the largest movements within the global Catholic Church and has been a significant part of Catholicism in the United Kingdom for nearly fifty years. In terms of theology, ethos and social structure it is poorly understood with little academic or critical analysis of the movement. This study seeks to address this through ethnographic research and theological analysis of the beliefs, behaviour and worldview of several expressions of the Catholic Charismatic Renewal in Britain and Northern Ireland. In doing so there is also an aim to evaluate the efficacy and value of three analytical approaches used by previous studies of religious groups and to consider their applicability in a broader context.
The research reveals a diverse movement that is expressed through a broad range of groups and devotions, from covenant communities to small parish groups. Some key themes in ethos and theology were evident in all expressions of the movement, most important amongst these being eschatology. The role of cognitive dissonance in the development of this eschatology is considered as is the integration of the Charismatic movement into the host Catholic Church. A central role for Marian devotion in this process of catholicisation is identified and associated with the diversity of current expressions which represent differing stages in this process.
The methodological approaches used are critically evaluated and, whilst value is identified in each one, the greatest potential for deep understanding and broader comparative studies is seen in the narrative approach put forward by James Hopewell. This approach is seen as allowing depth of understanding and a more nuanced consideration of apparently opposing beliefs or phenomena. Additionally, such a narrative approach is seen as having applicability beyond limited social and theological contexts.

Advisor: Percy, M
Essays in macroeconometrics

This thesis consists of three self-contained chapters.
The first chapter develops a method to explore the causal transmission of a catalyst variable through two endogenous variables of interest. The method is based on the reduced-form system formed from the conditional distribution of two endogenous variables given the catalyst and combines elements from instrumental variable analysis and recursive identification of structural vector autoregressions. Conditions for uniqueness of the causal transmission are provided.
The second chapter identifies and characterises periods of financial fragility over the period 1973–2016 within a simple regime-switching framework. Fragility is driven by high default risk and low profitability of intermediaries, as defined in Tsomocos (2003). Recessions occur primarily when fragility is high, but high fragility can occur without leading to recession. Credit growth is lower under high fragility, but it is not as significant a driver of regime changes when financial fragility is directly taken into account. Shocks have regime-dependent effects that are attributable primarily to switching dynamics as opposed to shock size. Finally, shocks are amplified through financial fragility, suggesting the presence of a debt-deflation channel.
The third chapter assesses the linkages between the real economy and the financial intermediation sector over the period 1999–2015 within a time-varying parameter framework with stochastic volatility. Low volatility and a period of protracted economic growth initiate a feedback loop between the real economy and the financial sector, consistent with the financial instability hypothesis of Minsky (1986). Shocks that adversely affect expectations of future economic growth have the greatest impact when macro-financial linkages are strongest. Augmenting the model with macroprudential capital requirements and monetary policy adjusted for the zero lower bound, we provide evidence that the timing of policy interventions matters. Counter-cyclical interventions produce a stabilising effect when implemented early but are also capable of exacerbating debt-deflation if employed too late in the financial cycle.

Advisor: Nielsen, B
Tsomocos, D
Investigation of ASPPs as regulators of pancreatic inflammation and tumorigenesis

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of unmet need with a 5-year survival following diagnosis of 3% with limited surgical, radiotherapy and chemotherapy treatment options. Central to PDAC tumorigenesis is acquisition of an oncogenic Kras mutation to drive acinar-to-ductal metaplasia and progression to PDAC that is potentiated by NF-kB deregulation. However, PDAC requires the additional loss of tumour suppressors such as p53, SMAD4 or p16. ASPP family members ASPP2 and iASPP regulate both p53 and NF-kB, and are classified as a tumour suppressor and oncogene respectively. However, the precise roles of ASPP2 and iASPP in pancreatic cancer are unknown. In this thesis I demonstrate that ASPP2 suppresses metastasis and iASPP suppresses the pro-inflammatory tumour microenvironment. In a mouse model of PDAC development, ASPP2-deficiency does not alter metaplasia, PanIN progression or primary PDAC onset. However, median survival due to metastasis is significantly reduced in an ASPP2-deficient PDAC model. I demonstrate ASPP2-deficient PDAC can result in increased squamous differentiation defined histologically or via increased p63 expression. I propose ASPP2 is a key suppressor ΔNp63 and the squamous PDAC subtype in vivo. Conversely, iASPP is a putative oncogene and high expression in cancer associates with poor prognosis. However, in a mouse model of PDAC, loss of iASPP accelerates PDAC onset and metastasis. I demonstrate that iASPP is a functional tumour suppressor of a pro-inflammatory phenotype in response to oncogenic Kras and pancreatitis. I propose ASPP2- and iASPP-deficient mouse models of PDAC represent in vivo the squamous and immunogenic subtypes of PDAC respectively; and are relevant tools to study mechanisms of metastasis and inflammation-driven carcinogenesis.

Keywords: iASPP
ASPP2
Pancreatic cancer
Kras
p53
Advisor: Lu, X
Harris, A
De Val, S