VictorJuiz/thesis huggingface dataset:
Registration and machine learning methods for brain imaging of Alzheimer's disease

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, characterised by memory loss and reduced cognitive function. One of the pathologic biomarkers of AD is the presence of neuritic plaques composed of beta amyloid peptides. Positron emission tomography (PET) imaging is increasingly used to assess the amyloid burden in patients with dementia, and therefore, tools for analysing amyloid PET scans could aid clinicians when diagnosing and treating AD. For this reason, this thesis presents novel methods for quantifying and classifying amyloid in brain PET images. The most important contributions made in this thesis are: 1) The formulation of a dual-modality deformable registration method, based on the demons framework, for simultaneously aligning PET and magnetic resonance (MR) images to a template space, in order to calculate standardised uptake value ratios (SUVRs). 2) The proposal of a novel machine learning method for classifying brain amyloid status, based on histograms of oriented image gradients. 3) An assessment of convolutional deep belief networks for amyloid status classification. 4) An initial investigation towards a complete classification framework for AD using multi-graph learning. The results of the registration experiments suggest that the proposed joint PET-MR registration method can perform as well as similar single-modality methods in terms of registration accuracy, and could provide an improved separation between populations of AD patients and healthy controls when used in the calculation of SUVRs. Although the investigation into convolutional deep belief networks indicated that, at present, they are impractical for amyloid status classification, our novel amyloid status classification method achieved a higher classification accuracy than two other established methods. Moreover, unlike SUVR, our proposed machine learning method does not require specific knowledge of neuroanatomy and can be applied to multiple amyloid PET tracers without substantial recalibration.

Advisor: Hutton, C
Schnabel, J
Motivation and reward learning: neural mechanisms, changes in depression and following pharmacological treatment

The primary goal of this thesis was the understanding of the cognitive and computational mechanisms of reward and effort guided processing and their change in depression and commonly used/putative treatments. In chapter 2, I developed a new paradigm that allowed me to examine the neural basis of concurrent learning about rewards and effort in a complex, naturalistic environment. Measuring brain activity using functional magnetic resonance imaging, I proposed a prefrontal cortical mechanism for overcoming behavioural biases generated by irrelevant reward features (Scholl et al., 2015). In chapter 3, I used this paradigm to measure the effects of prolonged administration of a commonly used antidepressant, a serotonin re-uptake inhibitor, which has previously been hypothesized to enhance learning and neural plasticity. I found that it increased neural learning signals for both reward and effort in a widespread network of brain areas, suggesting a general learning enhancing effect (Scholl et al., under review). In chapter 4, I measured whether a putative novel treatment for depression, the partial NMDA agonist d-cycloserine, could also influence learning. While I found this not to be the case, it led to a marked improvement in how participants integrated the available information to make decisions (Scholl et al., 2014). In chapter 5, I tested how these different aspects of reward-guided behaviour, some of which were changed in my pharmacological manipulation, are related to changes in depression. We found that dysphoric participants did not differ from healthy controls in how quickly they learnt appetitive or aversive/effortful information. However, when making decisions they used this learnt information less than healthy controls to determine their decisions. Together, these studies revealed that complex decisions require additional cognitive and neural mechanisms that go beyond those seen in the simplest learning tasks. These diverse mechanisms can be computationally teased apart, rely on different neural systems and can thus be influenced separately. Lastly, we found that common treatments of depression did not necessarily target the same mechanisms affected by depression, suggesting potential new avenues for new treatments.

Advisor: Harmer, C
Rushworth, M
Allocation of rights to tax active business income - an analysis from the perspective of Brazil, India and China

This thesis analyses whether the existing international framework for allocation of rights to tax active business income can be considered fair or equitable from the perspective of Brazil, India, and China (the BICs) and suggests steps that could be taken in the short and medium terms to advance fairness. Chapter I highlights the challenges in the framework from the standpoint of the BICs and also other developing countries. It is argued that an understanding of these concerns is important to achieve the OECD’s Base Erosion and Profit Shifting project’s aim of a certain and stable arrangement. Chapter II contends that fairness in both the rule-making process and the rules is critical to this end. Chapters III-V examine the evolution and development of the prevailing rules for division of rights to tax active business income and the key aspects of these rules from the BICs’ perspective based on the parameters for assessing procedural and substantive fairness established in chapter II. It is discussed that the BICs either had no or ineffective participation in the formulation of these rules. Resultantly, the BICs diverge from some of the basics of the rules towards positions that better account for these countries’ contributions in the generation of global profits. Chapter VI proposes enhancing the authority and legitimacy of the UN’s Committee of Experts on International Cooperation in Tax Matters as both a short and medium term option for fairer international taxation rule-making for the BICs, and, importantly, other developing countries as well. Chapter VII suggests a significant economic presence test for nexus along with a low rate withholding tax, and the greater use of the profit split method as steps towards a fairer allocation of taxing rights from the perspective of the BICs. Further analysis of theoretically superior but longer-term alternatives, such as global formulary apportionment, is also recommended.

Keywords: Inter-Nation Equity
BRICs
Law
Taxation
Advisor: Loutzenhiser, G
New migrants' home encounters: An ethnography of 'Romanian Roma' and the local state in Luton

This ethnographic study explores how 'Romanian Roma' migrants in the UK, without previous relationships to their place of arrival, negotiate their identity to make place in a diverse urban area. The thesis argues that state forms are (re)produced through embedded social relations. The restructuring of the UK welfare state, coupled with processes of labelling, means that the notion of public and private space is changing. Migrants' encounters with state actors in the home are increasingly important.
I lived with three families between January 2013 and March 2014, during a period of shifting labour market regulations and the end of European Union transitional controls in January 2014. Through mapping families’ relationships and connections, I identify encounters in the home with state actors regarding children as a defining feature of place-making. The thesis introduces the term 'home encounter' to trace the interplay of discourses and performances between state actors and those they identified as 'Romanian Roma'. Due to the restructuring of UK welfare, various roles assume different 'faces of the state'. These include education officers, health visitors, sub-contracted NGO workers, charismatic pastors and volunteers. The home encounter is presented as a public 'state act' (Bourdieu 2012) where negotiations of values take place in private space determining access to membership and welfare resources. In addition, blurring boundaries between welfare regulations and immigration control mean that these actors' seemingly small decisions have far-reaching consequences. The analysis raises questions of how to understand practices of government in diverse urban areas; the affect of labelling, place and performance on material power inequalities; and processes of discrimination and othering.

Advisor: Gidley, B
Banks, M
Textual and editorial conflict in Pascal’s Pensées

The history of publication of Pascal's Pensées is one of conflict and contention at many levels. This is studied in relation to four editions which have emerged from engagement with the fragmented text, each marking a milestone in the evolution of editorial practice and mastery over the work of the dead author. The text is presented as target, bystander, and agent of conflict. The first two chapters deal with motivation to publish, target readership, and the sources of conflict themselves. Chapter three examines these issues with respect to the original edition (L'Édition de Port-Royal), and the subsequent three chapters examine respectively the editions of Prosper Faugère, Léon Brunschvicg, and Louis Lafuma.
The narrative charts the gradual approach to the currently accepted presentation of the fragments, and the long persistence of efforts to imagine Pascal's plan for an apology for Christianity, against a reluctance to take account of the authority of existing documents. The reception of these editions provides clues to why the Pensées have an eternal youthfulness and a constant appeal to editors. I argue that the apology lies in the fragments, however they are arranged, that all editors have accepted their apologetic intent, and that their universal significance springs from the deep sensibility they express about the human condition.

Keywords: Pensées
Publication
Pascal
Advisor: Parish, R
MicroRNA release in acute myocardial infarction

Coronary heart disease (CHD) is the single biggest cause of death in the United Kingdom1. Primary percutaneous coronary intervention (primary PCI) has transformed the early treatment of acute myocardial infarction (MI), improving outcome by rapidly re-opening the occluded coronary artery, with a larger mortality benefit and reduced risk compared with thrombolysis.
Despite these advances, and even with the optimal treatment, some patients still sustain substantial myocardial damage leading to mortality and morbidity. MicroRNAs (miRs) are short non-coding RNAs with a role in regulating protein synthesis. Some miRs are cardiospecific, can be detected in plasma after a myocardial infarction and show promise as biomarkers and insights into the mechanisms of myocardial injury.
In this work, as part of the Oxford Acute MI (OxAMI) Programme, a cohort of patients recruited at the time of ST elevation MI underwent detailed clinical and microRNA analysis at the time of myocardial infarction. This work was validated using separate discovery and validation cohorts. The source of detected miRs was further analysed in an in-vitro endothelial cell culture model and by measuring miRs released into the venous drainage of the heart, the coronary sinus.
In the Discovery Cohort, miRs previously shown to be increased in myocardial infarction (e.g. miR-1, -133a, -499) were detectible in plasma after myocardial infarction, and this was confirmed in the validation cohort. Other miRs with a similar relationship were also identified (e.g. miR-30a, -378a, 125b). Microvascular obstruction was found to be associated with increased infarct size and also with release of microRNAs correlating with infarct size suggesting a link between microvascular obstruction and myocardial necrosis. Analysis of paired coronary artery and coronary sinus samples showed that these miRs increased down the myocardial gradient, suggesting myocardial release.
The culmination of this work was to use the experimental findings from circulating plasma, cultured endothelial cells and coronary sinus experiments to design a microRNA panel using a blood sample taken six hours after admission to use in a regression model which was more predictive of final infarct size than troponin alone.

Advisor: Channon, K
Comparing early parental warmth and effective management as predictors of child conduct and emotional problems

Introduction: Identifying aspects of parenting that are protective for child emotional and behavioural outcomes is important for informing parenting intervention. Attachment theory and social learning theory represent two major theories that propose different mechanisms for how parenting influences child functioning. The aim of this study was to compare dimensions of early positive parenting associated with these two theoretical frameworks as predictors of child conduct and emotional problems.
Method: Data were from a US based longitudinal study (the Early Steps study, Dishion et al., 2008) following a sample of 731 toddlers from age 2 to 7.5, from low income families and at high risk of early onset of child problem behaviours. Associations between observed parenting (age 2-3 and age 5) and parent reported child externalising and internalising behaviour (age 3, 4, 5 and 7.5) were examined in structural equation models.
Results: Parenting related to attachment theory ('warmth') had little short-term association with child outcomes, but over time this parenting dimension increasingly predicted lower levels of child problems. Parenting associated with social learning theory ('effective management') was related to lower child conduct and emotional problems short-term, but in the long-term it had no predictive effect on child functioning.
Discussion: Differences between parenting dimensions in terms of their respective short-term and long-term effects might be explained by the underlying mechanisms linking parenting and child outcomes. Attachment theory emphasises internal and emotional processes, and these may be slow building but more enduring. Social learning theory proposes that behaviours are driven largely by external motivations and inspirations, and these might be relatively instantaneous but short-lived.
Conclusion: Results of this study indicate that early childhood parenting associated with attachment theory is an important protective factor for children’s longitudinal outcomes. For enhancing longer term, more enduring outcomes, it is likely that parent intervention and prevention programmes in early childhood should emphasise programme components drawing on attachment theory. However, it would be necessary to test this before making any firm recommendations.

Keywords: Child externalising problems
Attachment theory
Parenting
Social learning theory
Child internalising problems
Advisor: Gardner, F
Bowes, L
Living in an age of gold: being a subject of the Roman Emperor

This thesis explores the perception of the emperor in the mentalités of his subjects, exploring the different ways he was understood. Drawing upon written material from Augustus to Alexander Severus, this thesis explores the roles he was cast in, alluding to a discourse concerning who the emperor was and what he should be, exploring similarities across the period. It is argued the participants in this conversation are not restricted to an elite, but also involved scrutiny from a wider population. Accordingly, this thesis is an alternative history about how the Emperor seemed.
It is split into three parts according to episodes of an emperor's life: Part 1 and Chapter 1 explore the nature of the succession, including a discussion of the scholarship concerning the nature of the emperor's power and its transmission. It explores the nature of the succession, the imperial family, and perception of this issue from the perspective of his subjects.
Part 2 explores the discourse about the emperor's conduct during his reign. Chapter 2 discusses the issues with the evidence, and how to glean a wider perspective. Chapter 3 is a thematic treatment of the 'topics of conversation' within the discourse, and each help to describe the 'thought-world' concerning the emperor, involving the fears and expectations of his roles in government, culture, and society; from the banal to the fantastic.
Part 3 and Chapter 4 concern the emperor's legacy. It discusses the impression of the emperor's timelessness, and the comparability of the emperorship. This is reflected in the afterlife of an emperor, showing the relevancy of dead emperors to subsequent generations, and is manifested in diverse ways, from historical discourse to the appearance of false emperors. Finally, comparability is stressed, opening possibilities for further study on the nature of the emperorship as an example of autocracy.

Keywords: Roman History
Autocracy
Emperors
Advisor: Purcell, N
Investigating mechanisms driving fibrosis in pathological rotator cuff tendons

Shoulder pain is common, often caused by rotator cuff inflammation and usually heals by fibrotic repair. The fibrotic signature associated with the resolution of inflammation is well documented in a number of human tissue pathologies, but not tendon. TGFβ and its associated superfamily are implicated as key drivers of fibrosis, and modulate extracellular matrix homeostasis. The aim of this thesis was principally to investigate the TGFβ axis in healthy and pathological tendons, and to study changes related to the epithelial to mesenchymal transition. We hypothesised that TGFβ family mediators would be dysregulated in pathological compared to healthy tendons. We also hypothesised that there would be evidence of epithelial to mesenchymal transition with tendon disease.
Healthy and diseased rotator cuff tendons were collected from patients presenting to an orthopaedic referral centre. Diseased tendinopathic (intact) and healthy rotator cuff tendons were collected via ultrasound-guided biopsy under general anaesthetic prior to surgery and torn tendons were collected during routine surgical debridement. Immunohistochemistry and qRT-PCR were used to investigate the protein and gene expression profiles of TGFβ superfamily members in these healthy and diseased rotator cuff tendons. Epithelial to mesenchymal transition was characterised with immunostaining for αSMA, E-Cadherin, and Vimentin. TLR4 and Collagen III were used to identify myofibroblast activation and collagen composition in tendon.
TGFβ signalling was dysregulated in human supraspinatus tendon pathology. Specifically, TGFβ-1, TGFβ R1 and TGFβ R2 proteins were significantly reduced (p&LT;0.01) in pathological compared to healthy supraspinatus tendons, suggesting these pathways become down regulated with established disease. At the mRNA level, TGFβ R1 was significantly decreased whereas TGFβ R2 was significantly increased (p&LT;0.01). BMP-2, BMP-7 and CTGF mRNA were unchanged with pathology. Immunostaining showed Vimentin was significantly decreased in pathology (p&LT;0.01), however αSMA, E-Cadherin and TLR4 remained unchanged.
Pathological tendons showed dysregulation of the TGFβ axis compared to healthy tissues. Evidence for EMT in pathological tendons was inconclusive. Whilst Vimentin expression significantly decreased with pathology, immunostaining suggested co-localisation of Vimentin and αSMA along the edge of a massive tendon tear. We propose the down-regulation of TGFβ pathways could be a protective response to limit hypertrophic fibrosis. The disruption of the TGFβ axis with tendon pathology compared to healthy tissues demonstrates the importance of these pathways in tendon homeostasis. In the presence of suppressed TGFβ levels, alternative pathways such as TNFα signalling may drive fibrosis. In Dupuytren's disease TNFα is implicated as an important driver of myofibroblast activity, and could be the prevailing signal in chronic tendon pathology.

Advisor: Dakin, S
Snelling, S
Transcriptional regulation of Eomesodermin and its roles in cell fate allocation during early mouse development

Early embryonic development is governed by a tightly regulated series of cell fate decisions to form an entire organism. Eomesodermin (Eomes) is a T-box transcription factor dynamically expressed in the extra-embryonic ectoderm, anterior-visceral endoderm (AVE) and primitive streak during mouse gastrulation. Previous work from our lab shows that Eomes is essential within the AVE for establishment of the anterior-posterior (A-P) axis and within the primitive streak for epithelial-to-mesenchymal transition, and specification of cardiac mesoderm and definitive endoderm. However, the cis-acting regulatory elements that control the critical spatiotemporal expression domains of Eomes are not fully understood. Also, whether Eomes plays a functional role in specification of other mesodermal lineages is unknown. Here, I demonstrate an essential enhancer 8kb downstream from the TSS is necessary and sufficient for the correct expression of Eomes in the AVE and primitive streak. Mutants harboring a deletion of this enhancer exhibit A-P patterning defects and derivatives of the anterior primitive streak are compromised. The discovery of this essential enhancer provides greater understanding into how this critical gene is regulated during development. Moreover, this is the first characterisation of an Eomes enhancer that drives AVE expression. Additionally, I show that Eomes is required for the specification of haematopoietic mesoderm. Thus, implicating Eomes as a central player in the allocation of multiple cell fates within the primitive streak.

Keywords: Enhancer
Eomes
Primitive streak
Haematopoeisis
Definitive endoderm
Gastrulation
Advisor: Robertson, E
Bikoff, E