VictorJuiz/thesis huggingface dataset:
Neurometabolites in anterior cingulate cortex in chronic fatigue syndrome: A magnetic resonance spectroscopy study at 7 Tesla

Background:
Chronic fatigue syndrome (CFS) is a disorder characterized by prolonged physical and mental fatigue that cannot be explained by another established medical diagnosis. The anterior cingulate cortex (ACC) and putamen are two regions involved in frontal-striatal neural circuitry, which may be related to the pathophysiology of CFS. The aim of this study was to investigate the concentrations of neurometabolites, including glutamate, gamma-aminobutyric acid (GABA) and glutathione, in the ACC and putamen, using magnetic resonance spectroscopy (MRS) at 7 Tesla (7T). In addition, this study also aimed to evaluate resting-state functional connectivity in CFS with functional magnetic resonance imaging (fMRI).
Methods:
This study involved 12 patients who met the Oxford criteria for CFS and 25 healthy controls. Participants rated themselves on the Chalder Fatigue Questionnaire (CFQ) and the Beck Depression Inventory (BDI). All participants had a single proton (1H) MRS and resting-state fMRI scan with a 7T Siemens MAGNETOM scanner (Siemens, Erlangen, Germany) with a Nova Medical 32 channel receive array head coil. Spectra were measured from voxels in the ACC (20 × 20 × 20 mm), putamen (10 × 16 × 20 mm) and occipital cortex (20 × 20 × 20 mm). Spectra were analysed with LCModel to obtain absolute concentrations of the neurochemicals. Differences in functional connectivity between CFS and healthy participants were tested using multivariate exploratory linear optimized decomposition into independent components (MELODIC) and dual regression.
Results:
Concentrations of putamen glutamate and glutamate+glutamine (Glx) were increased in CFS while that of ACC GABA was decreased. Putamen Glx and ACC glutamine were negatively associated with the severity of self-reported fatigue. There were main effects of CFS diagnosis on glutathione (GSH) and total creatine, indicating decreases of these neurometabolites in all the regions studied in CFS patients. In addition, the CFS patients demonstrated elevated functional connectivity between the default mode network and right supracalcarine cortex, precuneus cortex and dorsolateral prefrontal cortex.
Conclusions:
The increased putamen glutamate, decreased ACC GABA and elevated resting state functional connectivity of the default mode network suggest a hyperactive brain status in CFS. The global decrease of GSH and total creatine also suggest that CFS patients may have an abnormal bioenergetic status with higher oxidative stress.

Advisor: Cowen, P
The term Synderesis and its transformations: a conceptual history of Synderesis, ca. 1150-1450

This dissertation explores the development of the concept of synderesis between 1150 and 1450. In medieval moral psychology, synderesis referred to the innate capacity of the mind to know the first principles of natural law, or, alternatively, the will to follow these principles. But it was also interpreted as a mystical power of the soul, capable of uniting it to God. synderesis also appears in Late Medieval vernacular literature, as a character in moralising texts. By approaching synderesis from the point of view of conceptual history I synthesise these fields and explore how synderesis operated beyond the formal treatises of scholastic theology.
Chapter two explores how synderesis developed in medieval scholasticism from Peter Lombard up to Thomas Aquinas. Chapters three and four explore how the mystical interpretation of synderesis first proposed by Thomas Gallus of Vercelli was incorporated into the mystical treatise Itinerarium mentis in Deum by Bonaventure of Balneoregio. Here, I analyse when, where and how Bonaventure integrated this mystical interpretation into his pre-existing moral-psychological interpretation of it and how his use of synderesis relates to the historical context in which the Itinerarium was written. I argue that synderesis should be seen as existing on a continuum of interpretations between moral psychology and mysticism. After Bonaventure and Aquinas, the concept undergoes a period of stagnation in academia, which is the subject of Chapter five. However, synderesis also appears in a number of non-academic texts in which the moral-psychological and mystical interpretations of the term coexist. Chapter six explores how Late Medieval vernacular authors drew on previous scholastic discussions of the concept. I focus here in particular on Guillaume de Deguileville’s Le pèlerinage de l’âme, where synderesis appears not as the moral guide of the soul, but as the accuser of the soul before the court of heaven.

Keywords: Bonaventure
Synderesis
Scholasticism
Guillaume de Deguileville
Thomas Gallus
Thomas Aquinas
Conscience
Itinerarium mentis in Deum
Medieval Theology and Philosophy
Advisor: Smith, LJ
Sutherland, A
Law and monasticism in Gratian's Decretum

This thesis takes part in what some scholars have called a 'mini revolution.' Since Anders Winroth first announced in 1996 his startling discovery of what he calls the first recension of Gratian's Concordia discordantium canonum, commonly known as the Decretum, numerous articles have appeared examining some portion of the Decretum in light of Winroth's findings. But as productive as this 'mini revolution' has been, much work remains to be done. One such area ripe for investigation is Causae 16 to 20, where Gratian examines the extent to which the monastic order was subject to episcopal authority. Although a number of individual canons and Quaestiones have received competent scholarly attention, there exists no systematic study of Causae 16 to 20, whether of the first or second recension. My thesis then provides the first detailed examination of the composition and substance of the first recension of this portion of the Decretum.
It consists of two chapters and a critical edition of the first recension of Causae 16 to 20, which is found in Appendix 1. Chapter one examines the process by which Gratian organized and constructed these Causae. It argues that Gratian composed the bulk of these Causae around the 3L, the Tripartita and Anselm's Collectio canonum. For C.16, the 3L served as the inspiration for all but one of the seven questions, while the Tripartita served as the starting point for Causae 17 and 20. The inspiration and making of C.18 came from the Tripartita and the 3L. While Anselm's Collectio canonum served as the starting point for C.19. Chapter two explores in detail the substance of Causae 16 to 20. It argues that as a whole these Causae reveal Gratian to be 'pro-monastic' in outlook, that is, his views on individual topics favour monks more often than not. It argues that this can be seen not only in the views which he held, but also in how he arrived at his conclusions. This chapter also argues that such an outlook did not mean that Gratian thought that monks and monasteries should always be free from episcopal control or that bishops had no positive role to play in the life of monks and monasteries.

Advisor: Brand, P
Stochastic lattice-based models of diffusion in biological systems

Diffusion is a universal phenomenon, throughout both biological and physical sciences, and a range of deterministic and stochastic models are available to interrogate diffusion-driven processes. Stochastic models are more computationally intensive to simulate, but may be necessary in situations where deterministic models lead to qualitatively different results.
Stochastic lattice-based position-jump (LBPJ) models are a popular framework for representing diffusion. Particles reside within discrete compartments, and may jump to other compartments or react with other particles sharing the same compartment. When the number of particles to be simulated becomes large, however, the computational costs may grow infeasibly large. In this thesis, we propose two modified LBPJ models, both of which are significantly less computationally intensive to simulate than the standard framework.
The first model uses non-local jumping, allowing particles to move with a distribution of longer but less frequent jumps, rather than jumping exclusively to nearest neighbour compartments. It is seen that boundary conditions must be formulated carefully to maintain agreement with equivalent partial differential equation models.
The second model focuses on LBPJ models incorporating volume exclusion. Two common approaches are 'fully-excluding' models, where at most one particle can occupy each compartment, and 'partially-excluding' models, where larger compartments can contain a finite number of particles. We reconcile these two frameworks, showing that they make similar predictions for the mean and variance of particle numbers. Later chapters extend this work to non-uniform lattices, and consider how reactions between particles can be incorporated into partially-excluding models.
Throughout the thesis, we present mathematical derivations, and support these with the results of computational simulation, validating the agreement of our models' results with results from established modelling frameworks, and demonstrating the reduced computational cost of our approaches in comparison to standard LBPJ models.

Advisor: Baker, R
Yates, K
The neurobiological underpinnings of developmental stuttering

The aim of this thesis was to investigate the neural underpinnings of persistent developmental stuttering. We explored neural systems important for speech-motor integration and focused on subcortical control systems: the basal ganglia and cerebellum. A secondary aim of this work was to distinguish effects related to general traits of the disorder from those reflecting specific states of stuttered speech. To address these aims we used a variety of neuroimaging methodologies as well as an extensive neuropsychological and empirical test battery. Our examination of neural pathway microstructure using diffusion-tensor imaging replicated previous findings of widespread disorganisation of white matter in people who stutter. This disruption included all major white matter pathways leading in and out of the cerebellum. In our second, third, and fourth studies we examined functional activity at rest and during different types of speech. The brain networks used by people who stutter and controls largely overlapped. The brain regions that distinguished general traits and specific states of stuttering were somewhat task-specific. Subcortical activation in the basal ganglia and cerebellum was related to the frequency of dysfluent speech in the scanner. In our final study we examined performance on a variety of classical tasks of motor learning. We observed evidence of delayed learning in response to changes in environmental feedback in the stuttering group relative to controls. Within people who stutter, subgroups who differ according to heritability of the disorder may also differ in the balance of dopamine in the basal ganglia. Overall, we concluded that cerebellar alterations contribute to the general trait of stuttering, while basal ganglia disruption may reflect specific effects within stuttering. Our work supports a broader role of the subcortical system in speech production, generally.

Keywords: neuropsychology
basal ganglia
MRI
rfMRI
cerebellum
DTI
stuttering
fMRI
fluency disorder
movement disorder
Advisor: Watkins, K
Rapid identification of supernovae at SNO+

Core-collapse supernova are some of the most cataclysmic events known to occur in the universe. During the brief time of collapse and explosion, a supernova releases as much energy as the progenitor star does over its entire lifetime. 99% of this energy is thought to be emitted as neutrinos, detectable by SNO+ via charged and neutral current interactions. This thesis explores the use of distinctive supernova neutrino interactions, specifically inverse beta decay and 12C de-excitation, in order to rapidly tag supernova candidates on an event-by-event basis using a processor running near-line to the main SNO+ computing architecture. This was achieved via the design and construction of a prototype trigger system, known as the L3, running within the main SNO+ analysis software package RAT. Preliminary results over simulated supernova data at 10, 30 and 100 kpc are presented, alongside tests over early SNO+ darkrun data. Finally, L3 efficiency calculations are performed over Monte Carlo data in scintillator, with the prototype trigger demonstrating greater than 95% efficiency at tagging galactic supernova out to approximately 20 kpc.

Advisor: Biller, S
Investigating the mechanisms by which influenza A viruses induce and subsequently dampen the Type I interferon response

The activation of antiviral innate immune responses by influenza A viruses plays a keys role in influenza virus infections. The recognition of viral RNA by the pattern recognition receptor RIG-I leads to the induction of the expression of Type I Interferons, which induce an antiviral state, and to the activation of the inflammasome, which leads to inflammation. This thesis focuses on investigating both the mechanisms by which RIG-I is activated by influenza A viruses and the mechanisms by which influenza A viruses dampen the subsequent interferon response. In this thesis, I provide evidence to support the hypothesis that the depletion of free nucleoprotein within infected cells promotes the accumulation of immunostimulatory, internal deletion viral RNAs of approximately 50 to 75 nucleotides in length, and that these may be key in the activation of RIG-I. Furthermore, I provide preliminary evidence that the polymerases of avian adapted influenza virus strains may generate higher levels of these immunostimulatory RNAs, and speculate that this may be important in the innate immune over-activation and subsequent cytokine storm which occurs during human infections with a number of avian-adapted influenza A viruses.
Furthermore, I investigate previous reports that the localisation of the PB2 subunit of the influenza virus trimeric polymerase to the mitochondria is important in dampening the expression of interferon by seeking to characterise the functions of mitochondrial localised PB2. I demonstrate that mitochondrial localising PB2 is imported into the matrix space and identify a number of matrixlocalising interactors of PB2. This work demonstrates that mitochondrial PB2 is not correctly localised to interact with the mitochondrial antiviral signalling protein MAVS, which was previously believed to be the manner by which PB2 dampens the induction of interferon expression. However, I speculate that the interaction of PB2 with the matrix protein translation elongation factor Tu may mediate its dampening activity.

Advisor: Fodor, E
In vivo assessment of substrate utilisation in the hypertrophied heart; the role of glycolysis and glucose oxidation in hypertrophic progression

The work in this thesis investigates the role of glycolysis and glucose oxidation and the effects of metabolic modulation on the development of left ventricular hypertrophy (LVH) in the abdominal aortic constriction (AC) model.
Hypertrophy was induced via the surgical constriction of the abdominal aorta (AC) and through the combined use of cine MRI and dynamic nuclear polarization (DNP), hypertrophic development and progression was assessed. A 17 % increase in LV mass was observed within the AC group at 4, 9 and 14 weeks post-surgery accompanied by no evidence of functional decline. Increased incorporation into lactate was observed at 4 and 9 weeks post-surgery representative of enhanced glycolytic dependence. Increase glycolytic flux was confirmed in the isolated Langendorff-perfused heart at 10 weeks post-surgery. No metabolic changes were observed in vivo at 14 weeks post-surgery accompanied by no change in glycolytic flux in the perfused heart at 18 weeks post-surgery.
Treatment of the AC model with dichloroacetate (DCA; 0.75 g L-1) was associated with an elevation in pyruvate dehydrogenase (PDH) flux as expected. When treatment was given immediately post-surgery, a significant increase in LV mass was observed at 4 (23 %), 9 (27 %) and 14 (24 %) weeks post-surgery accompanied by functional decline at 4 and 9 weeks post-surgery. However, treatment of the AC model with DCA at 5 weeks post- surgery, following the establishment of hypertrophy, was associated with no significant difference in LV mass (12 % increase) at 9 weeks post-surgery, however an elevation in LV mass was still present at 14 weeks post-surgery and no functional decline was observed. Treatment with either a low dose (0.1 mg kg-1 day-1) or high dose (1 mg kg-1 day-1) of Ramipril at 5 weeks post-surgery, following the development hypertrophy, was associated with a normalisation of LV mass in the treated groups but was not associated with any metabolic changes.
This work clarifies the structural, functional and metabolic changes which occur during hypertrophic development and progression as well as the effects of different metabolic therapies. It highlights the potential of the combined use of DNP and cine MRI to further understand hypertrophic progression in patients and the effects of different therapies.

Advisor: Tyler, D
Carr, C
Heather, L
Probabilistic modelling of genomic trajectories

The recent advancement of whole-transcriptome gene expression quantification technology - particularly at the single-cell level - has created a wealth of biological data. An increasingly popular unsupervised analysis is to find one dimensional manifolds or trajectories through such data that track the development of some biological process. Such methods may be necessary due to the lack of explicit time series measurements or due to asynchronicity of the biological process at a given time.
This thesis aims to recast trajectory inference from high-dimensional "omics" data as a statistical latent variable problem. We begin by examining sources of uncertainty in current approaches and examine the consequences of propagating such uncertainty to downstream analyses. We also introduce a model of switch-like differentiation along trajectories. Next, we consider inferring such trajectories through parametric nonlinear factor analysis models and demonstrate that incorporating information about gene behaviour as informative Bayesian priors improves inference. We then consider the case of bifurcations in data and demonstrate the extent to which they may be modelled using a hierarchical mixture of factor analysers. Finally, we propose a novel type of latent variable model that performs inference of such trajectories in the presence of heterogeneous genetic and environmental backgrounds. We apply this to both single-cell and population-level cancer datasets and propose a nonparametric extension similar to Gaussian Process Latent Variable Models.

Advisor: Yau, C
Webber, C
Health economic aspects in the management of bipolar disorder

Bipolar disorder (BD) is one of the leading causes of disability worldwide and has a detrimental impact on health-related quality of life (HRQoL), and personal and social functioning. Despite this, there is insufficient knowledge of the costs, HRQoL implications relevant to BD, and the cost-effectiveness of current treatments for BD in the UK. This thesis aims to inform decisions about local and national service provision by applying a variety of health economic tools to build an economic case for BD.
First, economic evaluations of BD management strategies are systematically reviewed. A cost-of-illness study is then conducted to estimate the societal burden of BD in the UK and explore the factors that drive variations in these costs. The appropriateness of applying the EQ-5D-3L outcome measure in BD is assessed, and the feasibility of mapping disease-specific measures to the EQ-5D-3L is explored. Finally, a cost-utility analysis (CUA) is conducted to bring together evidence on the costs and outcomes associated with alternative psychological interventions in BD management.
This thesis makes critical contributions to multiple research domains, informing the allocation of scarce healthcare resources in this context. There is a sheer dearth of evidence on cost-effectiveness strategies for the long-term management of BD in the UK, especially the evidence for psychological therapies is limited. The annual societal costs associated with BD in the UK are estimated to be £5.14 billion, demonstrating the significant economic burden associated with this disease. The EQ-5D-3L instrument is found to be useful in measuring HRQoL in BD patients who predominantly experience depressive symptoms but is not sensitive enough to detect changes in individuals with mania. More psychometric evidence is therefore required before this instrument can be widely applied in economic evaluations of BD-related interventions. Finally, the CUA indicates that a novel structured psychoeducation intervention in individuals on remote mood monitoring in the UK is not cost-effective.

Keywords: cost-effectiveness
Cost-of-illness
Health economics
Bipolar disorder
Advisor: Simon, J
Wolstenholme, J
Geddes, J
Political and legal accountability in economic and monetary union

This thesis looks at the constitutional implications of the Euro crisis for the European Union and its Member States, which entails consideration of comparative public law as well as EU law. It focuses on political and legal accountability in Economic and Monetary Union, and examines three sets of issues: the revised EU economic governance framework and its bearing on national economic and fiscal policy; the respective roles of the EU and national institutions within this multi-level system of economic governance; and judicial review of economic and monetary policy measures at national and EU level. The new EU economic rules could potentially have a great impact on fundamental rights, the horizontal and vertical division of power in the EU, and the welfare state. It is hoped that the policy proposals put forward in this thesis will, if implemented, serve to strengthen political and legal accountability and bolster legitimacy in this pluralistic landscape.

Advisor: Craig, P