VictorJuiz/thesis huggingface dataset:
Creatine transport and its regulation in skeletal and smooth muscle

Despite the importance of creatine (Cr) in normal and pathological cellular metabolism, the control of intracellular Cr concentration, ([Cr]), is poorly understood. Cytosolic [Cr] is maintained at many times the passive electrochemical equilibrium value, and there is strong evidence for the existence of a Cr transporter in the cell membrane of several tissues. In this study a simple protocol for determining net creatine uptake or efflux was developed. Cr transport across the cell membrane of skeletal and smooth muscle, its modulation, and the relationship between transport and intracellular creatine were then investigated. Results from the cultured skeletal muscle cell line, G8, show that, as in other tissues, skeletal muscle Cr uptake is largely Na gradient - dependent, is electrogenic, and has a low Km for [Cr]. In this cell line several modulators were shown to increase creatine uptake; the agonists included catecholamines, IGF-I and insulin, triiodothyronine and amylin. By the use of selective agonists and antagonists the receptor subtype mediating the stimulation by catecholamines and the likely signalling pathway was identified. Similarly a tyrosine phosphorylation pathway was identified as responsible for the signal transduction of insulin and IGF-I. Evidence is provided for a role of the sodium potassium ATPase as a common mediator of the uptake signal provided by each of the positive modulators. In addition we confirm the low net creatine efflux seen in other skeletal muscle preparations. Investigation of creatine transport in the isolated perfused porcine carotid artery also identifies a sodium dependent concentrative creatine uptake and a negligible net creatine efflux. The uptake was shown to be positively modulated by isoproterenol (isoprenaline). These results are discussed in terms of the biochemical and hence functional implications for the muscle affected.
Probing and restoring disrupted thalamocortical interactions during Parkinson's disease and essential tremor

Parkinson’s disease (PD) and Essential Tremor (ET) are two movement disorders where impaired motor function can lead to severe disability. In conjunction with motor impairments, both disorders display augmented frequency-specific activity patterns across brain networks that converge at the thalamocortical (TC) level. In treating motor symptoms, the available therapies for PD and ET modulate these pathologically increased activity patterns. However, therapeutic interventions can also lead to the disruption of physiological brain activity and cause undesirable secondary effects. A major challenge delaying the development of selective neuromodulatory therapies is our limited understanding of the impact of neural activity on function and dysfunction. This thesis contributes to addressing this knowledge gap by probing the TC network dynamics that underlie aberrant synchrony in PD, and by exploring ways of restoring motor function in ET through temporally-specific perturbations of tremor-related TC interactions. By using a combination of tools that span from computational modelling, signal analysis and closed-loop stimulation algorithms we have found that: 1) transient events of high-power beta synchrony in PD are promoted by synaptic dynamics across the TC circuit; 2) the temporal patterning of beta activity in PD is mediated by unit and ensemble dynamic changes in TC temporal alignment; 3) phase-specific stimulation (Cagnan et al., 2017a) can bring kinetic and postural tremor control in ET patients with stable tremor properties, and 4) closed-loop algorithms using online estimates of phase and amplitude to trigger median nerve stimulation might be more effective in yielding tremor suppression in ET patients. Overall, the findings of this thesis contribute to the fields of neuroscience and neurotechnology by deepening our understanding on the dynamics of pathological neural synchrony and shedding light on the key features underlying the efficacy of selective neuromodulatory therapies.

Keywords: essential tremor
thalamocortical dynamics
closed-loop neuromodulation
Parkinson's disease
Advisor: Sharott, A
Brown, P
Cagnan, H
Gabapentin and pregabalin in bipolar disorder, anxiety states and insomnia: systematic review, meta-analysis and rationale

The gabapentinoids, gabapentin and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. A systematic review and meta-analysis of the evidence for three of their common psychiatric uses – bipolar disorder, anxiety disorders/states, and insomnia – was carried out. Published and unpublished literature were searched and a random-effects pairwise meta-analysis was performed for each outcome where possible. Efficacy and acceptability were assessed using only double-blind randomised controlled trials. Assessment of tolerability also included single blind or open-label trials and non-randomised evidence. Where a quantitative synthesis could not be conducted, results were presented narratively. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative state anxiety, with gabapentin showing a dose effect. In insomnia, results were inconclusive. There is moderate evidence of efficacy of gabapentinoids in state anxiety and anxiety disorders, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels. It may be possible to develop modified α2δ ligands, targeting particular subtypes or isoforms, with a more beneficial therapeutic profile. A future direction for clinical research would be to explore the targeted treatment of comorbid anxiety in bipolar disorder using gabapentinoids or modified α2δ ligands.

Advisor: Harrison, P
Cipriani, A
Having meanings in view: groundwork for a substantive account of rule-following

The present work is an attempt to lay the groundwork for an account of rule-following that is both philosophically substantive and partially reductive. It is philosophically substantive in contrast with the kind of discourses that exemplify a quietist approach to philosophy. It is partially reductive inasmuch as it proposes to reconstruct the phenomena of rule-following, linguistically or conceptually shaped meaning, and understanding out of materials that do not presuppose either, though without depriving itself altogether of properly intentional resources.
Ultimately, the present work aims to answer two questions: (i) which feature of signs are we responsive to in cases of rule-following? and (ii) what is the relation between these signs and our responses to them in such cases? It does so, not in sterile isolation from any historical anchorage, but through a critical engagement with the writings of three authors: McDowell, Merleau-Ponty and Wittgenstein. It is, we could say, an attempt at constructive philosophy which takes form in dialogue.

Keywords: McDowell
meaning
normativity
Merleau-Ponty
action
intentionality
Wittgenstein
rule-following
Advisor: Child, B
Mulhall, S
Supervoxel-based image registration and analysis with application to lung cancer

Lung diseases, including lung cancer, are amongst the largest burdens to healthcare systems worldwide. Improving the extraction of information from imaging data has the potential to provide more accurate diagnosis and more effective treatment. For example, assessing regional lung function could guide more effective radiotherapy treatment to spare well-functioning parts of the lungs. One meaningful regional representation is achieved by locally clustering similar image voxels together using the concept of supervoxels, which allows for bulk regional processing and analysis, whilst removing redundant information. This thesis aims to lay further foundations for supervoxel-based image analysis by presenting novel deformable lung image registration frameworks, as well as a method to estimate lung ventilation using supervoxels.
We demonstrate how a supervoxel-based image representation can be combined with graph cuts as a discrete optimisation-based approach to provide effcient and accurate 3D deformable image registration. Our work overcomes some of the previous limitations by posing the problem on a graph created by adjacent supervoxels. We further show that the application of a relaxed graph representation of the image, followed by guided image filtering over the estimated deformation field, allows us to model `sliding motion'. Applying this method to lung image registration results in highly accurate image registration and anatomically plausible estimations of the deformations.
The resulting deformation fields might be further applied to estimate lung ventilation maps. We present a novel approach for estimating regional lung ventilation from dynamic lung CT imaging. Our method combines a supervoxel-based image representation with deformable image registration, performed between peak breathing phases, during which we track changes in intensity for a number of layers of previously extracted supervoxels. Such a region-based approach is expected to be physiologically more consistent with lung anatomy than methods relying on voxel-wise relationships.
Our work also presents novel approaches for performing more accurate hyperpolarised 129Xenon MRI (XeMRI) analysis. We propose a multimodal lung image registration enhanced with personalised motion model approach derived from lung 4DCT. The approach with a prior motion model is particularly important for regions where there is not enough information to reliably drive the registration process, as in the case of XeMRI and proton density MRI (pMRI) to CT registration. Subsequently we introduce a framework for breathing motion correction of the dynamic sequence of XeMRI using a lung atlas-based approach. Such a method for the breathing motion correction is expected to facilitate the analysis of temporal lung ventilation.

Keywords: supervoxels
image registration
ventilation estimation
lung cancer
image analysis
Advisor: Schnabel, J
Grau, V
Anatomical visions: medical illustrations and (r)evolutionary bodies in the visual arts of modern China, 1851–1937

This dissertation examines anatomy, body imagery, and the modern visual information revolution in China from the late nineteenth to early twentieth century. Whereas scholarship on the advent of translated modernity in China has focused predominantly on the roles of literature and political thought, this dissertation argues that the veritable explosion of body imagery in China’s art and visual culture against the preexisting visual tradition points to a significant transformation in which the human body became a central object of visualisation and knowledge production. This seismic shift hinged on the plural anatomical visions of the body in a cultural space of Chinese intellectuals’ sustained epistemological and aesthetic quests to see the previously unseen. Their dialogues with European anatomical imagery in medicine and science occurred simultaneously with their engagement with Western aesthetic body imagery. As representations of the physical body increasingly became a site of cultural identity projection, anatomical imagery intersected with disparate discourses of the body such as gender and subjectivity, beauty and aesthetics, science and evolution, and nation and modernity themselves, collectively amounting to a new modern Chinese visualisation of the body politic.
Chapter One traces plural visions of anatomy beginning with the arrival of systematic Western anatomical imagery and the naturalistic visual world of Darwinian evolution theories in late-Qing China. It sets up the intellectual framework within which the image-making and knowledge-making about the body are examined in the interrelated webs of emerging medical-scientific knowledge, new aesthetic modes of representation, and changing political imperatives in an age of revolutions. The remaining four chapters each examine a separate body trope through in-depth case studies. Chapter Two considers the anatomical womb, through which reproduction was rendered knowable both medically and aesthetically. Chapter Three considers exposed body surfaces and the controversial issue of nudity, shedding light on an essential link between anatomy and art in the formulation of the nude in modern China. Chapter Four examines how the bodily representation of the Chinese masses coalesced around the figure of the hand in tandem with their emergence as a socio-political force, situating the imagery in Haeckelian ecology and inter-communist visual culture. The fifth and final chapter explores how the dead body was rendered anatomically visible as a leitmotif of martyrdom in the age of nationalism, war, and revolution.

Keywords: Body
Anatomy
Art
Modern China
Medical Illustrations
Evolutionary Theories
Advisor: McCausland, S
Chard, R
Exploring the role of blood pressure self-monitoring in the management of women with hypertensive pregnancies

This thesis aimed to examine the role of blood pressure self-monitoring (SMBP) for the management of hypertension in pregnancy. Hypertensive disorders of pregnancy (HDP) affect around one in ten pregnancies. They contribute to considerable maternal and fetal morbidity and mortality. Currently, pregnant women with hypertension have more frequent clinic surveillance to monitor for any deterioration in blood pressure and emerging pre-eclampsia or fetal complications. This places a considerable burden on both the woman and the health service and deterioration may occur between visits. An SMBP intervention for use in pregnancy hypertension was developed and tested using a mixed methods approach comprising a randomised controlled feasibility study and parallel qualitative studies.
The pilot randomised controlled trial compared SMBP with usual care (2:1) recruiting pregnant women from four UK maternity centres. 86 women with chronic hypertension (55 SMBP, 31 control) and 72 with gestational hypertension (49 SMBP, 23 control) were randomised and outcome data and analysis were completed for 154 (97%). There were high recruitment (71%), adherence (SMBP 5.5 days per week) and persistence rates (SMBP for >80% of enrolment time). There were similar quality of life scores between randomised groups and greater preference shown by participating women for BP self-monitoring versus usual clinic monitoring. There were no overall group differences in BP control.
Parallel qualitative studies explored the experiences and perceptions of pregnant women and their clinicians using the self-monitoring intervention. These included observations of 38 clinics and semi-structured interviews with 24 women and 8 clinicians. Women with hypertension were highly motivated to use BP self-monitoring. This enthusiasm was in the context of valued continuity of care from expert clinicians. Despite women’s and clinicians’ joint goal for a healthy mother and baby, there wasn’t always consensus regarding how best to achieve this. For example women and clinicians gave difference precedence to home and clinic BP readings with important implications for antihypertensive medication adherence which could ultimately affect maternal BP control.
These findings together suggest that SMBP is a feasible and acceptable intervention to trial on a larger scale for the management of hypertension in pregnancy. However, because women and their clinicians could ascribe different meanings to the home and clinic BP readings this in turn influenced subsequent perspectives around treatment. Clinicians could better support shared decision making with enhanced awareness of and discussion around women’s experiences of home monitoring and treatment concerns. Further research is needed to understand the relationship between home blood pressure readings and clinical outcomes to inform these discussions.

Keywords: blood pressure
self-monitoring
hypertensive disorders of pregnancy
Advisor: McManus, RJ
Chappell, L
Ziebland, S
Towards a structure-based understanding of WNT receptor function

The highly conserved WNT signalling pathways are vital during development and throughout the lives of animals, while aberrant WNT signalling is implicated in a range of degenerative diseases, as well as cancers. Cells detect WNT signals through members of the Frizzled (FZD1- 10) family of cell-surface receptor proteins, resulting in multiple possible outcomes including changes in gene expression and cell polarity. However, how WNT-FZD specificity is achieved, and how different WNT signalling modules are differentially activated by FZDs, remains unclear. It is also uncertain how the overall structure of FZD compares to other similar proteins and contributes to WNT signalling regulation.
In this thesis, work towards the determination of the first multidomain FZD structure is presented. The expression levels of a representative range of human FZDs are compared. The optimisation of expression and thermostability of candidate receptors for structural studies, through protein engineering, leading to poorly diffracting crystals, is detailed.
The crystal structure of the FZD3 extracellular domain in complex with a highly specific nanobody (Nb) is described, suggesting a role for the latter in inhibiting signalling. Conversely, a synthetic WNT signalling agonist has been created by fusing this Nb to a WNT-inhibitory protein domain that binds to the WNT coreceptor, LRP6. Functional dissection of FZD3 facilitated by this agonist confirms that the long C-terminal tail of FZD3 is dispensable for ‘canonical’ WNT signalling, whereas disruption of the intracellular loops abolishes this activity. Moreover, the mutation of glycine5.64f, perfectly conserved amongst FZD receptors and implicated in a developmental disorder, is shown to have no effect on ‘canonical’ signalling, and instead this residue may form part of a previously overlooked molecular ‘switch’ required for G protein-dependent signalling.
Finally, the crystal structures of the FZD10 and FZD3 extracellular domains contribute to a more complete understanding of the structural biology of these enigmatic receptors.

Advisor: Jones, Y
Zhao, Y
Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia

Allogeneic haematopoietic stem cell transplantation (allo-SCT) is the best established cellular immunotherapy and is a common treatment for acute myeloid leukaemia (AML). Allo-SCT relies on donor T cells identifying AML cells as foreign and eradicating them, which is known as graft-versus-leukaemia (GvL). Donor T cells recognise AML through interactions between their T cell receptor (TCR) and peptide antigens bound by human leukocyte antigen (HLA) on the surface of AML cells. Despite being administered for over 50 years, our understanding of the AML antigens that elicit a donor T cell response after allo-SCT is very limited.
Identification of antigens that mediate GvL may directly lead to improvements in selection of allo-SCT donors for treating AML patients. A donor whose cells can produce a specific alloimmune response against the recipient’s AML cells would reduce relapse. Furthermore, antigens represent potential targets for immunotherapy.
This study establishes a novel workflow to identify and characterise GvL antigens and the donor-derived T cells that respond to them. GvL antigens are likely to result from germline DNA variants that are present in a patient but absent in their allo-SCT donor. Exome and RNA sequencing were used to identify mismatched DNA variants between patient and donor that are expressed in AML. Candidate GvL antigens were identified using: (1) in silico HLA-binding prediction, and (2) mass spectrometry of peptides eluted from HLA on AML cells.
Predicted GvL peptide antigens were functionally screened, which led to the identification of 24 validated antigens from 9 patients. Of the antigen-specific T cell responses characterised, 86% stimulate CD4+ donor T cells. For a GvL antigen derived from the PADI4 gene, responses are HLA-DP restricted and donor T cells are CD4+ with a cytotoxic T helper 1 phenotype.
As a proof of concept, a T cell therapy was developed targeting the PADI4 antigen. Antigen-specific TCR sequences were identified and inserted into human T cells. These were then used to assess T cell-mediated killing of AML cells in vitro and in vivo, and also to investigate the mechanism of PADI4 antigen presentation by HLA.

Keywords: Cancer antigens
T cell therapy
Allogeneic stem cell transplantation
Acute myeloid leukaemia
Advisor: Vyas, P
All Jihad is local

The Islamic State of Iraq and Syria (ISIS) recruited an estimated 40,000 foreign fighters from over 100 countries from 2013 until approximately the end of 2015. This was one of the largest foreign fighter mobilizations to a single insurgent group fighting in a single civil war in the past 120 years. Based on the size and scale of this mobilization, it would seem as though ISIS foreign recruits came from every corner of the globe. Yet the vast majority of ISIS foreign fighters came from a small number of places around the world. This dissertation focuses on these places, which I call recruitment hubs, because they were sites of disproportionate recruitment. In the Middle East and North Africa (MENA), for example, 75 percent of ISIS foreign fighters were recruited from regions that constituted 11 percent of MENA’s total population.
Why were ISIS foreign fighters concentrated in these hubs and not others? How did these recruitment hubs form and function? And why were people recruited to become foreign fighters, as opposed to joining an armed rebellion or participating in protests in their own country? This dissertation argues that ISIS foreign fighter recruitment hubs were crucial to the group’s success attracting foreign fighters; not only because large numbers of fighters joined ISIS from hubs, but also because hubs affected the types of fighters who joined ISIS. This dissertation finds that there are some identifiable patterns in where hubs form, how they form, and why recruitment is so effective there. But it is much more difficult to predict whether recruitment hubs form for foreign fighting or other outcomes, like domestic insurgency. That is because the foreign fighting occurs in part due to highly contingent events – breaks in patterns of past relationships, the emergence of conflicts in foreign lands, and choices made by several individuals at critical junctures where potential alternatives existed.

Keywords: Islamic State of Iraq and Syria
insurgency
insurgent recruitment
terrorism
foreign fighting
civil wars
terrorist recruitment
Advisor: Varese, F