VictorJuiz/thesis huggingface dataset:
Mathematical modelling of calcium ions during ischaemic stroke

Stroke is a condition affecting over 100,000 people every year in the UK alone. There are two types of stroke: ischaemic, which is the more common and occurs when blood supply to the brain is blocked and haemorrhagic, where blood vessels in the brain burst, causing bleeding. After the occurrence of an ischaemic stroke, one typically observes three regions being formed, namely the ischaemic core, penumbra and the unaffected region. While cells in the ischaemic core die immediately due to lack of blood supply, there remains a chance to salvage those in the penumbra, as these cells are still supplied temporarily by peripheral vessels. Clinicians, however, still have difficulty identifying the penumbra, despite advances in medical technology.
To this end, our goal is to create a mathematical model that uses cell calcium ion concentration as a biomarker to predict in these three regions of the brain, given some decrease in blood flow, which is a clinically measureable input. This would allow our model to be used as a diagnostic tool for clinicians to determine which areas to apply reperfusion.
We find that our model is able to portray certain spatial inhomogeneities known as Turing patterns, which arise from one set of equations, with calcium concentration as its sole biomarker. This is a feature that, to our knowledge, has not been investigated in other models. The presence of Turing patterns allows us potentially to model the ischaemic core, penumbra and unaffected regions; however, the spatial inhomogeneities observed in our model simulations do not yet correspond to these regions due to the presence of higher-order modes. We, therefore, suggest ways to improve the model to make it a viable clinical tool.

Advisor: Payne, S
The clinical epidemiology of scrub typhus in humans, chiggers and rodents

Research on the natural history of scrub typhus took place predominantly before the 1970s. This project developed modern techniques to revisit fundamental aspects of the epidemiology and ecology of the disease in Thailand and Laos. Three sites of high scrub typhus disease transmission were identified. Vector chiggers and small mammal hosts were collected, identified and tested for Orientia tsutsugamushi, the causative agent and mapped using GIS. The complex ecological interactions of infected and uninfected vectors and hosts with habitats and seasons were investigated. A low-input targeted enrichment sequencing method was developed and applied to a subset of positive samples. Over 18 months, 244 small mammals and ~17,000 chiggers were tested resulting in 279 O. tsutsugamushi PCR positive samples. Sixty-nine positive human samples were collected. Overall 8.6% of individual chiggers and 25.9% of chigger pools tested positive. At most sites <1% of individual chiggers tested positive, whereas at the 3 highest-risk site 18% were positive. No consistent high-risk area of infection was identified within our study sites (~9km2). High-risk sites were associated with a lower diversity of chigger species, higher proportion of recognized vector species and a higher mean number of chiggers attached to hosts. The end of the dry season was most strongly associated with O. tsutsugamushi positivity. The extremely low quantities of DNA in these samples combined with the complex genome assembly created numerous challenges for sequencing and bioinformatics analysis. Phylogenetic clustering was evident among samples collected from the same sites, although strains with greater genetic differences also appear to co-exist even on the same host. In Thailand and Laos, human infections rise dramatically during the rainy season. However, corresponding proportions of infected chiggers remained stable, suggesting that human behaviour plays a critical role. Improving our understanding of risk behaviour could yield relatively simple interventions to reduce disease acquisition through public health education.

Advisor: Newton, P
Bowden, R
Day, N
Dissecting the function of the Leishmania flagellum in a CRISPR-Cas9 knockout screen

Eukaryotic cilia and flagella are conserved organelles with specialized structures and functions. Cilia and flagella can be well studied in parasites of the genus Leishmania, which possess at different stages in their life cycle either a motile 9 + 2 or immotile 9 + 0 flagellum. Much remains unknown about Leishmania-specific flagellar biology, for example whether flagellar motility is required throughout the Leishmania life cycle. More fundamentally, it is still not fully known how flagellar bending is controlled at a molecular level in motile cilia and flagella.
To dissect flagellar function in Leishmania with regard to these open questions, the Cas9 gene editing toolbox LeishGEdit was developed, enabling a knockout screen of ~450 proteins identified in the promastigote flagellum of L. mexicana. This identified 14 mutants with a flagellar curling phenotype. A systematic analysis of the curling phenotype showed that flagellar bending in Leishmania is supported by the extra-axonemal paraflagellar rod structure and regulated through central pair projections and inner dynein arm (IDA) f/l1 components. Further analysis of the IDA f/l1 tether/tether head (T/TH) complex identified LAX28 as a novel IDA f/l1 assembly factor. However, using the CRISPR-Cas9 toolbox not only allowed a dissection of the regulation of flagellar bending in vitro, but also enabled assessing the requirement for motility in vivo. By passaging a range of barcoded Leishmania motility mutants in pooled populations through sand flies and mice, flagellar-driven directional motility was shown to be essential for colonialization of the sand fly vector, but dispensable for survival in the mammalian host. Thus, this thesis shows the implementation of a powerful Cas9 toolbox that provided new insights into the regulation of flagellar bending and the importance of Leishmania motility in vivo.

Advisor: Gluenz, E
A physical-organic approach to asymmetric catalysis: design and synthesis of chiral ligands using multivariate modelling

Discovery of new asymmetric metal-catalyzed transformations is closely related to the development of efficient and robust chiral ligands, such that ligand optimisation is a crucial step in reaction development but its success is highly uncertain. Mostly based on trial-and-error, such a daunting task can be intellectually frustrating and exhausting, wherein the use of any predictive tool is much appreciated. The limited mechanistic knowledge in asymmetric catalysis is unfortunately prohibitive to the use of many computational techniques. As a result, we turn our attention toward multivariate modelling, a data-driven statistical approach which is believed to be a promising platform to rationally drive the successful identification of a highly enantioselective ligand.
In this work, we introduce the importance of ligands in asymmetric catalysis and detail the notion of ligand design, and more particularly, we fully report the multivariate modelling approach (Chapter 1). We then apply such a strategy on systems developed in our group where the ligand design previously failed using traditional approaches. For instance, Chapter 2 fully uses multivariate modelling to reoptimize a copper-catalysed asymmetric conjugate addition of alkylzirconium species that failed on sterically challenging linear substrates. While modelling this asymmetric transformation, we realized that conformational flexibility of ligands could produce large amplitudes of underestimated uncertainty in predictions. Thus, conformational effects on physical-organic descriptors are explored in Chapter 3 with the specific case of steric Sterimol parameters, from which new descriptors called wSterimol (“weighted Sterimol”) were developed. Inspired by the success of our approach in Chapter 2, the ligand design workflow is applied to the development of a copper-catalysed asymmetric conjugate addition to exocyclic enones (Chapter 4). Finally, we examine the remaining challenges for the data-driven approach to become a go-to method and we envision the future of ligand design in asymmetric catalysis (Chapter 5).

Keywords: Sterimol
linear free energy relationship
asymmetric conjugate addition
ligand design
quantitative structure−selectivity relationship
phosphoramidite
multivariate modeling
asymmetric catalysis
Advisor: Fletcher, S
Paton, R
Seismic tomography of the La Réunion mantle plume

This study aims to generate a multifrequency tomography model of the mantle beneath the Réunion hotspot, where a whole mantle conduit may be present.
From 2011 to 2016, the RHUM-RUM project (Réunion Hotspot Upper Mantle – Réunions Unterer Mantel) instrumented a 2000 km × 2000 km area of the Indian Ocean seafloor, islands and Madagascar with broadband seismometers and hydrophones. The central component was a 13-month deployment of 57 German and French Ocean Bottom Seismometers (OBS) deployed at 2300-5600 m depth. This was supplemented by deployments of 37 stations on Réunion, Mauritius, Rodrigues, the southern Seychelles, the Iles Eparses and southern Madagascar. More than 200 teleseismic events during the 13-month long deployment were recorded and additional 400 events before and after the main OBS deployment were recorded by permanent stations.
Here, I present the data yield, processing methods and P wave images based on over 55,000 multifrequency cross-correlations measurements in passbands between 30 and 2.7 seconds dominant periods. Ideally, all frequency bands that efficiently transmit body-waves would be used but this meets practical limits in the noise characteristics of ocean-bottom recordings. The multifrequency traveltime observations are embedded into a global ray theoretical inversion. This new high resolution tomographic model, which illuminates the mantle column beneath La Réunion and surrounding areas, is discussed and compared to existing global models.
The model reveals a massive upwelling rooted in the African LLVP. Branches tilting up- and outward from a central cusp at around 900 km above the CMB (∼2000 km depth), and connect to the hotspot locations of La Réunion, Afar, Kerguelen, and possibly Crozet. These mantle connections support evidence of long-standing observations of geochemical similarities across Indian Ocean hotspots.

Keywords: Tomography
Mantle plumes
Advisor: Sigloch, K
Pool boiling in electrical systems

This thesis presents the results of research into pool boiling in electrical systems, with particular application to stator end windings cooling. Pool boiling heat transfer characterisation of wire-wound motor windings geometry (MWG) surfaces was characterised, with MWG surfaces returning higher heat transfer even with area-compensation. Extant correlations were evaluated against both surfaces; the Rohsenow correlation with curve-fitting parameters was the best descriptor for both surfaces, whilst the Gorenflo-Kenning and unfitted Rohsenow provided good a priori predictive accuracy. Pool boiling of a heated vertical surface parallel to an unheated surface was shown to considerably enhance heat transfer coefficient at low heat flux, and considerably degrade heat transfer coefficient at high heat flux, when Bo < 0.58. Reducing liquid level below a similar level produced a marked deterioration in heat transfer from a horizontal surface. A semi-empirical model was developed to evaluate bulk void fraction for confined and unconfined mini-tube bundles. Heat transfer coefficient was shown to decline where void fraction exceeded a certain threshold. Exceeding the same bulk void fraction threshold anywhere in the column was shown to predict that dryout would occur first at the top tube in the column rather than at the bottom tube. The maximum power density of a mini-tube bundle was obtained around 30 MW m-3. Bubble nucleator devices were shown to be effective at mitigating against bundle effect by activating dormant nucleation sites. These novel discoveries enable stator end windings geometry and packaging to be optimised to maximise pool boiling heat transfer, in turn allowing the design of machines with higher power density and efficiency and cooled by a system that has the potential for entirely passive operation.

Advisor: Walsh, E
Problems with participation: critical deliberative democracy, embodied identity, and affect

Jürgen Habermas and Seyla Benhabib create normative models of moral and political decision-making that are intended to enable ordinary people to identify themselves and to emancipate themselves from unjust conditions. When creating these models, both thinkers endorse deliberative models of democracy that reflect the central tenets and core commitments of ‘discourse ethics’. Most importantly, Habermas and Benhabib claim that decisions about norms to govern society and institutional arrangements should only be treated as legitimate when they satisfy a number of demands. These demands include that the persons who create them recognize each other as worthy interlocutors with valid concerns and express themselves through modes of praxis and forms of communication that are devoid of coercion and domination-free. That said, in their normative models of moral and political decision-making, Habermas and Benhabib rely, albeit implicitly, upon a conception of the subjects who are involved as abstract and disembodied linguistic beings. Consequently, they tacitly overlook and bracket off a range of subtler, less obvious, and more insidious manifestations of power, along with a range of real-world problems with people’s participation in politics that they produce. To build a more nuanced account of these issues, this thesis develops a concept of ‘embodied identity’ that appreciates the personal-political significance of the body and the experience of living life within it as an embodied being. Subsequently, this thesis considers how treating individuals as embodied beings contributes to on-going discussions in contemporary political theory. These discussions include debates about how best to understand what makes contemporary society unfair or unjust and what can be done to ensure that the democratic, decision-making process is as inclusive and egalitarian as possible, given the reality of socio-cultural difference, contemporary society, and actual political praxis.

Advisor: Butt, D
Biophysical and functional studies of neurotensin receptor 1

G protein coupled receptors (GPCRs) are a large family of membrane proteins that facilitate diverse cellular signalling processes and represent significant drug targets. There has been considerable progress in understanding the molecular process of GPCR activation, but structural, biophysical & functional studies of GPCRs typically make use of a small number of well-studied receptors, sometimes with heavily modified sequences and often in the absence of the lipid environments in which GPCRs have evolved to be functional. In this thesis, the neurotensin receptor 1 (NTS1) is used as a model GPCR to explore aspects of receptor dynamics and function, with emphasis on the use of minimally modified receptor sequences. Firstly, using site-specific cysteine mutants and an E. coli expression system, the conformational dynamics of the proximal C-terminus of NTS1 were defined for the receptor in a native-like lipid environment, resolving a literature dispute concerning the structure of ‘helix 8’ for NTS1. Secondly, production of NTS1 and the heterotrimeric G proteins Gq and Gi1 was established using insect cell expression systems, and high-quality native mass spectra were obtained for NTS1 that demonstrate receptor palmitoylation, and pave the way for the study of post-translational modifications of GPCRs by native mass spectrometry. Thirdly, using a GTP turnover assay, lipids were identified which selectively enhanced NTS1-Gq over NTS1-Gi1 coupling, suggesting a role for membrane composition in selectivity of NTS1 signalling. Finally, the novel polymethacrylate (PMA) amphipathic polymer was used to establish detergent-free purification of NTS1, representing the first detergent-free purification of any membrane protein using PMA. The work presented here thus progresses the field, both in terms of our molecular understanding of GPCR signalling and in terms of technical advances that will facilitate further studies.

Advisor: Watts, A
The material culture of remembrance and identity

This thesis examines the relationship between material culture, war memory, and identity for South Africa, India, Canada, and Australia in the First World War’s aftermath 1918-1938. Their material culture of commemoration on the battlefields fell under the Imperial War Graves Commission’s remit; this complicated the decision-making processes for these sites, and caused them to serve as stages upon which relationships between national, imperial, collective, and individual identities were negotiated and performed in stone. Using five memorials in France and Belgium as case studies and also incorporating cemeteries, this thesis is a transnational, comparative, and interdisciplinary work. It advances new evidence for the spatial and conceptual relationships that existed between landscape, memorial, cemetery, the dead, and the living in imperial remembrance contexts, and uses representative engagements – objects, events, and decisions – to demonstrate how the articulation of identities was embedded in and navigated through them. The chapters interrogate the relationships between place, object, people, and distance, through the lens of absence and presence. They argue that links between landscape, material culture, and the dead created reciprocally conferred meanings; that memorials and cemeteries for India and the Dominions were objects with agency; and that connection across distance was crucial in how these places functioned as sites of identity. The material culture of remembrance is increasingly at the heart of First World War memory; as living memory has faded, it is the tangible remains – artefacts, memorials, and cemeteries – that we ask to tell us stories about our countries, our predecessors, and ourselves. Today, their contemporary relevance is prominently recognised in the public consciousness and media. It is critical that we have an understanding of these sites’ significance to the people who derived meaning from them at the time of their creation.

Keywords: war memory
national identity
Imperial War Graves Commission
British empire
cemeteries
memorials
Advisor: Gregory, A
Atkinson, J
Manifestation und Konstruktion von Frauenmystik. Prozessuales Schreiben in der oberdeutschen Überlieferung der Mechthild von Hackeborn

This thesis suggests a new methodological approach towards medieval mystical texts associated with a female author figure. Instead of a historical-critical method, it proposes adopting a perspective rooted in the individual manifestation that places the text within its cultural context within and outside the manuscript. The 'Liber specialis gratiae' by Mechthild of Hackeborn provides a case study due to its large transmission and its textual instability, resulting in a variety of functional usages. The distribution of manuscripts across a wide area offers insights into the way in which different monastic orders, monasteries, or even individual recipients read the text. Compared to texts transmitted only in a small number of manuscripts, the 'Liber specialis gratiae' therefore allows an examination of the different layers of reception. Passages of the text can be presented as prayer books, didactic manuals, hagiographic manuscripts as well as textual witnesses transmitting the 'Liber' as its only text. By rearranging different sections or just individual phrases, alternative ways of reading are offered. Simultaneously, the context of reception acquires significance, for example the way in which the manuscripts were produced, distributed, and kept within monasteries. The change from manuscript to print and its effect can also be observed, leading to differing manifestations. Moreover, the material offers insights into the fact that reception does not stop at the end of the manuscript era but continues into the period of printed editions and academic engagement with the text. Considering how Mechthild and the 'Liber' were perceived across time is therefore an integral part of this study.

Keywords: Mechthild von Hackeborn
Historiography
Mysticism
Hagiography
Advisor: Suerbaum, A
Detection of prognostically significant coronary artery disease in stress echocardiography using artificial intelligence

Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide, affecting 2.3 million people in the UK. Whilst CAD can be diagnosed through a variety of imaging modalities, stress echocardiography is the most commonly used technique, used in over 50% of hospitals in the UK. However, the current clinical standard for stress echo is very subjective and is only 81 % sensitive and 82% specific. Therefore, there is interest in the development of robust imaging biomarkers which can reliably and reproducibly provide a predictive index for prognostically significant CAD.
The aim of this thesis is to develop and test methods that improve clinical diagnosis of coronary artery disease in stress echocardiograms using machine learning for 1) image contouring 2) producing features from the contours and 3) predicting coronary artery disease.
A framework for auto contouring of stress echocardiograms was developed, initially using two and four chamber cardiac views for both contrast enhanced and noncontrast echocardiograms, which was later expanded to short-axis (SAX) views. Images were obtained from the prospective multisite EVAREST trial imaging database. The contouring technology was based on a U-net convolutional neural network (CNN) and was trained using contours of the endocardial border created manually, comprised of 5692 and 2182 frames for the contrast and non-contrast application, respectively. The autocontouring achieved a dice coefficient score of 93% for contrast images and 92% for non-contrast images.
Following autocontouring, features were generated from the 2-chamber (AP2) and 4- chamber (AP4) contour output. The feature generation methodology was validated by performing a retrospective study in 146 patients to compare the automated outputs of ejection fraction (EF) and global longitudinal strain (GLS) against equivalent measures generated using standard TomTec analysis software. EF demonstrated a root mean square error (RMSE) of 7.36. GLS demonstrated a RMSE of 2.76.
Following validations of contouring and feature calculation these features and additional novel features were inputted into a machine learning classifier to produce a binary high/low risk prediction for CAD. The training dataset consisted of 633 patients. The final trained model was an ensemble. The area under a Receiver Operator Characteristic Curve (AUROC) of 0.93 was obtained on the training data using a nested cross validation. The model was then validated in an entirely independent dataset and a similar AUROC of 0.93 was obtained. These results demonstrate the utility of artificial intelligence for automated echocardiography analysis and, for the first time, an ability to predict clinical outcome directly from echo images.

Advisor: Watkins, H
Leeson, P