VictorJuiz/thesis huggingface dataset:
The optimisation of HbA1c testing in UK primary care

Background. HbA1c monitoring to guide diabetes management usually requires more than one clinic appointment. Point-of-care (POC) testing allows testing and treatment changes in a single appointment, but trials of POC HbA1c testing have not been shown to benefit patients and the healthcare system. This work explores how HbA1c testing in primary care could be streamlined using POC testing. It comprises four pieces of work and is guided by complex intervention and test-evaluation frameworks.
Methods. Database analyses were used to describe current practice in HbA1c testing and identify factors associated with testing schedules not recommended by guidelines. Systematic review and meta-analysis was used to determine the most accurate POC device. A device was selected to use in a feasibility study to determine how POC HbA1c testing can be used in primary care consultations. Data on recruitment, care pathways, care delivery, satisfaction and behaviour were gathered using data collection forms and questionnaires. Qualitative interviews with patients and clinicians explored perceptions and barriers to POC testing.
Results. Database analyses showed that high or low HbA1c testing rates are associated with previous HbA1c levels and use of incentive schemes. Most POC HbA1c devices have a mean negative bias and large variability compared to laboratory methods. When POC HbA1c testing was used in GP practices, nurses used the result to make clinical decisions during the consultation. Nurse consultations were longer than GP consultations (22mins versus 11mins) and POC results were successfully uploaded to patient records. Patients liked POC testing and found it convenient. It helped some link their HbA1c result to recent behaviour. Clinicians found the tests easy to use but were concerned about cost.
Conclusion. POC testing can be effectively delivered in primary care but funding mechanisms are needed to encourage adoption. This work could inform the design of a randomised trial to test the effect on patient outcomes.

Advisor: Williams, V
Stevens, R
Farmer, A
The apologetic value of theological truth through story and pattern in the works of Dorothy L. Sayers

This thesis sets out to understand the theological method of Dorothy L. Sayers, a complex woman of letters. The preeminent argument is that a new and helpful paradigm for understanding Sayers' work and evaluating her contribution to Christian apologetics is her emphasis on accessing and expressing theological 'truth', through 'story' and 'pattern'. Sayers consistently explored theological truths in the context of dramatic narratives and orderly systems.
The primary research methodology is to find, read and use Sayers' own letters as the principal sources to shed light on her published work. The thesis seeks to show that recognising Sayers' passion for truth, through story and pattern makes a significant contribution towards understanding her canon as a unity. The thesis differs in perspective in this regard from other Sayers scholarship, which has placed emphasis on other particular theological motifs or literary points in her career as an author. Furthermore, this thesis will differ from other theological analyses of Sayers' work in that it engages with the full diversity of genres in Sayers' canon and does so from a rigorous theological perspective rather than by taking a biographical approach.
This thesis contributes to current theological understanding by bringing the work of a significant lay female Christian thinker of the twentieth century to the attention of scholarship. Sayers' work has continuing resonance for contemporary theologians who are interested in the role of narrative, drama and analogy in theology, and in the creative communication of theological ideas.

Advisor: Chapman, M
Ward, M
Structural studies of PfEMP1 bound to human cluster of differentiation 36 and of an unusual human antibody

In Plasmodium falciparum-infected humans, parasites escape from splenic clearance and cause severe or chronic symptoms partly through the action of the variable surface antigens expressed on the surfaces of infected erythrocytes, called P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 that interact with human Cluster of Differentiation 36 (CD36) receptor mediate the most common adhesion phenotype found in infected erythrocytes. Here the first crystal structure of CD36 in complex with a PfEMP1 CIDR domain is presented. Together with sequence analysis and biophysical data, it shows how parasite PfEMP1 proteins are able to diversify hugely while retaining a chemically conserved CD36 binding surface. This reveals insight into the structure and function of CD36 and shows how the parasite targets a region of CD36 that is critical for its physiological role, avoiding mutations in host receptors that would prevent parasite binding.
Repetitive interspersed family proteins (RIFINs) are the most abundant variant surface antigens in P. falciparum. However, unlike the well-studied PfEMP1, the function of RIFIN remains unclear. Recently, a subset of human antibodies was identified from malaria-endemic areas that can recognise varied RIFINs. These antibodies have the unique feature of the insertion of a human receptor, LAIR1 (CD305), into the third complementarity-determining region of their heavy chain. Here, the first structure of one of these unusual LAIR1-containing antibodies is presented. It reveals that the CDR loops are mostly occluded by the insert and form a surface that positions LAIR1 for antigen binding. The variable regions of the antibody therefore no longer perform their classical role in antigen recognition. Instead they act as an adaptor between a human LAIR1 insert with antigen binding properties and the immune-modulatory antibody constant regions.

Advisor: Higgins, M
Investigating follicle development using in vitro technologies

Patients with dysfunctional ovaries, such as those with premature ovarian insufficiency and granulosa cell tumours, do not have normal follicle development and may not respond to traditional assisted reproductive techniques. Using the reaggregated ovary (RO) technique, these patients' oocytes may be reaggregated with functional supporting cells and cultured in vitro to develop fertilisable eggs. However, current research using ROs have only used murine ovaries as a somatic cell source. In this thesis, with the aim of moving towards a clinical treatment, we assessed follicle development in ROs in vitro and progressed to using the technique with human tissues. To assess whether an older murine somatic cell source resulted in advanced follicle development, and how follicle development differed between transplanted and cultured ROs, ROs were generated using postnatal day 2 (P2) and P6 mouse ovaries. To investigate theca cell development in follicles from cultured tissue, mouse ovaries were cultured with mouse serum or encapsulated in hyaluronan hydrogels. Prior to generating and culturing chimeric human-mouse ROs (HuMoROs), competent handling and digestion of bovine cortical tissue was required. Broadly, ROs generated from both P2 and P6 exhibited similar follicle development in vitro after 14 d of culture, and follicles from cultured ROs were more developed than those from transplanted ROs. Theca cell development observed in follicles from cultured ovaries was still poorer than those from in vivo ovaries, even when ovaries were cultured in mouse serum or encapsulated in a hyaluronan hydrogel. Finally, some follicles containing potential human oocytes developed within the generated HuMoROs after 7 d of culture. These results have highlighted the potential of the RO technique as a method to generate fertilisable eggs and identified further aspects which need to be targeted in order to improve the success of the technique.

Keywords: Mouse
Ovary
Human
Tissue culture
Follicle development
Advisor: Williams, S
Wells, D
Mechanisms of clinical ototoxicity and inner ear protection

Clinical ototoxicity—permanent hearing loss caused by medications—is estimated to affect millions of patients annually. Two classes of drug are largely to blame: platinum-based chemotherapeutics, primarily cisplatin, and aminoglycoside antibiotics. Development of methods to prevent ototoxicity depends upon an understanding of its mechanisms and may benefit from an understanding of native protective pathways of the inner ear.
As the mechanisms behind cisplatin ototoxicity remain unclear, I first sought, and herein report, a refined mouse model of cisplatin ototoxicity which will allow for further in vivo investigation of cisplatin ototoxicity and potential methods for its prevention. This low-dose, multi-cycle model was found to accurately reproduce cisplatin ototoxicity as it has been described clinically and histopathologically.
I then used this mouse model of cisplatin ototoxicity to investigate cisplatin pharmacokinetics in the cochlea and their role in driving cisplatin ototoxicity. Cisplatin was found to be retained within the cochlea for months following its administration. This initial finding in mice was extended to cochlear tissue samples from deceased human patients. Analysis of intra-cochlear cisplatin distribution in murine and human tissue identified the stria vascularis region of the cochlea as a promising target for intervention.
With the nature of aminoglycoside ototoxicity better understood, I investigated a native inner ear protective pathway which could be leveraged to promote sensory hair cell survival. The improved hair cell survival that has previously been demonstrated as a result of heat stress was found to be mediated by cell-cell communication via extracellular vesicles. Further, hair cell protection against aminoglycosides could be reproduced through the application of exogenous, non-inner ear-derived extracellular vesicles.
In sum, these data provide new insight into mechanisms of ototoxicity and details of cellular pathways which can help protect against it.

Keywords: Cochlea
Utricle
Cisplatin
Ototoxicity
Aminoglycoside
Extracellular vesicle
Deafness
Advisor: Wood, M
Cunningham, L
Role of posttranslational modifications of histone proteins in epigenetics

Nature has evolved an additional level of genetic regulation by-passing direct changes in genetic code through the means of posttranslational modifications (PTMs) of nucleobases and histone proteins. Acetylation, methylation, phosphorylation, O-GlcNAcylation, ubiquitination, sumoylation, and ADP ribosylation are few common examples of various histone modifications. Identification of these modifications and subsequent access to homogeneously modified histone proteins are key for understanding the functional consequence of these PTMs. In this doctoral thesis, the role of PTMs of histone proteins in epigenetics was investigated with emphasis on understanding the role of O-GlcNAcylation in particular.
In the second chapter, the functional consequence of O-GlcNAcylation at histone protein, H2B-Ser112 was explored. Homogeneously GlcNAcylated histones and nucleosomes were synthesized using protein chemical reactions. Mass Spectrometry (MS) based quantitative interaction proteomics revealed a direct interaction between GlcNAcylated nucleosomes and the Facilitates Chromatin Transcription (FACT) complex. Preferential binding of FACT to GlcNAcylated nucleosomes provides a molecular mechanism for FACT-driven transcriptional control.
In the third chapter, the physical effect of O-GlcNAcylation on the nucleosome structure is described. Homogeneously GlcNAcylated histone protein, H2A-Thr101 was synthesized. The modified protein was used to reconstitute histone sub-complexes and nucleosomes. Various biophysical studies involving circular dichroism and native mass spectrometry revealed that H2A-T101 GlcNAcylation regulates the stability of the nucleosome structure, suggesting a role in transcriptional activation.
In the fourth chapter, we discuss an interesting scenario where two PTMs – O-GlcNAcylation and phosphorylation – can compete for the same modification site of histone protein, H2B-Ser36. The resulting outcome is possibly a competitive antagonism or cross-talk, which can modulate the overall control of chromatin regulation. Using a "Tag-and-modify" approach, modified histone proteins bearing both modifications was synthesized, and was later used for nucleosome reconstitution. Quantitative interaction proteomics experiments with the modified nucleosome revealed key interacting protein partners for both the modifications.

Keywords: MS-based interaction proteomics
O-GlcNAcylation
Epigenetics
Protein chemistry
Advisor: Davis, B
First-principles Fröhlich electron-phonon coupling and polarons in oxides and polar semiconductors

The Fröhlich coupling describes the interaction between electrons and infrared-active vibrations at long wavelength in polar semiconductors and insulators, and may result in the formation of polaronic quasiparticles. Polarons are electrons dressed by a phonon cloud, which can strongly affect the electronic properties of the crystal. Despite their ubiquitous role in a broad range of technologies, first-principles investigations of the electron-phonon interaction in polar materials are scarce. In this thesis we develop a general formalism for calculating the electron-phonon matrix element in polar semiconductors and insulators from first principles, which represents a generalization of the Fröhlich model and can be used to compute the polar electron-phonon coupling as a straightforward post-processing operation. We apply this procedure to explore an important material for photovoltaics, the hybrid lead halide perovskite CH3NH3PbI3. In this case we show that the temperature dependence of emission line broadening is dominated by Fröhlich coupling. Our method is formulated in conjunction with an ab initio interpolation technique based on maximally localized Wannier functions, which allows to describe all forms of electron-phonon coupling on the same footing. We demonstrate the validity of this approach on the prototypical examples GaN and SrTiO3. Focusing on anatase TiO2, a transition metal oxide of wide technological interest, we establish quantitatively the effect of including the ab initio Fröhlich coupling in the calculation of electron lifetimes. The rest of the thesis is devoted to exploring the quasiparticle properties in doped oxides. In particular, we investigate angle-resolved photoemission spectra from first principles in doped anatase TiO2 by proposing a novel framework that combines our ab initio matrix elements, including the dynamical screening arising from the added carriers, and the cumulant expansion approach. We compare our results with experimental data, and show that the transition from a polaronic to a Fermi liquid regime with increasing doping concentration originates from nonadiabatic polar electron-phonon coupling. We further validate this mechanism by calculating angle-resolved photoemission spectra in the ferromagnetic semiconductor EuO.

Keywords: First-principles calculations
polarons
electron-phonon coupling
Advisor: Giustino, F
Constructing the right to war: Alberico Gentili and his receptions in international law

This thesis explains the striking disparity between two narratives about Alberico Gentili, the early modern jurist widely identified as the founder of the classical laws of war. On the one hand, he is conventionally considered as a great humanizer of warfare, a man who tried to use the law to curtail the horrors of war. On the other hand, a few works have emerged suggesting that Gentili was in fact the first to introduce the concept of the enemy of mankind into international law, a concept generally used to justify ruthless forms of violence. In order to explain the tension between these narratives, the thesis investigates both what Gentili was seeking to achieve in his own epoch with his treatise on the laws of war, De iure belli, and how his work was subsequently received over time.
Based on an original methodology for the study of great thinkers in International Relations and beyond, the thesis makes the following two-fold argument. First, it argues that Gentili's famous treatise on the laws of war is the work of an absolutist who was attempting to elaborate and defend a controversial approach to war and its law. Gentili’s pioneering use of the concept of the enemy of mankind must be understood as the cornerstone of this absolutist project, as part and parcel of a broader attempt to grant unprecedented rights to a small group of sovereigns. Second, it argues that the conventional narrative about Gentili as the father of the classical laws of war and as an avant-garde humanitarian only emerged in the late nineteenth century, turning the Italian jurist into a cipher for a particular view of international law and modernity and developing a myth about the importance of his work. This narrative would eventually be enshrined in Carl Schmitt's deeply influential The Nomos of the Earth, and it continues to shape the story of the development of international relations and international law to this day.
In making this argument, the thesis challenges some conventional tenets of the history of international law and international relations, reveals a new facet of the disciplinary history of international law, and makes a broader claim about the need to examine debates about the ontology of war in historical perspective.

Advisor: Nicolaïdis, K
Keene, E
An evidence-based approach to the post-marketing withdrawal of medicinal products because of adverse reactions

Background: The aim of this thesis was to develop an evidence-based approach to the post-marketing withdrawal of medicinal products when harms are attributed to their use.
Methods: Electronic and non-electronic searches were conducted to identify medicinal products withdrawn from the market because of adverse reactions. Data relating to the time periods between launch, first adverse reaction reports and withdrawals, the mechanism through which the adverse reactions occurred, and the countries of withdrawal were extracted. Standard criteria were used to document the levels of evidence used by drug regulators to make the withdrawal decisions; scatter plots and two-by-two tables used to explore the trends over time. A previously published algorithm was used to examine the justification for withdrawals. To examine the benefits and harms of medicinal products before regulatory approval, searches were conducted on drug regulatory websites and scientific databases. The Cochrane criterion was used to examine the risk of bias, Review Manager Software for meta-analysis, and GRADE criterion to rate the quality of evidence.
Results: Improvements in pharmacovigilance over the past six decades have resulted in quicker detection of harms caused by approved medicinal products; however, there have not been corresponding improvements in how quickly harmful products are withdrawn from the market following the reports of harms. Harmful drugs are significantly less likely to be withdrawn in low resource settings. The quality of evidence in drug trials for which regulatory approval decisions are based is on the whole, poor. There is a lack of consistency in the methods used by drug regulators to assess the harms of medicinal products before granting marketing licences.
Conclusions: Universally accepted guidelines for deciding when to withdraw approved medicinal products from the market should be developed. Pharmacovigilance systems in low-resource settings should be strengthened. The methods used to assess harms in clinical trials require improvement.

Keywords: Systematic review
Adverse reaction
Drug withdrawal
Advisor: Heneghan, C
Aronson, J
Personalized recommender systems on the social web

An exponential increase in the usage of the World Wide Web (Web 2.0) has led to a wide collection of social platforms that harness people's online activities such as online shopping (e.g., eBay and Amazon), entertainment (e.g., YouTube and Last.fm), and social networking (e.g., Facebook and Twitter). This has led to an overabundance of information online, which is far too consuming for individual users to browse. As such, personalized recommender systems have emerged, which aim to tailor the online information presented to the user based on their preferences. Such recommender systems have been widely studied in the research community and are also commonly deployed in industry, e.g., music recommendation on Last.fm, item recommendation on Amazon.com, and friend recommendation on Twitter.
Despite the huge prevalence of using social annotations in personalized recommendation, a major outstanding problem is that in general they are redundant, sparse and ambiguous. Therefore, in this thesis, we first study and address this problem by proposing a recommendation-oriented deep neural model, in the context of tag-aware personalized recommendation. Here, we also propose hybrid deep learning and negative sampling to enhance the deep models' training efficiency. Furthermore, since users' real-time news preferences are sometimes correlated with their geographical context, we then investigate location-aware personalized news recommendation using geographical topic models, where topic feature modelling and the user's long-term personal interests are used to enhance the recommendation performance. Finally, to alleviate the need for powerful computing facilities to train deep recommendation models, we propose a novel ontology-based similarity to circumvent tag ambiguity and redundancy for applications in light-weight recommender systems on the Social Web.

Advisor: Lukasiewicz, T
Neural circuit mechanisms of memory coding in the Drosophila mushroom body

Learning allows animals to adapt their behaviour to changes in the environment. In humans and other mammals, memories are stored in the hippocampus and cerebellum, whereas in insects, they are stored inside the mushroom bodies (MB). Here, MB-intrinsic Kenyon cells (KCs) form plastic synapses to MB output neurons (MBONs) that are modulated by the reinforcing action of dopaminergic neurons (DANs).
Despite decades of research on the MB, the main neurotransmitter underlying the plastic KC → MBON synapse has remained a mystery. Here, I show that this synapse is cholinergic in the fruit fly Drosophila melanogaster. MBONs show fast excitatory responses to direct acetylcholine (ACh) application. KCs synthesise ACh-related proteins ChAT and VAChT. MBONs express and require nicotinic ACh receptors (nAChRs) to become fully activated by odour presentation. Lastly, artificial activation of KCs leads to MBON calcium responses that are blocked by nicotinic antagonists and genetic reduction of VAChT in KCs. Short neuropeptide F (sNPF) may play a role as a modulatory co-transmitter that can either excite or inhibit specific MBONs and DANs.
The retrieval of memories is state-dependent and known to potentially change the original memory. Fruit flies need to be hungry to express appetitive memories. Hunger state depends on insulin signalling that activates the GABAergic MBON MVP2, while appetitive memory retrieval depends on decreased activity in M4/6 MBONs. Here, I show that optogenetic MVP2 activation acutely inhibits M4/6 odour responses, rendering MVP2 an inhibitory MBON interneuron. I also show that other MBONs are functionally connected to DANs, thus linking memory reinforcement and retrieval pathways in a way that enables the updating of the original memory.
These findings show that associative memories in Drosophila are initially formed at cholinergic KC–MBON synapses, and can be retrieved and modified through an intricate KC–MBON–DAN network.

Keywords: mushroom body
sNPF
plasticity
memory
reconsolidation
learning
extinction
acetylcholine
Drosophila
Advisor: Waddell, S