VictorJuiz/thesis huggingface dataset:
Targeting protein-protein interactions for cancer therapy

Protein-protein interactions (PPIs) are key drug targets and recent breakthroughs in this area are providing insight into the types of molecules needed to selectively and potently inhibit a target traditionally seen as untractable. The rules that have been used to design classic substratecompetitive drugs (for example Lipinski's rule of five) may not apply in this new field in the same way. Here I present work performed in three systems that are well-validated drug targets for oncogenesis: the CDK2/cyclin A complex, the PLK1 Polobox domain and MDM2. In each case the site of the protein-protein interaction is defined and understood and the rationale for pharmaceutical intervention is clear. I use these as a model system to evaluate the characteristics of drugs that target protein-protein interaction sites and present work on the development of inhibitors as potential leads for subsequent drug development. In Chapter 1 I introduce the problems, challenges and rewards of PPI drug development; in Chapter 2 I present co-crystal structures of MDM2 with isoindolinone inhibitors; in Chapter 3 I detail attempts to co-crystallise the Plk1 Polobox with inhibitors and screen potential inhibitors; in Chapter 4 I present the results of screening to identify inhibitors of Cyclin A recruitment; and in Chapter 5 I discuss other strategies for inhibition of the CDK2/cyclin A complex, including results with a covalent inhibitor. Through these projects I have been able to demonstrate the wide applicability of the PPI inhibition approach, identify key features of drugs able to inhibit PPIs and contribute to drug design in each system.

Keywords: PPI
cancer
protein-protein interaction
CDK2/cyclin
Advisor: Endicott, J
Noble, M
Molecular aspects of antibody mediated T cell activation

The normal physiological activation of naive T cells requires the engagement of both the T cell receptor (TCR) and the co-stimulatory molecule, CD28. However, a group of monoclonal antibodies (mAbs) have been identiﬁed that are able to activate T cells in vitro and in vivo via CD28 engagement alone. Two deﬁning characteristics found in all CD28 superagonist mAbs are their membrane proximal CD28 epitopes and the requirement for mAb immobilisation. To investigate whether agonistic mAbs to similar cell molecules could be identiﬁed based on epitope position alone, mAbs to the inhibitory receptor PD-1 were generated and characterised. Using a drastic mutation-based epitope mapping technique, one mAb was identiﬁed with a membrane proximal epitope along with two other mAbs with membrane distal epitopes. These mAbs were tested for triggering activity in a hybridoma stimulation assay. mAb stimulation was observed with all three mAbs but only in cells expressing a PD-1 chimera that associated with the TCR and the strength of activation was dependent on epitope location. Cross-linking of a monomeric PD-1/CD28 chimera with a pair of anti-PD-1 mAbs resulted in signalling in this system, however, suggesting a role for ligand aggregation in addition to epitope position in mAb signalling. To further investigate the role of epitope position in CD28 superagonism, a cell line expressing a chimeric form of CD28 was created wherein the superagonistic mAb epitope was moved to a membrane distal position. When stimulated with a CD28 superagonist mAb signalling was no longer observed. However stimulation with another mAb that had an epitope to a membrane proximal location on the chimera resulted in superagonistic effect. These results show that epitope location is the dominant cause of T cell stimulation observed by CD28 superagonist mAbs and that epitope dependent mAb signalling is possible in other T cell surface molecules. The work described in this thesis has implications for both the development of immune modulating mAb therapeutics and for the general mechanism of triggering of cell surface receptors dependent on extrinsic tyrosine kinases.

Keywords: CD28
PD-1
superagonist
monoclonal antibody
kinetic segregation model
T cell activation
superagonism
monoclonal antibody triggering
T cell Triggering
Advisor: Davis, S
Palladium mediated allylic fluorination

In this thesis, the construction of the allylic fluorides under palladium catalysis was investigated.
Chapter 1 provides a general introduction to organofluorine compounds and the use of palladium for the formation of both Csp2- and Csp3-F bonds. The aims of the thesis are presented.
In Chapter 2 the identification that a p-nitrobenzoate is the optimum leaving group under Pd-catalysis to give allyl fluorides is described. A range of allylic fluorides was synthesized in 35->95% yield using the nucleophilic fluorinating reagent, TBAF(tBuOH)4. To further develop this transformation we have examined the effect of a variety of leaving groups and phosphine ligands. This methodology led to the development of the first transition metal mediated C-18F bond formation. The development of Ir-catalysed fluorination of allylic carbonates to give allylic fluorides is also discussed. This system provided access to branched, E- and Z-linear allylic fluorides in a regioselective manner. This methodology was also translated to 18F radiochemistry.
In Chapter 3 the synthesis of allylic fluorides via a C-H functionalisation with Pd and nucleophilic source of fluorine was investigated. Comprehensive screening of Pd sources, fluoride reagents and additives was performed. The presence of a quinone was found to be crucial for this transformation.
Chapter 4 describes the synthesis and characterization of a series of allylpalladium(II) complexes and their subsequent reactivity towards a range of electrophilic fluorination reagents.
Chapter 5 gives full experimental procedures and characterization data for all compounds.

Keywords: Palladium
fluorine
allylic
catalysis
Advisor: Gouverneur, V
Dynamic combinatorial mass spectrometry for 2-oxoglutarate oxygenase inhibition   

In the last decade, dynamic combinatorial mass spectrometry (DCMS) with protein targets has emerged as a promising method for the identification of enzyme-inhibitors. 2-Oxoglutarate (2OG) oxygenases are involved in important biological processes related to many diseases; several human 2OG oxygenases are targeted for pharmaceutical intervention. This thesis describes inhibition studies on three 2OG oxygenases using DCMS and structure activity relation (SAR) studies.
Disulphide based DCMS was used for the identification of N-oxalyl based lead inhibitors for the 2OG oxygenase AlkB from Escherichia coli. Crystallographic analyses of AlkB with a lead inhibitor assisted in the design of a second generation of inhibitors using N-oxalyl, pyridyl and quinolinyl scaffolds. Crystallographic and kinetic data of three potent and selective AlkB inhibitors validates the DCMS approach for the development of 2OG oxygenase inhibitors.
The hypoxia inducible factor hydroxylase, prolyl hydroxylase domain 2 (PHD2), was then used as the model enzyme for the development of a novel DCMS approach employing the reversible reaction of boronic acids with diols to form boronate esters. The ‘boronate’ DCMS method was used to identify pyridyl- substituted lead compounds. Further modification of the pyridine scaffold, based on structural analyses, led to the development of highly potent and selective PHD2 inhibitors.
To identify inhibitors for the fat mass and obesity associated protein (FTO), another 2OG oxygenase, an inhibition assay was developed. The inhibition assay was used in conjunction with a differential scanning fluorimetry (DSF) binding assay to identify isoquinolinyl and pyridyl inhibitor scaffolds, related to those used in the DCMS studies. FTO complexed structures of these compounds, and with a natural product anthraquinone, enabled the design and synthesis of new inhibitors that are both co-substrate and substrate competitors of FTO. One such compound proved to be a potent FTO inhibitor with improved selectivity over other 2OG oxygenases.
Overall, the work validates the use of DCMS methods for the development of potent and selective inhibitors for 2OG oxygenases, and by implication of other enzyme families.

Keywords: dynamic combinatorial mass spectrometry
inhibitor design
native mass spectrometry
2og oxygenases
Advisor: Schofield, C
The development of a complex dietary and physical activity intervention to improve glycaemic control and prevent undesirable weight gain using novel technology, in young adults with type 1 diabetes mellitus

Intensive insulin treatment for type 1 diabetes has been shown to prevent or delay the progression of microvascular and macrovascular complications. Improvements in glycaemic control however, may be associated with undesirable weight gain, which could interfere with treatment compliance. Physical activity may potentially improve insulin sensitivity, reduce insulin requirements and prevent undesirable weight gain. Current diabetes education programs provide little or no information on weight gain prevention, are resource intensive and have shown unsustainable improvements in glycaemic control. The use of e-health platforms in diabetes is a promising approach for sustainable education and support provision from a distance. The objective of this thesis was to provide a rationale and describe the processes required for the development of an intervention to improve glycaemic control without weight gain, using a mobile phone-based e-health platform in young adults with type 1 diabetes.
To further investigate the extent to which treatment intensification may lead to weight gain and physical activity reduces insulin requirements, two systematic reviews were conducted. The results of the reviews contributed to the development of the components and processes of the proposed intervention and helped in defining the specifications of the e-health platform through which the intervention would be delivered. A complete diabetes package would include sustained dietary education, portion control, carbohydrate counting and physical activity monitoring. Some of the components of the intervention were evaluated, including the validation of a novel carbohydrate and calorie counting smartphone application against standard food composition tables. A dietary audit provided information on patients’ ability to estimate the carbohydrate and calorie content of food from photographs, further highlighting the need for the proposed intervention.
This thesis provides a basis on which a formal evaluation of the different intervention components could be based, to determine their impact on the provision of diabetes care in clinical practice.

Keywords: young adults
type 1 diabetes
portion control
weight gain
e-health
diabetes education
insulin
carbohydrate counting
Advisor: Neil, HAW
Farmer, A
Imaging structural and functional brain changes associated with long-term learning

Learning induces functional and structural plasticity. This thesis used a range of neuroimaging approaches in both humans and rodents to address three main questions: (1) Can we predict learning performance using baseline imaging measures? (2) To what extent do performance outcomes or training amount determine experience-dependent plastic changes? (3) What biological mechanisms underlie white matter plasticity detected using MRI?
Effects of performance and amount of practice on brain structure were studied by varying the amount of juggling practice. Brain structure was found to predict performance on a complex juggling task before learning acquisition.
Both performance and practice were found to affect brain structure after learning. Overall, participants that achieved higher performances had higher grey matter (GM) and WM matter change. Also, participants that trained juggling for longer had higher positive brain changes than participants that practiced less.
The effects of juggling performance and practice in functional connectivity and GABA levels as measured by MR spectroscopy (MRS) were also investigated. High intensity training was found to decrease the motor resting-state network strength while lower intensity increased the network strength. The increase in strength was associated with a decrease in GABA concentration. A correlation was also found between motor resting-state strength change and GABA concentration change after learning.
Finally, since WM plasticity has not been thoroughly investigated and to understand which cellular events underlie WM change, an animal model of motor learning was combined with diffusion tensor imaging (DTI) and immunohistochemistry. Learning a novel motor task increased WM fractional anisotropy, an indirect measure of WM microstructure, in the contralateral hemisphere to the used paw. Immunohistochemistry staining with myelin basic protein (MBP) antibody of this region revealed higher myelin stain intensity for the learning group that correlated with performance in the task.

Keywords: Learning
Plasticity
MRI
Advisor: Johansen-Berg, H
Bannerman, D
Vital sign monitoring and data fusion in haemodialysis

Intra-dialytic hypotension (IDH) is the most common complication in haemodialysis (HD) treatment and has been linked with increased mortality in HD patients. Despite various approaches towards understanding the underlying physiological mechanisms giving rise to IDH, the causes of IDH are poorly understood. Heart Rate Variability (HRV) has previously been suggested as a predictive measure of IDH. In contrast to conventional spectral HRV measures in which the frequency bands are defined by fixed limits, a new spectral measure of HRV is introduced in which the breathing rate is used to identify and measure the physiologically-relevant peaks of the frequency spectrum. The ratio of peaks leading up to the IDH event was assessed as a possible measure for IDH prediction. Changes in the proposed measure correlate well with the magnitude of abrupt changes in blood pressure in patients with autonomic dysfunction, but there is no such correlation in patients without autonomic dysfunction.
At present, routine clinical vital sign monitoring beyond simple weight and blood pressure measurements at the start and end of each session has not established itself in clinical practice. To investigate the benefits of continuous vital sign monitoring in HD patients with regard to detecting and predicting IDH, different population-based and patient-specific models of normality were devised and tested on data from an observational study at the Oxford Renal Unit in which vital signs were recorded during HD sessions. Patient-specific models of normality performed better in distinguishing between IDH and non-IDH data, primarily due to the wide range of vital sign data included as part of the training data in the population-based models. Further, a patient-specific data fusion model was constructed using Parzen windows to estimate a probability density function from the training data consisting of vital signs from IDH-free sessions. Although the model was constructed using four vital sign inputs, novelty detection was found to be primarily driven by blood pressure decreases.

Keywords: Data Fusion
High-Dimensional Visualisation
Haemodialysis
Heart Rate Variability
Vital Sign Monitoring
Advisor: Tarassenko, L
Restitution from banks

This study analyses certain controversial issues commonly arising when a claim for restitution is brought against a bank. Chapter 1 considers the equitable claim traditionally labelled ‘knowing receipt’. Three issues are discussed: (i) the basis in principle of the claim for ‘knowing receipt’; (ii) whether the claim requires proof of fault on the part of the recipient; and (iii) whether the claim can be brought in relation to the receipt by a bank of a mortgage or guarantee offered to the bank in breach of trust or fiduciary duty. The conclusions are (i) that ‘knowing receipt’ is often a claim in unjust enrichment, though the dishonest recipient will also be liable for an equitable wrong; (ii) that when the unjust enrichment version of ‘knowing receipt’ is in issue, the claim should be one of strict liability; and (iii) a claim in unjust enrichment can be brought against a bank to defeat its interest in a mortgage or guarantee offered in breach of trust.
Chapters 2 to 4 concern a concept within the law of unjust enrichment that has come to be called ministerial receipt. A ministerial receipt is a receipt of money or property by an agent on behalf of his or her principal. Banks often receive money as agents on behalf of account holders. Chapters 2 and 3 analyse that concept as it is dealt with at common law and in equity respectively. At common law, ministerial receipt is a defence which exists only if the agent pays over the money in question before receiving notive of the right of the plaintiff to restitution. By contrast, ministerial receipt in equity operates to restrict a right to restitution which would otherwise arise. A claim for 'knowing receipt' cannot be brought against an agent in equity. Chapter 4 argues that the equitable tratement of agents is correct as a matter of principle, and that no common law claim in unjust enrichment should be maintainable against a person who receives as agent. Special attention is given to banks.
Chapter 5 analyses three other defences which a bank can plead in answer to restitutionary claims: 'good consideration', bona fide purchase and set off. It is concluded that there is no general defence of 'good consideration'; that the bank can plead bona fide purchase in relation to money deposited into an account in credit; and that in the context of combining two or more bank accounts set off is merely a species of bona fide purchase.

Keywords: banks
restitution
unjust enrichment
Advisor: Birks, P
Structural models of credit with default contagion

Multi-asset credit derivatives trade in huge volumes, yet no models exist that are capable of properly accounting for the spread behaviour of dependent companies. In this thesis we consider new ways of incorporating a richer and more realistic dependence structure into multi-firm models. We focus on the structural framework in which firm value is modelled as a geometric Brownian motion, with default as the first hitting time of an exponential default threshold. Specification of a dependence structure consisting of a common driving influence and firm-specific inter-company ties allows for both default causality and default asymmetry and we incorporate default contagion in the first passage framework for the first time. Building on the work by Zhou (2001a), we propose an analytical model for corporate bond yields in the presence of default contagion and two-firm credit default swap baskets. We derive closed-form solutions for credit spreads, and results clearly highlight the importance of dependence assumptions. Extending this framework numerically, we calculate CDS spreads for baskets of three firms with a wide variety of credit dependence specifications. We examine the impact of firm value correlation and credit contagion for symmetric and asymmetric baskets, and incorporate contagion that has a declining impact over time.
The idea of metamorphosis in some English Renaissance writers

This thesis explores the use made by Lyly, Spenser, Chapman and Marston of the idea of metamorphosis, with a brief epilogue on Jonson.
The two preliminary chapters define certain important contexts for the theme of metamorphosis in this period. Chapter I briefly considers Ovid's use of the theme, the Pythagorean and Platonic theory of transmigration, and the allegorization of metamorphosis. Medieval commentaries on the Metamorphoses are examined, but it is argued that Renaissance attitudes to Ovid and to metamorphosis are significantly different, being uniquely sensitive to both the poetic and metaphysical aspects. Renaissance responses to Apuleius' Golden Ass are also examined.
Chapter II studies other Renaissance contexts: in the philosophy of man, in magic, witchcraft and alchemy, and in the love-poetry of Petrarch and Ronsard. Neither Elizabethan lyric poetry nor the epyllion, however, make suggestive use of theltheme: it is explored more fully in larger structures or different poetic modes.
The next four chapters deal with the English writers. Lyly's plays use the theme of metamorphosis in two contexts: love, and the adulatory myths of the court. Chapter IV considers the complex and varied uses of metamorphosis in Spenser's Faerie Queene. It examines the treatment of of myth, the concepts behind the Garden of Adonis, and transformation as related to the theme of mutability.
Chapter V examines the idea of form, set against deformity or transformation, in Chapman's poetry: especially The Shadow of Night and Hero and Leander. Here the basic philosophic or metaphysical assumptions behind Renaissance views-of the myth of metamorphosis are defined.
Chapter VI deals with the satiric use of transformation by Marston. His Metamorphosis of Pigmalions Image is analysed as parodying the common image of metamorphosis as an effect of love. The satires present a negative image of transformation caused by man's guilt and folly.
The Epilogue, dealing with the negative image of transformation in Jonson's. plays and the positive one in the masques, concludes the study while suggesting further directions for exploration.
Unfading wonder: 'Meraviglia' as a path to poetic knowledge in Dante's Commedia and Ariosto's Orlando Furioso

My thesis considers wonder (meraviglia) as a path towards poetic knowledge as it appears in Dante’s Commedia and Ariosto’s Orlando furioso. In my textual analyses, I pursue manifestations of wonder as indicative of a specific moment of intellectual and philosophical inquiry that fills the gap between the dimension of the subject and that of the object, namely man and his world. Before embarking on close readings, in chapter one I disentangle the different components of wonder, tracing wonder’s earliest formulations back to Plato and Aristotle, and I re-define the fields of meraviglia’s neighbouring terms (stupore and ammirazione). My research aims to reassess the areas of wonder and of the marvellous, which literary critics have for too long confused, as active parts of the speculative discourses underlying both the Commedia and the Orlando furioso. As a result, in chapters two and three, I offer a picture of wonder which, in the Commedia, leads to experience of the divine dimension, bridging the human and the divine, but, in the Furioso, opens up a new interpretation of the earthly dimension, bridging the distances between men on earth and revealing the gnoseological bearing of its contradictions. This analysis demonstrates how differently the two authors relate to tradition: while Dante offers the first formulation of a redemptive Christian marvellous, linking pagan marvels to divine truth, Ariosto’s marvellous is to be seen as a climax to the liberation of wonder from medieval theological tenets, a process that gives birth to modern wonder. Through a diachronic and comparative investigation, I illuminate nuances of wonder that one could not discern by focussing on just one author or just one cultural period. The comparison between the two texts in light of wonder allows us to discover new paths within the poems, which show the connections between their marvellous features and their speculative drives.

Keywords: meraviglia
aesthetics
wonder
poetry
marvellous
Advisor: Gardini, N