VictorJuiz/thesis huggingface dataset:
The development of novel methods for the synthesis of histidine-containing peptides

The role of the amino-acid histidine in biologically important molecules and the problems encountered in its incorporation whether in protected or unprotected form into peptides, and recent work¹ establishing the importance of the location of the im-protecting group -N(π) being desirable are reviewed in the introduction.
In Chapter 1 the electrolytic deprotection of π-phenacyl-thyroliberin is described: it was found to produce a complex mixture. This and otherdifficulties encountered by co-workers led to the conclusion that π-phenacyl was unsuitable for general use as a histidine protecting group.
In Chapter 2, the investigation of the 1,1,l-trichlorobut-2-enyl group for histidine protection is described. A model compound- NI(1,1,l-trichlorobut-2-enyl)imidazole-was prepared and subjected to screening tests. A number of undesirable side-reactions including cis-trans isomerisation of the double bond were observed indicating that this is not a practical blocking group.
A novel strategy of histidine protection involving reducing the basicity of the imidazole ring by temporary substitution with electronwithdrawing groups is outlined in Chapter 3. A new synthesis of N(α) -protected diiodohistidine derivatives and tests demonstrating their stability to routine conditions encountered in peptide synthesis and deprotection by hydrogenolysis are described. A synthesis of thyroliberin indicated the potential of this strategy.
In Chapter 4 preparations of the corresponding 2,5-dibromoderivatives are described, and a solid phase synthesis of glycyl- L-histidyl-L-phenylalanine and a classical synthesis of thyroliberin are outlined. It was found however that although diiodination inhibited racemisation and dibromination was even more effective that direct blockade of the N(π) was indispensable for its complete prohibition.
A new optimised preparation for N(α) -t-butoxycarbonyl,N(π) - benzyloxymethyl-L-histidine² is described in Chapter 5, this being the first simple three-step synthesis of a N(π)-protected histidine derivative.
In Chapter 6 the use of N(α)-t-butoxycarbonyl ,N(π)-benzyloxymethyl- L-histidine as a protected intermediate in a number of demanding exercises, including the solid phase synthesis of angiotensin II and a solution synthesis of a histidyl-tryptophan dipeptide are demonstrated. No problems due to the histidine derivatives were encountered.
Methods of evaluating the degree of racemisation occurring in activated histidine derivatives are discussed in Chapter 7.

Advisor: Jones, J
MicroRNA expression and activity in high-grade serous ovarian cancer

miRNAs are critical modulators in the development and progression of cancer. Emerging evidence suggests that they are drivers of ovarian cancer. A better understanding of the molecular underpinnings of the development, progression and chemoresistance of the disease is critical for the development of new, more eﬀective therapies. Here we explore the expression patterns of miRNAs as they relate to gene expression, as they diﬀer across molecular subtypes of the disease.
We examine the correlation structure of miRNA expression with mRNA expression in two distinct genomic datasets and report on patterns in correlation structure in several subsets of the data. We ﬁnd that the datasets show consistency in their correlation structure, and in the speciﬁc miRNA-mRNA pairs that are either highly positively or negatively correlated. The data include a larger number of strong positive and strong negative correlations than would be expected by chance, indicating that biological relationships between the types of data are detectable in these datasets. We further ﬁnd an enrichment for positively-correlated miRNA-mRNA pairs in which the miRNA is encoded in close proximity to the mRNA. The correlation of miRNA and mRNA is apparently unaﬀected by miRNA and mRNA expression level; similarly the two molecular subtypes do not contain diﬀerences in their correlation.
We ﬁnd that the recently described poorer prognosis, or angiogenic, subtype has a generally lower miRNA activity than the second, non-angiogenic, subtype. The subtypes are characterized by a consistent pattern of diﬀerential miRNA expression. We also report on a switch-like relationship between the expression levels of certain miRNAs and the genes that are anticorrelated with them. We propose these miRNAs drive many of the diﬀerences in the subtypes both directly, by RISC-mediated repression of target messages and indirectly, by repressing transcription factors that regulate expression in the cell.
We build models of patient survival and time-to-relapse based on these miRNA expression data and inferred miRNA activity scores, using several types of univariate and variable selection models. We ﬁnd essentially no survival-predictive information provided by the RE score data. While the direct miRNA expression measurements may contain some predictive power, we ﬁnd that a larger dataset and the segretation of that dataset into distinct molecular phenotypes is likely to be necessary to produce a useful model of survival in ovarian cancer.

Keywords: genomics
miRNA
ovarian cancer
gene expression
classification
Advisor: Holmes, C
Quackenbush, J
Personal status law reform in Egypt: Women’s rights NGOs navigating between Islamic law and human rights

This thesis explores the ways in which Islamic law and human rights interact within the work of women’s rights non-governmental organizations (NGOs) that advocate the reform of the Egyptian Personal Status Law (PSL) in the period between 2006 and 2010.
The thesis shows the relevance of the human rights framework as well as the flexibility of Islamic legal discourse in the work of the NGOs. Drawing on both Islamic law and human rights enabled NGOs to develop a more gender-sensitive religious discourse, which supported their PSL reform demands. However the interaction between these two frameworks was largely affected by several important factors, which sometimes led NGOs to dilute some of their demands. These factors included the implications of the change in the form of Shari‘a as codified law under the modern nation-state; the Egyptian political context both internally and externally; the common local perception that human rights are a Western production and an extension of Western colonialism; the dominant religious but patriarchal discourse governing the PSL; the implications of activism through the NGO structure; and the personal religiosity of individual activists.
The thesis explores NGOs’ PSL reform demands in depth bearing in mind these factors. It investigates NGOs’ discourse and shows its strengths and weaknesses. It shows that the interaction between Islamic law and human rights within NGOs’ work in this particular Egyptian context produced reform demands that were innovative and practically appealing on one hand, but epistemologically problematic in some instances, on another.

Keywords: human rights
personal status law
family law
women's rights
Islamic law
NGO
Advisor: Pirie, F
Welchman, L
Investigating the role of iASPP in cutaneous disorders 

Desmosomes are intercellular junctions that anchor intermediate filaments to the sites of intercellular contacts. They are critical for maintaining the integrity of tissues that experience constant mechanical and structural stresses, like the skin and heart. Perturbation of desmosomal adhesion can lead to devastating epidermal and myocardial diseases. However, little is known about the regulators of desmosomes and the role of desmosomes in cell signalling events.
Recent work has suggested that iASPP, an inhibitor of the p53 family of proteins, localises at the intercalated discs where desmosomes reside. However, its role at the desmosomes has remained elusive. Thus, in this thesis, it was investigated whether iASPP is a dual function protein that links desmosome adhesion to gene expression and if desmosome-related diseases develop in the absence of iASPP. iASPP was found to be a novel regulator of desmosomes, co-localising with them by physically interacting with the desmosomal components desmoplakin and K5 intermediate filaments. Loss of iASPP resulted in increased phosphorylation and solubilisation of desmoplakin, leading to the formation of K5 aggregates. This culminated in disrupted intercellular adhesion and enhanced cellular migration. Consistent with the role of iASPP in the maintenance of desmosomal adhesion integrity, focal palmoplantar keratoderma was observed in iASPP-deficient mice — a disorder often associated with desmosome dysfunction. This was accompanied by disrupted intracellular signalling, as exemplified by the disrupted expression of differentiation markers; an increase in the thickness of cell layers expressing differentiation marker K1 was noted, and K5 and K6 cells were ectopically expressed throughout the diseased palmoplantar epidermis. Impaired intercellular adhesion and migration had consequences for wound healing, as iASPP-deficient mice exhibited delayed wound closure. Furthermore, defects in eyelid closure in iASPP-deficient mice were found to be due to increased apoptosis. The localisation of apoptotic cells at the leading edge of the eyelid epidermis implied that apoptosis might have occurred due to a loss of cell-matrix or cell-cell contact, i.e. anoikis. Taken together, these results suggest that iASPP is involved in pathological (palmoplantar keratoderma), physiological (wound healing) and developmental processes (embryonic eyelid closure) through its regulation of desmosomes and their dynamics. Therefore, iASPP represents a new candidate gene in cutaneous disorders and could be implicated in a variety of epidermal and myocardial diseases.

Keywords: developmental eyelid closure
iASPP
wound healing
palmoplantar keratoderma
desmosome
desmoplakin
Advisor: Lu, X
Infections and childhood cancer in Malawi

The causes of childhood cancers are not well understood. That infections are believed to play an important role in childhood cancer development is of particular interest in sub-Saharan Africa, where infectious diseases are common. The objectives of this thesis were to identify childhood cancers associated with HIV, malaria, EBV and HHV-8, and to investigate child and maternal factors associated with Burkitt lymphoma and Kaposi sarcoma.
In Blantyre, Malawi, 305 children diagnosed with cancer and 212 of their mothers, were recruited. Risk factor data were collected using a brief questionnaire and blood samples tested for infections.
Case-control analyses were conducted to compare 148 Burkitt lymphoma cases and 22 Kaposi sarcoma case with a control group comprising 104 children with cancers other than those known to be associated with HIV.
The prevalence of HIV was 6% among children with Burkitt lymphoma and 2% in controls (OR=12.4, 95% CI 1.3 to 116.2). Tumour risk increased with increasing litres of antibodies against EBV and malaria. In comparison with those who had low titres against both EBV and malaria, the highest risk of Burkitt lymphoma was among those with high titres against both infections (OR=13.2, 95% CI 3.8 to 46.6). Reported use of mosquito nets was protective against Burkitt lymphoma.
The prevalence of HIV was 81% among children with Kaposi sarcoma (OR=762.7, 95% CI 44 to 13376), and risk increased with increasing HHV-8 antibodies. Prevalence of infections was also examined among children with other cancer types and no associations were identified, although the number of cases was small. Few maternal factors were found to be associated with cancer in children.
This research demonstrates that infections play a particularly important role in increasing the risk of Burkitt lymphoma and Kaposi sarcoma in children in sub- Saharan Africa. Prevention or early treatment of these infections may be vital in the control of childhood cancer.

Advisor: Jaffe, H
Carpenter, L
Newton, R
Epic reduction: receptions of Homer and Virgil in modern American poetry

The aim of this project is to account for the widespread reception of the epics of Homer and Virgil by American poets of the twentieth century. Since 1914, an unprecedented number of new poems interpreting the Iliad, Odyssey and Aeneid have appeared in the United States.
The vast majority of these modern versions are short, combining epic and lyric impulses in a dialectical form of genre that is shaped, I propose, by two cultural movements of the twentieth century: Modernism, and American humanism. Modernist poetics created a focus on the fragmentary and imagistic aspects of Homer and Virgil; and humanist philosophy sparked a unique trend of undergraduate literature survey courses in American colleges and universities, in which for the first time, in the mid-twentieth century, hundreds of thousands of students were exposed to the epics in translation, and with minimal historical contextualisation, prompting a clear opportunity for personal appropriation on a broad scale.
These main matrices for the reception of epic in the United States in the twentieth century are set out in the introduction and first chapter of this thesis. In the five remaining chapters, I have identified secondary threads of historical influence, scrutinised alongside poems that developed in that context, including the rise of Freudian and related psychologies; the experience of modern warfare; American national politics; first- and second-wave feminism; and anxiety surrounding poetic belatedness.
Although modern American versions of epic have been recognised in recent scholarship on the reception of Classics in twentieth-century poetry in English, no comprehensive account of the extent of the phenomenon has yet been attempted. The foundation of my arguments is a catalogue of almost 400 poems referring to Homer and Virgil, written by over 175 different American poets from 1914 to the present. Using a comparative methodology (after T. Ziolkowski, Virgil and the Moderns, 1993), and models of reception from German and English reception theory (including C. Martindale, Redeeming the Text, 1993), the thesis contributes to the areas of classical reception studies and American literary history, and provides a starting point for considering future steps in the evolution of the epic genre.

Keywords: classical reception
Virgil
Homer
twentieth-century American poetry
modernism
Advisor: Harrison, S
Taplin, O
Isolated Ficus trees and conservation in human-modified landscapes

The destruction of tropical forests is the most concerning current threat to biodiversity. Although protected areas have long been used as the primary tool for biodiversity conservation, there is an increasing need to find suitable conservation strategies for the growing area of human-modified land. This thesis addresses three themes that have been identified as the most pressing areas for research in human-modified landscapes: biodiversity conservation beyond protected areas, forest restoration, and the human–environment relationship. By studying the interactions between birds, plants, and people with isolated Ficus (Moraceae) trees in Assam, India, this thesis reports several important findings: 1) isolated Ficus trees are extraordinarily important to frugivorous bird communities that inhabit human-modified landscapes; 2) the frugivores visiting these isolated trees still sustained the majority of ecological function found in trees close to the forest edge; 3) isolated Ficus trees are also exceptionally important feeding sites for insectivorous birds in human-modified landscapes, compared to other trees; 4) Ficus trees are better restoration nuclei than other isolated trees; 5) although the sacred status of Ficus trees in Assam has a major influence on their abundance and distribution, faith-based values are insufficient in ensuring their conservation. In conclusion, this thesis finds that isolated Ficus trees are critically important micro-sites for conservation in human-modified landscapes, the loss of which may lead to avifaunal collapse and a reduction in restoration potential. However, by stressing their ecological and cultural properties, it may be possible to build a strong case for the conservation of isolated Ficus trees in Assam and elsewhere.

Keywords: India
Frugivore
Conservation beyond protected areas
Assam
Birds
Advisor: Whittaker, R
Linguistic regulation and interactional reality: a sociolinguistic study of call centre service transactions

This thesis aims to contribute to the study of workplace talk, language and gender, and the sociolinguistics of globalization by exploring the phenomenon of ‘linguistic regulation’ in call centres. ‘Linguistic regulation’ refers to the practice, now widespread in the globalized service economy, of codifying and enforcing rules for employees’ use of language in service interactions with customers. Drawing on authentic service interactions from call centres in the UK and Denmark, and interviews and communication material from both those countries as well as Hong Kong and the Philippines, this study shows that linguistic regulation exerts a significant influence on the language used by call centre agents, and suggests that this has implications for all three areas of inquiry. In relation to the study of workplace talk, the findings raise questions about the degree of local management and individual speaker agency that has often been asserted in previous work. In the area of language and gender studies, the finding that female speakers in both countries show a higher degree of compliance with linguistic regulation than male ones is related to ongoing debates about the local variability of gender. It is argued that the field may benefit from supplementing the currently favoured locally-based methods with one which seeks to link linguistic behaviour with supra-local systems of inequality. Finally, in relation to the sociolinguistics of globalization, this thesis documents the existence of a distinct, globally prescribed, call centre style which is culturally marked as North-American. In practice, this style is locally inflected, with British agents exhibiting greater conformity to the prescriptions than their Danish counterparts. It is argued that this may be because the prescribed style conflicts with the Danish cultural preference for ‘getting to the point’. These findings highlight the importance of considering language in the context of a global system. The thesis concludes by considering what the research it is based on may contribute, not only to academic debates in sociolinguistics and the sociology of work, but also to professional discussions within the call centre industry.

Keywords: sociolinguistics
Danish
linguistic regulation
call centres
English
Advisor: Cameron, D
A study of NK-3 tachykinin receptors

The aim of this thesis was to determine the pharmacological characteristics and biochemical properties of NK-3 tachykinin receptors in the mammalian central nervous system (cerebral cortex and spinal cord) and periphery (guinea-pig ileum; GPILM).
The affinities of naturally-occurring tachykinins and several receptorselective analogues, for peripheral (GPILM) and central (guinea-pig cortex) NK-3 receptors (labelled with the selective NK-3 receptor ligand, [3H]-senktide) have been determined. A good correlation between affinities of the above peptides for NK-3 sites in the two tissues was obtained. The inhibition of [3H]-senktide binding by guanine nucleotides, in addition to the correlation between affinities of tachykinins at NK-3 sites and their biological potencies in contracting the rat portal vein (RPV; data from the literature), suggest that [3H]-senktide binding sites represent functional receptors.
Evidence for the coupling of GPILM and neonatal rat spinal cord (but not RPV or rat cerebral cortex) NK-3 receptors, to the hydrolysis of inositol phospholipids has been obtained. In GPILM, morphine was found to inhibit the formation of [3H]-inositol phosphates in response to the NK-3 agonist, senktide. This finding is in agreement with the hypothesis that the indirect contractile action of tachykinins in GPILM is due to the activation of neuronal NK-3 receptors and the release of acetylcholine (ACh). This idea has also been confirmed by contractile and [3H]-ACh release studies.
Autoradiographical studies in spinal cord, using [3H]-senktide, have shown the presence of NK-3 sites in the dorsal horn. These findings, taken together with the recent report that NK-3 agonists may be analgesic, suggest that the guinea-pig ileum might be a useful bioassay for the evaluation of potent and selective NK-3 agonists which may represent novel analgesic agents.

Advisor: Watson, S
An open source HPC-enabled model of cardiac defibrillation of the human heart

Sudden cardiac death following cardiac arrest is a major killer in the industrialised world. The leading cause of sudden cardiac death are disturbances in the normal electrical activation of cardiac tissue, known as cardiac arrhythmia, which severely compromise the ability of the heart to fulfill the body's demand of oxygen. Ventricular fibrillation (VF) is the most deadly form of cardiac arrhythmia. Furthermore, electrical defibrillation through the application of strong electric shocks to the heart is the only effective therapy against VF. Over the past decades, a large body of research has dealt with the study of the mechanisms underpinning the success or failure of defibrillation shocks. The main mechanism of shock failure involves shocks terminating VF but leaving the appropriate electrical substrate for new VF episodes to rapidly follow (i.e. shock-induced arrhythmogenesis).
A large number of models have been developed for the in silico study of shock-induced arrhythmogenesis, ranging from single cell models to three-dimensional ventricular models of small mammalian species. However, no extrapolation of the results obtained in the aforementioned studies has been done in human models of ventricular electrophysiology. The main reason is the large computational requirements associated with the solution of the bidomain equations of cardiac electrophysiology over large anatomically-accurate geometrical models including representation of fibre orientation and transmembrane kinetics.
In this Thesis we develop simulation technology for the study of cardiac defibrillation in the human heart in the framework of the open source simulation environment Chaste. The advances include the development of novel computational and numerical techniques for the solution of the bidomain equations in large-scale high performance computing resources. More specifically, we have considered the implementation of effective domain decomposition, the development of new numerical techniques for the reduction of communication in Chaste's finite element method (FEM) solver, and the development of mesh-independent preconditioners for the solution of the linear system arising from the FEM discretisation of the bidomain equations.
The developments presented in this Thesis have brought Chaste to the level of performance and functionality required to perform bidomain simulations with large three-dimensional cardiac geometries made of tens of millions of nodes and including accurate representation of fibre orientation and membrane kinetics. This advances have enabled the in silico study of shock-induced arrhythmogenesis for the first time in the human heart, therefore bridging an important gap in the field of cardiac defibrillation research.

Keywords: Chaste
computational cardiac electrophysiology
parallel computing
software engineering
cardiac defibrillation
linear solvers
finite element method
preconditioning
bidomain equations
Advisor: Pitt-Francis, J
Rodriguez, B
Kay, D