VictorJuiz/thesis huggingface dataset:
Analysis of the extracellular battlefield of potato blight disease
Keywords: infestans
mass spectrometry
hydrolases
protease
proteomics
tomato

Antagonistic interactions between plant and pathogens trigger plant immune responses that rely on complex signalling networks in which molecules and proteins of diverse nature interact to avoid pathogen colonisation. On their side, plant pathogens have developed mechanisms to suppress plant immunity. Secreted hydrolases play a key role in early plant immunity as they can release pathogen molecules in the apoplast that can be sensed by plant receptors and pathogens secrete inhibitors to supress their activity. This suppression of hydrolase activities can help the pathogen to overcome plant defences and establish a compatible interaction causing disease. In this thesis we investigated apoplastic hydrolytic activities during infection by the causal agent of potato blight disease: the oomycete Phytophthora infestans. In chapter 2, we monitored the impact of leaf detachment in infection assays in the model organism Nicotiana benthamiana. We addressed the hydrolytic activity changes on the apoplast upon detachment and we used proteomics to examine protein changes in apoplast and total extract. We then assessed the impact of detachment in specific immune responses triggered by pathogen-associated molecular patterns and effectors. In chapter 3, we used ABPP coupled with mass spectrometry to study the active proteome of the tomato apoplast during early infection of P. infestans. We compared abundance and activity data to identify putative post translational regulation of apoplastic hydrolases activity. Additionally, we performed convolution ABPP coupled with mass spectrometry to discover novel suppressed tomato hydrolases upon P. infestans infection. Finally in chapter 4, we characterised a novel secreted cysteine protease from P. infestans using transient expression in planta. We confirmed the activity of the novel P. infestans protease and its inhibition by protease secreted inhibitors from P. infestans using ABPP and substrate-specific activity assays. Furthermore, we compared the expression patterns of the P. infestans protease and inhibitors throughout the time course of infection. Altogether, the present thesis provides an overview of how plant immunity is affected in detached leaves infection assays. It also provides evidence for novel apoplastic hydrolytic activity in the context the potato blight disease and dwells into the impact of apoplastic proteases in immunity.
Regulatory network analyses highlight transcription factor cooperation in haematopoiesis and leukaemogenesis
Keywords: GRN
leukaemia
combinatorial logic
MLL-rearranged leukaemia
network
tanscription factor
haematopoiesis
endothelial-to-haematopoietic transition
gene regulatory network

The regulation of gene expression is a complex process that confers cell identity and drives cell differentiation. Transcription factors (TFs) are an important modulator of gene expression and are critical to understanding the regulatory code characterising cell behaviour. However, TFs function in cooperation with one another, acting as a complex combinatorial code to enact gene regulation. Gene regulatory network (GRN) models are used to describe the regulation of genes and to account for this combinatorial code. When the regulatory code underpinning normal cell behaviour goes awry this can lead to abnormal GRNs and the development of disease. This poses two questions: how does TF cooperation drive cellular processes, and how are normal GRNs deregulated in disease?
Haematopoietic stem cells are first established in the developing embryo through a process known as the endothelial-to-haematopoietic transition (EHT). EHT involves dynamic gene regulation across well-defined populations, and is critically dependent on the master TF regulator, RUNX1. EHT is therefore a fascinating system to study TF regulation in driving a complex developmental process. When haematopoietic GRNs are misregulated this can lead to disease. A common childhood leukaemia involves chromosomal rearrangements resulting in novel Mixed Lineage Leukaemia (MLL) fusion proteins that aberrantly drive transcription. MLLrearranged leukaemias are considered a wholly transcriptional disease, and as such are uniquely suited for studying through GRN approaches.
In this thesis, the study of GRNs underpinning normal and malignant haematopoietic processes revealed insights into the role of TF cooperation. Notably, Runx1 cooperates with TFs to drive repression of a transiently activated network during EHT. In MLL-AF4 leukaemia, MLL-AF4 drives TF cooperation by altering the chromatin environment and encouraging local TF binding, and within this MLL-AF4 context RUNX1 activity is biased towards activation. RUNX1 was also found to cooperate with MYB to synergistically activate BCL2 and MYC, promoting leukaemogenesis.
Cyclin F: roles in genome stability and oncogenic pathways
Keywords: KRAS
DIA vs DDA mass spectrometry
E3 ubiquitin ligases
Cyclin F
RTK inhibitors
F-box proteins
EXO1
DNA repair
ionising radiation
ubiquitin-proteasome system

F-box proteins are a family of substrate recruitment factors that assemble into multi-subunit complexes known as SCFs to ubiquitylate their substrates and thereby alter their fate, ex. by directing them to the proteasome for degradation. Cyclin F is the founding member of this family, and it has been identified by our lab to be protecting cells against ionising radiation (IR). This discovery is the result of a CRISPR screen focused on the ubiquitin system in cells treated with IR. Data from my affinity purification and mass spectrometry studies revealed that EXO1 is the Cyclin F substrate responsible for this phenotype. EXO1 is an exonuclease whose upregulation has been shown to drive DNA hyper-resection which impedes DNA repair. I report that SCF-Cyclin F targets EXO1 for proteasomal degradation in the G2/M phases of the cell cycle and upon challenging the cells with IR, and that this is dependent on a phosphorylation event by the kinase CDK2. Using cell survival assays I prove that IR-sensitivity in cells lacking Cyclin F can be fully rescued by EXO1 depletion, underlining the IR-sensitising effects of EXO1 accumulation. I also demonstrate that Cyclin F is involved in a regulatory loop with the most frequently mutated oncoprotein, RAS. Using affinity purification to pull-down active RAS, I show that Cyclin F loss contributes to suppressing RAS activity. This effect is reflected in the cellular response to RTK inhibitor therapy, whereby the signature RTK inhibitor resistance of RAS mutant cells is attenuated in Cyclin F depleted settings. Results from a deep proteomic study of the Cyclin F-KRAS axis present valuable insights into the implicated pathways and demonstrate clinically-exploitable weaknesses of this axis. Together, results from both projects highlight novel roles for Cyclin F in genome stability maintenance and oncogenic pathways.
A framework for the study of “Mercury Jars” and other stoneware from the Temasek Period of Singapore, alongside 12th to 14th-century stoneware from Kota Cina, Sumatra
Keywords: mercury jar
southeast asia
scanning electron microscopy
glaze
stoneware
body paste
clay
sem-eds
ceramics
archaeology

This dissertation concerns the study of stoneware vessels, an often-overlooked corpus of material in Southeast Asian archaeology due to the relative ease with which peculiarities in earthenware clay can be studied and the intricate decorations and glazes of porcelains are more easily catalogued and correlated.
These so-called “functional” and “trade” wares are used as proxies to investigate trends of ceramic production, trade and exchange in Southeast Asia during the 12th-15th centuries, a period marked by the fragmentation of centralised political control and the emergence of “atomistic” trading-posts and city-states such as Kota Cina and Singapore, which are taken as the temporal ends of this period in this study.
It may be hoped that through the high-resolution scanning electron microscope study of these materials, that in addition to insights on these aforementioned trends, so as to demonstrate the further potential of this overlooked material in future studies of Southeast Asian history.
Sixteenth century printing types and ornaments of Scotland with an introductory survey of the Scottish book trade
Keywords: sixteenth century
Scotland
type ornaments
16th century
type
printing
type-founding
book trade
Scottish book trade
book industries
book industry

This thesis comprises a catalogue of the sixteenth century printing types and ornaments of Scotland, along with an introductory survey of the Scottish book trade. It is divided into two parts, and includes an appendix describing the 337 books discussed in the study.
The first part surveys the Scottish booktrade from its first stirrings in the late fifteenth century until the departure of King James VI to England in 1603. It considers, in particular, the European context of the trade, showing the strong connections Scottish writers and booksellers had with continental printers. Using the typographic evidence presented in the second part of this thesis, it is argued that Scottish printers had neither the resources nor the ability to compete with their continental counterparts in distributing such books, and therefore had to rely almost exclusively on the patronage of the Crown and the Scottish government for the survival of their businesses. The consequent manipulation of the press, by both Catholics and Protestant alike, is considered in this context, as is the increasingly sophisticated efforts of the English to control the trade of printed books in Scotland. The first section concludes by discussing the part that the Scottish booktrade played in the evolution of Scottish literary culture and education.
The second part comprises a catalogue of the sixteenth century printing types and ornaments of Scotland. This section is intended to provide evidence about the supply and distribution of typographical materials throughout the country, discussing the connections earlier printers had with suppliers in France, England, and the Low Countries, as well as the various trends in design that were favoured by an increasingly sophisticated Scottish literary market. The catalogue itself comprises 76 type synopses assembled by the author, as well as reproductions of 35 alphabets, 8 factotums, 12 printers’ devices, 1 title-page border, 6 Coats of Arms, 27 woodcuts, and 31 head and tailpieces, accompanied by extensive notes, covering aspects of provenance, supply, design, and use by other printers.
The appendix describes the 337 books discussed in this thesis, giving short-titles, collations, descriptions of ornamentation, a census of copies, and references for each item. Extended notes are also provided for most books, detailing relevant bibliographical information, much of which is derived from the surviving printers’ inventories. This section assigns new dates and printers to a number of Scottish books based on the evidence presented in part two. Previously unrecorded variants based on a first-hand examination of the books are also included.
Number of words in this thesis: 100,888.
Developing a framework for modelling outcomes in diabetes - A case study with ASCEND
Keywords: Health economics
Disease simulation model
Diabetes

Decision-analytic modelling is used to synthesise clinical and economic data to evaluate health outcomes and costs of novel healthcare interventions. Diabetes is associated with disabling and costly complications which develop over time, and such models are crucial to capture the impact of treatment over a person's lifetime. Most diabetes simulation models to date are based on risk equations estimated using data from the UK Prospective Diabetes Study (UKPDS), a study conducted more than two decades ago, and may not reflect contemporary event rates given changes in treatment and management of diabetes and its complications.
A Study of Cardiovascular Events iN Diabetes (ASCEND) recruited 15,480 participants with diabetes without previous cardiovascular disease, and is one of the largest diabetes trials conducted to date. Using data from the ASCEND study, I found the UKPDS risk equations to overpredict cardiovascular events and mortality, further adding to the evidence base that the UKPDS risk equations are unsuitable for use in contemporary cohorts. I developed a new framework for modelling long-term health outcomes and costs which can be used to assess cost-effectiveness of treatments for people with diabetes without previous cardiovascular disease. New risk equations were estimated using the ASCEND data, and these were integrated into a simulation model which predicts the likelihood of occurrence of cardiovascular, bleeding, cancer, lower-limb amputation, end-stage renal disease and death events over the lifetime of a patient given their baseline characteristics. The simulation model was externally validated in a cohort of 18,250 participants with diabetes without cardiovascular disease identified from the UK Biobank, a longitudinal prospective observational cohort. The simulation model performed well generally. Where discrepancies between model predictions and observed event rates were found, the reasons behind the discrepancies were identified. A novel issue-driven approach was developed to update the risk equations. New estimates of hospital costs and health-related quality of life (QoL) associated with the adverse events in the simulation model were also derived from the ASCEND study and incorporated into the simulation model to quantify the impact of treatments on lifetime cost and QoL.
To demonstrate an application of the framework, I assessed the cost-effectiveness of aspirin for the primary prevention of cardiovascular disease in people with diabetes. In this population, it is still uncertain if the cardiovascular benefits of aspirin use outweigh the bleeding risks. Using the latest evidence available, I demonstrate that aspirin is likely to be cost-effective in the cohort of UK Biobank participants with diabetes without previous cardiovascular disease. However, significant uncertainties in the results warrant further research.
Sounding margins : musical representations of white South Africa
Keywords: white people
South Africa
music
white South Africa
musical representations
intellectual life

White South African culture is not a monolith. Neither was Apartheid. Neither is the pan-Africanist hegemony proclaimed over the New South Africa in the name of the ‘African Renaissance’. It is these highly politicized premises that inform the five case studies undertaken in this thesis — case studies that aim to explore the role music can play as a cultural mediator, acting as a sign-system of difference in the postcolonial sphere in general and in the South African context in particular. Post-Apartheid South Africa presents a time and place where Western musical culture is an uncomfortable, disturbing practice of survival and supplementarity — between art and politics, past and present, the public and the private. Our musicological solutions to political problems, and our attempts to find them, are, I believe, important and exemplary. My reading of art music in South Africa as part of a large and ambitious social and political experiment — the outcome of which hangs in the balance —- makes music a crucial site of imagining more composite, unfinished identities. White South African protest, fears, hopes and strategies are explored in the music of John Joubert, Arnold van Wyk, Stefans Grové, and in the literary texts of N.P. van Wyk Louw, André P. Brink and Breyten Breytenbach. My approach is unashamedly interdisciplinary and intentionally eclectic. Musicology has the chance to show, in the South African context, how difference can be productively engaged with and accepted in a way that does not undermine its significance. By exploring the merits of the postcolonialposition, I also hope to show how South African musicology can contribute to modes of musicological discourse aligned to postmodern thought.
The compatibility of modified nucleic acids with enzymatic copying and ligand selection
Keywords: PCR/qPCR
SELEX
DNA encoded library
aptamers
modified nucleic acids

Modified nucleic acids have important applications in molecular biology, genetics and genomics. Here I report a series of modified 5-aminomethyl-deoxyuridine (5-AM-dU) analogues with different functional groups on the 5-position of the pyrimidine ring. These modified 5-AM-dU nucleotides were evaluated in primer extension and polymerase chain reaction (PCR) amplification assays and were shown to be compatible with the polymerase enzymes. In total, six 5-AM-dU analogues with either stabilising or destabilising functional groups were prepared and efficiently incorporated by polymerases. Another modified nucleoside, the fluorescent quadracyclic adenine analogue qAN1 (qAN1) is incorporated with low efficiency in PCR. I was able to show that when this highly duplex stabilising modification is paired with the complementary duplex-destabilising 5-AM-dU, PCR amplification becomes possible. This is because the stabilising effects of one analogue offsets the destabilising properties of the other. Two destabilising thymidine analogues with hydrophobic functional groups at the 5′ position of the nucleobase enabled the use of qAN1 in place of deoxyadenosine at full substitution. In combination, these artificial qAN1-5-AM-dU base pairs allow the preparation chemically modified DNA in which all the A and T nucleobases are modified. These chemically modified 5-AM-dU analogues were used into SELEX to generate a series of aptamers through in vitro selection. In parallel, similar approaches were used to construct modified nucleic acid libraries with aminoethyl glycine (AEG) substituents on thymidine.
Readers of Erasmus: humanism and the English Reformation, 1500-1550
Keywords: Desiderius Erasmus
English Reformation
Renaissance humanism
readers

This dissertation is a study of the reception of Desiderius Erasmus (d.1536) in England in the first half of the sixteenth century, spanning the period between his first visit to the country (1499-1500) and the landmark publication of the English Paraphrases (1548-52). In these years, Erasmus was transformed from an obscure Augustinian canon into Europe’s most celebrated writer. Yet his rise to fame occurred just as the continent descended into religious turmoil. As a result, Erasmus’ reputation, scholarly methods and faith came under increasing scrutiny. In few regions was this process as complex as in England, where the Dutchman had long been in contact with the royal family, patrons and scholarly community. This thesis thus explores Erasmus’ changing place in English intellectual life in the sixteenth century, asking how his status as a humanist and theologian shifted against the backdrop of the English reformation.
This thesis primarily investigates these transformations from the perspective of Erasmus’ readers. The heart of this study is an analysis of several hundred surviving editions of the scholar’s works in repositories across the UK and elsewhere, tracing the ownership, circulation and annotation of his writings by English men and women in the early sixteenth century. Erasmus’ readership was extremely varied and this survey looks at a wide cross-section of readers, from kings, queens and courtiers, to scholars, clerics and members of the religious orders.
This thesis argues that readers took a far more critical approach to Erasmus’ writings than usually supposed. Challenges emerged from both within and outside the humanist community. Working from the margins, they sought to improve the scholar’s books, often reworking his ideas in the light of different scholarly and confessional agendas. These processes led to the fragmentation of his writings and the application of ever more sophisticated historical and scholarly techniques for understanding his work.
Discharge of contractual obligations
Keywords: conditions subsequent
waiver
implied conditions
discharge of contractual obligations
breach
common mistake
anticipatory breach
frustration
repudiation
mistake
conditions precedent
failure of condition
estoppel
contract
termination
promissory conditions
concurrent conditions
conditions

Modern orthodoxy claims that the English law of contract recognises three distinct doctrines that discharge parties from their contractual obligations: (i) termination for breach, (ii) frustration, and (iii) common mistake. This thesis challenges the modern orthodoxy. It argues that each ‘doctrine’ is best explained as an instance of discharge for failure of condition. The reason one or both parties are discharged from their obligations is that their obligations are expressly or implicitly conditional upon the existence of particular facts or the occurrence of particular events that do not exist or have not occurred.
The central claim made in this thesis is not new. It is broadly consistent with how these ‘doctrines’ have been understood for hundreds of years. But the modern view is that the law has moved on. This thesis takes aim at this view and argues either that the law has not moved on or that where the law has moved on, it has taken a wrong turn.
In explaining these instances of discharge in this way, this thesis illuminates the relationships between seemingly disparate areas of contract law and provides a coherent and compelling explanation of each. It also grounds the justifications for these instances of discharge in the parties’ agreement. Finally, this thesis shows how the failure of condition model can provide better answers to difficult questions that arise on the orthodox approach.
Ultimately, this thesis challenges current perceptions of contract law and demonstrates the lessons that are to be learnt from understanding the basis of discharge in these cases. It is the failure to appreciate the nature of the concepts in play that has caused so many of the modern problems in the law of discharge of contractual obligations.