VictorJuiz/thesis huggingface dataset:
Studies towards the total synthesis of (+)-lophotoxin and site-selective modification of the thiopeptide anticancer natural product Thiostrepton

Chapter 1: Introduction
The isolation, biological activity and importance of the furanocembranoid family of natural products is outlined and a review of synthetic efforts towards their total synthesis provided. Both classical and catalytic methods for the synthesis of polysubstituted furan heterocycles are summarised, with an emphasis on olefin metathesis methods and their impact on the field.
Chapter 2: Methodology Development and Model Studies Towards (+)-Lophotoxin
The development of a temporary-silicon-tether ring-closing metathesis approach to trisubstituted furans is described. The discovery of Brønsted acid and photochemical cyclisation conditions is discussed and the scope of all procedures evaluated. The results of model studies towards to a total synthesis of (+)-lophotoxin are also reported.
Chapter 3: Progress Towards the Total Synthesis of (+)-Lophotoxin
The development of the retrosynthetic strategy and current progress towards a total synthesis of (+)-lophotoxin is discussed. Asymmetric routes to two key fragments are described, along with their union, and the application of the photochemical aromatisation procedure to the furan core of (+)-lophotoxin is disclosed.
Chapter 4: Site-selective Modification of the Thiopeptide Anticancer Agent Thiostrepton
This chapter focusses on a separate project, which aimed to provide synthetic tools to assist in structure-activity investigations of the natural product Thiostrepton. The natural product and its biological activity are introduced along with previous examples of its modification. The development of a general site-selective acylation reaction and the synthesis of a library of analogues is discussed. The results of their biological evaluation is also reported.

Advisor: Donohoe, T
Wetting behaviour of colloid-polymer mixtures in confinement

We study the wetting behaviour of phase-separating colloid-polymer mixtures in confinement. The phase separation is due to the depletion attraction between the colloids mediated by the polymers and bears similarities to ordinary phase separation of oil and water. We use laser scanning confocal microscopy to investigate the behaviour of our colloidal mixture in the vicinity of different substrates, which serve as the confining walls. The glass walls used are chemically modified with two types of polymer, polyacrylamide and chitosan, and we also use clean glass as a reference. We find that the polymer grafting of the surfaces has a pronounced effect on the wetting behaviour. Here, we observe the formation of colloidal liquid droplets, which implies that the coated walls are partially wet. This geometry allows for the determination of the contact angle. The shape of the droplet is theoretically described by the interplay between gravity and interfacial curvature, with the contact angle entering as a boundary condition. The reconstructed interfacial drop profiles are then fitted to the theoretical model to quantitatively study its variation as a function of colloid-polymer state point, properties of the confining wall, and droplet size. We also visually observe Cahn's wetting transition from partial to complete wetting in three series of state points as we move closer to the binodal. This enables us to estimate the wetting transition line in our phase diagram. In addition, we disperse polyacrylamide-coated silica beads into our colloid-polymer mixtures to observe the wetting effects near curved surfaces. We generate theoretical plots based on the conditions of mechanical equilibrium, and compare to the experiments. Our studies shine light on partial wetting phenomena for systems where the interfacial roughness is comparable to the other relevant lengthscales in the system, such as the droplet size or the curvature of the surface.

Advisor: Aarts, D
My enemy or my brother? Spanish representations of Muslim and Jewish culture during the colonial campaigns in Morocco, 1909-1927

This thesis examines Spanish representations of Muslim and Jewish cultures in Morocco during the colonial campaigns in the Rif (1909-1927) in relation to constructions of Spanish identity during this period. It focuses on visual and textual narratives in the press (colonial photojournalism) and on three literary texts: Carmen de Burgos' En la guerra (1909), Ernesto Giménez Caballero's Notas marruecas de un soldado (1923) and Arturo Barea's La ruta (1943). The analysis undertaken centres on the use of the motifs of the body and the city and references to the medieval Castilian ballad tradition, the Romancero, by writers and photographers to explore the cultural relationship between Spain and North Africa.
The chapters explore the delineation of boundaries between Spanish and Moroccan cultures by contemporary commentators and the power structures that underpin those boundaries, considering the different hierarchies that are established in Spain’s relationship with Moroccan Muslims and Jews. Chapter 1 concerns the socio-historical context of the colonial campaigns and highlights the significance of the question of Spain’s identity in relation to Morocco during this period. Chapter 2 compares representations of cultural and ethnic affinity between Spain and Morocco, arguing that beyond merely serving as a tool of colonial domination, they are harnessed in some cases to support the colonial venture, in others to challenge it, and yet in others to explore the pre-modern origins of the Spanish nation. In many of the examples examined, a process of self-Orientalisation is observed, where the 'Orientalist' and colonialist gaze is turned back on Spain as well as on Morocco. Chapter 3 examines representations of Muslim and Jewish alterity, arguing that these assertions of difference reveal Spanish anxieties about non-difference from North Africa, cultural regression, national fragmentation, and Spain's ability to dominate the protectorate. I conclude that these anxieties provide the fundamental underpinning to Spanish constructions of Morocco during the Rif War, and that this self-awareness about non-difference and failures of domination unsettles the predominant paradigm of discourse analysis within colonial studies.

Keywords: Orientalist
Twentieth century Spain
Colonial studies
Visual studies
Advisor: de Ros, X
The accountability state: US federal inspectors general and the pursuit of democratic integrity, 1978-2012

US federal inspectors general (IGs), have proliferated across the government since 1978. However, the success of the IGs in effecting accountability, and the import of the kind of accountability they bring, has been little studied by public administration scholars; much of the existing scholarship offers, at best, qualified endorsement of their work. Similarly, few democratic theorists have considered the significance of the multiplying ‘monitory’ bodies of accountability – of which the IGs are a prominent example – in contemporary democracies.
Using evidence provided in a historical overview of the IG community and three detailed case studies of IGs (Departments of State, Justice, and Homeland Security), I argue that despite certain failures and limitations, the IGs play an important and unrecognised role in the process of democratic accountability. They do not always contribute successfully to ‘direct’ accountability in the form of sanctions and immediate bureaucratic reforms, and indeed, at times have undermined the very efficiency and integrity they are tasked with promoting. However, their import lies primarily in their enabling function as narrative-builders and conduits of information in a wider 'web of accountability'. Their narratives are used instrumentally by the courts, Congress, the media and civil society; they thus have an indispensable function as legitimate and 'neutral' sources of information in processes of public accountability.
I contribute to three distinct literatures in making this argument. First, I make numerous concrete claims about the micro-foundations of the process of accountability, and thus address certain concerns of public administration scholars. These propositions regard the factors that condition the success and form of accountability that is effected by inspectors general (as preserving either efficiency or democratic values), and are supported by the historical narratives in the three case studies. Second, I contribute to the burgeoning field of 'accountability studies' by attempting to link these micro-foundations to a specification of the meaning of public accountability and its relation to broader democratic values. Third, I offer evidence for democratic theorists, who ask how contemporary democratic values and legitimacy are affected by processes of accountability.

Advisor: King, D
Quantification of regional cardiac function: clinically-motivated algorithm development and application to cardiac magnetic resonance and computed tomography

Techniques described to date for the reproducible and noninvasive quantification of regional cardiac function have been largely relegated to research settings due to time-consuming and cumbersome image acquisition and analysis. In this thesis, feature tracking algorithms are developed for 2-D+Time cardiac magnetic resonance (CMR) and 3-D+Time cardiac computed tomography (CCT) image sequences that are easily acquired clinically, while emphasising reproducibility and automation in their design.
First, a commercially-implemented CMR feature tracking algorithm for the analysis of steady state free precession (SSFP) cine series is evaluated in patients with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), which primarily affect the left ventricle (LV) and right ventricle (RV), respectively, and functional impairment compared with control populations is found in both cases. The limitations of this implementation are then used to guide development of an automated algorithm for the same purpose, making use of fully convolutional neural networks (CNN) for segmentation and spline registration across all frames simultaneously for tracking. This study is performed in the subjects with HCM, and functional impairment is again identified in disease subjects. Finally, as myocardial contraction is inherently a 3-D phenomenon, a technique is developed for quantification of regional function from 3-D+Time functional CCT studies using simultaneous registration of automatically generated Loop subdivision surface models for tracking. This study is performed in canine mongrels, and compared with the current state of the art technique for CCT functional analysis.
This work demonstrates the feasibility of automated, reproducible cardiac functional analysis from CMR and CCT image sequences. While work remains to be done in extending the principles demonstrated and modular components described to fully automated whole-heart analysis, it is hoped that this thesis will accelerate the clinical adoption of regional functional analysis.

Keywords: Cardiac Computed Tomography
Mesh Registration
Cardiac Magnetic Resonance
Regional Cardiac Function
Medical Image Analysis
Deep Learning
Advisor: Noble, J
Biographies of a reformation: religious change and confessional coexistence in Upper Lusatia, c. 1520-1635

This thesis investigates how religious coexistence functioned in the multiconfessional region of Upper Lusatia in Western Bohemia. Lutherans and Catholics found a feasible modus vivendi through written agreements and regular negotiations. This meant that the Habsburg king of Bohemia ruled over a Lutheran region. He knew of the situation in Lusatia but was not willing to intervene decisively to reintroduce Catholicism. Lutherans and Catholics in Upper Lusatia shared spaces, objects and rituals. Catholics adopted elements previously seen as a firm part of a Lutheran confessional culture. Lutherans, too, were willing to incorporate Catholic elements into their religiosity. Some of these overlaps were subconscious, while others were a conscious choice. Later generations of historians fashioned these complex processes of change into a neater Reformation narrative.
This research provides a narrative of the Reformation in Upper Lusatia and engages with three historiographical paradigms. Firstly, the results show that the concept of the 'urban Reformation', where towns are seen as centres of Lutheranism has to be reassessed, particularly in towns in former East Germany, where much work remains to be done. Secondly, it shows that in a region like Upper Lusatia which did not have a political centre, undergoing a complex Reformation, there was no clear confessionalization process. As other studies have found similar tendencies elsewhere in the Holy Roman Empire, the usefulness of the confessionalization paradigm is increasingly questionable. Thirdly, the example of dissenting religious groups cautions us that it is not helpful to push the idea of toleration in early modern Europe too far. In the case of Upper Lusatia, the coexistence of two confessions, Lutherans and Catholics, meant that others were excluded.

Advisor: Roper, L
Quantitative approaches to investigating epithelial morphogenesis

Morphogenesis - the generation of biological shape and form - is fascinating, and its study promises to shed light on a wide range of developmental defects and inform strategies for the artificial growth of organs. Recently, the experimental study of morphogenesis has thrived due to a rise in quantitative methods.The resulting avalanche of quantitative data requires us to rethink the scientific method. We need to design quantitative hypotheses through mathematical models, make quantitative experimental predictions, devise methods for quantitative data analysis, and design methods for quantitative inference using models and data. This thesis aims to enable this transition for the integrative analysis of morphogenesis in epithelia, one of the major tissue types in animals. We begin by conducting the first systematic numerical analysis of a widely used cell-based model of epithelia, the vertex model, and estimate to what extent quantitative model predictions may be influenced by parameter values and implementation details. We then apply this model to a key question in developmental biology by constructing a quantitative theory for tissue size control in the embryonic epidermis of the fruit fly Drosophila, using the model to predict the outcomes of future experiments. Subsequently, we devise a method for estimating mechanical parameters of vertex models from imaging data and quantifying the uncertainty associated with such estimates. Finally, we propose a novel algorithm for robust cell tracking in live-imaging microscopy videos of epithelial tissues that illustrates how graph theoretic concepts may be used to overcome challenges in quantitative data analysis. Together, the contributions in this thesis will enable the quantitative study of epithelia for a wide range of applications.

Keywords: vertex model
Bayesian inference
tissue size control
cell tracking
Advisor: Baker, R
Fletcher, A
When David takes over Goliath: emerging market firms, M&amp;A; strategy, and post-acquisition integration

Over the past decades, Chinese firms have become major competitors in the global M&A; space. The present thesis examines one of China’s largest and most technology-intensive state-owned enterprises and its acquisitions-based internationalization strategy via a qualitative comparative case study-based research design. Contrary to existing research on firm internationalization that focuses on factors external to the firm, this thesis finds that entry mode decisions can be best explained by explanatory variables internal to the firm. In the area of China business studies, this thesis challenges widely held notions of Chinese state-owned enterprise executives and finds that managerial behaviour at these firms can be characterized as largely rational. Extant management scholarship focuses on the efficiency maximizing function of firm-internal markets. This thesis finds that reliance on internal markets is driven by the objective of effectiveness maximization. Internal markets are a critical post-acquisition integration value driver and integral component of a hybrid approach to post-acquisition integration that combines hierarchical and market-based forms of coordination and that challenges the “light touch” concept widely held in China business studies. Extant studies on knowledge transfer highlight capabilities, motivations, and network positioning as explanatory variables for a firm’s absorptive capacity. In contrast, this thesis focuses on “failure avoidance” driven managerial behaviour as the main constraint on a firm’s ability to exploit knowledge from its acquisitions. This thesis contributes to the literature by i) exploring an understudied empirical setting (i.e. Chinese state-owned enterprise), ii) answering calls for greater research on post-acquisition integration and the underlying firm-internal mechanisms and dynamics below the level of the firm, and iii) by augmenting existing management theoretical concepts (i.e. firm internal dynamics as entry mode determinants, internal markets as post-acquisition integration value drivers, and managerial behaviour as constraint on absorptive capacity).

Advisor: Sako, M
Thun, E
Goblet cell differentiation in human colorectal cancer cell lines

Goblet cells are one of the three fully differentiated lineages in human colonic crypts. They play an important role in protecting epithelial cells from direct contact with luminal contents by secreting mucus, which consists of MUC2, TFF3 and other constituents. The goblet cell differentiation, however, is largely dysregulated in human colorectal cancers. Abundant expression of MUC2 is often observed in signet ring carcinomas and mucinous carcinomas that are associated with unsatisfactory prognosis. Despite the significant roles of goblet cells, its genetic nature and exact regulatory mechanisms remain incompletely understood.
In this thesis, the goblet cell differentiation at mRNA and protein levels was characterised in a panel of 64 human colorectal cancer cell lines. Microarray analysis on the bulk population of these cell lines reveals the genes differentially expressed in goblet cell-positive cell lines, including AKR1B10, AGR3 and the cellular surface protein CA12 (Chapter 3). In addition, a novel protocol is developed for isolation and sequencing of RNA from the fixed and FACS purified cells. Using this protocol, the first goblet cell transcriptome is profiled in LS180 cancer cell line, and the goblet cell-specific genes are identified, including TFF3 and SPDEF (Chapter 4). The co-expression patterns of TFF3 and MUC2 is further investigated. In a subset of cancer cell lines, TFF3 recognises the goblet cells that cannot produce MUC2, suggesting additional regulatory mechanisms are required for its expression. The dysregulated regulation of TFF3 may provide additional evidence in colorectal cancer classification. The transcriptional regulation of ATOH1 and SPDEF on goblet cell differentiation is also demonstrated. Knock-down of either transcriptional factor decreases the goblet cell numbers, while double knock-down completely depletes goblet cell formation, suggesting the co-operative regulation of SPDEF and ATOH1 on goblet cell differentiation. In addition, CA12-positive but not -negative cells can give rise to goblet cells with the expression of MUC2, TFF3 and SPDEF. This indicates CA12 may act as a potential cellular surface marker to identify goblet cell progenitors (Chapter 5).
In summary, this thesis screens goblet cells in colorectal cancer cell lines and characterise the first goblet cell transcriptome, which provides the foundation to understand regulatory control of goblet cell differentiation.

Advisor: Bodmer, W
Ultrasound-mediated transport of nanoparticles and the influence of particle density

Cancer therapeutics are limited in efficacy by poor penetration into tumour tissue. This doctoral thesis aims to explore how changing the density of a therapeutic could influence its ultrasound-mediated delivery and penetration depth, thereby testing the hypothesis that increasing particle density increases penetration depth of nanoparticles under ultrasound exposure. Density-enhanced transport in the presence of ultrasound-induced cavitation is studied utilising a combination of numerical simulations, in vitro and in vivo experimental models.
The penetration depth of nanoparticles of different densities was first predicted using a computational model to assess the magnitude of acoustic and fluid dynamic forces on a spherical nanoparticle in the presence or absence of a cavitating microbubble. This simulation showed that a denser particle will be transported further when exposed to ultrasound. Furthermore, cavitation was identified as fundamental for enhanced transport, with forcing due to microstreaming dominating the transport behaviour. These predictions were validated and supported experimentally using an in vitro model, where a fivefold increase in particle density resulted in a 43 % increase in peak particle penetration depth.
To form a closer analogue to the tumour environment, a three-dimensional flow-vessel phantom was then implemented, where the penetration depths of three density-contrasting nanoparticles with unique fluorescent tags – co-delivered with either a micro- or a nano-scale cavitation agent – were studied. A trend between nanoparticle density and extravasation depth was again discernible, with the densest particles penetrating the furthest. However, the choice of cavitation agent often had a greater influence on particle transport.
Finally, experiments were performed in a tumour-bearing mouse model, where the bio-distribution of fluorescent nanoparticles was assessed after ultrasound exposure. A bistatic HIFU setup was used to activate cavitation agents, and passive acoustic mapping was implemented to detect cavitation activity within the tumour site. Density-contrasting fluorescent nanoparticles were used as mock therapeutics, and were successfully detected in ex vivo tumours through IVIS imaging. However, due to experimental limitations, the influence of nanoparticle density on ultrasound-mediated drug delivery in vivo could not be determined, and so recommendations are made for how the hypothesis can be further validated.

Advisor: Coussios, C
Stride, E
Interrogating the intersection of genetic- and gender-based risk for multiple sclerosis

Multiple sclerosis (MS) has no effective prevention or cure and only limited treat- ment options. Significant progress has been made in finding genetic susceptibility loci, but it is still mostly unclear how genetic variants associated with disease are implicated in MS pathogenesis. Meanwhile, epidemiologically, it has long been clear that women get MS two or three times more frequently than men do. It is also known that there is substantial sexual dimorphism in immune regulation. The analysis presented here attempts to triangulate genetic and sex-based risk for MS, first, in order to understand quantitatively the relationship between sex and genetic risk and, second, to highlight particular genes implicated by both genetics and gender in MS etiology. First, I use a Bayesian framework to assess the relationship between male and female effect sizes at variants previously shown to be associated with MS. I show that the effect size of genetic variants for MS risk is systematically lower in females than males, with female effect size esti- mated at 0.42 times male effect size. Second, I use genome-wide RNAseq data to characterize differential transcription between the sexes, finding over 5000 genes to be differentially expressed, but I do not find sexual dimorphism in cis-eQTL effect sizes. I highlight a subset of genes whose expression is affected by an MS risk variant and whose expression is sexually dimorphic. Several of these genes have functions consistent with complicity in MS. Together, these analyses demon- strate methodology to integrate genetic and genomic data in the context of sexual dimorphism in order to explore the mechanism of disease.

Advisor: McVean, G