VictorJuiz/thesis huggingface dataset:
Total synthesis of (–)-nakadomarin A and an approach to the diazatricyclic core of the madangamines

This dissertation describes work towards two marine alkaloid natural products of the manzamine family. The total synthesis of (–)-nakadomarin A, via two conceptually different strategies is described along with the development of a novel nitro-Mannich-Mannich cascade reaction, which has been applied in a synthesis of the diazatricyclic core of the madangamines.
A short and highly stereoselective synthesis of (–)-nakadomarin A has been developed. A sequential alkyne ring-closing metathesis/syn selective reduction strategy enabled the stereoselective construction of the Z-configured alkene in the fifteen-membered macrocycle of the molecule. ‘Matched’ catalyst and substrate control facilitated a highly diastereoselective nitro olefin Michael addition to fix two of the four stereocentres in one key step. Furthermore, a nitro-Mannich/lactamization cascade, furan N-acyl iminium ion cyclisation and alkene ring-closing metathesis enabled the total synthesis of the natural product in 19 steps.
In collaboration with Prof. Amir Hoveyda and Prof. Richard Schrock, an alternative approach to a highly Z-selective macrocyclic ring closure in the synthesis of (–)-nakadomarin A has been developed. Three diene substrates were prepared and the Z-selectivity of alkene ring-closing metathesis investigated using a range of molybdenum MAP (monoaryloxide pyrrolide) catalysts. Initial studies using these catalysts produced promising results (Z:E = ~1.2:1), relative to commercially available ruthenium metathesis catalysts (Z:E = 2:3). Using a recently developed chiral tungsten MAP complex, alkene ring-closing metathesis was found to proceed in excellent yield (90%) with exceptional Z:E-selectivity (Z:E ~1.2:1) and requiring only low catalyst loadings (5 mol%).
A novel nitro-Mannich-Mannich cyclisation cascade has been developed allowing access to highly functionalized piperidines. Application of this unprecedented mode of reactivity using a substrate derived from a Michael-addition of methylcyanoacetate to a functionalized cyclic nitro olefin allowed the preparation of a cis-fused 6,6’-bicycle in excellent yield. Further elaboration of this 6,6’-bicycle enabled the synthesis of the diazatricyclic core of the madangamine alkaloids to be achieved.

Advisor: Dixon, D
An edition with commentary of the Speculum huius vite, a fifteenth-century pastoral manual in English

The Speculum huius vite is a pastoral manual composed in English around the end of the fourteenth century. It is, on one level, an abbreviated version of the Prick of Conscience, arguably one of the most popular English texts of the late middle ages; but the Speculum is more than simply an abbreviation of a popular text, since it refashions its source to accommodate a new emphasis and new material, including a commentary on the ten commandments and some shorter exhortations to the clergy and laity regarding humility and modesty. Evidence from the two manuscripts of the Speculum (Bodleian MS Additional A. 268, fols. 117r-139r, and Dublin Trinity Coll. MS 155, pp. 149-238) and from two related manuscripts of the Prick of Conscience (Cambridge University Library MS Dd.12.69, fols. 37r-97v and Cambridge, Mass., Harvard University Library MS 155, fols. 1-77) indicates that two revisions were involved in the production of the Speculum from the Prick of Conscience. The dialect of the poem has been extensively studied to determine whether it is possible to make any conjectures concerning the geographical source of the first and second revisions of the text. The text was probably used for catechetical instruction, private reading, and preaching within the tradition of English catechetical manuals produced after the Fourth Lateran Council. The thesis provides a description of the manuscripts of the text (Chapter One), discussions of the historical context of the poem (Chapter Two), the sources and immediate context of the poem (Chapter Three), the relationship of the manuscripts (Chapter Four), and the language and dialect of the text (Chapter Five). These are followed by notes on editorial procedure, an edition of the text, a glossary, notes to the text, and a bibliography.
Evolution of PHDs as oxygen sensors: mechanistic and structural studies of the PHD of Trichoplax adhaerens, the simplest animal, and mechanistic studies of a PHD-like enzyme of the protist Monosiga brevicollis 

This work aimed to investigate the evolutionary origin of the involvement of the HIF Prolyl Hydroxylases (PHDs) in oxygen sensing. The α/β-heterodimer HIF (Hypoxia Inducible Factor) is a master regulator of oxygen homoeostasis in metazoans. In the nucleus, HIF binds to the Hypoxia Responsive Elements and forms a transcriptional complex that activates the transcription of a multitude of downstream genes. Under normoxic conditions, the Fe(II)- and oxygen-dependent PHDs catalyse 4R-prolyl-hydroxylation of the HIF α-subunit, which subsequently leads to its degradation.
It had previously been proposed that the evolution of the HIF-pathway, shared by all metazoans but not found in other organisms, is linked to the rapid diversification of multicellular life during the Cambrian Explosion. This work investigates the structural and biochemical properties of a PHD of the basal metazoan Trichoplax adhaerens (taPHD), and a PHD-like enzyme of the protist Monosiga brevicollis (mbP4H).
Two crystal structures of taPHD were obtained (1.2-1.3 Å), one containing a Trichoplax adhaerens HIFα subunit peptide (taODD). Comparison with crystal structures of human PHD2 showed a high degree of conservation of structural features and enzyme-substrate interactions. The prolyl-residue of taODD, shown to be hydroxylated by taPHD, is occupying the C4-endo conformation in the crystal structure, supporting the previously proposed mechanism of HIFα hydroxylation by PHD2 in humans. A conservation of biochemical properties with human PHD2, such as the formation of a stable enzyme-Fe(II)-2OG complex, was observed and could therefore be key to oxygen sensing by the PHDs.
mbP4H was shown to catalyse 4R-prolyl-hydroxylation of taODD. It was proposed that the native substrate of mbP4H is a protein containing a prolyl-hydroxylation site similar to taODD, possibly with a YXXLAP motif. The study of biochemical properties and substrate selectivity of mbP4H suggests that the precursor of PHDs may have had similar properties to mbP4H. Further work on mbP4H could therefore yield clues about the evolutionary origin of HIF-prolyl hydroxylases in oxygen sensing and probe the previously proposed connection between metazoan life and HIF–mediated oxygen sensing.

Keywords: crystal Structure
evolution
Monosiga brevicollis
PHD
oxygen Sensing
Trichoplax adhaerens
Advisor: Schofield, C
Economic openness, power, and conflict

Economic integration between major powers has long been viewed as a force for international stability. The intuitive logic is appealing: states that are trading with and investing in each other stand to lose if that commerce is jeopardized by conflict. Yet there are sound reasons for supposing that such deepening economic integration can also shift the balance of power between major states, by causing follower economies – states that are not among the most developed in the international system – to grow faster than leading economies, and economic size and development are what underpin national material capabilities. Moreover, a rich body of theory and history suggests that such shifts in the balance of power make interstate war more likely. This dissertation argues, therefore, that economic integration can actually be a potent cause of security competition and war. A theoretical framework that unites economic theory on the differential growth impact of trade, financial flows, and technology diffusion with realist arguments on the conflict implications of polarity shifts and dynamic power differentials is constructed. It is then explored using evidence from three key historical cases: the rise of the Dutch Republic during the 1581-1648 period, the relative decline of the United Kingdom and the relative rise of other great powers between 1870 and 1914, and the differential growth rates and corresponding tensions of 1945-89. Certain scope conditions and qualifications notwithstanding, the empirical evidence supports the theoretical framework. As such, the argument that deepening economic integration raises the mutual cost of fighting and thereby makes conflict less likely is not directly refuted, but an important countervailing mechanism is found to be at work. Such a finding has implications for debates over the security implications of economic globalization, the foundations of realist theory, and the causes and potential consequences of the rise of new powers today.

Advisor: Snidal, D
High resolution spectroscopy of open shell clusters

The microwave spectrum of the open-shell van der Waals complex NO-HF has been recorded in the region 6-20GHz using a pulsed nozzle Fourier transform microwave spectrometer. This is the first observation of the microwave spectrum of a open-shell van der Waals complex between two molecules. The spectrum exhibits a rich hyperfine structure with the observation of intermolecular hyperfine interactions in an isolated system providing a sensitive probe of electron transfer in the complex.
The spectrum consists of four fine structure transitions 5/2(e)-3/2(e), 3/2(e)-1/2(e), 5/2(f)-3/2(f), 3/2(f)-1/2(f) which have been fitted to a semi-rigid Hamiltonian developed to include the effects of the orbital and spin angular momenta of the unpaired electron on NO. A new treatment to account for the intermolecular hyperfine interaction was developed. The structure of the complex has been determined and is significantly bent with an angle of between 37 degrees and 49 degrees between the NO internuclear axis and the a-axis of the complex. The Renner-Teller parameter, epsilon 2, is very large and negative having the value of -10 449.32(4)GHz indicating that configuration with the unpaired electron in the plane of the complex is more stable.
The analysis of the hyperfine interactions of the hydrogen and fluorine nuclei uses two constants for each nucleus, one for the spatial relationship between the magnetic moments of the unpaired electron and the nuclear magnetic moment and a Fermi-contact term.
The Fermi-contact term for hydrogen is the first strong evidence of intermolecular charge transfer in an isolated van der Waals molecule.

Keywords: van-der-Waals
microwave
spectroscopy
Advisor: Howard, B
Computational methods for the study of immunoglobulin aggregation

Protein aggregation is a major challenge in the development of antibody-based therapeutics. Therapeutic antibodies are produced and stored in high concentrations and under fluctuating conditions unfavourable for their stability. Aggregation of these proteins in solution leads to serious consequences for patients, with the initiation of immune reactions, which have the potential to be fatal, and in the loss of clinical potency. The types of aggregates formed by antibodies, and the processes that lead to their propagation are poorly understood. By studying these molecules via computational approaches, we are able to simulate and probe their tendency to aggregate on experimentally comparable timescales.
By performing small numbers of coarse grained simulations of immunoglobulin frag- ments it is shown that specific regions of proteins are involved in self-self interactions, and these regions are targets for reducing the self-association of experimental molecules. Techniques developed here are integrated within a high throughput approach that is able to generate information on aggregation for a large number of candidate antibody structures.
The methodology was refined via development of a novel technique for coarse grained simulations of oligosaccharides. This method was initially tested on glycolipids, and then extended to glycoproteins. The primary outcome is a coarse grained model for a glyco- sylated antibody Fc fragment. The glycosylated Fc was then simulated, and compared to experimental data. Coarse grained simulations support the hypothesis that the protein be- comes more flexible in the absence of glycosylation.

Keywords: Molecular Dynamics
Biophysics
Computational Biochemistry
Advisor: Sansom, MSP
Gallagher, T
Christian attitudes to Islam

The purpose of the study is to compare the attitudes to Islam of Samuel Crowther, Edward Blyden, and Walter Miller in the light of their work in West Africa. Their careers overlapped to some extent. Crowther was active from 1841-1891, Blyden from 1851-1912, Miller from 1897-1952.
Each man was involved in missionary activity. For Crowther and Miller this was life-long. In Blyden's case, the break came in 1886, when he resigned as a Presbyterian minister, to become what he called 'a minister of Truth 1 . After this date his career became more controversial. Like the other two, he continued to be interested in the theory and practice of mission among Muslims and in a critical comparison of Christianity and Islam, as religious systems which could secure liberation for Africans from all forms of slavery, whether physical, cultural or spiritual.
The study consists of nine chapters which provide a systematic analysis of the central theme. The introductory section discusses purpose, method and scope. Chapter one consists of an analysis of Christian attitudes to Islam, which serves as the basis for a comparison of the attitudes of Crowther, Blyden arid Miller in the final chapter. The second chapter deals with the nineteenth century background to the work of the three men. The following chapters deal, successively, with the life and attitude to Islam of each man. The chapters on attitudes are divided, thematically, in order to discuss the various aspects more systematically. The concluding chapter contains a comparative assessment. Two appendices (concerned vrith Blyden and Miller, respectively), a full list of sources, and a bibliography, complete the study.
The epidemiology and virulence factors of pneumocystis

Pneumocystis is a diverse group of fungi found in the lungs of mammals, and can cause a fatal pneumonia in immunosuppressed humans. The project focussed on two main areas of Pneumocystis biology. The first part investigated the transmission of P. jiroveci between humans and comprised three studies. The first study demonstrated direct transmission between a mother and her infant who had Pneumocystis pneumonia, PCP, contemporaneously. The second investigated transmission of P. jiroveci between health care workers and patients with PCP. P. jiroveci was identified in HCW samples but the genotyping data did not demonstrate direct transmission between the HCW and the patients. The third study examined a representative distribution of P. jiroveci genotypes within a whole human lung and identified two foci of infection.
The second main area of research investigated PRT1, a multigene family, encoding a protein with homology to KEX-like proteases. The first part of this study attempted to identify the original single-copy PRT1 gene that encodes the progenitor kexin-like protease. Inconclusive sequence data was obtained. The second part of this study examined regulation of PRT1 gene expression, initially using an assay that characterised the length polymorphisms within the proline rich region of the PRT1 gene. In the complex populations of rat-derived Pneumocystis used it was difficult to distinguish reliable differences between the cDNA (expressed) and genomic DNA proline rich region profiles.
Subsequent investigations used simple rat-derived Pneumocystis populations that were derived from inocula of 10 Pneumocystis organisms intratracheally injected into nude rats. The catalytic domain of PRT1 was sequenced from cDNA and genomic copies from each of the five low-dose populations. Two majority sequence types were identified, one genomic and the other cDNA. Three of the populations contained a cDNA majority sequence type, implying that some form of regulation of expression was occurring. This hypothesis was further investigated using a second set of simple populations, hybridisation techniques and 5' RACE.

Advisor: Wakefield, A
Britain and Central Europe, 1918-1932

This thesis is a study of British policy towards three Central European states in the wake of World War I. The aim of this thesis is to illustrate the continual British attempts to promote a union or at least economic cooperation in 'Danubia'.
The first section concerns Anglo-Austrian relations. Chapter I. deals with British plans for the federalisation of the Habsburg Monarchy during the war. Chapter II. compares the Austrian policy of the British Delegation in Paris, the Foreign Office in London, and the Military Representative in Vienna. Chapter III. explains British involvement in the reconstruction of Austria. Chapter IV. traces the reasons for British disentanglement from Austrian affairs after the failed * Eastern Locarno'.
The second section deals with the x special relationship' between London and Budapest. Chapter I. highlights the role of two British individuals in exploding the x Hungarian myth' in London. Chapter II. shows how the Bolshevik Revolution affected British diplomatic activities in Hungary. Chapter III. documents British involvement in the establishment of the Horthy regime. Chapter IV. analyses the impact of Anglo-French rivalry in Budapest on the whole of Central Europe. Chapter V. elaborates on British economic policy and the rehabilitation of the 'Pariah of the New Europe'. Chapter VI. illustrates the gradual cooling in Anglo-Hungarian relations.
The third section concerns Czechoslovakia. Chapter I. examines the conflict between Czechophiles and Czechophobes in London. Chapter II. is an account of British efforts to prevent French domination in Prague. Chapter III. deals with the manoeuvres of Benes in London and Paris, and the cooling in Anglo-Czech relations. Chapter IV. explores the origins of British indifference towards Czechoslovakia, which resulted in the Munich crisis.
The thesis concludes that Britain lost interest in Central Europe because of its failed efforts to promote reconcilation in the Danubian triangle.
Model testing of foundations for offshore wind turbines

Suction caissons are a new foundation option for offshore wind turbines. This thesis is focussed on the behaviour of suction caisson foundations in sand and in clay during installation, and under subsequent vertical and combined moment-lateral loadings. The research is based on extensive experimental work carried out using model scaled caissons. The analysis of the results allowed the determination of parameters for hyperplasticity models. Model caissons were vertically loaded in loose and dense sands to study in service states and plastic behaviour. Bearing capacity increased with the length of the caisson skirt. The bearing capacity formulation showed that the angle of friction mobilised was close to the critical state value for loose sands and close to those of peak values due to dilation for dense sands. The vertical load increased, though at a lower rate than during initial penetration, after large plastic displacements occurred. A hardening law formulation including this observed behaviour is suggested. In sand the installation of caissons by suction showed a drastic reduction in the net vertical load required to penetrate the caisson into the ground compared with that required to install caissons by pushing. This occurred due to the hydraulic gradients created by the suction. The theoretical formulations of the yield surface and flow rule were calibrated from the results of moment loading tests under low constant vertical loads. The fact that caissons exhibit moment capacity under tension loads was considered in the yield surface formulation. Results from symmetric and non symmetric cyclic moment loading tests showed that Masing’s rules were obeyed. Fully drained conditions, partially drained and undrained conditions were studied. Caisson rotation velocities scaled in the laboratory to represent those in the field induced undrained response for relevant periods of wave loading, a wide range of seabed permeabilities and prototype caisson dimensions. Under undrained conditions and low constant vertical loads the moment capacity of suction caissons was very small. Under partially drained conditions the moment capacity decreased with the increase of excess pore pressure. In clay, vertical cyclic loading around a mean vertical load of zero showed that in the short term the negative excess pore pressures generated during suction installation reduced vertical displacements. The yield surface and the flow rule were determined from moment swipe and constant vertical load tests. The moment capacity was found to depend on the ratio between the preload Vo and the ultimate bearing capacity Vu. Gapping response was observed during cyclic moment loading tests, but starting at smaller normalised rotations than in the field. The hysteresis loop shape obtained during gapping cannot be reproduced by means of the Masing’s rules.

Keywords: offshore
sand
foundation
Advisor: Houlsby, G
Cross-cultural poetics in Kateb, Salih, Djebar and Dib

The present study elaborates a poetics of cross-cultural writing. Its primary theoretical reference is the ‘cross-cultural poetics’ (poétique de la relation) of Edouard Glissant: a set of poetic tropes and narrative structural strategies that he identifies in the mixed cultural setting of the Caribbean, in Le Discours antillais.
My thesis argues that if these poetic strategies are indeed a response to specific social, cultural and political situations, then if analogous situations were considered elsewhere, we might expect an analogous poetics to arise. Taking North Africa as an example context, and specifically the novels of the Algerians Kateb Yacine, Assia Djebar, Mohammed Dib, and the Sudanese Tayeb Salih, I argue that these writers’ complex poetic strategies engage with – indeed, help to articulate – analogous socio-political concerns arising in their homelands.
The formal poetical analysis of these authors is based on several key thematic tropes and structural strategies that Glissant advocates in his cross-cultural poetics. My five chapters consider roots and origins, living landscapes, silence and screams, literary opacity, and structural polyphony. They also develop a new critical vocabulary to describe how Glissant’s poetical strategies might take form at a close textual level; my analysis reveals a complex, and reciprocal, relationship between poetic expression and socio-political context.
Glissant’s work is therefore shown to be more broadly relevant, but the founding tenets of his theory are also interrogated and questioned; the comparison with a North African setting entails a (re)assessment of the underlying conceptions of Glissant’s poetics – of the implicit logic by which he connects poetic form to social, cultural and political factors. These factors, for Glissant, also display a clear overlap with the (post)colonial; in studying cross-culturality, the postcolonial, and the poetics engendered by their overlapping, my thesis presents a specific critical focus for the postcolonial literary field.

Keywords: Edouard Glissant
Kateb Yacine
postcolonial literature
cross-cultural
Mohammed Dib
francophone literature
Assia Djebar
poetics
Tayeb Salih
Advisor: Hiddleston, J