VictorJuiz/thesis huggingface dataset:
Surface changes to human erythrocytes on infection by Plasmodium falciparum malaria

Of the four Plasmodium species which cause malaria in humans, P. falciparum is responsible for the majority of the morbidity and mortality associated with this disease. The surface expression of parasite-derived proteins in the middle of the asexual cycle coincides with two important modifications of the host erythrocyte. First, a protective immune response is directed against a family of variant antigens, known as P. falciparum Erythrocyte Membrane Protein-1 (PfEMPl). Second, ligands are detected at the surface which mediate the specific cytoadherence of infected erythrocytes to vascular endothelium, such that infected cells are sequestered away from the peripheral circulation in deep vascular beds. The potentially fatal syndrome known as cerebral malaria can ensue when infected cells sequester at high density in the brain. Indirect studies have shown that the antigenic and adhesive phenotypes at the surface are linked to the expression of PfEMPl. However, there is a paucity of biochemical data which relate to PfEMPl, and this problem is addressed in this thesis.
This study has confirmed, at the biochemical level, inferences from serology that clonal antigenic variation occurred rapidly. Variation produced a number of novel antigenic and adhesive phenotypes which were associated with unique forms of PfEMPl.
Further insights into the mechanism of sequestration were possible because of the finding that single infected erythrocytes had the capacity to bind to at least three putative endothelial cell receptors; CD36, Intercellular Adhesion Molecule-1 (ICAM1), and Thrombospondin (TSP). It was demonstrated for the first time that PfEMPl was responsible for cytoadherence to CD36 and ICAM1, but was probably not involved in adhesion to TSP. Extensive analysis with sequence-specific proteases proved that adhesive interactions with each receptor were separable properties of the surface, and facilitated the proposal of a domain model for PfEMPl.
Detailed analysis of the antigenic and adhesive phenotypes of a series of clonally-derived parasites demonstrated that infected cells expressing all variant antigenic types could adhere to CD36 whereas adhesion to ICAM1 was seen in a restricted subset. This may be clinically relevant if, as current data suggests, adhesion of infected cells to ICAM1 is important in the development of cerebral malaria. Identification of all ICAM1 binding phenotypes could lead to the design of novel therapeutic strategies for this life-threatening condition.

Advisor: Newbold, C
Strands in the theory of meaning from Frege to Wittgenstein

Chapter 1. Wittgenstein's conception of Philosophy I begin by comparing Wittgenstein's conception of philosophy to Russell's, noting that they held different views of philo- sophy in relation to natural science. Wittgenstein's method of examples' is compared with the Socratic method. Might philosophy be different from what it in fact is? Wittgenstein was a philosopher of language; the theory of meaning as fundamental. Examples given of the Private Lan- guage Argument and the philosophy of mathematics. Recapitu- lation. Appendix 1. Translation of 'Ober Dogmatistnus' from Wittgenstein und der Wiener Xreis. (pp 182 - 184) Appendix 2. Translation of a chapter of the Big Typescript on the nature of philosophy (pp 406 - 435). Corresponding passages noted.
Chapter 2 . Preliminary considerations in the Tractatus A sketch of the genesis of the Tractatus, showing that Wittgenstein placed great emphasis on the doctrine of showing and saying. Tractatus concerned with a perfect language? No, but with the conditions for any language. 'Ordinary' and 'logical' propositions in the Moore notes were not explained adequately. The possibility of 'semantic ascent' in relation to the doc- trine of saying and showing. Sketch of the picture theory. Explanation of the difference between 'abbilden', 'darstellen' and 'vertreten'. Discussion of isomorphism and the relation between language and ontology. Example taken of relation"of Names and Objects. Structure and form. Comparison with Frege, and Frege's problems with 'the concept horse'. Waismann's criticism of Frege's use of Bedeutung repudiated.
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Single photon sources in the infrared

This thesis reports the study of single photon sources that emit one infrared wavelength photon at a time, creating cavity quantum electrodynamical effects for applications such as quantum information processing. This work considers two major single photon sources: a) InAs single quantum dots and b) single carbon nanotubes, which both emit in the infrared range.
Photonic crystal slabs and photonic crystal waveguides are served as distinctive passive devices with manipulated photonic band-gaps to control the propagating light. A simulation of leaky modes of two-dimensional photonic crystal slabs is introduced to constrain model parameters in the device design. Fullerenes are used as fluorescent material to achieve resonance of a leaky mode with excitation 1492 nm and emission at 1519 nm and to see enhancement of the PL. We include novel characterization techniques and PL measurements to show sharp emission peaks from single quantum dots and successfully couple them to micro-cavities. The strong coupling effect is observed and is amongst the best examples of cavity-dot structures achieved to date.
Single-walled carbon nanotubes have shown anti-bunched light emission, thus we systematically study them as another possible candidate of single photon sources. PLE spectra show clear evidence of the existence of excited states, and time evolution measurements reveal the disorder induced diffusion, which separate the tubes into a series of quantum dots. These strongly confined states are concluded as the origin of the possibility that single-walled carbon nanotubes are single photon sources.

Keywords: quantum dots
carbon nanotubes
single photon sources
Advisor: Taylor, R
Syncrip regulates mRNA localisation and translation at the drosophila neuromuscular junction

Evidence in different systems suggests that local translation is involved in synaptic plasticity in both neuron and muscle, but the mechanism by which this occurs is still poorly understood. The mRNA-binding protein Syncrip is conserved from fly to mammals and is thought to be involved in localized translation in both oocytes and neurons. Previous work has shown that Syncrip associates with mRNAs encoding key synaptic proteins at the Drosophila larval neuromuscular junction. Here I show that Syncrip is necessary for the structure and function of the neuromuscular junction. First, the loss of Syncrip leads to overgrowth of the neuromuscular junction. Second, Syncrip is required for proper expression of the Ca2+-sensor Synaptotagmin1 at the presynapse, and loss of Syncrip causes a decrease in vesicle release probability. Third, while it was not possible to measure mRNA distribution in neurons, Syncrip mutants, like other perturbations in synaptic plasticity, correlate with changes in mRNA localization in muscle. Fourth, the overexpression and loss of Syncrip function suggest that the nuclear and nucleolar trafficking of the eukaryotic translation initiation factor eIF4E may be important to regulating synaptic morphology. These data suggest that Syncrip is involved in mRNA localization and translation in synaptic plasticity.

Keywords: translation
mRNA localization
neuromuscular junction
syncrip
drosophila
Advisor: Davis, I
Robustness of self-tuning controllers

Over the last decade, considerable effort has been devoted to the implementation and analysis of self-tuning controllers on systems which are assumed to be represented exactly by linear dynamical models. In this thesis we examine the robustness of the self-tuning controller, when applied to systems consisting of a nominal linear plant which may have linear or nonlinear perturbations. Robust stability is the primary criterion and most of the results are for the Clarke-Gawthrop version of the self-tuning controller. Conditions are derived for the robust stability of the adaptively controlled system in terms of the design choices available to the engineer setting up the self-tuning controller. These are strong stability results in that they are in terms of both 12 and 1∞ stability. The results are shown to be applicable to the general delay case and in the presence of non-zero mean disturbances. Preliminary results are also obtained for the robust stability of the explicit self-tuning controller.

Advisor: Gawthrop, P
Novel di-branched monosaccharides and imino sugars

Branched chain sugars display a varied and valuable range of biological activities. This thesis concerns the synthesis of 3,5-di-C-methyl-D-glucose, a potential inhibitor of glycogen phosphorylase (GP), and therefore a proposed therapeutic agent for type 2 diabetes. Chapter 1 looks at the occurrence of branched sugars in the natural world and current therapies for type 2 diabetes. Inhibition of GP is explored, and the molecular modelling studies which led to the design of the project target. Chapter 1 also looks into the development of new foodstuffs, the chemistry and biochemistry of imino sugars and branched hydroxy proline analogues.
In Chapter 2, a range of different approaches to 3,5-di-C-methyl-D-glucose are investigated. Most of the initial investigations were carried out on the L-enantiomer, a readily available test system deriving from 2-C-methyl-D-ribono lactone. 2-C-Methyl-D-ribono lactone is synthesised rapidly from D-glucose in a one-pot reaction; as the key starting material for this work, the scalability of this process was investigated. One of the attempted syntheses of di-C-methyl glucose lead to the development of a route towards 3,5-di-C-methyl fructose, a novel dibranched ketose sugar. It was envisaged that through an enzymatic transformation, it might be possible to produce 3,5-di-C-methyl glucose stereoselectively. Synthesis of both enantiomers of 3,5-di-C-methyl glucose and mannose are reported, alongside results of GPb inhibition studies. Analysis of the preferred ring size of a range of di-C-methyl branched sugars and sugar lactones generated in this work is also presented.
Chapter 3 explores the chemistry of 2,4-di-C-methyl-L-arabinono lactone, a key intermediate in the synthesis of 3,5-di-C-methyl-L-glucose. From this lactone a novel deoxy sugar, 2-deoxy-2,4-di-C-methyl-L-arabinono lactone, was generated. Routes towards a selection of imino sugars were explored, resulting in the synthesis of a methyl branched isofagomine analogue. A substituted aziridine was synthesised, from which a route to a di-C-methyl branched piperidine was proposed, and a pyrrolidine. Also presented is a synthesis of a dihydroxy di-C-methyl branched proline analogue.
Detailed NMR analysis of several of the sugars generated in this work was carried out by Dr M. Wormald, of the University of Oxford Biochemistry department. The results of these investigations are presented in the Appendix.
Throughout this work, the presence of quaternary centres has posed a problem with the assignment of relative configuration. As a result, this work has been greatly supported by X-ray crystallography, and the structures shown herein were wholly generated by me. Several other crystals were run during the course of this work, not all pertaining to these projects, and are provided in the CD appendix.

Keywords: sugars
glucose
diabetes
carbohydrate
glycogen phosphorylase
imino
branched
Advisor: Fleet, G
Knowledge by way of prophecy

This thesis investigates whether beliefs acquired by way of prophecy are safe. By ‘prophecy’ I have in mind the presentation of the prophetic method as found in the Guide of the Perplexed, which was Moses Maimonides’ philosophical masterpiece. And by ‘safe’ I have in mind the work by Timothy Williamson on the safety condition for knowledge. Both authors have proven to be dominant forces on these respective topics. The significance of this investigation derives from the centrality of prophecy to the three monotheistic religions. My main goal in this thesis is to identify those safety risks associated with the prophetic method. In this manner I aim to undermine any presumption in favor of prophetic beliefs as a whole being safe. Importantly, this general conclusion does not entail of a specific prophetic belief p that p is unsafe. Additionally, the scope of these results is restricted to the model of prophecy found in the Guide.
The thesis begins with a critical elucidation of Williamson’s extensive work on the safety condition for knowledge. Particular attention is paid to those issues related to method individuation and Williamson’s cumulative conception of bases. Matters concerning these two topics inform the reading of Maimonides on prophecy found in the second chapter. In particular, I argue that Maimonides should be read as defending a cumulative conception of prophecy. As I emphasize several times during the chapter, the epistemology of prophecy cannot be reduced to the epistemology of testimony since prophecy for Maimonides does not involve the transfer of a proposition from God to the prophet. The third chapter is devoted to identifying those elements of the prophetic method that involve room for error. I argue that while all belief-forming methods in a fallibilist epistemology contain room for error, some are riskier than others. Prophecy should be considered one of the riskier sort. The fourth and final chapter shifts attention to non-standard semantics for ‘knows,’ David Lewis’s in particular. I argue that the interaction between such semantics and the laws governing prophecy in Jewish law is problematic. In particular, I demonstrate that such semantics destabilize the prophetic phenomenon. As such, we must either choose invariantism and gain stability, or choose non-standard semantics for ‘knows’ and live with this lack of stability.

Keywords: Timothy Williamson
Moses Maimonides
Knowledge
Prophecy
Guide of the Perplexed
Advisor: Hawthorne, J
The influence of selected flavonoids on the survival of retinal ganglion cells subjected to different types of oxidative stress

The general aim of the thesis was to deduce whether selected naturally occurring flavonoids (genistein, epicatechin gallate (EC), epigallocatechin gallate (EGCG), baicalin) attenuate various secondary insults that may cause death of ganglion cells in primary open angle glaucoma (POAG).
An ischemic insult to the rat retina significantly causes the inner retina to degenerate indexed by changes of various antigens, proteins and mRNAs located to amacrine and ganglion cells. These changes are blunted in animals treated with genistein as has been shown for ECGC.
Studies conducted on cells (RGC-5 cells) in culture showed that hydrogen peroxide, L-buthionine sulfoximine (BSO)/glutamate and serum deprivation (mimicking oxidative stress), rotenone, sodium azide (affecting mitochondria function in specific ways) and light (where the mitochondria are generally affected) all generated reactive oxygen species and caused death of RGC-5 cells. EGCG was able to attenuate cell death caused by hydrogen peroxide, sodium azide and rotenone. Only EC was able to attenuate BSO/glutamate-induced cell death, in addition to cell death caused by hydrogen peroxide and rotenone. Genistein had no positive effect on cell death in experiments carried out on RGC-5 cells.
Exposure of RGC-5 cells to flavonoids showed that EC and EGCG increased the mRNA expression of endogenous antioxidants such as HO-1 (heme oxygenase 1) and Nrf-2 (nuclear erythroid factor-2-related factor 2). Light insult, rotenone and sodium azide activate the p38 (protein kinase 38) pathway, while only light and rotenone activate the JNK (c-Jun amino-terminal kinase) pathway. Serum deprivation affects mitochondrial apoptotic proteins causing an increase in the ratio of Bax/Bcl2 (Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2). An insult of light to RGC-5 cells, unlike that induced by sodium azide, is inhibited by necrostatin-1 and causes an activation of AIF (apoptosis-inducing factor) with alpha-fodrin being unaffected. These studies suggest that ganglion cell death caused by insults as may occur in POAG involves various cellular signaling pathways. The selected flavonoids have diverse actions in increasing cellular defense mechanisms, and in negating the effects of ischemia and specific types of oxidative stress. The results argue for the possible use of flavonoids in the treatment of POAG to slow down ganglion cell death.

Keywords: retinal ganglion cells
Flavonoids
glaucoma
neuroprotection
Advisor: Osborne, N
Design and synthesis of myo-inositol (1,4,5)-trisphosphate receptor antagonists

<p>Well-regulated Ca2+ signalling is essential for every living organism, and disruption of this signalling can lead to diseases including heart failure, neurological disorders and diabetes. Intracellular Ca2+ levels are regulated by influx of extracellular Ca2+ through channels located in the cell membrane. In addition, release of Ca2+ from intracellular stores also plays an important role in controlling intracellular Ca2+ concentration. Of the three types of intracellular Ca2+ stores that have been characterised those with D-myo-Inositol 1,4,5 trisphosphate receptors (InsP3 Rs) showed a close relationship with cell proliferation. Hence, selective blockage of InsP3 Rs will allow better understanding of Ca2+ signalling and might also unveil novel treatment for cancers, in the long term. There were no selective InsP3 Rs antagonists known at the start of these studies. Based on the crystal structure of InsP3 Rs bound to InsP3 and SAR studies of InsP3, we designed and tested several InsP3 analogues. Compound 15, 16 and 23 acted as InsP3 R antagonists, though their selectivity for InsP3 Rs was not completely determined. Furthermore, we also attempted to improve the potency of 16 via substitution at the 1-postion phosphate. By considering the interaction formed between adenophosphostins and InsP3 Rs compounds (53-55) were designed and synthesised.</p> <p>In addition, analogues of compound 92, selected from an in silico screen, have led to the discovery of another novel scaffold that acts as an InsP3 R antagonist.</p>

Keywords: Calcium release
antagonist
inositol
inositol trisphosphates
IP3
Advisor: Conway, S
Well-posedness of dynamics of microstructure in solids

In this thesis, the problem of well-posedness of nonlinear viscoelasticity under the assumptions allowing for phase transformations in solids is considered. In one space dimension we prove existence and uniqueness of the solutions for the quasistatic version of the model using approximating sequences corresponding to the case when initial data takes finitely many values. This special case also provides upper and lower bounds for the solutions which are interesting in their own rights. We also show equivalence of the existence theory we develop with that of gradient flows when the stored-energy function is assumed to be -convex. Asymptotic behaviour of the solutions as time goes to infinity is then investigated and stabilization results are obtained by means of a new argument. Finally, we look at the problem from the viewpoint of curves of maximal slope and follow a time-discretization approach. We introduce a three-dimensional method based on composition of time-increments, as a result of which we are able to deal with the physical requirement of frame-indifference. In order to test this method and distinguish the difficulties for possible generalizations, we look at the problem in a convex setting. At the end we are able to obtain convergence of the minimization scheme as time step goes to zero.
Arginine methylation on E2F1

E2F1 is a transcription factor which paradoxically has major influence on both apoptosis and cell cycle progression. One of the most important questions in E2F1 biology therefore is the mechanism underlying regulation of these opposing physiological outcomes.
Post-translational modifications (PTM) provide proteins with an additional layer of complexity, potentially altering interactions with partner DNA and protein. The importance of arginine methylation has recently been implicated in modulating the activity of the tumour suppression pathway proteins, p53 and E2F1. Previous studies have established that the methyltransferase, PRMT5, is responsible for the symmetrical dimethylation of E2F1, which inhibits its pro-apoptotic activity.
In this thesis, E2F1 was found to be a substrate of PRMT1, which catalysed asymmetrical dimethylation of E2F1 at arginine 109. In addition, a positive correlation was found between the percentage of apoptotic cells and levels of PRMT1. Conversely, an increase in cancer cell colony formation was shown when the site of PRMT1 methylation on E2F1 was changed from arginine to lysine at position 109. These findings suggested a growth inhibition effect by PRMT1 methylation on E2F1.
At the transcriptional level, depletion of PRMT1 increased E2F1 binding to the promoter region of Cdc6, a cell cycle regulator, and decreased binding to the promoter region of Apaf1, which has a pro- apoptotic role. Genome-wide ChIP-sequencing technology was undertaken and results further clarified that the depletion of PRMT1 preferably enriched E2F1 binding to promoters of positive regulators of cell proliferation and promoters of the cell cycle.
Collectively, the findings of this thesis suggested that the opposing roles E2F1 demonstrated in promoting both cell proliferation and apoptosis was due to different types of arginine methylation which trigger E2F1 binding to different promoters.
Lastly, arginine methylation was shown to influence protein-protein interactions. PRMT5 induction resulted in the identification by mass spectrometry of β-catenin as an E2F1 interacting partner. As the Wnt/β-catenin signalling pathway is broadly recognised as having pro- cell proliferation activity, this finding is consistent with previous reports that suggest the oncogenic role PRMT5 methylation has on E2F1.

Keywords: E2F1
PTM
PRMT
arginine methylation
Advisor: La Thangue, N
The experience of peripheral regions in an age of industrialisation

This thesis addresses the unresolved question of whether industrialisation helps or hinders progress in the peripheral regions of developing economies. Devon is seen as a 'sample of space' within which the breaking down of regional identities by changes in the Victorian transport infrastructure can be monitored. As the county's fortunes were thus primarily dependent upon the course of development in the wider national economy the survey of changes in economic activity within Devon is concerned mainly with relating internal adjustments to external pressures and opportunities. The balance of these appears to have resulted in a demand 'leakage* from the county's economy, and a net outwards flow of migrants, for there was a chronic deficit in Devon's balance of payments with the rest of Britain. This was probably exacerbated by an outflow of capital. But the relative contraction of employment within the county took a selective form in accordance with the developing specialisation of activity across the' national economic space. On the evidence of comparative wages in agriculture it seems that direct external demand was of central importance to the elimination of spatial differentials after 1870. But for the county as a whole there was no narrowing of the large shortfall between local wages and the national average before 1914. Sectors that benefited from external demand were few in number and their linkages with the rest of Devon's economy were too weak to stimulate general growth in the county, and the relatively unchanging distribution of demand throughout the nation that this refle-cted helped to maintain residual regional barriers to internal adjustment. The British economy was mature enough to pull the least developed regions away from pre-industrial levels of poverty but there was no inherent tendency to eliminate the broad tail which lagged behind the cutting edge of industrialisation.