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This thesis is divided into three main parts. In the first of these (comprising chapters 1 and 2) we present the physical context of the research and cover the basic geometric background we will need to use throughout the rest of this thesis. In the second part (comprising chapters 3 to 5) we motivate and develop the strong homogeneity theorem for supergravity backgrounds. We go on to prove it directly for a number of top-dimensional Poincaré supergravities and furthermore demonstrate how it also generically applies to dimensional reductions of those theories. In the third part (comprising chapters 6 and 7) we show how further specialising to the case of symmetric backgrounds allows us to compute complete classifications of such backgrounds. We demonstrate this by classifying all symmetric type IIB supergravity backgrounds. Next we apply an algorithm for computing the supersymmetry of symmetric backgrounds and use this to classify all supersymmetric symmetric M-theory backgrounds.

For bladder tissue-engineering, there is a need for a surrogate epithelial cell source for patients whose own bladder epithelial cells (urothelial cells) are compromised by disease or cancer. Current work in the field has focused on attempting to differentiate various types of stem cells into urothelial cells using conditioned medium, co-culture or specific factors. These approaches have lacked clear focus, making it obvious that a better understanding of the transcription factors underlying urothelial lineage, development, and cell differentiation is necessary. The aim of the work presented in this thesis was to acquire specific knowledge regarding transcription factors involved in urothelial cell differentiation, which could be applied to an in vitro transdifferentiation approach of cell reprogramming. Since buccal mucosa is readily available, and already used as a grafted tissue for urology surgical applications, buccal epithelial cells were identified as a potential starting cell type. An in vitro comparison of human buccal epithelial cells to urothelial cells revealed that buccal epithelial cells had weak transcript and protein expression of four transcription factors that play key roles in urothelial cell differentiation: ELF3, FOXA1, GATA3 and PPARγ. Since ELF3 and FOXA1 have been previously shown to act downstream of PPARγ in urothelial cells, PPARγ and GATA3 were chosen as key upstream transcription factors to overexpress in buccal epithelial cells. Investigation into PPARγ expression in human urothelial cells revealed that of the two main PPARγ protein isoforms, PPARγ1 was most critical for urothelial cell differentiation. Knockdown of GATA3 expression in urothelial cells using specific siRNA revealed an important role for GATA3 in maintaining the differentiated state of urothelium. Individual overexpression of GATA3 and PPARγ1 in human buccal epithelial cells was unable to cause complete transdifferentiation to urothelial cells, but each resulted in the upregulation of downstream genes that play critical roles in urothelial cell differentiation and barrier formation. This work revealed key differences in transcription factor expression between buccal epithelial cells and urothelial cells, allowing for a better understanding of transcription factors involved in urothelial cell differentiation. The work provides a starting point for future urothelial-type cell reprogramming efforts which will likely require combined overexpression of several of these identified transcription factors to achieve complete transdifferentiation.

This thesis is based on a study of miracle stories recorded by Anglo-Saxon ecclesiastical writers in the early part of the eighth century. It responds to a number of previous works which have concentrated solely on the miracle stories told by Bede, and argues that the stories of all the writers are the product of the historical situation. The idea that such stories were produced in order to respond to claims made in Irish or Continental hagiography, or by Anglo-Saxon paganism, is rejected; instead, we need to accept the assertion of the authors that these events were recorded because they were believed to have happened and to be of historical importance. Therefore, they provide an insight into the way that these authors approached the writing of history; an analysis of those involved in the stories, of the circumstances of the events, and of the likely transmission, suggests a close-knit circle of mainly noble monastics on whom the writers depended for information, and for whom they wrote. The miracle stories disclose that this approach to history was heavily informed by theological ideas, and by the bias of the author and his/her community. Precisely because the miracle material is to modern eyes unusual (if not incredible), these stories enable us better to understand the mind and methods of the writers on whom much of our knowledge early Anglo-Saxon history depends.

Magnesium (Mg24) is essential for normal functioning of the heart. It is the second most abundant divalent cation in living cells and plays vital roles in cellular regulation. Preservation of intracellular Mg 24 concentration ([Mg24]) is essential in the heart. The concentration of ionized Mg 24 is similar in both the extracellular and intracellular milieu of cardiac myocytes although a large electrochemical gradient exists which will tend to promote Mg24 influx across the sarcolemmal membrane. Therefore homeostatic mechanism(s) must exist which will extrude Mg 24 against this gradient. The existence of a Na/Mg2 counterport mechanism or an ATP driven pump for the extrusion of Mg 2 from the cell has been suggested. This work examines various possible mechanisms for Mg 24 extrusion. In a series of experiments, the effects on Mg 24 efflux and contractile force, of increased and decreased extracellular sodium [Na *], lithium chloride, specific ion channel inhibitors, osmotic shock, metabolic inhibition and global ischaemia, in the isolated, perfused (5 ml mm", 37°C) and paced (20V, I msec, 4-6 Hz) rat-heart were investigated in an attempt to characterize further, the mechanism of Mg 24 transport. Following a recovery period of 20 mm, the heart was perfused with a nominally Mg2tfree Krebs-Henseleit (1(H) solution, which facilitates the measurement of Mg24 in effluent samples using a spectroscopic method. Perfusion of the isolated heart with Mg 2 -free KH containing increased [Na], in chloride, nitrate, isethionate or sulphate forms, all promoted a large and significant (P C 0.05) Mg2t efflux. This efflux was, in general, accompanied by an increase in contractile force. Typically, net total Mg 24 efflux in elevated [Na']. (as NaCl), measured over a period of 10 min was 590.1 ± 26.7 ng (100 mg tissue)" (mean and SEM, n = 6) compared to 376.1 ± 17.9 ng (100 mg tissue)" (n = 7) in controls. However, lithium chloride also promoted significant (P C 0.05) increases in Mg 2 efflux and contractile force. Mg 2 efflux in response to elevated (Na*], was significantly inhibited by 10" M and 10 M amiloride, but not by 10 M ouabain. Propranolol (10" M) and 10 7 M verapamil inhibited Mg2t efflux under control conditions. Niflumic acid (10' M) produced a small but delayed response in Mg2t efflux, under both control conditions and in response to increased [Na']... whereas 103 M Ibrosemide elicited a large and significant increase under these conditions. Both niflumic acid and ifirosemide inhibited contractile force. Osmotic shock induced by either sucrose, glucose or fructose resulted in a significant (P < 0.01) increase in Mg2t efilux and a concomitant increase in contractile force, both of which were found to be dose related. Metabolic inhibition with either rotenone, potassium cyanide (KCN) or oligomycin B promoted small but not significant increases in Mg 2 efflux and these were accompanied by significant decreases in force of contraction of the heart. Uncoupling phosphorylation and oxidation using dinitrophenol (DNP) elicited a highly significant increase in Mg 2t efflux and a concomitant decrease in force. Lactate dehydrogenase activity did not significantly increase during perfusion of the heart with either increased [Na t] 0 or DMP, suggesting that cell damage was not responsible for the Mg2t effiux. When electrically paced or spontaneously beating hearts were subjected to 10 min of global ischaemia, a significant increase in Mg2 efilux occurred together with a concomitant decrease in force of contraction. The responses in electrically paced hearts were more pronounced than in spontaneously beating hearts. These results suggest the possibility of a small amiloride and propranolol sensitive component to Mg 2 efflux, which could be a NaVMg2t counterport mechanism. However, since lithium chloride, sucrose, glucose and fructose also elicit Mg2t efflux, it is concluded that the response to these and to elevated [Na - ],, may be osmotic in origin. A further mechanism involving chloride transport and/or intracellular Ca2t may also exist and it appears that Mg 2t efflux is linked either to the proton gradient in the mitochondria, or to intracellular pH or to ATP production. Dietary studies showed that the heart is able to conserve Mg 2 at the expense of other organs, but that young rats are more adversely affected by low dietary Mg2t intake than older rats.

The two molecular forms, I and II, of α-galactosidase from immature, mature (resting) and germinated vicia faba seeds have been studied. The enzymes have been purified by a multistage procedure and, in particular, the effect these stages have upon the relative isoenzyme levels has been investigated. Upon purification in Mcllvaine buffer the relative isoenzym pattern for mature seeds was seen to change from the low molecular weight enzyme being the major form in the crude extract, through the two molecular forms being almost equal after the citric acid precipitation and ammonium sulphate fractionation, to the high molecular weight enzyme being the major form after the final purification stage of dialysis. A parallel purification carried out in Acetate buffer introduced a time lag between the change in isoenzyme levels found upon acid precipitation in the McIlvaine system. Purification of extracts of whole (testas intact) immature seeds in Mcllvaine buffer showed enzyme to be the dominant form throughout all the purification stages, while beans devoid of testas produced extracts where enzyme j was the greater. Drying the green immature beans in the presence of testas gave the normal mature bean isoenzyme patterns, while drying in the absence of testas, or where the testa has been replaced by a non-physiological covering produced extracts where enzyme remained the major isoenzyme throughout all stages of purification. Enzyme was the more abundant isoenzyme in the crude McIlvaine buffer extracts from germinated seeds, with small amounts of enzyme appearing upon purification. A preparation of α-galactosidase when incubated with a 30 - 65% ammonium sulphate fraction from green bean testa was observed to convert in vitro to an enzyme with very similar physical properties to enzyme from mature seeds. Some factors affecting this conversion have been investigated and it appears that the active component in the green testa is proteinaceous. The physiological role of CX-galactosidases in seeds has been considered. Attempts were made to modify galactomannans by hydrolysis with CX-galactosidases, so as to produce galactose-depleted products which would form stronger gels with K-carrageenan than would the parent galactomannans. vicia faba enzymes failed to produce any significant hydrolysis whereas coffee and clover enzymes increased the mannose/galactose6ratio but also appeared to hydrolyse the mannan backbone so that gel formation was inhibited. This was believed to be due to the presence of contaminating fB-mannanase. Unsuccessful attempts were made to remove this activity from clover enzyme by several purification stages culminating in affinity chromatography.