Search

The liver contains a number of tissue-associated lymphocyte populations, of which many have been implicated in the pathogenesis of chronic liver diseases. γδ T cells, particularly the Vδ2neg subset, are known to comprise a substantial proportion of tissue-associated lymphocytes, although their immunobiology remains poorly understood. Here, the localisation, TCR diversity, immunophenotype and function of human intrahepatic γδ T cells was explored with an emphasis on highlighting any potential role in chronic liver disease and also to further understanding of tissue-associated γδ T cells, using the liver as a model tissue. Intrahepatic γδ T cells were predominantly localised in the sinusoids and did not increase in frequency with chronic inflammation. Vδ2neg cells exhibited private TCR clonal focussing, with complex CDR3 regions suggestive of antigen-driven expansions, concordant with a loss of naive-like CD27hi cells present in the periphery. Expanded clonotypes were phenotypically TEM- or TEMRA-like, with TEMRA-like clonotypes shared between liver and blood and resembling vasculature-associated virus-specific CD8⁺ T cells while TEM clonotypes were identified only in the liver and resembled tissue-resident CD8⁺ T cells. These findings suggest that disease has minimal impact on intrahepatic γδ T cells, while supporting an adaptive paradigm for these cells in the formation of tissue-associated subsets.

This thesis describes the preparation, structure and activity of a range of binary, ternary and quaternary molybdenum nitrides. It has been shown that all of the samples analysed can be formed through the reaction of the respective molybdate precursor with either ammonia or 3:1 H2/N2 gas mixture. The structures of the nitrides have been studied in detail. These structural findings were then linked to the activity potential of the materials to act as stores of activated nitrogen. The main body of work focused on the ternary molybdenum nitrides of cobalt, iron and nickel with a view to understanding their differences and similarities. Full structural analysis was performed using powder X-ray diffraction (PXRD) and neutron diffraction (PND). The activity of the nitrides was examined by reaction with 3:1 H2/N2 and with 3:1 H2/Ar at various temperatures. Particular attention was paid to the reactivity of lattice nitrogen. The cobalt molybdenum nitride was shown to be special case in this regard where the nitrogen is mobile and relocates within the lattice to a different crystallographic site. This mobility and relocation is concomitant with the loss of 50% of the lattice nitrogen from the system resulting in a phase change from Co3Mo3N to the unprecedented Co6Mo6N phase. The physical and chemical properties of this novel phase have been fully characterised and studied. Interestingly, the isostructual Fe3Mo3N behaves differently and the nitrogen remains fixed and the structure and stoichiometry constant throughout the testing procedure. Further studies of the ternary molybdenum nitrides extended to nickel molybdenum nitride, which was shown to be the least active when tested under both gas mixtures, and analogously to the iron molybdenum nitride the nitrogen is fixed within the β-Mn structured nitride. Further investigations were undertaken, resulting in the successful formation of a series of quaternary nitrides (Fe3-xCoxMo3N). These materials show properties similar to the Co-Mo-N system when the material is cobalt rich and behave similarly to the Fe-Mo-N system when iron rich.

This thesis describes the synthesis of 2-C-branched carbohydrate derivatives from ketohexoses and some useful synthetic applications thereof. Chapter 1 encompasses a general introduction to branched-chain sugars, with the emphasis upon 2C- hydroxymethyl and -methyl branched sugars. Strategies for their synthesis are discussed, both from nucleophilic and electrophilic carbohydrate derivatives. Some synthetic applications of carbohydrates and consequently branched carbohydrates are highlighted, with a view to the derivatisation of a proposed chiron from the Kiliani ascension of L-sorbose, 2-C-hydroxymethyl2,3: 5,6-di-O-isopropylidene-L-gulono,1,4-lactone. In chapter 2, the Kiliani ascension of L-sorbose and two subsequent complementary di-O-isopropylidene protections of the branched-chain lactones generated (thermodynamic and kinetic) are discussed. Further studies into the same transformations of three other ketohexoses, D-fructose, D-tagatose and D-psicose are then discussed. Further useful synthetic derivatives of the three major isomeric L-sorbose-derived branched di-protected lactones: selective deprotections and cleavage of C5-C6 bonds. One major area wh!ch utilizes carbohydrate building blocks is iminosugar synthesis. Iminosugars are the major compound class of interest in the realm of glycosidase inhibition, and also have other therapeutic properties, thus making them desirable synthetic targets. The application of 2-C- . branched sugar derivatives in the synthesis of novel iminosugars is proposed. Chapter 4 describes the syntheses of eight novel 2-C- hydroxymethyl and -methyl branched iminosugars from the major thermodynamic product (2-C-hydroxymethyl-2,3 :5,6-di-O-isopropylidene-L-gulono-l ,4-lactone) obtained from the Kiliani ascension of L-sorbose, as described in chapter 2. The syntheses of two additional novel iminosugars from isomeric 2,3:5,6-di-O-isopropylidene branched derivatives is described. Some results of inhibitory activity follow the synthetic results. The last two chapters provide a general introduction to macrocycles, and some synthetic investigations into macrocycles based on open-chain sugar amino acids (SAAs). SAA-derived macrocycles are structural hybrids of macrocyclic peptides and cyclodextrins. Strategies for the synthesis of large rings and previous work on D-galactose-derived-SAA macrocycles within the group is described with a view to the extension of this work towards novel asymmetric macrocycles with functionalisable rings. Chapter 6 reports synthetic investigations into three related families of macrocycles, each based on an open-chain galacto SAA. The pure galacto SAA macrocycles are revisited and two novel families of macrocycles are born, one containing proteinogenic amino acids and the other incorporating branched-chain SAAs. The branched-chain SAA itself is derived from 2-C-hydroxymethyl-2,3 :5,6-di-O-isopropylidene-D-mannono-l ,4-lactone, the major protected Kiliani lactone derived from D-fructose. Two major improvements to the original methodology for macrocycle formation are reported. Some structural analysis of macrocylic compounds through NMR and CD spectroscopy.