<p>Development in the field of materials science is propagated by the synthesis of polynuclear metal-containing complexes, that exhibit enhanced chemical and physical properties. This thesis describes the synthesis of new metal-containing linear polymers and dendritic molecules.</p> <p>Chapter 1 presents an overview of the field of metal-containing polymers, with particular attention to the synthesis of polymers via condensation polymerisation. This review includes the various types of metal-containing condensation polymers and the applications of these materials, where available. This discussion is followed by a brief summary of metal-containing dendrimers, which includes a concise description of their structure and applications in general.</p> <p>There are two routes to preparing metal-containing polymers. Chapter 2 describes the synthesis of three bifunctional organometallic monomers, of the general type [M]-O-{2,6-(CH2OH)2-4-CH3-C6H2}, where [M] represents the various metal-containing moieties, (&eta / 5-C5H5)(CO)2 Fe(CH2)3 (25), (&eta / 5-C5H4-CH2CH2CH2-)Re(CO)3 (26) and Fpdendr (27). These monomers were prepared using 2,6-bis(hydroxymethyl)-p-cresol as the key reagent. The monomers were used in classical polycondensation reactions with terephthaloyl chloride using ambient temperature solution techniques. This yielded new low molecular weight oligomeric polyesters, that were characterised using FTIR and 1HNMR spectroscopy, differential scanning calorimetry, thermogravimetric analysis and sizeexclusion chromatography.</p> <p>In Chapter 3, an alternate route to metal-containing polymers is described. In this case, bifunctional organic monomers were polymerised to give preformed organic polymers. Two types of organic polymers were prepared, viz. polyesters (with pendant vinyl moieties) and polyimines (with &alpha / -diimine units along the polymer backbone). Functionalisation of these preformed organic polymers with various metal sources was attempted. Hydrozirconation reactions of the vinyl polyesters with Schwartz&rsquo / s reagent, Cp2Zr(H)Cl, were attempted and were largely unsuccessful. Competing reactions with the ester functionality prevailed, preventing the desired reaction. Reaction of the polyimines with PdCl2(COD) yielded insoluble, intractable metal-containing oligomers. Partial characterisation of the complexes is described.</p> <p>The synthesis of new poly(propylene imine) iminopyridyl metallodendrimers is described in Chapter 4. Schiff-base condensation reaction of the commercially available DAB dendrimers with 2-pyridinecarboxaldehyde, gave the dendrimers 51, 52, and 53, with four, eight and sixteen pyridylimine functionalities respectively on the periphery. Successful complexation reactions with PdCl2(COD), PtCl2(COD) and CuCl2 produced the corresponding metal-containing dendrimers, with either PdCl2 (54, 55, 56), PtCl2 (57) or CuCl2 (58) moieties bound on the periphery. The metallodendrimers were insoluble in the more common organic solvents, and were characterised by IR and 1H-NMR spectroscopy and microanalysis where possible. Dendrimers with salicylaldiminato ligands on the periphery were prepared by reacting the DAB dendrimers with salicylaldehyde. These ligands were reacted with various metal acetates in an attempt to prepare new metalcontaining salicylaldimine dendrimers. This work yielded either paramagnetic metal complexes or insoluble, intractable compounds.</p> <p>Chapter 5 describes the applications of the catalyst precursors (54, 55, 56, 57, 58), discussed in Chapter 4, in the polymerisation of ethylene and the use of complexes 54 and 55 as Heck cross-coupling catalyst precursors. The complexes all showed catalytic activity toward ethylene polymerisation. A discussion of their activity, the polyethylene molecular weight and microstructure is presented in this chapter. The precursors 54 and 55 are also effective catalysts in the Heck reactions, coupling iodobenzene with methyl acrylate, styrene and 1-octene in high conversions.</p> <p>General conclusions are given in Chapter 6.</p>

Despite the importance of proper synaptogenesis in the CNS, the molecular mechanisms that regulate the formation and development of synapses remain poorly understood. Indeed, the mechanisms through which initial synaptic contacts are established and modified during synaptogenesis have not been fully determined and a precise understanding of these mechanisms may shed light on synaptic development, plasticity and many CNS developmental diseases. The development and formation of spiny synapses has been thought to occur via filopodia shortening followed by the recruitment of proper postsynaptic proteins, however the precise function of filopodia remains controversial. Thus the goal of this study was to investigate the dynamics of dendritic filopodia and determine their role in the development of synaptic contacts. We initially define and characterize short lipidated motifs that are sufficient to induce process outgrowth. Indeed, the palmitoylated protein motifs of GAP-43 and paralemmin are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and dendritic branches in neurons. We showed that the morphological changes induced by these FIMs (filopodia inducing motifs) require on-going protein palmitoylation and are modulated by a specific GTPase, Cdc42, that regulates actin dynamics. We also show that their function is palmitoylation dependent and is dynamically regulated by reversible protein palmitoylation. Significantly, our work suggests a general role for those palmitoylated motifs in the development of structures important for synapse formation and maturation. We combined several approaches to monitor the formation and development of filopodia. We show that filopodia continuously explore the environment and probe for appropriate contacts with presynaptic partners. We find that shortly after establishing a contact with axons, filopodia induce the recruitment of presynaptic elements. Remarkably, we find that expression of acylated motifs or the constitutively active form of cdc-42 enhances filopodia number and motility, but reduces the recruitment of synaptophysin positive presynaptic elements and the probability of forming stable axo-dendritic contacts. We provide evidence for the rapid transformation of filopodia to spines within hours of imaging live neurons and reveal potential molecules that accelerate this process.

Prostate cancer (PC) is the most common visceral cancer amongst men in Australia and elsewhere in the world. The American Cancer Society estimated that in 2006, PC alone would account for about 33% of newly diagnosed cancer in men, and be responsible for 9% of cancer related deaths in men. In men with advanced, metastatic PC, hormone therapy is widely accepted as the treatment of choice and produces good initial responses in most patients. However, many patients will relapse and become resistant to further hormone manipulation. Currently used treatment modalities for these patients are intended to palliate symptoms and therefore improve quality of life; the long term survival benefit of currently used management strategies is marginal at best. The limited treatment modalities with survival benefit for patients with advanced PC results in the need for development of novel therapies. Enhancement of the natural anti-tumour defences of the immune system to recognise and destroy tumour cells appears as a favourable alternative to prior therapies. Use of autologous dendritic cells (DC) as stimulators of an anti-tumour response has shown promise in several phase I, II and III trials. The Mater Medical Research Institute has developed a novel system for the isolation of blood DC (BDC). This system utilizes an antibody selection system based on a human/mouse chimeric CMRF-56 (huCMRF-56) monoclonal antibody (mAb) which has been engineered from the prototype murine IgG1 CMRF-56 mAb. Pre-clinical studies have demonstrated that the huCMRF-56 mAb isolates a CMRF-56+ cell population comparable to that obtained with the murine IgG1 CMRF-56 mAb with a sufficient CMRF-56+ BDC purity and yield to warrant its use as a BDC based immunotherapy. The objective of this research project was to validate the use of the huCMRF-56 mAb isolated BDC preparations in PC immunotherapy. This was achieved by; i) determining the optimal concentration of the huCMRF-56 mAb at which to perform isolations in order to obtain a CMRF-56+ cellular preparation with purity, yield and cellular composition, in terms of DC subsets, B cells, monocytes and contaminating cells, comparable to that obtained with the murine mAb, which has shown efficacy in in vitro studies; ii) Demonstrating that CMRF-56+ preparations obtained from PC patients using the huCMRF-56 BDC mAb are comparable to those from healthy donors (HD) and iii) demonstrating functional capacity of both freshly isolated and cryopreserved CMRF-56+ BDC isolated preparations to induce anti-tumour cytotoxic T lymphocyte (CTL) responses in both HD and PC patients. These studies utilised the appropriate immunostaining techniques and flow cytometry to determine the CMRF-56+ cell yield, CMRF-56+ BDC purity and viability of the preparation. To determine functional capacity CMRF-56+ preparations were isolated from HD and PC patients, and loaded with the prostate tumour associated antigens (TAA) and control antigen peptides: prostate specific antigen-3 (PSA-3), prostatic acid phosphatase- 5 (PAP-5), prostatic specific membrane antigen-2 (PSMA-2), flu matrix protein (FMP) and/or melanoma antigen recognised by T cells (MART). Co-culture experiments were set up with autologous peripheral blood mononuclear cells (PBMC) and induction of CTL responses were assessed using pentamer staining and ELISPOT assay. The working concentration of the huCMRF-56 mAb of 1.28mg/ml was determined to immunoselect a cellular preparation with maximal BDC purity, BDC yield and total viable cell number. Phenotyping studies of this preparation demonstrated it to be predominately comprised of antigen presenting cells (APC) and enriched for BDC with several BDC subsets immunoselected. CMRF-56+ preparations immunoselected from HD and PC donors were similar and comparable to previously described preparations immunoselected using the original murine CMRF-56 mAb. From antigen loaded CMRF-56+ preparations, specific major histocompatibility complex (MHC) class 1 restricted CD8 lymphocyte responses were generated against prostate TAAs in 2 of 5 HD and 1of 3 PC donors and against FMP in 1 of 3 PC and 5 of 5 HD. Cryopreserved antigen loaded CMRF-56+ BDC preparations from HD generated antigen specific FMP or MART-1 CTL responses in 3 of 4 HD, however anti-prostate TAA CTL responses were not observed. The humanised CMRF-56 mAb immunoselects a cellular preparation enriched in BDC and capable of effective uptake and presentation of antigen. The CMRF-56+ BDC enriched preparation, loaded with PC TAA is capable of inducing specific anti tumour responses in vitro. While further preclinical studies are required, the preparation, loaded with PC TAA shows promise as a potential immunotherapy for PC.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Göteborg : Univ. , 2008. / Härtill 3 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thesis (Ph.D.)--University of Melbourne, Dept. of Medical Biology, 2006. / Typescript. Includes bibliographical references (leaves 189-208).

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2008. / Includes bibliographical references (leaves 71-92). Also available in electronic version.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.