School of Chemistry - Theses
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ItemNMR studies of amyloid ab-peptide in membranes(University of Melbourne, 2006)
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ItemThe effects of ultrasound on the molecular, structural and nutritional aspects of dairy proteins( 2021)Process improvement and product improvement in the dairy processing industry is an ongoing dynamic process. Ultrasound processing technology for food processing is in its developmental stages, and dairy sector is a key area for potential applications. The use of low frequency and high frequency ultrasound to modify functional properties of dairy streams is being widely studied by seeking to modify the protein and lipid components of milk. The effects of ultrasound on size of lipid globules and lipid oxidation volatiles have been studied. The effects on functional properties of milk proteins such as viscosity, gelation, heat stability etc. have been documented. However, the present literature lacks information on the effects that ultrasound processing may have on the fundamental properties of dairy proteins. Therefore, it is of importance to document the effects of ultrasound processing on the molecular, structural and nutritional aspects of dairy proteins. As such, the effects of ultrasound processing on dairy proteins have been studied in the context of the amino acid composition, amyloid modifications, and bioactive peptides released. This work aims to bridge the gap in existing literature attempting to illuminate upon these fundamental aspects. Chapter 1 in this thesis introduces the premise of this research by discussing the fundamental properties ultrasound technology and presents dairy proteins as the central theme of this research. A systematic review of literature in Chapter 2 attempts to build familiarity with the effects of processing on milk proteins; and discusses the potential applications of ultrasound in the dairy industry – noting the studies done on whey are caseins. This chapter also discusses the research areas which could be addressed to answer questions related to the objectives of current PhD work. To encourage the application of ultrasound for dairy processing, it would be of significance to understand the extent of operating parameters that ensure nutritional integrity and food safety. The amino acid integrity of skim milk proteins after sonication along with the potential of ultrasound to modify secondary structural conformations of milk proteins has been demonstrated in Chapter 4. Chapter 5 expands the objectives of Chapter 4 into whole milk systems, taking into account milk lipids and the potential for oxidation of lipids on sonication. In Chapter 5 an effort has been made to better understand the underlying cause of lipid oxidation observed due to ultrasound processing of milk lipids. The observations from this study suggest that the enhanced mass transfer of oxygen due to ultrasonic shear forces makes oxygen non-limiting in lipid phase and increases auto-oxidation reactions. An assessment of amino acid integrity of full cream milk after ultrasound treatment confirmed oxidative stability of milk proteins. These findings complement the data in Chapter 4. Along with amino acid integrity, Chapter 4 also demonstrates that the secondary structural conformations of milk proteins can be modified by ultrasound. The work in Chapter 6 builds up greater understanding on such changes by studying the effects of low frequency ultrasound on isolated beta-lactoglobulin (b-lg). b-lg is a b-sheet rich protein with amyloidogenic potential. The effects of high shear and high temperature microenvironments produced by ultrasonic waves were studied on b-lg aggregation. Ultrasound induced formation of amyloid crystals in dilute b-lg solutions at neutral pH and ambient bulk temperatures. The theoretical reasoning for the aggregation phenomenon substantially adds to the understanding of protein energy landscape. Chapter 7 focusses on nutritional properties of milk proteins. It examines the effect of ultrasound pre-treatment on the release of BCM-7 bioactive peptide from milk by simulated gastro-intestinal digestion (SGID), and the effect on overall protein digestibility. It demonstrates that ultrasound processing could be used to downregulate the release of undesirable BCM-7 bioactive peptide in milk, by affecting the rate of enzymatic hydrolysis of certain intermediate peptide fragments. The findings from this body of work add to the existing knowledge for improved use of ultrasound to ensure nutritional integrity of dairy proteins and lipids, minimising oxidative damage. It also builds on current understanding of ultrasound induced protein restructuring and its potential for modification of peptide release from dairy proteins.
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ItemThe Evaluation of Oxorhenium(V) and Oxotechnetium(V) Complexes for the Diagnosis of Alzheimer’s Disease( 2020)Alzheimer’s disease (AD) is the most common neurodegenerative condition and is characterised by the presence of insoluble deposits within the brain that primarily consist of aggregated forms of the amyloid-beta (AB) peptide. The role that AB plays in the development and progression of AD remains uncertain. Accurate diagnostic information for suspected AD patients is imperative for the development of patient care plans, potential therapeutics and may aid in further understanding of AD pathology. The development of radiotracers that can bind to AB is of great interest as they can allow estimation of the plaque burden in patients that may have AD. Such compounds must bind specifically to AB plaques and be able to cross the blood brain barrier (BBB). Technetium-99m is the most commonly utilised radionuclide for single-photon-emission computed tomography (SPECT) imaging. This is attributed to its widely applicable half-life of six hours and its availability from benchtop generators. Lipophilic, charge-neutral technetium complexes have been shown to cross the BBB and this sets a precedent for the development of diagnostic amyloid-targeting complexes using the technetium-99m radionuclide. As there are no stable isotopes of technetium, its group seven congener rhenium is utilised for exploratory synthesis and characterisation. Ligands of a pyridyl-N3S donor set and their corresponding oxorhenium(V) complexes have been synthesised and characterised as models for the potential to incorporate amyloid-targeting groups directly into rhenium and technetium complexes. The small, charge-neutral complexes [ReOL30] and [ReOL31] were analysed by X-ray crystallography and the ligand H2L30-Trt was successfully radiolabelled with technetium-99m under mild conditions using a kit-based approach. A series of tetradentate N3S ligands that directly incorporate a styrylpyridyl amyloid-targeting group have been characterised and the corresponding oxorhenium(V) complexes show excellent binding to AB plaques on human brain tissue. The ligands H2L34-Trt and H2L35-Trt were both radiolabelled with technetium-99m under mild conditions and were shown to be suitably lipophilic for BBB permeability. The biological properties of the two technetium-99m complexes were examined by biodistribution experiments in wild-type mice. The styrylpyridyl complexes [ReOL34-36] confirm that the direct incorporation of amyloid targeting groups to metal complexes is a viable strategy in the design of radiotracers for assisting in the diagnosis of Alzheimer’s disease. Further work is required to improve the BBB permeability of this class of compounds. The design of technetium complexes with very high specificity for diagnostic targets is of great interest in the diagnosis of AD as well as other diseases. A bidentate pyridyl thiosemicarbazide ligand that includes a 1,2,4,5-tetrazine group was synthesised to form 2:1 complexes with the oxorhenium(V) and oxotechnetium(V) cores. The tetrazine groups of the rhenium complex [ReO(HL38)2]+ were shown to rapidly react with a simple transcyclooctene by an inverse electron demand Diels-Alder reaction under mild conditions. The corresponding technetium 99m complex [99mTc][TcO(HL38)2]+ was also synthesised. There exist many diagnostic and therapeutic applications for the tetrazine-containing complex [ReO(HL38)2]+ in bioorthogonal reactions for excellent pathological selectivity.