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A Dissertation Submitted to the Faculty of SCience University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Doctor of Philosophy / Living cells are highly auto-dynamic entities which means that the underlying biochemistry is equally dynamic, a reality which is ignored by most researchers. Theoretical studies indicate that such a state must be due to the existence of oscillatory variations in the levels and activities of key components in the cell. In this study, the dynamic behaviour of four major, interrelated areas of cell biochemistry (phosphorylation, dephosphorylation, the terminal reaction of glycolysis and the amount of soluble protein) were examined and all systems found to oscillate in murine erythroleukaemic cells (MEL) and, where examined, also in the human HL-60 leukaemic cell line. (Abbreviation abstract) / AC 2018

A Dissertation Submitted to the Faculty of Science University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Doctor of Philosophy / Living cells are highly auto-dynamic entities which means that the underlying biochemistry is equally dynamic, a reality which is ignored by most researchers. Theoretical studies indicate that such a state must be due to the existence of oscillatory variations in the levels and activities of key components in the cell. In this study, the dynamic behaviour of four major, interrelated areas of cell biochemistry (phosphorylation, dephosphorylation, the terminal reaction of glycolysis and the amount of soluble protein) were examined and all systems found to oscillate in murine erythroleukaemic cells (MEL) and, where examined, also in the human HL-6Q leukaemic cell line. certain processes have been shown to be oscillatory for the first time ( phosphorylation potential, the lactate dehydrogenase active isozyme level and aspects of the regulation thereof). While others have been shown to occur at a higher frequency than previously reported (phosphotyrosine phosphatase activity, the activity and apparent isozyme pattern of lactate dehydrogenase, the amount of extractable protein). All rhythms are shown (for the first time) to be complex and to involve several contributing periodicities, some modulating the period and amplitude of the observed oscillation. The frequencies are very high (periods of 1-20 minutes and probably Less) and the amplitudes are equally high (variations in magnitude of as much as a hundred fold). Phosphorylation processes, currently of particular interest with regard to the nature and control of cell proliferation are thus found to be more highly dynamic than previously believed, a fact which throws some doubt on the current ideas on cell proliferation. The actual lactate dehydrogenase (LDH) active isozyme pattern is shown not to be constant (as generally believed) but to vary at high frequency (possibly due to phosphorylation of the the enzyme) while the kinetics and specificity of the lone isozyme in murine erythroleukaemic cells appear to be varying at equally high frequency due to the action of regulators (perhaps arising elsewhere within the glycolytic pathway). Similar results were obtained with HL-60 leukaemic cells with at least two of the isozymes varying in level, to some extent independently. The hormone, insulin, and the inducer of cell differentiation, HMBA (hexamethylenebisacetamide), have been found to affect the dynamics of the four systems although, because of the complexity of the rhythms the actual effects on the dynamics are not easily defined. Insulin has a marked effect on the mean level of the activity of the LDH isozyme. The fact that all oscillations are seen despite no attempt being made to synchronise the cell population suggests the existence of communication between cells but how this can occur when the rhythms are of such high frequency is intriguing. All the results add further support for the long standing view of my supervisor, that the properties and behaviour of cells reflect the internal dynamics and that differentiation, cancer and intracellular signalling occur through changes in the pattern of temporal organisation of cellular oscillations. / AC2018

A Dissertation Submitted to the Faculty of Science University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Doctor of Philosophy Johannesburg 1994 / Living cells are highly auto-dynamic entities which means that the underlying biochemistry is equally dynamic, a reality which is ignored by most researchers. Theoretical studies indicate that such a state must be due to the existence of oscillatory variations in the levels and activities of key components in the cell. In this study, the dynamic behaviour of four major, interrelated areas of cell biochemistry (phosphorylation, dephosphorylation, the terminal reaction of glycolysis and the amount of soluble protein) were examined and all systems found to oscillate in murine erythroleukaemic cells (MEL) and, where examined, also in the human HL-6Q leukaemic cell line. [Abbreviated Abstract. Open document to view full version] / MT2017

"Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, affecting approximately 20 million people worldwide. AD pathology is primarily characterized by the formation of extracellular amyloid plaques resulting from the aggregation of insoluble amyloid-beta 1-42 (A-beta), and neurofibrillary tangles (NFT’s) resulting from intracellular aggregation of hyperphosphorylated tau protein. The current FDA-approved AD treatments do not stop or reverse neurodegeneration, but only treat the symptoms by increasing acetylcholine neurotransmitter. Our laboratory is attempting to provide an additional therapeutic approach by using neurotrophic factors to block apoptosis or to restore neurons. We previously demonstrated that, in an in vitro model for AD, hEPN-1 neurotrophic factor mimetics can block synthetic A-beta-induced neuronal cell death when added to cultures, presumably by blocking caspase activation. In this thesis, we extended these findings to study the effect of A-beta and hEPN-1 on tau hyperphosphorylation (as measured by immunoblots with phospho-specific antibodies) and nuclear DNA fragmentation (as measured by TUNEL staining), both in vitro and in vivo in AD transgenic mice. We found that A-beta induces the hyperphosphorylation of tau in both mouse N2a and human SHSY neuronal cells, and that hEPN-1 may lower this phosphorylation in N2a cells. Furthermore, we discovered that hEPN-1 can reduce nuclear DNA fragmentation when added both simultaneously to A-beta and 3 and 6 hours post A-beta addition. Finally, in vivo hEPN-1 may lower both tau hyperphosphorylation and caspase-7 related protein (C7RP) in AD transgenic (Tg) mice. The overall results validate our in vitro AD model, show the efficacy of hEPN-1 at blocking A-beta-induced DNA fragmentation even when added post-insult, and show that hEPN-1 may work in an AD mouse model. However, more studies must be conducted to confirm these findings. "

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