The ideal of artificial intelligence can firstly be set as the ability of a mechanical (or electronic) agent to be able to, as a human, observe, reason, learn, communicate and act in complex environments and secondly, to explain this type of behaviour in humans, animals or any other type of agent. The aim of this study is firstly to determine whether this ideal is feasible and secondly, to look at the physicalist premise thereof, viz., everything is physical according to Dooyeweerd’s view of the creation, fall and redemption motive. First we determine the essence of artificial intelligence through the Curch–Turing thesis. We then place the essence of artificial intelligence alongside the essence of life firstly to see whether the construction of an artificial intelligence agent is possible and whether the subject artificial intelligence has something to say regarding intelligent behaviour in humans, animals and similar agents. Lastly we look at the physicalist premise of artificial intelligence viz., everything is physical from the reformative creation, fall and redemption motive. The Church–Turing thesis forms the boundary of what is feasible in artificial intelligence and what is not feasible. Every component of the thesis is limited to the arithmetic law sphere of Being, i.e. the succession of discrete elements in a set of elements. Any effort to reduce the spatial aspect of the being to the arithmetic aspect of Being, like the enumeration of irrational numbers, ends in an antinomy. Any artificial intelligence agent is in its nature limited to the arithmetic law sphere of Being. The structural intertwinement, which such an artificial intelligence agent has with its underlying physical components is, in contrast with living organisms that of an irreversible grounded enkapsis. Life and mind has, in contrast to the arithmetic seclusion of an artificial intelligence agent, a fullness and totality. It has an ability to unlock Being in its fullness, which comes to the fore in a way that any living organism unlocks the plastic horizon of Being in the respective internal and phenomenological horizons. The unlocking of the spatial aspect plays a key role with its kernel of totality, simultaneity and continuousness. In both these horizons, the organism is in a living enkapsis with both its underlying physical substrate and the physical things in its external surroundings. The ideal of artificial intelligence is thus a phantasm. The only comment it can give on biology is that which has to do with the succession of discrete elements in a system. Hempel’s dilemma and the halting problem expose the physicalist point of departure of everything is physical as a religious premise, which is not empirically verifiable. Instead of getting a better view of Being the contours of meaning of life as well as all the supra physical aspects of Being fades away or is denied with concealment of Being. The only way in which we can get the broadest possible insight into Being is in the light of the Word of God. / Thesis (M.Phil.)--North-West University, Potchefstroom Campus, 2011.

The ideal of artificial intelligence can firstly be set as the ability of a mechanical (or electronic) agent to be able to, as a human, observe, reason, learn, communicate and act in complex environments and secondly, to explain this type of behaviour in humans, animals or any other type of agent. The aim of this study is firstly to determine whether this ideal is feasible and secondly, to look at the physicalist premise thereof, viz., everything is physical according to Dooyeweerd’s view of the creation, fall and redemption motive. First we determine the essence of artificial intelligence through the Curch–Turing thesis. We then place the essence of artificial intelligence alongside the essence of life firstly to see whether the construction of an artificial intelligence agent is possible and whether the subject artificial intelligence has something to say regarding intelligent behaviour in humans, animals and similar agents. Lastly we look at the physicalist premise of artificial intelligence viz., everything is physical from the reformative creation, fall and redemption motive. The Church–Turing thesis forms the boundary of what is feasible in artificial intelligence and what is not feasible. Every component of the thesis is limited to the arithmetic law sphere of Being, i.e. the succession of discrete elements in a set of elements. Any effort to reduce the spatial aspect of the being to the arithmetic aspect of Being, like the enumeration of irrational numbers, ends in an antinomy. Any artificial intelligence agent is in its nature limited to the arithmetic law sphere of Being. The structural intertwinement, which such an artificial intelligence agent has with its underlying physical components is, in contrast with living organisms that of an irreversible grounded enkapsis. Life and mind has, in contrast to the arithmetic seclusion of an artificial intelligence agent, a fullness and totality. It has an ability to unlock Being in its fullness, which comes to the fore in a way that any living organism unlocks the plastic horizon of Being in the respective internal and phenomenological horizons. The unlocking of the spatial aspect plays a key role with its kernel of totality, simultaneity and continuousness. In both these horizons, the organism is in a living enkapsis with both its underlying physical substrate and the physical things in its external surroundings. The ideal of artificial intelligence is thus a phantasm. The only comment it can give on biology is that which has to do with the succession of discrete elements in a system. Hempel’s dilemma and the halting problem expose the physicalist point of departure of everything is physical as a religious premise, which is not empirically verifiable. Instead of getting a better view of Being the contours of meaning of life as well as all the supra physical aspects of Being fades away or is denied with concealment of Being. The only way in which we can get the broadest possible insight into Being is in the light of the Word of God. / Thesis (M.Phil.)--North-West University, Potchefstroom Campus, 2011.

Many irreversible antagonists are known to bind irreversibly to pharmacological receptors. However, few studies suggest that these irreversible antagonists may also display irreversible non-specific antagonism by binding irreversibly to non-syntopic binding sites on the receptor macromolecule, whereby they modulate the signal transduction of these receptors or reduce the agonist binding affmity. The aim of this study was to investigate whether the classical irreversible antagonists phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible nonspecific antagonism at various G protein-coupled receptor (GPCR) types. In addition, the subcellular mechanism whereby benextramine displays irreversible non-specific antagonism was investigated. Three cell lines were employed to investigate the antagonism by these irreversible antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine a2A-adrenoceptor (a2A-AR) at higher (a2A-H) or lower (a2A-L) numbers, human neuroblastoma (SH-SY5Y) cells that endogenously express muscarinic acetylcholine receptors (mACh-Rs), and SH-SY5Y cells transfected (5HT2A-SH-SY5Y)o express the human 5HT2A-serotonirne ceptor (5HTZA-R).C ells of the appropriate cell line were pre-treated at the appropriate concentrations and incubation times with an appropriate irreversible antagonist, with or without an appropriate reversible competitive antagonist at a sufficient concentration to protect the specific receptors. This was followed by washing procedures with drug-free media to rinse any unbound or reversibly bound drugs from the cells. When appropriate, cell membranes were prepared. Receptor function was evaluated by measuring whole-cell [3H]-cAMP or [3H]-IPx acumulation, or the binding of [35S]-GTPyS to membraness. Receptor concentrations were determined from radioligand-binding assays. In addition, the constitutive [35S]-GTPyS binding to Go protein before and after pre-treatment with benextramine was investigated. Results suggest that phenoxybenzamine (100 uM, 20 minutes) and benextramine (10 uM, 20 minutes) display irreversible non-specific antagonism at a2A-ARs when measuring Gi-mediated effects in a2A-L cells, but the affinity for a2A-ARs in a2A-H cells was not changed. In addition, it was found that the observed irreversible nonspecific antagonism by benextramine appears to be time- and concentration-dependent. When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35S]-GTPyS to a2A-H membranes with protected a2A-ARs, but did not modulate the constitutive binding of [35S]-GTPyS to Go. In addition, benextramine displays irreversible non-specific antagonism by inhibiting the G,-mediated effects of a2A-ARs in a2A-H cells and the Gq-mediated effects of mACh-Rs or 5HT2A-Rs in SH-SY5Y or 5HT2A-SH-SY5Y cells respectively. 4-DAMP mustard (100 uM, 20 minutes) did not display irreversible non-specific antagonism at mACh-Rs in SH-SY5Y cells, but irreversible non-specific antagonism was observed when the incubation time was increased (100 uM, 60 minutes). In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non-specific antagonism at typical experimental conditions. These findings confirm concerns in literature and supports the possibility that more irreversible antagonists could display irreversible non-specific antagonism, and that could influence the interpretation of data obtained with such drugs. In addition, benextramine may prove to be a useful experimental drug in studying GPCR signalling. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.

Many irreversible antagonists are known to bind irreversibly to pharmacological receptors. However, few studies suggest that these irreversible antagonists may also display irreversible non-specific antagonism by binding irreversibly to non-syntopic binding sites on the receptor macromolecule, whereby they modulate the signal transduction of these receptors or reduce the agonist binding affmity. The aim of this study was to investigate whether the classical irreversible antagonists phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible nonspecific antagonism at various G protein-coupled receptor (GPCR) types. In addition, the subcellular mechanism whereby benextramine displays irreversible non-specific antagonism was investigated. Three cell lines were employed to investigate the antagonism by these irreversible antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine a2A-adrenoceptor (a2A-AR) at higher (a2A-H) or lower (a2A-L) numbers, human neuroblastoma (SH-SY5Y) cells that endogenously express muscarinic acetylcholine receptors (mACh-Rs), and SH-SY5Y cells transfected (5HT2A-SH-SY5Y)o express the human 5HT2A-serotonirne ceptor (5HTZA-R).C ells of the appropriate cell line were pre-treated at the appropriate concentrations and incubation times with an appropriate irreversible antagonist, with or without an appropriate reversible competitive antagonist at a sufficient concentration to protect the specific receptors. This was followed by washing procedures with drug-free media to rinse any unbound or reversibly bound drugs from the cells. When appropriate, cell membranes were prepared. Receptor function was evaluated by measuring whole-cell [3H]-cAMP or [3H]-IPx acumulation, or the binding of [35S]-GTPyS to membraness. Receptor concentrations were determined from radioligand-binding assays. In addition, the constitutive [35S]-GTPyS binding to Go protein before and after pre-treatment with benextramine was investigated. Results suggest that phenoxybenzamine (100 uM, 20 minutes) and benextramine (10 uM, 20 minutes) display irreversible non-specific antagonism at a2A-ARs when measuring Gi-mediated effects in a2A-L cells, but the affinity for a2A-ARs in a2A-H cells was not changed. In addition, it was found that the observed irreversible nonspecific antagonism by benextramine appears to be time- and concentration-dependent. When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35S]-GTPyS to a2A-H membranes with protected a2A-ARs, but did not modulate the constitutive binding of [35S]-GTPyS to Go. In addition, benextramine displays irreversible non-specific antagonism by inhibiting the G,-mediated effects of a2A-ARs in a2A-H cells and the Gq-mediated effects of mACh-Rs or 5HT2A-Rs in SH-SY5Y or 5HT2A-SH-SY5Y cells respectively. 4-DAMP mustard (100 uM, 20 minutes) did not display irreversible non-specific antagonism at mACh-Rs in SH-SY5Y cells, but irreversible non-specific antagonism was observed when the incubation time was increased (100 uM, 60 minutes). In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non-specific antagonism at typical experimental conditions. These findings confirm concerns in literature and supports the possibility that more irreversible antagonists could display irreversible non-specific antagonism, and that could influence the interpretation of data obtained with such drugs. In addition, benextramine may prove to be a useful experimental drug in studying GPCR signalling. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.