In silico characterization of missense mutations in infectious diseases: case studies of tuberculosis and COVID-19
- Authors: Barozi, Victor
- Date: 2023-10-13
- Subjects: Microbial mutation , COVID-19 (Disease) , Drug resistance in microorganisms , Antitubercular agents , Tuberculosis , Molecular dynamics , Single nucleotide polymorphisms
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431626 , vital:72791 , DOI 10.21504/10962/431626
- Description: One of the greatest challenges facing modern medicine and the global public health today is antimicrobial drug resistance (AMR). This “silent pandemic,” as coined by the world health organization (WHO), is steadily increasing with an estimated 4.95 million mortalities attributed to AMR in 2019, 1.27 million of which were directly linked to AMR. Some of the contributors to AMR include self-prescription, drug overuse, sub-optimal drug prescriptions by health workers, and inaccessibility to drugs, especially in remote areas, which leads to poor adherence. The situation is aggravated by the upsurge of new zoonotic infections like the coronavirus disease 2019, which present unique challenges and take the bulk of resources hence stunting the fight against AMR. Quite alarming still is our current antimicrobial arsenal, which hasn’t had any novel antimicrobial drug discovery/addition, of a new class, since the 1980s. This puts a burden on the existing broad-spectrum antimicrobial drugs which are already struggling against multi-drug resistant strains like multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Besides the search for new antimicrobial agents, the other avenue for addressing AMR is studying drug resistance mechanisms, especially single nucleotide polymorphisms (SNPs), that change drug target characteristics. With the advancement of computational power and data storage resources, computational approaches can be applied in mutational studies to provide insight into the drug resistance mechanisms with an aim to inform future drug design and development. Therefore, in the first part of this thesis, we employ integrative in silico approaches, including 3D structure modeling, molecular dynamic (MD) simulations, comparative essential dynamics (ED), and protein network analysis approaches i.e., dynamic residue network (DRN) analysis to decipher drug resistance mechanisms in tuberculosis (TB). This involved an investigation of the drug resistance mutations in the catalase-peroxidase (KatG) and pyrazinamidase (MtPncA) enzymes which are responsible for activation of TB first-line drugs; Isoniazid (INH) and Pyrazinamide (PZA), respectively. In the case of KatG, eleven high confidence (HC) KatG mutations associated with a high prevalence of phenotypic INH resistance were identified and their 3D structures modeled before subjecting them to MD simulations. Global analysis showed an unstable KatG structure and active site environment in the mutants compared to the wildtype. Active site dynamics in the mutants compromised cofactor (heme) interactions resulting in less bonds/interactions compared to the wildtype. Given the importance of the heme, reduced interactions affect enzyme function. Trajectory analysis also showed asymmetric protomer behavior both in the wildtype and mutant systems. DRN analysis identified the KatG dimerization domain and C-terminal domain as functionally important and influential in the enzyme function as per betweenness centrality and eigenvector centrality distribution. In the case of the MtPncA enzyme, our main focus was on understanding the MtPncA binding ability of Nicotinamide (an analogue of PZA) in comparison to PZA, especially in the presence of 82 resistance conferring MtPncA mutations. Like in KatG, the mutant structures were modeled and subjected to MD simulations and analysis. Interestingly, more MtPncA mutants favored NAM interactions compared to PZA i.e., 34 MtPncA mutants steadily coordinated NAM compared to 21 in the case of PZA. Trajectory and ligand interaction analysis showed how increased active site lid loop dynamics affect the NAM binding, especially in the systems with the active site mutations i.e., H51Y, W68R, C72R, L82R, K96N, L159N, and L159R. This led to fewer protein-ligand interactions and eventually ligand ejection. Network analysis further identified the protein core, metal binding site (MBS), and substrate binding site as the most important regions of the enzyme. Furthermore, the degree of centrality analysis showed how specific MtPncA mutations i.e., C14H, F17D, and T412P, interrupt intra-protein communication from the MtPncA core to the MBS, affecting enzyme activity. The analysis of KatG and MtPncA enzyme mutations not only identified the effects of mutations on enzyme behaviour and communication, but also established a framework of computational approaches that can be used for mutational studies in any protein. Besides AMR, the continued encroachment of wildlife habitats due to population growth has exposed humans to wildlife pathogens leading to zoonotic diseases, a recent example being coronavirus disease 2019 (COVID-19). In the second part of the thesis, the established computational approaches in Part 1, were employed to investigate the changes in inter-protein interactions and communication patterns between the severe acute respiratory coronavirus 2 (SARS-CoV-2) with the human host receptor protein (ACE2: angiotensin-converting enzyme 2) consequent to mutations in the SARS-CoV-2 receptor binding domain (RBD). Here, the focus was on RBD mutations of the Omicron sub-lineages. We identified four Omicron-sub lineages with RBD mutations i.e., BA.1, BA.2, BA.3 and BA.4. Each sub-lineage mutations were modeled into RBD structure in complex with the hACE2. MD analysis of the RBD-hACE2 complex highlighted how the RBD mutations change the conformational flexibility of both the RBD and hACE2 compared to the wildtype (WT). Furthermore, DRN analysis identified novel allosteric paths composed of residues with high betweenness and eigenvector centralities linking the RBD to the hACE2 in both the wildtype and mutant systems. Interestingly, these paths were modified with the progression of Omicron sub-lineages, highlighting how the virus evolution affects protein interaction. Lastly, the effect of mutations on S RBD and hACE2 interaction was investigated from the hACE2 perspective by focusing on mutations in the hACE2 protein. Here, naturally occurring hACE2 polymorphisms in African populations i.e., S19P, K26R, M82I, K341R, N546D, and D597Q, were identified and their effects on RBD-hACE2 interactions investigated in presence of the Omicron BA.4/5 RBD mutations. The hACE2 polymorphisms subtly affected the complex dynamics; however, RBD-hACE2 interaction analysis showed that hACE2 mutations effect the complex formation and interaction. Here, the K26R mutation favored RBD-hACE2 interactions, whereas S19P resulted in fewer inter-protein interactions than the reference system. The M82I mutation resulted in a higher RBD-hACE2 binding energy compared to the wildtype meaning that the mutation might not favor RBD binding to the hACE2. On the other hand, K341R had the most RBD-hACE2 interactions suggesting that it probably favors RBD binding to the hACE2. N546D and D597Q had diminutive differences to the reference system. Interestingly, the network of high betweenness centrality residues linking the two proteins, as seen in the previous paragraph, were maintained/modified in presence of hACE2 mutations. HACE2 mutations also changed the enzyme network patterns resulting in a concentration of high eigenvector centrality residues around the zinc-binding and active site region, ultimately influencing the enzyme functionality. Altogether, the thesis highlights fundamental structural and network changes consequent to mutations both in TB and COVID-19 proteins of interest using in silico approaches. These approaches not only provide a new context on impact of mutations in TB and COVID target proteins, but also presents a framework that be implemented in other protein mutation studies. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2023
- Full Text:
- Authors: Barozi, Victor
- Date: 2023-10-13
- Subjects: Microbial mutation , COVID-19 (Disease) , Drug resistance in microorganisms , Antitubercular agents , Tuberculosis , Molecular dynamics , Single nucleotide polymorphisms
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431626 , vital:72791 , DOI 10.21504/10962/431626
- Description: One of the greatest challenges facing modern medicine and the global public health today is antimicrobial drug resistance (AMR). This “silent pandemic,” as coined by the world health organization (WHO), is steadily increasing with an estimated 4.95 million mortalities attributed to AMR in 2019, 1.27 million of which were directly linked to AMR. Some of the contributors to AMR include self-prescription, drug overuse, sub-optimal drug prescriptions by health workers, and inaccessibility to drugs, especially in remote areas, which leads to poor adherence. The situation is aggravated by the upsurge of new zoonotic infections like the coronavirus disease 2019, which present unique challenges and take the bulk of resources hence stunting the fight against AMR. Quite alarming still is our current antimicrobial arsenal, which hasn’t had any novel antimicrobial drug discovery/addition, of a new class, since the 1980s. This puts a burden on the existing broad-spectrum antimicrobial drugs which are already struggling against multi-drug resistant strains like multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Besides the search for new antimicrobial agents, the other avenue for addressing AMR is studying drug resistance mechanisms, especially single nucleotide polymorphisms (SNPs), that change drug target characteristics. With the advancement of computational power and data storage resources, computational approaches can be applied in mutational studies to provide insight into the drug resistance mechanisms with an aim to inform future drug design and development. Therefore, in the first part of this thesis, we employ integrative in silico approaches, including 3D structure modeling, molecular dynamic (MD) simulations, comparative essential dynamics (ED), and protein network analysis approaches i.e., dynamic residue network (DRN) analysis to decipher drug resistance mechanisms in tuberculosis (TB). This involved an investigation of the drug resistance mutations in the catalase-peroxidase (KatG) and pyrazinamidase (MtPncA) enzymes which are responsible for activation of TB first-line drugs; Isoniazid (INH) and Pyrazinamide (PZA), respectively. In the case of KatG, eleven high confidence (HC) KatG mutations associated with a high prevalence of phenotypic INH resistance were identified and their 3D structures modeled before subjecting them to MD simulations. Global analysis showed an unstable KatG structure and active site environment in the mutants compared to the wildtype. Active site dynamics in the mutants compromised cofactor (heme) interactions resulting in less bonds/interactions compared to the wildtype. Given the importance of the heme, reduced interactions affect enzyme function. Trajectory analysis also showed asymmetric protomer behavior both in the wildtype and mutant systems. DRN analysis identified the KatG dimerization domain and C-terminal domain as functionally important and influential in the enzyme function as per betweenness centrality and eigenvector centrality distribution. In the case of the MtPncA enzyme, our main focus was on understanding the MtPncA binding ability of Nicotinamide (an analogue of PZA) in comparison to PZA, especially in the presence of 82 resistance conferring MtPncA mutations. Like in KatG, the mutant structures were modeled and subjected to MD simulations and analysis. Interestingly, more MtPncA mutants favored NAM interactions compared to PZA i.e., 34 MtPncA mutants steadily coordinated NAM compared to 21 in the case of PZA. Trajectory and ligand interaction analysis showed how increased active site lid loop dynamics affect the NAM binding, especially in the systems with the active site mutations i.e., H51Y, W68R, C72R, L82R, K96N, L159N, and L159R. This led to fewer protein-ligand interactions and eventually ligand ejection. Network analysis further identified the protein core, metal binding site (MBS), and substrate binding site as the most important regions of the enzyme. Furthermore, the degree of centrality analysis showed how specific MtPncA mutations i.e., C14H, F17D, and T412P, interrupt intra-protein communication from the MtPncA core to the MBS, affecting enzyme activity. The analysis of KatG and MtPncA enzyme mutations not only identified the effects of mutations on enzyme behaviour and communication, but also established a framework of computational approaches that can be used for mutational studies in any protein. Besides AMR, the continued encroachment of wildlife habitats due to population growth has exposed humans to wildlife pathogens leading to zoonotic diseases, a recent example being coronavirus disease 2019 (COVID-19). In the second part of the thesis, the established computational approaches in Part 1, were employed to investigate the changes in inter-protein interactions and communication patterns between the severe acute respiratory coronavirus 2 (SARS-CoV-2) with the human host receptor protein (ACE2: angiotensin-converting enzyme 2) consequent to mutations in the SARS-CoV-2 receptor binding domain (RBD). Here, the focus was on RBD mutations of the Omicron sub-lineages. We identified four Omicron-sub lineages with RBD mutations i.e., BA.1, BA.2, BA.3 and BA.4. Each sub-lineage mutations were modeled into RBD structure in complex with the hACE2. MD analysis of the RBD-hACE2 complex highlighted how the RBD mutations change the conformational flexibility of both the RBD and hACE2 compared to the wildtype (WT). Furthermore, DRN analysis identified novel allosteric paths composed of residues with high betweenness and eigenvector centralities linking the RBD to the hACE2 in both the wildtype and mutant systems. Interestingly, these paths were modified with the progression of Omicron sub-lineages, highlighting how the virus evolution affects protein interaction. Lastly, the effect of mutations on S RBD and hACE2 interaction was investigated from the hACE2 perspective by focusing on mutations in the hACE2 protein. Here, naturally occurring hACE2 polymorphisms in African populations i.e., S19P, K26R, M82I, K341R, N546D, and D597Q, were identified and their effects on RBD-hACE2 interactions investigated in presence of the Omicron BA.4/5 RBD mutations. The hACE2 polymorphisms subtly affected the complex dynamics; however, RBD-hACE2 interaction analysis showed that hACE2 mutations effect the complex formation and interaction. Here, the K26R mutation favored RBD-hACE2 interactions, whereas S19P resulted in fewer inter-protein interactions than the reference system. The M82I mutation resulted in a higher RBD-hACE2 binding energy compared to the wildtype meaning that the mutation might not favor RBD binding to the hACE2. On the other hand, K341R had the most RBD-hACE2 interactions suggesting that it probably favors RBD binding to the hACE2. N546D and D597Q had diminutive differences to the reference system. Interestingly, the network of high betweenness centrality residues linking the two proteins, as seen in the previous paragraph, were maintained/modified in presence of hACE2 mutations. HACE2 mutations also changed the enzyme network patterns resulting in a concentration of high eigenvector centrality residues around the zinc-binding and active site region, ultimately influencing the enzyme functionality. Altogether, the thesis highlights fundamental structural and network changes consequent to mutations both in TB and COVID-19 proteins of interest using in silico approaches. These approaches not only provide a new context on impact of mutations in TB and COVID target proteins, but also presents a framework that be implemented in other protein mutation studies. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2023
- Full Text:
Prediction of mass spectra using an ab initio approach
- Authors: Novokoza, Yolanda
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/${Handle} , vital:72818
- Description: Access restricted. Expected release date in 2025. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
- Authors: Novokoza, Yolanda
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/${Handle} , vital:72818
- Description: Access restricted. Expected release date in 2025. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
The heterologous expression and in vitro biochemical characterization of the Hsp70 escort protein 1 and mitochondrial Hsp70 partner proteins of the Trypanosoma brucei parasite and humans
- Authors: Mahlalela, Maduma Ernst
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431832 , vital:72807 , DOI 10.21504/10962/431832
- Description: The 70 kDa family of heat shock proteins (Hsp70) plays a central role in the maintenance of cellular proteostasis, with paralogues occurring in all the major compartments of the eukaryotic cell. Hsp70s act in conjunction with proteins known as co-chaperones, as part of the larger molecular chaperone network. In the mitochondrion, Hsp70 (mtHsp70) is responsible for the import of proteins synthesized in the cytosol, protein folding in the matrix and the maintenance of the iron-sulphur cluster. In human cells mtHsp70 (HSPA9) is also referred to as mortalin, as the knockdown of the protein leads to cell mortality. Trypanosoma brucei is the causative agent of sleeping sickness in humans and nagana in animals. In the T. brucei parasite there are three identical mtHsp70 (TbmtHsp70) proteins that are produced, forming part of the Hsp70 machinery that is essential for parasite survival. In humans, the levels of HSPA9 are often elevated in non-communicable diseases such as cancer and neurodegeneration. Despite their vital cellular roles, mtHsp70s are characteristically prone to self-aggregation. The binding of the Hsp70 escort protein (Hep1) is required to prevent the aggregation of mtHsp70 proteins, enabling the proteins to function. In many non-communicable diseases, mtHsp70 and other molecular chaperones such as heat shock protein 90 (Hsp90) are being investigated as potential drug targets. Existing anti-trypanosomal drugs for treating sleeping sickness are toxic, having adverse side effects that are potentially lethal. Investigations into Hsp70s, and other molecular chaperones, form part of the research into the discovery of novel and efficacious therapeutics. This is the first study to characterise Hep1 and investigate its partnership with mtHsp70 in T. brucei. The overall aim of this study was to comparatively assess the T. brucei and human mtHsp70/Hep1 partnerships. The putative T. brucei Hep1 (TbHep1) orthologue was analysed in silico, and it was found to possess a zinc finger domain consisting of anti-parallel β-sheets that are characteristic of canonical Hep1 proteins, whilst the N-terminal domain was unstructured. Based on sequence analysis, the regions outside of the zinc finger domains lacked conservation. Despite the lack of sequence conservation, the N- and C-terminal regions of TbHep1 shared segments of similarity with Hep1 orthologues of other kinetoplastid and trypanosomal orthologues. The same held true for the N- and C-termini of human Hep1 (HsHep1) when compared to other Hep1 orthologues of mammalian origin. Biochemical analysis revealed TbmtHsp70 and HSPA9 to be prone to self-aggregation, which was reduced by co-expression with TbHep1 and HsHep1, respectively. Recently Hep1 proteins have been determined to be present in the cytosol. In this study, TbHep1 and HsHep1 also interacted with the cytosolic Hsp70s, HSPA1A and TbHsp70, by preventing their thermally induced aggregation and stimulating their ATPase activities. TbHep1 and HsHep1 also suppressed the thermally induced aggregation of the model substrates malate dehydrogenase and citrate synthase, independently of Hsp70. To date, only two Hep1 orthologues, HsHep1 and LbHep1, have been found to function in a similar manner to a J-protein co-chaperone by stimulating the ATPase activities of their partner mtHsp70 proteins. In this study, TbHep1 stimulated the ATPase activity of TbmtHsp70. HsHep1 also stimulated the ATPase activity of TbmtHsp70. However, the mechanism of action still needs to be determined. This study also explored the potential of the Hep1 orthologues to be functionally activated by oxidative stress, which is prevalent in mitochondria. The abilities of TbHep1 and HsHep1 to reduce the thermally induced aggregation of malate dehydrogenase were enhanced under oxidative conditions. Disrupting the function of Hep1 has been found to eventually lead to cell death, and given the critical role played by mtHsp70 in the cell, this partnership could be exploited as a potential drug target. In conclusion, this study demonstrated that TbHep1 and HsHep1 functionally interact with mtHsp70s, whilst also possessing independent chaperone activities that are also potentially influenced by the environmental redox state. , Thesis (PhD) -- Faculty of Science, Biotechnology Innovation Centre, 2023
- Full Text:
- Authors: Mahlalela, Maduma Ernst
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431832 , vital:72807 , DOI 10.21504/10962/431832
- Description: The 70 kDa family of heat shock proteins (Hsp70) plays a central role in the maintenance of cellular proteostasis, with paralogues occurring in all the major compartments of the eukaryotic cell. Hsp70s act in conjunction with proteins known as co-chaperones, as part of the larger molecular chaperone network. In the mitochondrion, Hsp70 (mtHsp70) is responsible for the import of proteins synthesized in the cytosol, protein folding in the matrix and the maintenance of the iron-sulphur cluster. In human cells mtHsp70 (HSPA9) is also referred to as mortalin, as the knockdown of the protein leads to cell mortality. Trypanosoma brucei is the causative agent of sleeping sickness in humans and nagana in animals. In the T. brucei parasite there are three identical mtHsp70 (TbmtHsp70) proteins that are produced, forming part of the Hsp70 machinery that is essential for parasite survival. In humans, the levels of HSPA9 are often elevated in non-communicable diseases such as cancer and neurodegeneration. Despite their vital cellular roles, mtHsp70s are characteristically prone to self-aggregation. The binding of the Hsp70 escort protein (Hep1) is required to prevent the aggregation of mtHsp70 proteins, enabling the proteins to function. In many non-communicable diseases, mtHsp70 and other molecular chaperones such as heat shock protein 90 (Hsp90) are being investigated as potential drug targets. Existing anti-trypanosomal drugs for treating sleeping sickness are toxic, having adverse side effects that are potentially lethal. Investigations into Hsp70s, and other molecular chaperones, form part of the research into the discovery of novel and efficacious therapeutics. This is the first study to characterise Hep1 and investigate its partnership with mtHsp70 in T. brucei. The overall aim of this study was to comparatively assess the T. brucei and human mtHsp70/Hep1 partnerships. The putative T. brucei Hep1 (TbHep1) orthologue was analysed in silico, and it was found to possess a zinc finger domain consisting of anti-parallel β-sheets that are characteristic of canonical Hep1 proteins, whilst the N-terminal domain was unstructured. Based on sequence analysis, the regions outside of the zinc finger domains lacked conservation. Despite the lack of sequence conservation, the N- and C-terminal regions of TbHep1 shared segments of similarity with Hep1 orthologues of other kinetoplastid and trypanosomal orthologues. The same held true for the N- and C-termini of human Hep1 (HsHep1) when compared to other Hep1 orthologues of mammalian origin. Biochemical analysis revealed TbmtHsp70 and HSPA9 to be prone to self-aggregation, which was reduced by co-expression with TbHep1 and HsHep1, respectively. Recently Hep1 proteins have been determined to be present in the cytosol. In this study, TbHep1 and HsHep1 also interacted with the cytosolic Hsp70s, HSPA1A and TbHsp70, by preventing their thermally induced aggregation and stimulating their ATPase activities. TbHep1 and HsHep1 also suppressed the thermally induced aggregation of the model substrates malate dehydrogenase and citrate synthase, independently of Hsp70. To date, only two Hep1 orthologues, HsHep1 and LbHep1, have been found to function in a similar manner to a J-protein co-chaperone by stimulating the ATPase activities of their partner mtHsp70 proteins. In this study, TbHep1 stimulated the ATPase activity of TbmtHsp70. HsHep1 also stimulated the ATPase activity of TbmtHsp70. However, the mechanism of action still needs to be determined. This study also explored the potential of the Hep1 orthologues to be functionally activated by oxidative stress, which is prevalent in mitochondria. The abilities of TbHep1 and HsHep1 to reduce the thermally induced aggregation of malate dehydrogenase were enhanced under oxidative conditions. Disrupting the function of Hep1 has been found to eventually lead to cell death, and given the critical role played by mtHsp70 in the cell, this partnership could be exploited as a potential drug target. In conclusion, this study demonstrated that TbHep1 and HsHep1 functionally interact with mtHsp70s, whilst also possessing independent chaperone activities that are also potentially influenced by the environmental redox state. , Thesis (PhD) -- Faculty of Science, Biotechnology Innovation Centre, 2023
- Full Text:
The morphogenesis of higher education leadership: a social realist exploratory journey
- Authors: Andrews, Ruth
- Date: 2023-10-13
- Subjects: Educational leadership South Africa , Education, Higher South Africa , Critical realism , Social realism , Educational change South Africa , Transformational leadership
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/442897 , vital:74051 , DOI 10.21504/10962/442897
- Description: The purpose of the study underpinning this thesis was to explore the tensions experienced by university leaders as they balance politics, power and the academic project whilst pursuing their ultimate concerns in the world. Universities are undergoing constant change, particularly in the present time of hypercomplexity, where the discourses of globalisation and neoliberalism condition higher education institutions and their leaders. This predisposes universities to operate as a market economy rather than as a public good. University leaders are under immense pressure as they seek to reposition themselves and exercise their agency in steering their institutions in a landscape fraught with complexity and contestation about the very nature of the modern university. The study was located in a traditional university in South Africa, which added another layer of complexity given the history of Apartheid and, the use of education as a means of discriminating against the black majority population, and the subsequent attempts by the government to transform the system following the first democratic election of 1994. Bhaskar’s (1989) critical realism and Archer’s (1998, 2000) social realism were used to frame the study theoretically. Bhaskar argues for the understanding of the world as an ‘open system’ in which experiences and events emerge from the tendential interplay of mechanisms at a layer of reality not directly accessible to empirical observation. Archer’s (2000) social realism draws on critical realism to provide a set of tools that allows an exploration of the social world in more detail. This study draws on the tools of analytical dualism, or the temporary separation of structure, culture and agency for analytical purposes, and Archer’s (1998) morphogenetic framework, which allows for the exploration of change, or non-change, over time. The overarching goal of the study was to explore how leaders at one South African university were enabled and constrained as they exercised their agency in the pursuit of projects they had identified to address their ultimate concerns about the world more generally and higher education in particular. However, the study also sought to explore the construct of leadership itself in a specific context by using Archer’s (2007, 2012) theoretical work on reflexivity. The study drew on in-depth interviews with senior leaders at the institution, including two vice-chancellors. The interviews were subjected to analysis, and the inferential tools of abduction and retroduction were used to identify the interplay of mechanisms located at the level of the Real, the deepest layer of reality posited by Bhaskar (1978), which led to the events and experiences reported by leaders. A literature review was used to identify additional theories that were used in the processes of abduction and retroduction. The study revealed that change, or rather non-change, is often concealed in cultural rhetoric veiled in leadership practices in acts assimilating past ideology and codified rules and practices with new codified rules and practices. Leaders often draw on powerful relational networks as they reflexively exercise their agency, and these networks can also work to constrain change. , Thesis (PhD) -- Faculty of Education, Education 2023
- Full Text:
- Authors: Andrews, Ruth
- Date: 2023-10-13
- Subjects: Educational leadership South Africa , Education, Higher South Africa , Critical realism , Social realism , Educational change South Africa , Transformational leadership
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/442897 , vital:74051 , DOI 10.21504/10962/442897
- Description: The purpose of the study underpinning this thesis was to explore the tensions experienced by university leaders as they balance politics, power and the academic project whilst pursuing their ultimate concerns in the world. Universities are undergoing constant change, particularly in the present time of hypercomplexity, where the discourses of globalisation and neoliberalism condition higher education institutions and their leaders. This predisposes universities to operate as a market economy rather than as a public good. University leaders are under immense pressure as they seek to reposition themselves and exercise their agency in steering their institutions in a landscape fraught with complexity and contestation about the very nature of the modern university. The study was located in a traditional university in South Africa, which added another layer of complexity given the history of Apartheid and, the use of education as a means of discriminating against the black majority population, and the subsequent attempts by the government to transform the system following the first democratic election of 1994. Bhaskar’s (1989) critical realism and Archer’s (1998, 2000) social realism were used to frame the study theoretically. Bhaskar argues for the understanding of the world as an ‘open system’ in which experiences and events emerge from the tendential interplay of mechanisms at a layer of reality not directly accessible to empirical observation. Archer’s (2000) social realism draws on critical realism to provide a set of tools that allows an exploration of the social world in more detail. This study draws on the tools of analytical dualism, or the temporary separation of structure, culture and agency for analytical purposes, and Archer’s (1998) morphogenetic framework, which allows for the exploration of change, or non-change, over time. The overarching goal of the study was to explore how leaders at one South African university were enabled and constrained as they exercised their agency in the pursuit of projects they had identified to address their ultimate concerns about the world more generally and higher education in particular. However, the study also sought to explore the construct of leadership itself in a specific context by using Archer’s (2007, 2012) theoretical work on reflexivity. The study drew on in-depth interviews with senior leaders at the institution, including two vice-chancellors. The interviews were subjected to analysis, and the inferential tools of abduction and retroduction were used to identify the interplay of mechanisms located at the level of the Real, the deepest layer of reality posited by Bhaskar (1978), which led to the events and experiences reported by leaders. A literature review was used to identify additional theories that were used in the processes of abduction and retroduction. The study revealed that change, or rather non-change, is often concealed in cultural rhetoric veiled in leadership practices in acts assimilating past ideology and codified rules and practices with new codified rules and practices. Leaders often draw on powerful relational networks as they reflexively exercise their agency, and these networks can also work to constrain change. , Thesis (PhD) -- Faculty of Education, Education 2023
- Full Text:
Wildlife-vehicle collisions mitigation measures using road ecological data and deep learning
- Authors: Nandutu, Irene
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431907 , vital:72814
- Description: Access restricted. Expected release in 2025. , Thesis (PhD) -- Faculty of Science, Mathematics, 2023
- Full Text:
- Authors: Nandutu, Irene
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431907 , vital:72814
- Description: Access restricted. Expected release in 2025. , Thesis (PhD) -- Faculty of Science, Mathematics, 2023
- Full Text:
“How do you feel about the abortion?”: pre-termination of pregnancy counselling in the public health sector in the Eastern Cape
- Authors: Du Toit, Ryan Rudolph
- Date: 2023-10-13
- Subjects: Abortion counseling South Africa Eastern Cape , Conversation analysis , Discursive psychology , Public health South Africa , Reproductive justice , Abortion Psychological aspects
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/437238 , vital:73355 , DOI 10.21504/10962/437239
- Description: Pre-abortion counselling, as an aspect of abortion provision, has received growing research interest in various contexts. Much of the research has primarily focused on whether abortion counselling takes place, the experiences of women and/or counsellors (usually through retrospective interviews and surveys), and the content discussed during the counselling session (often policy regulated). Such research has proven vital to addressing the various reproductive issues facing women seeking an abortion worldwide. However, little research has focused on how pre-abortion counselling as an everyday institutional practice is conducted at a conversational level in the medical setting. By drawing on both conversation analysis and discursive psychology, this study explored how pre-abortion counselling was conducted in the public health sector in South Africa. The study involved recording the conversation during pre-abortion counselling and analysing it in terms of its content, in particular, the discourses drawn on by all parties involved, and its structure and delivery. The data were collected from three public hospitals in the Eastern Cape of South Africa and involved the audio recording of pre-abortion counselling sessions as part of abortion services. In total, 28 counselling sessions were recorded: 21 were individual sessions, and 7 were group counselling sessions. At two of the sites, counselling was conducted by registered midwives who worked at the hospital. At one site, an external Christian organisation volunteered trained counsellors to counsel women at the hospital free of charge. Using conversation analysis, counselling sessions were analysed in terms of the main projects. Seven key projects were identified: (1) Context setting, (2) History taking, (3) Establishing reason for abortion, (4) Presenting options, (5) Providing procedural information, (6) Obtaining verbal informed consent, and (7) Discussion of family planning. Each project is explored in terms of what discourses and subject positions featured when speakers were orienting to a specific project. This process highlighted how the conversational projects and their respective goals enable the deployment of certain problematic discourses and interactive/reflexive positionings. Discourse analysis revealed a clustering of discourses around two central themes. In the first clustering, the discourses were primarily used to discuss the (1) medically related issues underpinning the abortion procedure [medical discourse, responsibilization discourse, risk discourse, and discourse of support]. Talk using these discourses positioned women as patients needing medical intervention, responsibilised women for conceiving, playing an active role in their termination, and navigating all the psychological and physical risks “associated” with abortion. The discourse of support illustrates how support was spoken about in the interaction whereby patients were constructed as subjects who required support and nurses/counsellors as the ones who offered the support. In the second clustering, the discourses (2) focused on women and the foetus. These discourses [reproductive choice, religious, pronatalist, and foetal personhood discourses] positioned women as being responsible for making a choice regarding their pregnancy and the consequences that may result. In addition, a religious discourse coupled with a pronatalist discourse was used to construct the pregnancy and motherhood as desirable and part of “God’s plan”, whereas the foetus was spoken about as a “gift from God”. The foetal personhood discourse was used to construct the foetus as a living and functional human. This research provides evidence of how abortion counselling is problematic at various levels. At a practical level, there is a lack of standardisation in the delivery of abortion counselling (e.g., variation in key projects, where the counselling is mandated, time taken, nurse/counsellor training, content and format – group vs. individual counselling). At a discursive level, the use of certain discourses works to render the counselling directive through : (1) awfulizing abortion by providing misinformation about the abortion procedure, foetus and post-abortion psychological distress, (2) chastising and responsibilising women for conceiving, (3) constructing abortion as immoral, the ending of life and not in line with God’s plan, (4) constructing parenthood as the preferred choice, (5) delegitimising abortion as a resolution for pregnancy when compared to the other options (e.g., parenting or adoption), and finally (6) providing counselling that does not take into account the broader socio-political contexts. Recommendations for future research are put forward, and a call to move to a reparative justice framework is made by highlighting how it can be used to identify and understand reproductive injustices as they occur along four intersecting dimensions: (1) Individual material, (2) Collective material, (3) Individual symbolic, and (4) Collective symbolic. , Thesis (PhD) -- Faculty of Humanities, Psychology, 2023
- Full Text:
- Authors: Du Toit, Ryan Rudolph
- Date: 2023-10-13
- Subjects: Abortion counseling South Africa Eastern Cape , Conversation analysis , Discursive psychology , Public health South Africa , Reproductive justice , Abortion Psychological aspects
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/437238 , vital:73355 , DOI 10.21504/10962/437239
- Description: Pre-abortion counselling, as an aspect of abortion provision, has received growing research interest in various contexts. Much of the research has primarily focused on whether abortion counselling takes place, the experiences of women and/or counsellors (usually through retrospective interviews and surveys), and the content discussed during the counselling session (often policy regulated). Such research has proven vital to addressing the various reproductive issues facing women seeking an abortion worldwide. However, little research has focused on how pre-abortion counselling as an everyday institutional practice is conducted at a conversational level in the medical setting. By drawing on both conversation analysis and discursive psychology, this study explored how pre-abortion counselling was conducted in the public health sector in South Africa. The study involved recording the conversation during pre-abortion counselling and analysing it in terms of its content, in particular, the discourses drawn on by all parties involved, and its structure and delivery. The data were collected from three public hospitals in the Eastern Cape of South Africa and involved the audio recording of pre-abortion counselling sessions as part of abortion services. In total, 28 counselling sessions were recorded: 21 were individual sessions, and 7 were group counselling sessions. At two of the sites, counselling was conducted by registered midwives who worked at the hospital. At one site, an external Christian organisation volunteered trained counsellors to counsel women at the hospital free of charge. Using conversation analysis, counselling sessions were analysed in terms of the main projects. Seven key projects were identified: (1) Context setting, (2) History taking, (3) Establishing reason for abortion, (4) Presenting options, (5) Providing procedural information, (6) Obtaining verbal informed consent, and (7) Discussion of family planning. Each project is explored in terms of what discourses and subject positions featured when speakers were orienting to a specific project. This process highlighted how the conversational projects and their respective goals enable the deployment of certain problematic discourses and interactive/reflexive positionings. Discourse analysis revealed a clustering of discourses around two central themes. In the first clustering, the discourses were primarily used to discuss the (1) medically related issues underpinning the abortion procedure [medical discourse, responsibilization discourse, risk discourse, and discourse of support]. Talk using these discourses positioned women as patients needing medical intervention, responsibilised women for conceiving, playing an active role in their termination, and navigating all the psychological and physical risks “associated” with abortion. The discourse of support illustrates how support was spoken about in the interaction whereby patients were constructed as subjects who required support and nurses/counsellors as the ones who offered the support. In the second clustering, the discourses (2) focused on women and the foetus. These discourses [reproductive choice, religious, pronatalist, and foetal personhood discourses] positioned women as being responsible for making a choice regarding their pregnancy and the consequences that may result. In addition, a religious discourse coupled with a pronatalist discourse was used to construct the pregnancy and motherhood as desirable and part of “God’s plan”, whereas the foetus was spoken about as a “gift from God”. The foetal personhood discourse was used to construct the foetus as a living and functional human. This research provides evidence of how abortion counselling is problematic at various levels. At a practical level, there is a lack of standardisation in the delivery of abortion counselling (e.g., variation in key projects, where the counselling is mandated, time taken, nurse/counsellor training, content and format – group vs. individual counselling). At a discursive level, the use of certain discourses works to render the counselling directive through : (1) awfulizing abortion by providing misinformation about the abortion procedure, foetus and post-abortion psychological distress, (2) chastising and responsibilising women for conceiving, (3) constructing abortion as immoral, the ending of life and not in line with God’s plan, (4) constructing parenthood as the preferred choice, (5) delegitimising abortion as a resolution for pregnancy when compared to the other options (e.g., parenting or adoption), and finally (6) providing counselling that does not take into account the broader socio-political contexts. Recommendations for future research are put forward, and a call to move to a reparative justice framework is made by highlighting how it can be used to identify and understand reproductive injustices as they occur along four intersecting dimensions: (1) Individual material, (2) Collective material, (3) Individual symbolic, and (4) Collective symbolic. , Thesis (PhD) -- Faculty of Humanities, Psychology, 2023
- Full Text:
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