The relationship between human, social and financial capital and small and medium enterprise (SME) performance in South Africa
- Authors: Siso, Masiso Nomakha
- Date: 2024-10-11
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/462823 , vital:76338
- Description: The COVID-19 pandemic has had a severe impact on developing countries, exacerbating economic stagnation, high poverty rates, and unemployment. South Africa, in particular, faces significant challenges, with a 35.3 percent unemployment rate and a 17.4 percent GDP decline in 2021. Small and Medium Enterprises (SMEs) are crucial during these economic challenges, traditionally employing a substantial workforce and contributing significantly to the GDP. Despite their importance, SMEs often struggle, with a small percentage surviving the initial two years. Limited research has been conducted on the resources and capabilities crucial for enterprise performance in South Africa. While studies in developed countries exist, few explore the relationship between resources and capabilities facilitating SME performance in developing contexts. This study focuses on human capital, bonding, bridging, and linking social capital, and financial capital as key resources and capabilities. Given the backdrop that many entrepreneurs in South Africa may not possess formal education or extensive work experience, this study contends that financial literacy—encompassing financial knowledge, behaviour, and attitude—serves as a proxy for human capital. Additionally, a notable portion of entrepreneurs in South Africa face a deficit in the skills and knowledge essential for identifying entrepreneurial opportunities. Even among those possessing these capabilities, the challenge lies in the lack of necessary resources, including social and financial capital, to effectively transform such prospects into viable new ventures. This study employed a causal research design and adopted a quantitative research approach within a post-positivist paradigm. The primary objective was to investigate the relationship between the following independent variables; human (where financial literacy was used as a proxy which consisted of financial knowledge, attitude and behaviour), bonding, bridging and linking social capital, and financial capital and the dependent variable; SME performance. An online self-administered questionnaire was used to gather data from SME owners/managers. A pilot study was undertaken, in which an electronic link to the questionnaire was sent to potential respondents. Potential respondents were identified using purposive and convenience sampling methods. Data collection yielded 334 usable responses from SME owners/managers in South Africa. After cleaning the data, the analysis examined the relationship between independent and dependent variables. Confirmatory Factor Analysis (CFA) and Cronbach Alpha Coefficient analysis were used to confirm the validity and reliability of the measurement instrument, respectively. Descriptive statistics, regression, and correlation results were reported. Furthermore, a group mean analysis, including independent sample t-tests and one-way ANOVAs, were performed to investigate potential significant differences in variables based on demographic and enterprise related variables. The findings revealed a significant positive relationship between financial capital and SME performance. This indicates that an entrepreneur's ability to access financial capital or possess financial capital contributes to the performance and success of enterprises in South Africa. This finding underscores the crucial role of financial capital in facilitating the growth and sustainability of enterprises, as it provides a buffer against unfavourable economic shocks, enables entrepreneurs to pursue more capital-intensive strategies, and affords them more time to learn and overcome challenges. Conversely, no significant relationships were found between financial knowledge, behaviour, and attitude, bonding, bridging, and linking social capital, and SME performance. This study contributes to the development of SMEs in South Africa by identifying the critical resources and capabilities essential for their survival and growth. Additionally, it offers valuable recommendations for policymakers to create a conducive environment for entrepreneurs and suggests potential educational initiatives and support structures. Furthermore, this study advocates for the exploration of innovative financing approaches to build a financial cushion and bolster resilience against economic upheavals. , Thesis (MCom) -- Faculty of Commerce, Economics and Economic History, 2024
- Full Text:
- Authors: Siso, Masiso Nomakha
- Date: 2024-10-11
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/462823 , vital:76338
- Description: The COVID-19 pandemic has had a severe impact on developing countries, exacerbating economic stagnation, high poverty rates, and unemployment. South Africa, in particular, faces significant challenges, with a 35.3 percent unemployment rate and a 17.4 percent GDP decline in 2021. Small and Medium Enterprises (SMEs) are crucial during these economic challenges, traditionally employing a substantial workforce and contributing significantly to the GDP. Despite their importance, SMEs often struggle, with a small percentage surviving the initial two years. Limited research has been conducted on the resources and capabilities crucial for enterprise performance in South Africa. While studies in developed countries exist, few explore the relationship between resources and capabilities facilitating SME performance in developing contexts. This study focuses on human capital, bonding, bridging, and linking social capital, and financial capital as key resources and capabilities. Given the backdrop that many entrepreneurs in South Africa may not possess formal education or extensive work experience, this study contends that financial literacy—encompassing financial knowledge, behaviour, and attitude—serves as a proxy for human capital. Additionally, a notable portion of entrepreneurs in South Africa face a deficit in the skills and knowledge essential for identifying entrepreneurial opportunities. Even among those possessing these capabilities, the challenge lies in the lack of necessary resources, including social and financial capital, to effectively transform such prospects into viable new ventures. This study employed a causal research design and adopted a quantitative research approach within a post-positivist paradigm. The primary objective was to investigate the relationship between the following independent variables; human (where financial literacy was used as a proxy which consisted of financial knowledge, attitude and behaviour), bonding, bridging and linking social capital, and financial capital and the dependent variable; SME performance. An online self-administered questionnaire was used to gather data from SME owners/managers. A pilot study was undertaken, in which an electronic link to the questionnaire was sent to potential respondents. Potential respondents were identified using purposive and convenience sampling methods. Data collection yielded 334 usable responses from SME owners/managers in South Africa. After cleaning the data, the analysis examined the relationship between independent and dependent variables. Confirmatory Factor Analysis (CFA) and Cronbach Alpha Coefficient analysis were used to confirm the validity and reliability of the measurement instrument, respectively. Descriptive statistics, regression, and correlation results were reported. Furthermore, a group mean analysis, including independent sample t-tests and one-way ANOVAs, were performed to investigate potential significant differences in variables based on demographic and enterprise related variables. The findings revealed a significant positive relationship between financial capital and SME performance. This indicates that an entrepreneur's ability to access financial capital or possess financial capital contributes to the performance and success of enterprises in South Africa. This finding underscores the crucial role of financial capital in facilitating the growth and sustainability of enterprises, as it provides a buffer against unfavourable economic shocks, enables entrepreneurs to pursue more capital-intensive strategies, and affords them more time to learn and overcome challenges. Conversely, no significant relationships were found between financial knowledge, behaviour, and attitude, bonding, bridging, and linking social capital, and SME performance. This study contributes to the development of SMEs in South Africa by identifying the critical resources and capabilities essential for their survival and growth. Additionally, it offers valuable recommendations for policymakers to create a conducive environment for entrepreneurs and suggests potential educational initiatives and support structures. Furthermore, this study advocates for the exploration of innovative financing approaches to build a financial cushion and bolster resilience against economic upheavals. , Thesis (MCom) -- Faculty of Commerce, Economics and Economic History, 2024
- Full Text:
Rapid Synthesis of Thiol-Co-Capped CdTe/CdSe/ZnSe Multi-Core-Shell QDs and Their Encapsulation in Liposomes and Chitosan Nanoparticles; Comparative Bio-compatibility Studies Using Hela and Vero Cells
- Authors: Daramola, Olamide Abiodun
- Date: 2023-03-31
- Subjects: Chitosan , Chitosan nanoparticles , Quantum dots , Liposomes , Toxicity , Cadmium telluride , Cadmium selenide , Zinc selenide
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422617 , vital:71962 , DOI 10.21504/10962/422617
- Description: The common method that has been used to reduce the toxicity posed to living cells by CdTe Quantum Dots (QDs) is through the synthesis of CdTe multi-core-shells nanoparticles. In this process, the surface of CdTe QDs is usually coated by less toxic ZnS or ZnSe shells. This heterostructure compound does not only reduce the toxicity of CdTe QDs but can also be used in applications such as deep tissue imaging. The heterostructures can be in numerous forms such as CdTe/CdSe/ZnSe or CdTe/CdSe/ZnS or CdTe/CdS/ZnS multi-core-shell QDs. However, the drawbacks attributed to the fabrication of these compounds is long synthesis times (6- 24 h) in achieving the highest wavelength emission maxima. Others are the use of toxic reagents and poor reproducibility of synthesized materials. An additional problem is that the ZnSe or ZnS coating is insufficient to completely protect the highly toxic Cd metal from escaping into immediate solution. This limits their use in biochemistry and with living systems. Liposomes and biopolymers such as chitosan are known to be environmentally friendly compounds that have been used in various studies as delivery systems for QDs and model drugs for drug delivery applications. They are generally non-toxic and highly bio-compatible. In this study, the rapid synthesis of thiol-co-capped CdTe/CdSe/ZnSe multi-core-shell QDs with a maximum reaction time of 35 mins, gave reliable QDs with emission maxima at 625 nm. The multi-core-shell QDs were encapsulated in two different bio-compatible environments, namely liposome and chitosan nanoparticles (CNP) at 14 different formulations (F) for liposome and 12 different formulations for CNP. Cytotoxicity and florescence imaging studies using HeLa and Vero cells, were used to investigate the improved bio-compatibility. Various characterization techniques were used to elucidate the optical properties, morphology and physico-chemical properties of the QDs and nanocomposites. Two of the best formulations, QD-liposome vesicles (LVs)-F12 and QD-CNP-F9 (with chitosan), demonstrated high loading efficiencies of 42 ± 6 % and 59 ± 5 %, respectively. While the plain CdTe QDs showed high toxicity, some of the encapsulated materials, QD-LVs-F1 and F12, depicted no-toxicity against the cells (IC50 > 0.5 mg/ml). The QDs also retained most of their fluorescence and properties and could easily be tracked in cells and visualized around the nucleus, indicating the successful internalization of the QDs in the cytosol. These results shows that encapsulation of CdTe multi-core-shell QDs in liposomes produce better bio-compatibility compared to multi-core-shell QDs and better than CNP coating. These particles therefore show good promise in cell-labelling, drug delivery studies. Their core-shell nanoparticles have also shown good behavior in enhancing the memory of a device which is based on some recent collaborated works. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
- Authors: Daramola, Olamide Abiodun
- Date: 2023-03-31
- Subjects: Chitosan , Chitosan nanoparticles , Quantum dots , Liposomes , Toxicity , Cadmium telluride , Cadmium selenide , Zinc selenide
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422617 , vital:71962 , DOI 10.21504/10962/422617
- Description: The common method that has been used to reduce the toxicity posed to living cells by CdTe Quantum Dots (QDs) is through the synthesis of CdTe multi-core-shells nanoparticles. In this process, the surface of CdTe QDs is usually coated by less toxic ZnS or ZnSe shells. This heterostructure compound does not only reduce the toxicity of CdTe QDs but can also be used in applications such as deep tissue imaging. The heterostructures can be in numerous forms such as CdTe/CdSe/ZnSe or CdTe/CdSe/ZnS or CdTe/CdS/ZnS multi-core-shell QDs. However, the drawbacks attributed to the fabrication of these compounds is long synthesis times (6- 24 h) in achieving the highest wavelength emission maxima. Others are the use of toxic reagents and poor reproducibility of synthesized materials. An additional problem is that the ZnSe or ZnS coating is insufficient to completely protect the highly toxic Cd metal from escaping into immediate solution. This limits their use in biochemistry and with living systems. Liposomes and biopolymers such as chitosan are known to be environmentally friendly compounds that have been used in various studies as delivery systems for QDs and model drugs for drug delivery applications. They are generally non-toxic and highly bio-compatible. In this study, the rapid synthesis of thiol-co-capped CdTe/CdSe/ZnSe multi-core-shell QDs with a maximum reaction time of 35 mins, gave reliable QDs with emission maxima at 625 nm. The multi-core-shell QDs were encapsulated in two different bio-compatible environments, namely liposome and chitosan nanoparticles (CNP) at 14 different formulations (F) for liposome and 12 different formulations for CNP. Cytotoxicity and florescence imaging studies using HeLa and Vero cells, were used to investigate the improved bio-compatibility. Various characterization techniques were used to elucidate the optical properties, morphology and physico-chemical properties of the QDs and nanocomposites. Two of the best formulations, QD-liposome vesicles (LVs)-F12 and QD-CNP-F9 (with chitosan), demonstrated high loading efficiencies of 42 ± 6 % and 59 ± 5 %, respectively. While the plain CdTe QDs showed high toxicity, some of the encapsulated materials, QD-LVs-F1 and F12, depicted no-toxicity against the cells (IC50 > 0.5 mg/ml). The QDs also retained most of their fluorescence and properties and could easily be tracked in cells and visualized around the nucleus, indicating the successful internalization of the QDs in the cytosol. These results shows that encapsulation of CdTe multi-core-shell QDs in liposomes produce better bio-compatibility compared to multi-core-shell QDs and better than CNP coating. These particles therefore show good promise in cell-labelling, drug delivery studies. Their core-shell nanoparticles have also shown good behavior in enhancing the memory of a device which is based on some recent collaborated works. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
- Full Text:
An investigation of how a visual teaching approach can possibly address issues of mathematics anxiety at a selected school in the Oshikoto region of Namibia
- Ngonga, Daniel Nghifikepunye
- Authors: Ngonga, Daniel Nghifikepunye
- Date: 2022-04-08
- Subjects: Visual learning Namibia , Math anxiety Namibia , Mathematics Study and teaching Namibia , After-school programs Namibia , Mathematics Study and teaching Activity programs
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290637 , vital:56770
- Description: This Namibian case study aimed to explore a visual teaching approach (VTA) used by three selected teachers to address issues of mathematics anxiety (MA). The three teachers took part in an intervention program that was looking at how a VTA could be grown in the context of an after-school club (ASC) at my school. The selected teachers were the senior primary teachers at my school. The focus of the research was on how they taught mathematics using visuals after participating in an intervention programme. Their VTA made use of manipulatives, visuals, and concrete materials. The learners of the participating teachers completed a big MA pre-test, small MA tests, and a big MA post-test to determine their levels of MA as the teaching programme unfolded. The study hoped to create awareness amongst teachers and education researchers about the significant use of a VTA in the teaching and learning of mathematics to address issues of MA among the learners. It aimed to answer three research questions. One was on teachers’ use of a VTA in the context of an ASC; the second one was on comparisons of learners’ MA big pre and post-tests to detect any change of MA, and the last was on the enabling and constraining factors encountered when using a VTA. The main argument was that a VTA can encourage learners to be more confident and less anxious about doing mathematics. This study was framed by a constructivist perspective and its design and methodology were underpinned by an interpretive paradigm. This mixed-method research study employed video-recorded observations and stimulated recall interviews, learners’ MA test results, and the teachers’ focus group interviews as the means of collecting data. To generate rich data and support validity, four lessons per selected teacher were observed and video recorded; 54 learners completed the MA tests of 16 questions, and three teachers answered seven questions each in the focus group interview (FGI) after the stimulus recall interviews (SRI) which were done immediately after the lesson presentations. The study found that the participating teachers incorporated a variety of visuals into their lessons to make the mathematics fun, inspiring, visible, hands-on, and activity-oriented. They engaged the learners and also found that the use of visuals motivated learners and reduced their MA. , Thesis (MED) -- Faculty of Education, Education, 2022
- Full Text:
- Authors: Ngonga, Daniel Nghifikepunye
- Date: 2022-04-08
- Subjects: Visual learning Namibia , Math anxiety Namibia , Mathematics Study and teaching Namibia , After-school programs Namibia , Mathematics Study and teaching Activity programs
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/290637 , vital:56770
- Description: This Namibian case study aimed to explore a visual teaching approach (VTA) used by three selected teachers to address issues of mathematics anxiety (MA). The three teachers took part in an intervention program that was looking at how a VTA could be grown in the context of an after-school club (ASC) at my school. The selected teachers were the senior primary teachers at my school. The focus of the research was on how they taught mathematics using visuals after participating in an intervention programme. Their VTA made use of manipulatives, visuals, and concrete materials. The learners of the participating teachers completed a big MA pre-test, small MA tests, and a big MA post-test to determine their levels of MA as the teaching programme unfolded. The study hoped to create awareness amongst teachers and education researchers about the significant use of a VTA in the teaching and learning of mathematics to address issues of MA among the learners. It aimed to answer three research questions. One was on teachers’ use of a VTA in the context of an ASC; the second one was on comparisons of learners’ MA big pre and post-tests to detect any change of MA, and the last was on the enabling and constraining factors encountered when using a VTA. The main argument was that a VTA can encourage learners to be more confident and less anxious about doing mathematics. This study was framed by a constructivist perspective and its design and methodology were underpinned by an interpretive paradigm. This mixed-method research study employed video-recorded observations and stimulated recall interviews, learners’ MA test results, and the teachers’ focus group interviews as the means of collecting data. To generate rich data and support validity, four lessons per selected teacher were observed and video recorded; 54 learners completed the MA tests of 16 questions, and three teachers answered seven questions each in the focus group interview (FGI) after the stimulus recall interviews (SRI) which were done immediately after the lesson presentations. The study found that the participating teachers incorporated a variety of visuals into their lessons to make the mathematics fun, inspiring, visible, hands-on, and activity-oriented. They engaged the learners and also found that the use of visuals motivated learners and reduced their MA. , Thesis (MED) -- Faculty of Education, Education, 2022
- Full Text:
Application of computer-aided drug design for identification of P. falciparum inhibitors
- Authors: Diallo, Bakary N’tji
- Date: 2021-10-29
- Subjects: Plasmodium falciparum , Malaria -- Chemotherapy , Molecular dynamics , Antimalarials , Cheminformatics , Drug development , Ligand binding (Biochemistry) , Plasmodium falciparum1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) , South African Natural Compounds Database
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/192798 , vital:45265 , 10.21504/10962/192798
- Description: Malaria is a millennia-old disease with the first recorded cases dating back to 2700 BC found in Chinese medical records, and later in other civilizations. It has claimed human lives to such an extent that there are a notable associated socio-economic consequences. Currently, according to the World Health Organization (WHO), Africa holds the highest disease burden with 94% of deaths and 82% of cases with P. falciparum having ~100% prevalence. Chemotherapy, such as artemisinin combination therapy, has been and continues to be the work horse in the fight against the disease, together with seasonal malaria chemoprevention and the use of insecticides. Natural products such as quinine and artemisinin are particularly important in terms of their antimalarial activity. The emphasis in current chemotherapy research is the need for time and cost-effective workflows focussed on new mechanisms of action (MoAs) covering the target candidate profiles (TCPs). Despite a decline in cases over the past decades with, countries increasingly becoming certified malaria free, a stalling trend has been observed in the past five years resulting in missing the 2020 Global Technical Strategy (GTS) milestones. With no effective vaccine, a reduction in funding, slower drug approval than resistance emergence from resistant and invasive vectors, and threats in diagnosis with the pfhrp2/3 gene deletion, malaria remains a major health concern. Motivated by these reasons, the primary aim of this work was a contribution to the antimalarial pipeline through in silico approaches focusing on P. falciparum. We first intended an exploration of malarial targets through a proteome scale screening on 36 targets using multiple metrics to account for the multi-objective nature of drug discovery. The continuous growth of structural data offers the ideal scenario for mining new MoAs covering antimalarials TCPs. This was combined with a repurposing strategy using a set of orally available FDA approved drugs. Further, use was made of time- and cost-effective strategies combining QVina-W efficiency metrics that integrate molecular properties, GRIM rescoring for molecular interactions and a hydrogen mass repartitioning (HMR) molecular dynamics (MD) scheme for accelerated development of antimalarials in the context of resistance. This pipeline further integrates a complex ranking for better drug-target selectivity, and normalization strategies to overcome docking scoring function bias. The different metrics, ranking, normalization strategies and their combinations were first assessed using their mean ranking error (MRE). A version combining all metrics was used to select 36 unique protein-ligand complexes, assessed in MD, with the final retention of 25. From the 16 in vitro tested hits of the 25, fingolimod, abiraterone, prazosin, and terazosin showed antiplasmodial activity with IC50 2.21, 3.37, 16.67 and 34.72 μM respectively and of these, only fingolimod was found to be not safe with respect to human cell viability. These compounds were predicted active on different molecular targets, abiraterone was predicted to interact with a putative liver-stage essential target, hence promising as a transmission-blocking agent. The pipeline had a promising 25% hit rate considering the proteome-scale and use of cost-effective approaches. Secondly, we focused on Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) using a more extensive screening pipeline to overcome some of the current in silico screening limitations. Starting from the ZINC lead-like library of ~3M, hierarchical ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches with molecular docking and re-scoring using eleven scoring functions (SFs) were used. Later ranking with an exponential consensus strategy was included. Selected hits were further assessed through Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), advanced MD sampling in a ligand pulling simulations and (Weighted Histogram Analysis Method) WHAM analysis for umbrella sampling (US) to derive binding free energies. Four leads had better predicted affinities in US than LC5, a 280 nM potent PfDXR inhibitor with ZINC000050633276 showing a promising binding of -20.43 kcal/mol. As shown with fosmidomycin, DXR inhibition offers fast acting compounds fulfilling antimalarials TCP1. Yet, fosmidomycin has a high polarity causing its short half-life and hampering its clinical use. These leads scaffolds are different from fosmidomycin and hence may offer better pharmacokinetic and pharmacodynamic properties and may also be promising for lead optimization. A combined analysis of residues’ contributions to the free energy of binding in MM-PBSA and to steered molecular dynamics (SMD) Fmax indicated GLU233, CYS268, SER270, TRP296, and HIS341 as exploitable for compound optimization. Finally, we updated the SANCDB library with new NPs and their commercially available analogs as a solution to NP availability. The library is extended to 1005 compounds from its initial 600 compounds and the database is integrated to Mcule and Molport APIs for analogs automatic update. The new set may contribute to virtual screening and to antimalarials as the most effective ones have NP origin. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
- Authors: Diallo, Bakary N’tji
- Date: 2021-10-29
- Subjects: Plasmodium falciparum , Malaria -- Chemotherapy , Molecular dynamics , Antimalarials , Cheminformatics , Drug development , Ligand binding (Biochemistry) , Plasmodium falciparum1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) , South African Natural Compounds Database
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/192798 , vital:45265 , 10.21504/10962/192798
- Description: Malaria is a millennia-old disease with the first recorded cases dating back to 2700 BC found in Chinese medical records, and later in other civilizations. It has claimed human lives to such an extent that there are a notable associated socio-economic consequences. Currently, according to the World Health Organization (WHO), Africa holds the highest disease burden with 94% of deaths and 82% of cases with P. falciparum having ~100% prevalence. Chemotherapy, such as artemisinin combination therapy, has been and continues to be the work horse in the fight against the disease, together with seasonal malaria chemoprevention and the use of insecticides. Natural products such as quinine and artemisinin are particularly important in terms of their antimalarial activity. The emphasis in current chemotherapy research is the need for time and cost-effective workflows focussed on new mechanisms of action (MoAs) covering the target candidate profiles (TCPs). Despite a decline in cases over the past decades with, countries increasingly becoming certified malaria free, a stalling trend has been observed in the past five years resulting in missing the 2020 Global Technical Strategy (GTS) milestones. With no effective vaccine, a reduction in funding, slower drug approval than resistance emergence from resistant and invasive vectors, and threats in diagnosis with the pfhrp2/3 gene deletion, malaria remains a major health concern. Motivated by these reasons, the primary aim of this work was a contribution to the antimalarial pipeline through in silico approaches focusing on P. falciparum. We first intended an exploration of malarial targets through a proteome scale screening on 36 targets using multiple metrics to account for the multi-objective nature of drug discovery. The continuous growth of structural data offers the ideal scenario for mining new MoAs covering antimalarials TCPs. This was combined with a repurposing strategy using a set of orally available FDA approved drugs. Further, use was made of time- and cost-effective strategies combining QVina-W efficiency metrics that integrate molecular properties, GRIM rescoring for molecular interactions and a hydrogen mass repartitioning (HMR) molecular dynamics (MD) scheme for accelerated development of antimalarials in the context of resistance. This pipeline further integrates a complex ranking for better drug-target selectivity, and normalization strategies to overcome docking scoring function bias. The different metrics, ranking, normalization strategies and their combinations were first assessed using their mean ranking error (MRE). A version combining all metrics was used to select 36 unique protein-ligand complexes, assessed in MD, with the final retention of 25. From the 16 in vitro tested hits of the 25, fingolimod, abiraterone, prazosin, and terazosin showed antiplasmodial activity with IC50 2.21, 3.37, 16.67 and 34.72 μM respectively and of these, only fingolimod was found to be not safe with respect to human cell viability. These compounds were predicted active on different molecular targets, abiraterone was predicted to interact with a putative liver-stage essential target, hence promising as a transmission-blocking agent. The pipeline had a promising 25% hit rate considering the proteome-scale and use of cost-effective approaches. Secondly, we focused on Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) using a more extensive screening pipeline to overcome some of the current in silico screening limitations. Starting from the ZINC lead-like library of ~3M, hierarchical ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches with molecular docking and re-scoring using eleven scoring functions (SFs) were used. Later ranking with an exponential consensus strategy was included. Selected hits were further assessed through Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), advanced MD sampling in a ligand pulling simulations and (Weighted Histogram Analysis Method) WHAM analysis for umbrella sampling (US) to derive binding free energies. Four leads had better predicted affinities in US than LC5, a 280 nM potent PfDXR inhibitor with ZINC000050633276 showing a promising binding of -20.43 kcal/mol. As shown with fosmidomycin, DXR inhibition offers fast acting compounds fulfilling antimalarials TCP1. Yet, fosmidomycin has a high polarity causing its short half-life and hampering its clinical use. These leads scaffolds are different from fosmidomycin and hence may offer better pharmacokinetic and pharmacodynamic properties and may also be promising for lead optimization. A combined analysis of residues’ contributions to the free energy of binding in MM-PBSA and to steered molecular dynamics (SMD) Fmax indicated GLU233, CYS268, SER270, TRP296, and HIS341 as exploitable for compound optimization. Finally, we updated the SANCDB library with new NPs and their commercially available analogs as a solution to NP availability. The library is extended to 1005 compounds from its initial 600 compounds and the database is integrated to Mcule and Molport APIs for analogs automatic update. The new set may contribute to virtual screening and to antimalarials as the most effective ones have NP origin. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Full Text:
Ilmenite megacryst-hosted melt inclusions from the Monastery kimberlite: implications for kimberlite origins
- Authors: Van Huyssteen, Aiden
- Date: 2021-04
- Subjects: To be added
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/178387 , vital:42935
- Description: Polymineralic inclusions encapsulating a daughter assemblage of crystalline phases (including silicates, oxides, and carbonates) and an amorphous glass phase, hosted in ilmenite megacrysts from the Monastery kimberlite, were investigated texturally and geochemically in order to constrain their melt origin, modeof formation, and evolution prior to quenching. The isolated nature of the melt inclusions within the ilmenite megacrysts provides an opportunity to study components of primary kimberlitic magma captured within the SCLM (4.5–6 GPa) that has been isolated from pervasive modifying processes that are common in kimberlites. The common daughter phase assemblage within the melt inclusions comprises serpentine, phlogopite, calcite, spinel, kassite, perovskite, ilmenite, and glass. The glass is Si-Mg-Fe-rich, with low Al2O3 contents. It is also K2O- and TiO2-free, with variably depleted REE. In composition, serpentine forms a crystalline equivalent to the glass. However, these phases are optically distinct. Serpentine represents two modes of formation: (i) discrete euhedral grains set within a glass matrix that represent a primary phase, crystallising directly from the entrapped melts, and (ii) as patches of partially crystallised glass that represent a secondary phase formed by the devitrification of the glass. Spinel and phlogopite form along early kimberlitic evolutionary trends and record the depletion of the melt in TiO2, Al2O3, and K2O, which typically decreases from the core to the rim of the crystals. Volatile and alkali-bearing minerals (calcite, apatite, phlogopite) crystallised within the melt inclusions from the captured alkali-rich carbonated-silicate kimberlite melt. The daughter mineral assemblage initially crystallised as euhedral and subhedral grains with a uniform composition under equilibrium conditions. Subsequent crystallisation formed grains that exhibit magmatic zoning due to their crystallisation in a progressively depleted melt. Lastly, the crystallisation of skeletal oxide grains occurred under disequilibrium conditions, at a stage of magma ascent with rapidly changing variables including temperature, melt viscosity, and diffusivity. Prior to complete crystallisation, the residual Si-Mg-Fe melt of this crystallisation process was quenched to form the observed glass. The phases that constitute the common daughter assemblage show large variations in modal proportions, forming a continuum from silicate-rich to carbonate-rich endmember inclusions, with certain daughter phases absent in some inclusions. This suggests that the melt was heterogenous at the time of capture and comprised immiscible silicic/oxidic and carbonate melts. Phase separation, therefore, may have started prior to capturing of magma batches as inclusions in ilmenite, but further segregation and crystallisation continued after these batches had become isolated from the megacryst matrix as melt inclusions. The immiscibility and co-existence of the silicic/oxidic and carbonate melts is preserved by textural features between calcite and glass, such as rounded globules of calcite grains set within a silicate glass matrix, calcite forming the matrix for euhedral silicate and oxide minerals, and calcite occupying the interior void of skeletal oxide grains set within a silicate glass matrix. Furthermore, spherulitic globular domains of Ca- and Ti-rich glasses set within a matrix of the Si-Mg-Fe glass suggest that the silicic/oxidic melt underwent further segregation into oxide-rich (Ca-Ti) and silicate-rich (Si-Mg-Fe-Al-K-Ti) melts, potentially crystallising the oxide and silicate minerals of the daughter assemblage, respectively. The abundance of incompatible trace elements and the Cr-poor composition of secondary low-Mg ilmenite as a daughter mineral within the melt inclusions (~1400 ppm Nb; <0.1 wt% Cr2O3; <0.1 wt% MgO), in addition to the Cr-poor composition of the other daughter phases within the inclusions (i.e. <0.1 wt% Cr2O3 for phlogopite and spinel), indicate that they crystallised from a similar melt as the Cr-poor, but high Mg-ilmenite megacrysts (~1400 ppm Nb; <0.1 wt% Cr2O3; ~10 wt% MgO). Furthermore, the melt inclusions are randomly distributed and no textural and/or geochemical evidence for melt infiltration of the ilmenite megacrysts was associated with the melt inclusions. These features are consistent with a primary origin for the melt inclusions which implies a cognate relationship between the megacrysts and the captured kimberlite melt. , Thesis (MSc) -- Faculty of Science, Geology, 2021
- Full Text:
- Authors: Van Huyssteen, Aiden
- Date: 2021-04
- Subjects: To be added
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/178387 , vital:42935
- Description: Polymineralic inclusions encapsulating a daughter assemblage of crystalline phases (including silicates, oxides, and carbonates) and an amorphous glass phase, hosted in ilmenite megacrysts from the Monastery kimberlite, were investigated texturally and geochemically in order to constrain their melt origin, modeof formation, and evolution prior to quenching. The isolated nature of the melt inclusions within the ilmenite megacrysts provides an opportunity to study components of primary kimberlitic magma captured within the SCLM (4.5–6 GPa) that has been isolated from pervasive modifying processes that are common in kimberlites. The common daughter phase assemblage within the melt inclusions comprises serpentine, phlogopite, calcite, spinel, kassite, perovskite, ilmenite, and glass. The glass is Si-Mg-Fe-rich, with low Al2O3 contents. It is also K2O- and TiO2-free, with variably depleted REE. In composition, serpentine forms a crystalline equivalent to the glass. However, these phases are optically distinct. Serpentine represents two modes of formation: (i) discrete euhedral grains set within a glass matrix that represent a primary phase, crystallising directly from the entrapped melts, and (ii) as patches of partially crystallised glass that represent a secondary phase formed by the devitrification of the glass. Spinel and phlogopite form along early kimberlitic evolutionary trends and record the depletion of the melt in TiO2, Al2O3, and K2O, which typically decreases from the core to the rim of the crystals. Volatile and alkali-bearing minerals (calcite, apatite, phlogopite) crystallised within the melt inclusions from the captured alkali-rich carbonated-silicate kimberlite melt. The daughter mineral assemblage initially crystallised as euhedral and subhedral grains with a uniform composition under equilibrium conditions. Subsequent crystallisation formed grains that exhibit magmatic zoning due to their crystallisation in a progressively depleted melt. Lastly, the crystallisation of skeletal oxide grains occurred under disequilibrium conditions, at a stage of magma ascent with rapidly changing variables including temperature, melt viscosity, and diffusivity. Prior to complete crystallisation, the residual Si-Mg-Fe melt of this crystallisation process was quenched to form the observed glass. The phases that constitute the common daughter assemblage show large variations in modal proportions, forming a continuum from silicate-rich to carbonate-rich endmember inclusions, with certain daughter phases absent in some inclusions. This suggests that the melt was heterogenous at the time of capture and comprised immiscible silicic/oxidic and carbonate melts. Phase separation, therefore, may have started prior to capturing of magma batches as inclusions in ilmenite, but further segregation and crystallisation continued after these batches had become isolated from the megacryst matrix as melt inclusions. The immiscibility and co-existence of the silicic/oxidic and carbonate melts is preserved by textural features between calcite and glass, such as rounded globules of calcite grains set within a silicate glass matrix, calcite forming the matrix for euhedral silicate and oxide minerals, and calcite occupying the interior void of skeletal oxide grains set within a silicate glass matrix. Furthermore, spherulitic globular domains of Ca- and Ti-rich glasses set within a matrix of the Si-Mg-Fe glass suggest that the silicic/oxidic melt underwent further segregation into oxide-rich (Ca-Ti) and silicate-rich (Si-Mg-Fe-Al-K-Ti) melts, potentially crystallising the oxide and silicate minerals of the daughter assemblage, respectively. The abundance of incompatible trace elements and the Cr-poor composition of secondary low-Mg ilmenite as a daughter mineral within the melt inclusions (~1400 ppm Nb; <0.1 wt% Cr2O3; <0.1 wt% MgO), in addition to the Cr-poor composition of the other daughter phases within the inclusions (i.e. <0.1 wt% Cr2O3 for phlogopite and spinel), indicate that they crystallised from a similar melt as the Cr-poor, but high Mg-ilmenite megacrysts (~1400 ppm Nb; <0.1 wt% Cr2O3; ~10 wt% MgO). Furthermore, the melt inclusions are randomly distributed and no textural and/or geochemical evidence for melt infiltration of the ilmenite megacrysts was associated with the melt inclusions. These features are consistent with a primary origin for the melt inclusions which implies a cognate relationship between the megacrysts and the captured kimberlite melt. , Thesis (MSc) -- Faculty of Science, Geology, 2021
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