A statistical study of travelling ionospheric disturbances over the African-European and American sectors
- Authors: Thaganyana, Golekamang Piet
- Date: 2023-03-31
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422541 , vital:71956 , DOI 10.21504/10962/422543
- Description: This research presents a long-term statistical study of travelling ionospheric disturbances (TIDs) of low- and high-latitude origin over the American and African-European sectors between 2010 and 2018. The TIDs of low latitude origin (hereafter known as poleward TIDs) were studied in both quiet and disturbed conditions, whereas the equatorward TIDs were only studied during quiet conditions. The Kp > 4 and Dst_ -50 nT was used as a criterion for geomagnetic disturbed conditions, while the four geomagnetically quiet days were selected each month based on Kp < 3. Observations of TIDs are made using Global Navigational Satellite Systems (GNSS) total electron content derived data. During quiet conditions, seven and two transhemispheric TIDs were identified over the African-European and American sectors, respectively. The observed TIDs originated from the wintertime hemisphere and propagated into the summertime hemisphere. The horizontal velocity, periods, and horizontal wavelengths of TIDs are in range of cH = 120-274 m/s, 48-80 min and _H = 379-1104 km, respectively. These quiet-time equatorward TIDs have been associated with tertiary gravity waves (GWs) from the dissipation of secondary GWs which are in turn generated from the dissipation of mountain waves (MWs) as a result of excited orographic forcing. The poleward TIDs during geomagnetically quiet conditions over the African and American sectors occur mainly during local daytime. Poleward TIDs were observed mostly in the African-European sector than the American sector. Their horizontal propagation velocities and periods range between 129-280 m/s and 39-70 min over African-European and American sectors. Although the mechanisms responsible for launching quiet-time poleward TIDs have not been established in this study, lower atmospheric processes such as convection systems, sudden stratospheric warming and cold weather fronts may have a role in their generation. During geomagnetic storms in the African sector, almost all poleward TIDs (with the exception of two cases) during the main phase were large-scale with horizontal velocities and periods ranging from 250-503 m/s and 30 min to 2 hours. During recovery phase, poleward TIDs fall under the category of medium scale. In the American sector, the majority of poleward TIDs occurred during the storm's main phase, as opposed to the African-European sector, which experienced a significant number of poleward TIDs during the recovery phase. The periods and horizontal velocities of TIDs range from 45 min-1.5 h and 180-296 m/s during main phase. During the recovery phase, the horizontal velocity and period range from 177-271 m/s and 40-1.5 h, respectively. Overall, it has been shown that statistically, changes in equatorial electrodynamics related to enhanced eastward electric _eld and hence increased equatorial electrojet (vertical E_B drift) correlates highly with the reported poleward TIDs. , Thesis (PhD) -- Faculty of Science, Physics and Electronics, 2023
- Full Text:
- Authors: Thaganyana, Golekamang Piet
- Date: 2023-03-31
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/422541 , vital:71956 , DOI 10.21504/10962/422543
- Description: This research presents a long-term statistical study of travelling ionospheric disturbances (TIDs) of low- and high-latitude origin over the American and African-European sectors between 2010 and 2018. The TIDs of low latitude origin (hereafter known as poleward TIDs) were studied in both quiet and disturbed conditions, whereas the equatorward TIDs were only studied during quiet conditions. The Kp > 4 and Dst_ -50 nT was used as a criterion for geomagnetic disturbed conditions, while the four geomagnetically quiet days were selected each month based on Kp < 3. Observations of TIDs are made using Global Navigational Satellite Systems (GNSS) total electron content derived data. During quiet conditions, seven and two transhemispheric TIDs were identified over the African-European and American sectors, respectively. The observed TIDs originated from the wintertime hemisphere and propagated into the summertime hemisphere. The horizontal velocity, periods, and horizontal wavelengths of TIDs are in range of cH = 120-274 m/s, 48-80 min and _H = 379-1104 km, respectively. These quiet-time equatorward TIDs have been associated with tertiary gravity waves (GWs) from the dissipation of secondary GWs which are in turn generated from the dissipation of mountain waves (MWs) as a result of excited orographic forcing. The poleward TIDs during geomagnetically quiet conditions over the African and American sectors occur mainly during local daytime. Poleward TIDs were observed mostly in the African-European sector than the American sector. Their horizontal propagation velocities and periods range between 129-280 m/s and 39-70 min over African-European and American sectors. Although the mechanisms responsible for launching quiet-time poleward TIDs have not been established in this study, lower atmospheric processes such as convection systems, sudden stratospheric warming and cold weather fronts may have a role in their generation. During geomagnetic storms in the African sector, almost all poleward TIDs (with the exception of two cases) during the main phase were large-scale with horizontal velocities and periods ranging from 250-503 m/s and 30 min to 2 hours. During recovery phase, poleward TIDs fall under the category of medium scale. In the American sector, the majority of poleward TIDs occurred during the storm's main phase, as opposed to the African-European sector, which experienced a significant number of poleward TIDs during the recovery phase. The periods and horizontal velocities of TIDs range from 45 min-1.5 h and 180-296 m/s during main phase. During the recovery phase, the horizontal velocity and period range from 177-271 m/s and 40-1.5 h, respectively. Overall, it has been shown that statistically, changes in equatorial electrodynamics related to enhanced eastward electric _eld and hence increased equatorial electrojet (vertical E_B drift) correlates highly with the reported poleward TIDs. , Thesis (PhD) -- Faculty of Science, Physics and Electronics, 2023
- Full Text:
An in-depth investigation of an early literacy intervention in Grade R in the Eastern Cape Province, South Africa
- Authors: Hodgskiss, Jennifer Adelé
- Date: 2023-03-29
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/366222 , vital:65844
- Description: Thesis embargoed. Expected release date early 2025. , Thesis (PhD) -- Faculty of Education, Education, 2023
- Full Text:
- Authors: Hodgskiss, Jennifer Adelé
- Date: 2023-03-29
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/366222 , vital:65844
- Description: Thesis embargoed. Expected release date early 2025. , Thesis (PhD) -- Faculty of Education, Education, 2023
- Full Text:
Identification of novel compounds against Plasmodium falciparum Cytochrome bc1 Complex inhibiting the trans-membrane electron transfer pathway: an In Silico study
- Authors: Chebon, Lorna Jemosop
- Date: 2022-10-14
- Subjects: Malaria , Plasmodium falciparum , Molecular dynamics , Antimalarials , Molecules Models , Docking , Cytochromes , Drug resistance , Computer simulation , Drugs Computer-aided design , System analysis
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/365666 , vital:65774 , DOI https://doi.org/10.21504/10962/365666
- Description: Malaria continues to be a burden globally with a myriad of challenges deterring eradication efforts. With most antimalarials facing drug resistance, such as atovaquone (ATQ), alternative compounds that can withstand resistance are warranted. The Plasmodium falciparum cytochrome b (PfCytb), a subunit of P. falciparum cytochrome bc1 complex, is a validated drug target. Structurally, cytochrome b, cytochrome c1, and iron sulphur protein (ISP) subunits form the catalytic domain of the protein complex having heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors. These cofactos have redox centres to aid in the electron transfer (ET) process. These subunits promote ET mainly through the enzyme’s ubiquinol oxidation (Qo) and ubiquinone reduction (Qi) processes in the catalytic domain. ATQ drug has been used in the prevention and treatment of uncomplicated malaria by targeting PfCytb protein. Once the mitochondrial transmembrane ET pathway is inhibited, it causes a collapse in its membrane potential. Previously reported ATQ drug resistance has been associated with the point mutations Y268C, Y268N and Y268S. Thus, in finding alternatives to the ATQ drug, this research aimed to: i) employ in silico approaches incorporating protein into phospholipid bilayer for the first time to understand the parasites’ resistance mechanism; ii) determine any sequence and structural differences that could be explored in drug design studies; and iii) screen for PfCytb-iron sulphur protein (Cytb-ISP) hit compounds from South African natural compound database (SANCDB) and Medicines for Malaria Venture (MMV) that can withstand the identified mutations. Using computational tools, comparative sequence and structural analyses were performed on the cytochrome b protein, where the ultimate focus was on P. falciparum cytochrome b and its human homolog. Through multiple sequence alignment, motif discovery and phylogeny, differences between P. falciparum and H. sapiens cytochrome b were identified. Protein modelling of both P. falciparum and H. sapiens cytochrome b - iron sulphur protein (PfCytb-ISP and HsCytb-ISP) was performed. Results showed that at the sequence level, there were few amino acid residue differences because the protein is highly conserved. Important to note is the four-residue deletion in Plasmodium spp. absent in the human homolog. Motif analysis discovered five unique motifs in P. falciparum cytochrome b protein which were mapped onto the predicted protein model. These motifs were not in regions of functional importance; hence their function is still unknown. At a structural level, the four-residue deletion was observed to alter the Qo substrate binding pocket as reported in previous studies and confirmed in this study. This deletion resulted in a 0.83 Å structural displacement. Also, there are currently no in silico studies that have performed experiments with P. falciparum cytochrome b protein incorporated into a phospholipid bilayer. Using 350 ns molecular dynamics (MD) simulations of the holo and ATQ-bound systems, the study highlighted the resistance mechanism of the parasite protein where the loss of active site residue-residue interactions was identified, all linked to the three mutations. The identified compromised interactions are likely to destabilise the protein’s function, specifically in the Qo substrate binding site. This showed the possible effect of mutations on ATQ drug activity, where all three mutations were reported to share a similar resistance mechanism. Thereafter, this research work utilised in silico approaches where both Qo active site and interface pocket were targeted by screening the South African natural compounds database (SANCDB) and Medicines for Malaria Venture (MMV) compounds to identify novel selective hits. SANCDB compounds are known for their structural complexity that preserves the potency of the drug molecule. Both SANCDB and MMV compounds have not been explored as inhibitors against the PfCytb drug target. Molecular docking, molecular dynamics (MD) simulations, principal component, and dynamic residue network (DRN; global and local) analyses were utilised to identify and confirm the potential selective inhibitors. Docking results identified compounds that bound selectively onto PfCytb-ISP with a binding energy ≤ -8.7 kcal/mol-1. Further, this work validated a total of eight potential selective compounds to inhibit PfCytb-ISP protein (Qo active site) not only in the wild-type but also in the presence of the point mutations Y268C, Y268N and Y268S. The selective binding of these hit compounds could be linked to the differences reported at sequence/residue level in chapter 3. DRN and residue contact map analyses of the eight compounds in holo and ligand-bound systems revealed reduced residue interactions and decreased protein communication. This suggests that the eight compounds show the possibility of inhibiting the parasite and disrupting important residue-residue interactions. Additionally, 13 selective compounds were identified to bind at the protein’s heterodimer interface, where global and local analysis confirmed their effect on active site residues (distal location) as well as on the communication network. Based on the sequence differences between PfCytb and the human homolog, these findings suggest these selective compounds as potential allosteric modulators of the parasite enzyme, which may serve as possible replacements of the already resistant ATQ drug. Therefore, these findings pave the way for further in vitro studies to establish their anti-plasmodial inhibition levels. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
- Full Text:
- Authors: Chebon, Lorna Jemosop
- Date: 2022-10-14
- Subjects: Malaria , Plasmodium falciparum , Molecular dynamics , Antimalarials , Molecules Models , Docking , Cytochromes , Drug resistance , Computer simulation , Drugs Computer-aided design , System analysis
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/365666 , vital:65774 , DOI https://doi.org/10.21504/10962/365666
- Description: Malaria continues to be a burden globally with a myriad of challenges deterring eradication efforts. With most antimalarials facing drug resistance, such as atovaquone (ATQ), alternative compounds that can withstand resistance are warranted. The Plasmodium falciparum cytochrome b (PfCytb), a subunit of P. falciparum cytochrome bc1 complex, is a validated drug target. Structurally, cytochrome b, cytochrome c1, and iron sulphur protein (ISP) subunits form the catalytic domain of the protein complex having heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors. These cofactos have redox centres to aid in the electron transfer (ET) process. These subunits promote ET mainly through the enzyme’s ubiquinol oxidation (Qo) and ubiquinone reduction (Qi) processes in the catalytic domain. ATQ drug has been used in the prevention and treatment of uncomplicated malaria by targeting PfCytb protein. Once the mitochondrial transmembrane ET pathway is inhibited, it causes a collapse in its membrane potential. Previously reported ATQ drug resistance has been associated with the point mutations Y268C, Y268N and Y268S. Thus, in finding alternatives to the ATQ drug, this research aimed to: i) employ in silico approaches incorporating protein into phospholipid bilayer for the first time to understand the parasites’ resistance mechanism; ii) determine any sequence and structural differences that could be explored in drug design studies; and iii) screen for PfCytb-iron sulphur protein (Cytb-ISP) hit compounds from South African natural compound database (SANCDB) and Medicines for Malaria Venture (MMV) that can withstand the identified mutations. Using computational tools, comparative sequence and structural analyses were performed on the cytochrome b protein, where the ultimate focus was on P. falciparum cytochrome b and its human homolog. Through multiple sequence alignment, motif discovery and phylogeny, differences between P. falciparum and H. sapiens cytochrome b were identified. Protein modelling of both P. falciparum and H. sapiens cytochrome b - iron sulphur protein (PfCytb-ISP and HsCytb-ISP) was performed. Results showed that at the sequence level, there were few amino acid residue differences because the protein is highly conserved. Important to note is the four-residue deletion in Plasmodium spp. absent in the human homolog. Motif analysis discovered five unique motifs in P. falciparum cytochrome b protein which were mapped onto the predicted protein model. These motifs were not in regions of functional importance; hence their function is still unknown. At a structural level, the four-residue deletion was observed to alter the Qo substrate binding pocket as reported in previous studies and confirmed in this study. This deletion resulted in a 0.83 Å structural displacement. Also, there are currently no in silico studies that have performed experiments with P. falciparum cytochrome b protein incorporated into a phospholipid bilayer. Using 350 ns molecular dynamics (MD) simulations of the holo and ATQ-bound systems, the study highlighted the resistance mechanism of the parasite protein where the loss of active site residue-residue interactions was identified, all linked to the three mutations. The identified compromised interactions are likely to destabilise the protein’s function, specifically in the Qo substrate binding site. This showed the possible effect of mutations on ATQ drug activity, where all three mutations were reported to share a similar resistance mechanism. Thereafter, this research work utilised in silico approaches where both Qo active site and interface pocket were targeted by screening the South African natural compounds database (SANCDB) and Medicines for Malaria Venture (MMV) compounds to identify novel selective hits. SANCDB compounds are known for their structural complexity that preserves the potency of the drug molecule. Both SANCDB and MMV compounds have not been explored as inhibitors against the PfCytb drug target. Molecular docking, molecular dynamics (MD) simulations, principal component, and dynamic residue network (DRN; global and local) analyses were utilised to identify and confirm the potential selective inhibitors. Docking results identified compounds that bound selectively onto PfCytb-ISP with a binding energy ≤ -8.7 kcal/mol-1. Further, this work validated a total of eight potential selective compounds to inhibit PfCytb-ISP protein (Qo active site) not only in the wild-type but also in the presence of the point mutations Y268C, Y268N and Y268S. The selective binding of these hit compounds could be linked to the differences reported at sequence/residue level in chapter 3. DRN and residue contact map analyses of the eight compounds in holo and ligand-bound systems revealed reduced residue interactions and decreased protein communication. This suggests that the eight compounds show the possibility of inhibiting the parasite and disrupting important residue-residue interactions. Additionally, 13 selective compounds were identified to bind at the protein’s heterodimer interface, where global and local analysis confirmed their effect on active site residues (distal location) as well as on the communication network. Based on the sequence differences between PfCytb and the human homolog, these findings suggest these selective compounds as potential allosteric modulators of the parasite enzyme, which may serve as possible replacements of the already resistant ATQ drug. Therefore, these findings pave the way for further in vitro studies to establish their anti-plasmodial inhibition levels. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
- Full Text:
- «
- ‹
- 1
- ›
- »