Psychofortology of adults recovering from substance-use disorders
- Authors: Bubb, Tanielle Carmen
- Date: 2011
- Subjects: Substance-related disorders -- Therapy , Substance abuse -- Treatment , Substance abuse
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:9870 , http://hdl.handle.net/10948/d1008117 , Substance-related disorders -- Therapy , Substance abuse -- Treatment , Substance abuse
- Description: Evaluating the psychofortology of adults recovering from a substance-use disorder has been identified as a research priority in South Africa. This is in line with calls from researchers in diverse fields of psychology for more attention to the resilience, strengths, resources and capacities of people. This study therefore aimed to explore and describe the coping resources, sense of coherence, happiness and satisfaction with life of adults recovering from a substance-use disorder within the Nelson Mandela Metropole. The sample consisted of 99 voluntary participants from various managed recovery centres within the Nelson Mandela Metropole. Participants were given a package of questionnaires to complete under the supervision of the researcher. The assessment consisted of a biographical questionnaire and four standardized paper and pencil measures namely; the Coping Resources Inventory (CRI), the Sense of Coherence Scale (SOC-29), the Affectometer 2 (AFM-2) and the Satisfaction with Life Scale (SWLS). A quantitative, non-experimental exploratory-descriptive research method was used. Data was analysed using descriptive statistics and the Pearson product-moment correlation coefficient. Key findings include the following: Results on the CRI revealed low average mean scores on both the Coping Resources Inventory and within all the five subscales. Results of the SOC-29 revealed a high average mean score for sense of coherence. Results of the AFM-2 revealed that more positive affect than negative affect is present, resulting in happiness. Results of the SWLS revealed an average level of satisfaction with life, with most participants’ reporting neutral levels of satisfaction with life. There were significant positive correlations between the coping resources, sense of coherence, happiness and satisfaction with life of the sample. This implies that these constructs can be categorized under the subdiscipline of psychofortology. Overall, these findings emphasized the need for more research into adults recovering from a substance-use disorder.
- Full Text:
- Date Issued: 2011
- Authors: Bubb, Tanielle Carmen
- Date: 2011
- Subjects: Substance-related disorders -- Therapy , Substance abuse -- Treatment , Substance abuse
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:9870 , http://hdl.handle.net/10948/d1008117 , Substance-related disorders -- Therapy , Substance abuse -- Treatment , Substance abuse
- Description: Evaluating the psychofortology of adults recovering from a substance-use disorder has been identified as a research priority in South Africa. This is in line with calls from researchers in diverse fields of psychology for more attention to the resilience, strengths, resources and capacities of people. This study therefore aimed to explore and describe the coping resources, sense of coherence, happiness and satisfaction with life of adults recovering from a substance-use disorder within the Nelson Mandela Metropole. The sample consisted of 99 voluntary participants from various managed recovery centres within the Nelson Mandela Metropole. Participants were given a package of questionnaires to complete under the supervision of the researcher. The assessment consisted of a biographical questionnaire and four standardized paper and pencil measures namely; the Coping Resources Inventory (CRI), the Sense of Coherence Scale (SOC-29), the Affectometer 2 (AFM-2) and the Satisfaction with Life Scale (SWLS). A quantitative, non-experimental exploratory-descriptive research method was used. Data was analysed using descriptive statistics and the Pearson product-moment correlation coefficient. Key findings include the following: Results on the CRI revealed low average mean scores on both the Coping Resources Inventory and within all the five subscales. Results of the SOC-29 revealed a high average mean score for sense of coherence. Results of the AFM-2 revealed that more positive affect than negative affect is present, resulting in happiness. Results of the SWLS revealed an average level of satisfaction with life, with most participants’ reporting neutral levels of satisfaction with life. There were significant positive correlations between the coping resources, sense of coherence, happiness and satisfaction with life of the sample. This implies that these constructs can be categorized under the subdiscipline of psychofortology. Overall, these findings emphasized the need for more research into adults recovering from a substance-use disorder.
- Full Text:
- Date Issued: 2011
The druggable antimalarial target 1-deoxy-D-xylulose-5-phosphate reductoisomerase: purfication, kinetic characterization and inhibition studies
- Authors: Goble, Jessica Leigh
- Date: 2011
- Subjects: Antimalarials -- Development Plasmodium falciparum Drug development Plasmodium falciparum -- Purification Plasmodium falciparum -- Inhibitors Enzyme kinetics Malaria -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3949 , http://hdl.handle.net/10962/d1004008
- Description: Plasmodium falciparum 1–deoxy–D–xylulose–5 phosphatereductoisomerase (PfDXR) plays a role in isoprenoid biosynthesis in the malaria parasite and is absent in the human host, making this parasite enzyme an attractive target for antimalarial drug design. To characterize PfDXR, it is necessary to produce large quantities of the enzyme in a soluble and functional form. However, the over–production of malarial proteins in prokaryotic host systems often results in the formation of truncated proteins or insoluble protein aggregates. A heterologous expression system was developed for the production of active PfDXR using codon harmonization and tight control of expression in the presence of lac repressor. Yields of up to 2 mg/l of enzyme were reported using the optimised expression system, which is 8 to 10– fold greater than previously reported yields. The kinetic parameters Km, Vmax and kcat were determined for PfDXR; values reported in this study were consistent with those reported in the literature for other DXR enzymes. A three–dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure–checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non–apicomplexan DXR proteins. Residues Val44 and Asn45, essential for NADPH binding; and catalytic hatch residues Lys224 and Lys226, which are unique to the species of Plasmodium, were mutated to resemble those of E. coli DXR. Interestingly,these mutations resulted in significant reductions in substrate affinity, when compared to the unmutated PfDXR. Mutant enzymes PfDXR(VN43,44AG) and PfDXR(KK224,226NS) also demonstrated a decreased ability to turnover substrate by 4–fold and 2–fold respectively. This study indicates a difference in the role of the catalytic hatch of PfDXR with regards to the way in which it captures substrates. The study also highlights subtle differences in cofactor binding to PfDXR, compared with the well characterized EcDXR enzyme. The validated PfDXR model was also used to develop a novel efficient in silico screening method for potential tool compounds for use in the rational design of novel DXR inhibitors. Following in silico screening of 46 potential DXR inhibitors, a two–tiered in vitro screening approach was undertaken. DXR inhibition was assessed for the 46 novel compounds using an NADPH– ependant DXP enzyme inhibition assay and antimalarial potential was assessed using P.falciparum–infected erythrocyte growth assays. Select compounds were tested in human cells in order to determine whether they were toxic to the host. From the parallel in silico and in vitro drug screening, it was evident that only a single compound demonstrated reasonable potential binding to DXR (determined using in silico docking), inhibited DXR in vitro and inhibited P. falciparum growth, without being toxic to human cells. Its potential as a lead compound in antimalarial drug development is therefore feasible. Two outcomes were evident from this work. Firstly, analogues of known antimalarial natural products can be screened against malaria, which may then lead towards the rational design of novel compounds that are effective against a specific antimalarial drug target enzyme, such as PfDXR. Secondly, the rational design of novel compounds against a specific antimalarial drug target enzyme can be untaken by adopting a coupled in silico and in vitro approach to drug discovery.
- Full Text:
- Date Issued: 2011
- Authors: Goble, Jessica Leigh
- Date: 2011
- Subjects: Antimalarials -- Development Plasmodium falciparum Drug development Plasmodium falciparum -- Purification Plasmodium falciparum -- Inhibitors Enzyme kinetics Malaria -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3949 , http://hdl.handle.net/10962/d1004008
- Description: Plasmodium falciparum 1–deoxy–D–xylulose–5 phosphatereductoisomerase (PfDXR) plays a role in isoprenoid biosynthesis in the malaria parasite and is absent in the human host, making this parasite enzyme an attractive target for antimalarial drug design. To characterize PfDXR, it is necessary to produce large quantities of the enzyme in a soluble and functional form. However, the over–production of malarial proteins in prokaryotic host systems often results in the formation of truncated proteins or insoluble protein aggregates. A heterologous expression system was developed for the production of active PfDXR using codon harmonization and tight control of expression in the presence of lac repressor. Yields of up to 2 mg/l of enzyme were reported using the optimised expression system, which is 8 to 10– fold greater than previously reported yields. The kinetic parameters Km, Vmax and kcat were determined for PfDXR; values reported in this study were consistent with those reported in the literature for other DXR enzymes. A three–dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure–checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non–apicomplexan DXR proteins. Residues Val44 and Asn45, essential for NADPH binding; and catalytic hatch residues Lys224 and Lys226, which are unique to the species of Plasmodium, were mutated to resemble those of E. coli DXR. Interestingly,these mutations resulted in significant reductions in substrate affinity, when compared to the unmutated PfDXR. Mutant enzymes PfDXR(VN43,44AG) and PfDXR(KK224,226NS) also demonstrated a decreased ability to turnover substrate by 4–fold and 2–fold respectively. This study indicates a difference in the role of the catalytic hatch of PfDXR with regards to the way in which it captures substrates. The study also highlights subtle differences in cofactor binding to PfDXR, compared with the well characterized EcDXR enzyme. The validated PfDXR model was also used to develop a novel efficient in silico screening method for potential tool compounds for use in the rational design of novel DXR inhibitors. Following in silico screening of 46 potential DXR inhibitors, a two–tiered in vitro screening approach was undertaken. DXR inhibition was assessed for the 46 novel compounds using an NADPH– ependant DXP enzyme inhibition assay and antimalarial potential was assessed using P.falciparum–infected erythrocyte growth assays. Select compounds were tested in human cells in order to determine whether they were toxic to the host. From the parallel in silico and in vitro drug screening, it was evident that only a single compound demonstrated reasonable potential binding to DXR (determined using in silico docking), inhibited DXR in vitro and inhibited P. falciparum growth, without being toxic to human cells. Its potential as a lead compound in antimalarial drug development is therefore feasible. Two outcomes were evident from this work. Firstly, analogues of known antimalarial natural products can be screened against malaria, which may then lead towards the rational design of novel compounds that are effective against a specific antimalarial drug target enzyme, such as PfDXR. Secondly, the rational design of novel compounds against a specific antimalarial drug target enzyme can be untaken by adopting a coupled in silico and in vitro approach to drug discovery.
- Full Text:
- Date Issued: 2011
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