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Palmitoylation in neurodegeneration : analysis of cysteine-string protein mutants linked with neuronal ceroid lipofuscinosis
Get PDFNeuronal Ceroid Lipofuscinoses (NCLs) are neurodegenerative lysosomal-storage disorders characterized by intracellular accumulation of autofluorescent material. Mutations in the DNAJC5 gene encoding Cysteine-String Protein alpha (CSPα) cause autosomal-dominant adult-onset NCL (ANCL). The disease-causing mutations occur within the cysteine-stringdomain (CSD), a region of the protein that is extensively palmitoylated. It has been shown that the ANCL CSPα mutants form aggregates and that this is dependent on palmitoylation. As aggregation is a common feature of neurodegenerative disorders, aggregates formed in ANCL are likely to contribute, together with loss-of-function effects, to disease pathology. The aims of this project were to: (i) investigate features of CSPα that are important for aggregate formation; (ii) identify molecular changes that occur in ANCL; and (iii) identify mechanisms regulating CSPα turnover to provide insight into pathways that might be perturbed in ANCL. A cluster of palmitoylated cysteines in the CSD were identified as essential for aggregation of the ANCL CSPα mutants, further supporting an association between palmitoylation and aggregation. Analysis of the expression levels of different proteins in post-mortem brain revealed a massive increase in expression of the palmitoyl thioesterase enzyme PPT1 in ANCL samples, which is intriguing as PPT1 functions to depalmitoylate proteins during their degradation and mutations in the PPT1 gene cause infantile NCL. Further analysis identified several other proteins that had altered expression levels including α-synuclein. Degradation of both wild-type and mutant CSPα proteins was mediated by the proteasome but was independent of lysine ubiquitination. This pathway mediated rapid degradation of non-palmitoylated protein, and blocking proteasome activity enhanced the formation of mutant aggregates. It will be important in future work to determine how mutations in CSPα affect protein degradation pathways to cause the characteristic NCL lysosomal morphology, and whether there is a role for the lysosome in degradation of palmitoylated or aggregated CSPα.Neuronal Ceroid Lipofuscinoses (NCLs) are neurodegenerative lysosomal-storage disorders characterized by intracellular accumulation of autofluorescent material. Mutations in the DNAJC5 gene encoding Cysteine-String Protein alpha (CSPα) cause autosomal-dominant adult-onset NCL (ANCL). The disease-causing mutations occur within the cysteine-stringdomain (CSD), a region of the protein that is extensively palmitoylated. It has been shown that the ANCL CSPα mutants form aggregates and that this is dependent on palmitoylation. As aggregation is a common feature of neurodegenerative disorders, aggregates formed in ANCL are likely to contribute, together with loss-of-function effects, to disease pathology. The aims of this project were to: (i) investigate features of CSPα that are important for aggregate formation; (ii) identify molecular changes that occur in ANCL; and (iii) identify mechanisms regulating CSPα turnover to provide insight into pathways that might be perturbed in ANCL. A cluster of palmitoylated cysteines in the CSD were identified as essential for aggregation of the ANCL CSPα mutants, further supporting an association between palmitoylation and aggregation. Analysis of the expression levels of different proteins in post-mortem brain revealed a massive increase in expression of the palmitoyl thioesterase enzyme PPT1 in ANCL samples, which is intriguing as PPT1 functions to depalmitoylate proteins during their degradation and mutations in the PPT1 gene cause infantile NCL. Further analysis identified several other proteins that had altered expression levels including α-synuclein. Degradation of both wild-type and mutant CSPα proteins was mediated by the proteasome but was independent of lysine ubiquitination. This pathway mediated rapid degradation of non-palmitoylated protein, and blocking proteasome activity enhanced the formation of mutant aggregates. It will be important in future work to determine how mutations in CSPα affect protein degradation pathways to cause the characteristic NCL lysosomal morphology, and whether there is a role for the lysosome in degradation of palmitoylated or aggregated CSPα
The influence of contexts on entrepreneurial practices : a qualitative study
Get PDFWhile it has long been recognised that access to various resources facilitates entrepreneurial processes, little is known about the influence of diverse contexts on the capital accumulation practices of entrepreneurs. Based on the lived experiences of 10 craft entrepreneurs, this thesis seeks to advance knowledge by developing a theory of practice which explains how embeddedness in multiple contexts affects entrepreneurs' resource management practices. Specifically, this study focuses on the effects of embeddedness in households and communities on the capital conversion and sharing practices of craft entrepreneurs. In doing so, it enhances understanding of entrepreneurs' social, spatial and temporal contexts. First, this study reveals a range of hitherto unidentified conversion processes, many of which involve the accumulation of multiple forms of capital, highlighting the complex nature of capital transformations. It also identifies a range of inhibitors and facilitators of these processes, which can be conversion-specific and can derive from household and community embeddedness. Second, the findings show that household members help entrepreneurs not only by providing free resources, but also by developing their psychological capital through boosting self-efficacy, hope, optimism and resilience. Such emotional support is found to be particularly helpful in times of anxiety and stress and reliant upon household members' understanding of the entrepreneur. However, this study also demonstrates that household members' needs, problems and opinions can inhibit entrepreneurial practices, calling attention to the multifaceted relationship between business and family. Third, the data show the significant impact of embeddedness in communities upon entrepreneurs' actions. Participants are found to employ strategic actions to meet the expectations of community members and to conceal non-conforming traits and behaviours. Furthermore, it is revealed that community norms can lead entrepreneurs to share their various resources and engage in social entrepreneurial practices. Throughout, entrepreneurs' embeddedness within and negotiation between these social and spatial contexts is shown to be dependent upon their temporal contexts, further attesting to the considerable impacts of contexts upon entrepreneurs.While it has long been recognised that access to various resources facilitates entrepreneurial processes, little is known about the influence of diverse contexts on the capital accumulation practices of entrepreneurs. Based on the lived experiences of 10 craft entrepreneurs, this thesis seeks to advance knowledge by developing a theory of practice which explains how embeddedness in multiple contexts affects entrepreneurs' resource management practices. Specifically, this study focuses on the effects of embeddedness in households and communities on the capital conversion and sharing practices of craft entrepreneurs. In doing so, it enhances understanding of entrepreneurs' social, spatial and temporal contexts. First, this study reveals a range of hitherto unidentified conversion processes, many of which involve the accumulation of multiple forms of capital, highlighting the complex nature of capital transformations. It also identifies a range of inhibitors and facilitators of these processes, which can be conversion-specific and can derive from household and community embeddedness. Second, the findings show that household members help entrepreneurs not only by providing free resources, but also by developing their psychological capital through boosting self-efficacy, hope, optimism and resilience. Such emotional support is found to be particularly helpful in times of anxiety and stress and reliant upon household members' understanding of the entrepreneur. However, this study also demonstrates that household members' needs, problems and opinions can inhibit entrepreneurial practices, calling attention to the multifaceted relationship between business and family. Third, the data show the significant impact of embeddedness in communities upon entrepreneurs' actions. Participants are found to employ strategic actions to meet the expectations of community members and to conceal non-conforming traits and behaviours. Furthermore, it is revealed that community norms can lead entrepreneurs to share their various resources and engage in social entrepreneurial practices. Throughout, entrepreneurs' embeddedness within and negotiation between these social and spatial contexts is shown to be dependent upon their temporal contexts, further attesting to the considerable impacts of contexts upon entrepreneurs
The Kilbrandon ethos in practice: the antinomy of care and conduct in the children's hearings system : an investigation into the characteristically unitary nature of the Scottish system of children's hearings
Get PDFThis thesis investigates the characteristically unitary nature of the children's hearings system ("CHS") by reference to legal process and decision-making practice. It argues that it is possible to distil from the system's constitutional document, the Kilbrandon Report, a general philosophy (herein termed the "Kilbrandon ethos") which should, in principle, underlie the current practice of the CHS. Broadly, this ethos rests on the unitary nature of the system, which involves dealing with all children "in trouble" alike, procedurally and philosophically, whether it is their own actions or those of others that bring them to the attention of the system's gatekeepers.;The thesis argues that it follows from the Kilbrandon ethos that all children referred to children's reporters ("reporters"), and by reporters to children's hearings, ought to be dealt with in a similar manner, irrespective of the reason for which they are referred, and thereby explores whether differences in process and decision-making practice apply to different "types" of referral. Bringing together juvenile justice theory, original archival research, doctrinal analysis, classification theory, and the findings of an empirical study on reporter decision-making, the thesis contends that, while the Kilbrandon ethos has proved remarkably resilient, there are, nevertheless, indications that grounds of referral are not entirely interchangeable as access points to the CHS.;In particular, it finds that referrals based on the offence ground and, more broadly, referrals based on grounds relating to the child's conduct, are dealt with differently from referrals based on care and protection grounds. The thesis considers the implications of such differences in approach and explores possible responses to bolster the Kilbrandon ethos in practice.This thesis investigates the characteristically unitary nature of the children's hearings system ("CHS") by reference to legal process and decision-making practice. It argues that it is possible to distil from the system's constitutional document, the Kilbrandon Report, a general philosophy (herein termed the "Kilbrandon ethos") which should, in principle, underlie the current practice of the CHS. Broadly, this ethos rests on the unitary nature of the system, which involves dealing with all children "in trouble" alike, procedurally and philosophically, whether it is their own actions or those of others that bring them to the attention of the system's gatekeepers.;The thesis argues that it follows from the Kilbrandon ethos that all children referred to children's reporters ("reporters"), and by reporters to children's hearings, ought to be dealt with in a similar manner, irrespective of the reason for which they are referred, and thereby explores whether differences in process and decision-making practice apply to different "types" of referral. Bringing together juvenile justice theory, original archival research, doctrinal analysis, classification theory, and the findings of an empirical study on reporter decision-making, the thesis contends that, while the Kilbrandon ethos has proved remarkably resilient, there are, nevertheless, indications that grounds of referral are not entirely interchangeable as access points to the CHS.;In particular, it finds that referrals based on the offence ground and, more broadly, referrals based on grounds relating to the child's conduct, are dealt with differently from referrals based on care and protection grounds. The thesis considers the implications of such differences in approach and explores possible responses to bolster the Kilbrandon ethos in practice
Control of crystalline particle properties by spray drying
Get PDFAlthough spray drying has been common place in the pharmaceutical industry for decades, the integration of the technique into continuous manufacturing can offer an extensive array of particle engineering applications. Continuous manufacturing aims to deliver consistent and sustainable drug products of a better and higher quality. Spray drying is a continuous processing technique typically adopted for amorphous solid production. However, the unique conditions of the technique can also can be adapted and applied to crystallisation enabling particle property engineering. The semi-continuous lab-scale Büchi B-290 Mini spray dryer is widely available and has been previously studied extensively for particle engineering and as a development platform for applications including pulmonary drug delivery, sustained release formulations and amorphous solid dispersions.The focus of this work is to engineer and enhance particle properties through the use of the Büchi spray dryer. Particle formation has been investigated, with specific focus in terms of polymorph formation in carbamazepine, to develop a predictive model for crystallisability and for co-spray drying of metformin hydrochloride with mannitol and lactose. Particle formation has been described in terms of theoretical drying kinetics and combined with off line characterisation to determine size and form of product. The metastable polymorph, form IV, of carbamazepine was made reproducibly by spray drying with the combination of rapid evaporation and product isolation shown to be crucial to prevention of solution mediated transformation. The application of non-invasive Raman spectroscopy was also utilised to assess product form. A crystallisability predictive model based on a Random Forest method was successfully produced through combining molecular descriptors with published and experimental outcomes. The model provided up to 79 % accuracy in predicting whether an amorphous or crystalline product would be expected from rapid drying. This shows considerable utility in streamlining process development. Finally, co-spray drying in the Büchi system using a three-fluid nozzle was used to produce multicomponent composite particles comprising of two crystallite phases. The effect of process configuration and material properties on the resultant particles was assessed using particle sizing, SEM, XRPD and Raman mapping. The results were compared on the basis of theoretical drying kinetics to assess the ability to predict the resultant particle morphology. Four multicomponent composite particles were produced by co-spray drying from metformin hydrochloride (MF), mannitol and lactose. MF-mannitol composites produced three-phase physical mixtures with both components present on the particle surfaces. The particle surface compositions were contradictory to the expected particle outcomes from the drying parameters. MF-lactose composite particle also produce three-phase physical mixtures with a relatively equal distribution of components present on particle surface. This is consistent with the expected particle from the drying parameters. The different particle outcomes suggest that co-spray drying of miscible multicomponent feeds using the three-fluid nozzle is highly dependent on the drying parameters for each component due to equal mixing of the feed at atomisation of droplets.Although spray drying has been common place in the pharmaceutical industry for decades, the integration of the technique into continuous manufacturing can offer an extensive array of particle engineering applications. Continuous manufacturing aims to deliver consistent and sustainable drug products of a better and higher quality. Spray drying is a continuous processing technique typically adopted for amorphous solid production. However, the unique conditions of the technique can also can be adapted and applied to crystallisation enabling particle property engineering. The semi-continuous lab-scale Büchi B-290 Mini spray dryer is widely available and has been previously studied extensively for particle engineering and as a development platform for applications including pulmonary drug delivery, sustained release formulations and amorphous solid dispersions.The focus of this work is to engineer and enhance particle properties through the use of the Büchi spray dryer. Particle formation has been investigated, with specific focus in terms of polymorph formation in carbamazepine, to develop a predictive model for crystallisability and for co-spray drying of metformin hydrochloride with mannitol and lactose. Particle formation has been described in terms of theoretical drying kinetics and combined with off line characterisation to determine size and form of product. The metastable polymorph, form IV, of carbamazepine was made reproducibly by spray drying with the combination of rapid evaporation and product isolation shown to be crucial to prevention of solution mediated transformation. The application of non-invasive Raman spectroscopy was also utilised to assess product form. A crystallisability predictive model based on a Random Forest method was successfully produced through combining molecular descriptors with published and experimental outcomes. The model provided up to 79 % accuracy in predicting whether an amorphous or crystalline product would be expected from rapid drying. This shows considerable utility in streamlining process development. Finally, co-spray drying in the Büchi system using a three-fluid nozzle was used to produce multicomponent composite particles comprising of two crystallite phases. The effect of process configuration and material properties on the resultant particles was assessed using particle sizing, SEM, XRPD and Raman mapping. The results were compared on the basis of theoretical drying kinetics to assess the ability to predict the resultant particle morphology. Four multicomponent composite particles were produced by co-spray drying from metformin hydrochloride (MF), mannitol and lactose. MF-mannitol composites produced three-phase physical mixtures with both components present on the particle surfaces. The particle surface compositions were contradictory to the expected particle outcomes from the drying parameters. MF-lactose composite particle also produce three-phase physical mixtures with a relatively equal distribution of components present on particle surface. This is consistent with the expected particle from the drying parameters. The different particle outcomes suggest that co-spray drying of miscible multicomponent feeds using the three-fluid nozzle is highly dependent on the drying parameters for each component due to equal mixing of the feed at atomisation of droplets
Exploiting cooperative effects in s-Block organometallics for new applications in synthesis and catalysis
Get PDFThis thesis was previously restricted to Strathclyde users only from 10 July 2017 until 1 August 2022.Focussing on group 1 and group 2 metals, this thesis advances the use of polar organometallics in catalysis, in particular intermolecular hydroamination processes; as well as other key stoichiometric transformations, namely deprotonative metallation and C-F bond activation.Group 1 alkyl compounds MCH2SiMe3 (M = Li, Na or K) have proved to be efficient catalysts for intermolecular hydroamination of a wide range of substituted vinylarenes and alkynes at room temperature and with short timescales. Similarly,advancing in the concept of s-block cooperative bimetallic catalysis, alkali-metal magnesiate complexes [MMg(CH2SiMe3)3] and [(donor)2M2Mg(CH2SiMe3)4] (M = Li,Na or K) have shown that they can also act as catalysts for these hydroamination processes, although longer times and high temperature conditions are required in some cases. Reactivity studies show an alkali-metal effect with potassium being significally more reactive than lithium. New insights into the constitution of the potential organometallic intermediates involved in these processes have also been gained by combining X-Ray crystallographic and NMR studies (including DOSY NMR).The second part of this thesis assesses cooperative effects of single-metal organomagnesium complexes in deprotonation and C-F bond activation processes.Using a specially designed metallating base, which combines within the same molecule a sterically demanding β-diketiminate ligand with a kinetically activatedTMP base [DippNacnacMg(TMP)], regioselective magnesiation of heterocyclic and aromatic molecules, including pyrazine or 1,2,4,5-tetrafluorobenzene, can be achieved at room temperature. Structural studies of these metallated intermediates have revealed a crucial stabilising role of the β-diketiminate ligand, which facilitates the trapping of the sensitive anions formed. Additionally, they have provided important clues to rationalise the stability of these species in solution. Contrastingly [DippNacnacMg(THF)Bu] complex is a much more kinetically retarded base, which fails to metallate these substrates promoting in some cases, when confronted with fluoroarenes, C-F bond activation process via nucleophilic aromatic substitution.Focussing on group 1 and group 2 metals, this thesis advances the use of polar organometallics in catalysis, in particular intermolecular hydroamination processes; as well as other key stoichiometric transformations, namely deprotonative metallation and C-F bond activation.Group 1 alkyl compounds MCH2SiMe3 (M = Li, Na or K) have proved to be efficient catalysts for intermolecular hydroamination of a wide range of substituted vinylarenes and alkynes at room temperature and with short timescales. Similarly,advancing in the concept of s-block cooperative bimetallic catalysis, alkali-metal magnesiate complexes [MMg(CH2SiMe3)3] and [(donor)2M2Mg(CH2SiMe3)4] (M = Li,Na or K) have shown that they can also act as catalysts for these hydroamination processes, although longer times and high temperature conditions are required in some cases. Reactivity studies show an alkali-metal effect with potassium being significally more reactive than lithium. New insights into the constitution of the potential organometallic intermediates involved in these processes have also been gained by combining X-Ray crystallographic and NMR studies (including DOSY NMR).The second part of this thesis assesses cooperative effects of single-metal organomagnesium complexes in deprotonation and C-F bond activation processes.Using a specially designed metallating base, which combines within the same molecule a sterically demanding β-diketiminate ligand with a kinetically activatedTMP base [DippNacnacMg(TMP)], regioselective magnesiation of heterocyclic and aromatic molecules, including pyrazine or 1,2,4,5-tetrafluorobenzene, can be achieved at room temperature. Structural studies of these metallated intermediates have revealed a crucial stabilising role of the β-diketiminate ligand, which facilitates the trapping of the sensitive anions formed. Additionally, they have provided important clues to rationalise the stability of these species in solution. Contrastingly [DippNacnacMg(THF)Bu] complex is a much more kinetically retarded base, which fails to metallate these substrates promoting in some cases, when confronted with fluoroarenes, C-F bond activation process via nucleophilic aromatic substitution
Going backwards to go forwards : the potential use of mediaeval tubers as future medicine
Get PDFPreviously held under moratorium from 19th October 2017 until 19th October 2022.Obesity and undernourishment are two extremes with a common underlying aetiology – food intake and hunger. Both of these issues are becoming increasingly problematic worldwide, therefore there is a need to develop new therapies to address such issues. Investigation of a forgotten, mediaeval Scottish plant may hold the key to combatting both. Lathyrus linifolius (LL) tubers were once used as an appetite suppressant in times when food was scarce. Additionally, they are thought to be able to quench thirst, and increase alertness. The aims of this study were: 1) to collect and identify these tubers and develop a method using ISSR-PCR to confirm their identity for future commercialisation; 2) investigate the in vivo effects of the tuber in terms of food intake, water intake, body weight and physical activity; 3) identify possible active components in the tuber and assess the biological activity of crude extracts obtained via Soxhlet extraction; and, 4) re-assess the in vivo effects by conducting RNA sequencing on hypothalamic tissue. LL tubers had no effect on food intake, water intake, body weight or physical activity in vivo. However, evidence was generated in this study which suggests the tuber had an effect at gene expression level within the hypothalamus, which is the primary centre for appetite control. Specifically, genes involved in the hypothalamic-pituitary-adrenal axis (HPA) were effected including growth hormone (GH), lutinising hormone (LH), serotonin (5-HT), brain-derived neurotropic factor (BDNF), kisspeptin, kisspeptin receptor, prolactin (PRL), adiponectin, peptide YY (PYY) and neurotrophic receptor tyrosine kinase 3 (NTRK3). The cause of the effects are unknown, however it may be due to multiple compounds present within the tuber. Investigation of such compounds led to the identification of a novel compound, lathyrosaponin A. The biological activity of this compound remains unknown, however, the crude extract from which it was identified showed significant (P<0.01) inhibition of α-glucosidase. The results of this study confirm possible appetite suppressing effects of LL tubers, which correlate with their mediaeval use. Going backwards to investigate plants once used as human therapies may be the key to combating worldwide issues today.Obesity and undernourishment are two extremes with a common underlying aetiology – food intake and hunger. Both of these issues are becoming increasingly problematic worldwide, therefore there is a need to develop new therapies to address such issues. Investigation of a forgotten, mediaeval Scottish plant may hold the key to combatting both. Lathyrus linifolius (LL) tubers were once used as an appetite suppressant in times when food was scarce. Additionally, they are thought to be able to quench thirst, and increase alertness. The aims of this study were: 1) to collect and identify these tubers and develop a method using ISSR-PCR to confirm their identity for future commercialisation; 2) investigate the in vivo effects of the tuber in terms of food intake, water intake, body weight and physical activity; 3) identify possible active components in the tuber and assess the biological activity of crude extracts obtained via Soxhlet extraction; and, 4) re-assess the in vivo effects by conducting RNA sequencing on hypothalamic tissue. LL tubers had no effect on food intake, water intake, body weight or physical activity in vivo. However, evidence was generated in this study which suggests the tuber had an effect at gene expression level within the hypothalamus, which is the primary centre for appetite control. Specifically, genes involved in the hypothalamic-pituitary-adrenal axis (HPA) were effected including growth hormone (GH), lutinising hormone (LH), serotonin (5-HT), brain-derived neurotropic factor (BDNF), kisspeptin, kisspeptin receptor, prolactin (PRL), adiponectin, peptide YY (PYY) and neurotrophic receptor tyrosine kinase 3 (NTRK3). The cause of the effects are unknown, however it may be due to multiple compounds present within the tuber. Investigation of such compounds led to the identification of a novel compound, lathyrosaponin A. The biological activity of this compound remains unknown, however, the crude extract from which it was identified showed significant (P<0.01) inhibition of α-glucosidase. The results of this study confirm possible appetite suppressing effects of LL tubers, which correlate with their mediaeval use. Going backwards to investigate plants once used as human therapies may be the key to combating worldwide issues today
Novel amorphous silica and silica xerogels for the adsorption of organic pollutants from water
Get PDFThis thesis was previously held under moratorium from 9th November 2017 until 9th November 2022.The demand on water supplies is becoming more intensive, thus the need for innovative and cost effective produced water treatment technologies is rising. Produced water is the largest by-product generated by oil and gas extraction, hence, there are significant quantities requiring remediation. Furthermore, over recent years, the presence of other organics known as Endocrine Disrupting Chemicals (EDCs) in various sewage discharges, fresh- and estuarine-waters, has been extensively reported, becoming an increasing source of concern. Membranes are a promising technology for water remediation and the use of an adsorption media as a prior treatment could make them a potentially cost-effective option. Among solid sorbents, hydrophobic aerogels exhibit attractive properties for oil spill applications; however, very few studies have investigated their adsorption performance at low organic concentrations and the cost of functionalisation of these materials, hinder their use as sorbents in the final stages of produced water treatments. This work studies the adsorption of benzene, toluene and the EDC 3,4-dichloroaniline (3,4-DCA) below their solubility limits on hydrophilic and hydrophobic samples of the novel amorphous silica Quartzene and on silica xerogels, synthesised by a low cost and environmentally friendly synthesis, inspired from the work of Bangi, Rao A.P., Hirashima and Rao A.V. [1]. All adsorbents used in this study were also characterised by SEM, FTIR and BET analysis. The full adsorption capacity of hydrophilic Quartzene was achieved in less than 10 h, with 70-90% of uptake in the first 6 h. Adsorption capacities were found to be up to 264 mg/g for benzene and 78.8 mg/g for toluene. Hydrophobic Quartzene, demonstrated an equilibrium value four times higher that of the hydrophilic analogue, reached in less than 3 h at a concentration of 200 ppm benzene. With regard to the synthesised xerogels, evaporation rates and the optimal combination of reactants were identified, in order to obtain the desired degree of hydrophobicity and a surface area mainly due to pores with sufficient dimension to allow pollutant penetration. The so synthesised xerogels adsorb dissolved benzene and 3,4-DCA from water, showing no damage of the granules after days of rotary stirring, suggesting potential re-use. The adsorption behaviour is described by a two-step mechanism, with equilibrium times of ~24 h, with adsorption capacities up to 75 mg/g for benzene and 12.5 g for 3,4-DCA. Micro Column Rapid Breakthrough tests coupled with Sequential Injection Analyses were also conducted, in order to obtain a preliminary evaluation of the adsorbents operative feasibility under conditions more similar to those typically used in water treatment facilities. Micro-columns were designed and 3D printed in methacrylate. Automated solid-phase extraction was used to verify desorption of the analytes by methanol injection. The removal efficiency of the hydrophobic sample of Quartzene was found to be >5.85 mg/g of benzene, with an initial concentration of 73.3 mg/L. The removal efficiency of the silica xerogels was found to be >22.62 mg/g for benzene, with an initial concentration of 105.12 mg/L; the corresponding uptakes of 3,4-DCA were found to be >4.63 mg/g and >7.17 mg/g, respectively, at flowrates of 1.8 mL/min and 0.6 mL/min and with an initial concentration of 16-20 mg/L. Higher removal efficiencies coupled with higher rate of adsorption, which would lead to lower Empty Bed Contact Times (EBCTs), would be required for all the sorbents tested here to be used for treatment of produced water prior to a membrane configuration, especially in offshore facilities. The rate of adsorption of 3,4-DCA, and the related adsorption capacity of the silica xerogels studied here could be promising for large scale application to removal of pesticides and other organic micropollutants, as filling of filters, cartridges or permeable reactive barriers.The demand on water supplies is becoming more intensive, thus the need for innovative and cost effective produced water treatment technologies is rising. Produced water is the largest by-product generated by oil and gas extraction, hence, there are significant quantities requiring remediation. Furthermore, over recent years, the presence of other organics known as Endocrine Disrupting Chemicals (EDCs) in various sewage discharges, fresh- and estuarine-waters, has been extensively reported, becoming an increasing source of concern. Membranes are a promising technology for water remediation and the use of an adsorption media as a prior treatment could make them a potentially cost-effective option. Among solid sorbents, hydrophobic aerogels exhibit attractive properties for oil spill applications; however, very few studies have investigated their adsorption performance at low organic concentrations and the cost of functionalisation of these materials, hinder their use as sorbents in the final stages of produced water treatments. This work studies the adsorption of benzene, toluene and the EDC 3,4-dichloroaniline (3,4-DCA) below their solubility limits on hydrophilic and hydrophobic samples of the novel amorphous silica Quartzene and on silica xerogels, synthesised by a low cost and environmentally friendly synthesis, inspired from the work of Bangi, Rao A.P., Hirashima and Rao A.V. [1]. All adsorbents used in this study were also characterised by SEM, FTIR and BET analysis. The full adsorption capacity of hydrophilic Quartzene was achieved in less than 10 h, with 70-90% of uptake in the first 6 h. Adsorption capacities were found to be up to 264 mg/g for benzene and 78.8 mg/g for toluene. Hydrophobic Quartzene, demonstrated an equilibrium value four times higher that of the hydrophilic analogue, reached in less than 3 h at a concentration of 200 ppm benzene. With regard to the synthesised xerogels, evaporation rates and the optimal combination of reactants were identified, in order to obtain the desired degree of hydrophobicity and a surface area mainly due to pores with sufficient dimension to allow pollutant penetration. The so synthesised xerogels adsorb dissolved benzene and 3,4-DCA from water, showing no damage of the granules after days of rotary stirring, suggesting potential re-use. The adsorption behaviour is described by a two-step mechanism, with equilibrium times of ~24 h, with adsorption capacities up to 75 mg/g for benzene and 12.5 g for 3,4-DCA. Micro Column Rapid Breakthrough tests coupled with Sequential Injection Analyses were also conducted, in order to obtain a preliminary evaluation of the adsorbents operative feasibility under conditions more similar to those typically used in water treatment facilities. Micro-columns were designed and 3D printed in methacrylate. Automated solid-phase extraction was used to verify desorption of the analytes by methanol injection. The removal efficiency of the hydrophobic sample of Quartzene was found to be >5.85 mg/g of benzene, with an initial concentration of 73.3 mg/L. The removal efficiency of the silica xerogels was found to be >22.62 mg/g for benzene, with an initial concentration of 105.12 mg/L; the corresponding uptakes of 3,4-DCA were found to be >4.63 mg/g and >7.17 mg/g, respectively, at flowrates of 1.8 mL/min and 0.6 mL/min and with an initial concentration of 16-20 mg/L. Higher removal efficiencies coupled with higher rate of adsorption, which would lead to lower Empty Bed Contact Times (EBCTs), would be required for all the sorbents tested here to be used for treatment of produced water prior to a membrane configuration, especially in offshore facilities. The rate of adsorption of 3,4-DCA, and the related adsorption capacity of the silica xerogels studied here could be promising for large scale application to removal of pesticides and other organic micropollutants, as filling of filters, cartridges or permeable reactive barriers
Efficient discretisation and domain decomposition preconditioners for incompressible fluid mechanics
Get PDFSolving the linear elasticity and Stokes equations by an optimal domain decomposition method derived algebraically involves the use of non standard interface conditions whose discretisation is not trivial. For this reason the use of approximation methods such as hybrid discontinuous Galerkin appears as an appropriate strategy: on the one hand they provide the best compromise in terms of the number of degrees of freedom in between standard continuous and discontinuous Galerkin methods, and on the other hand the degrees of freedom used in the non standard interface conditions are naturally defined at the boundary between elements. In this manuscript we present the coupling between a well chosen discretisation method (hybrid discontinuous Galerkin) and a novel and efficient domain decomposition method to solve the Stokes system. An analysis of the boundary value problem with non standard condition is provided as well as the numerical evidence showing the advantages of the new method. Furthermore, we present and analyse a stabilisation method for the presented discretisation that allows the use of the same polynomial degrees for velocity and pressure discrete spaces. The original definition of the domain decomposition preconditioners is one-level, this is, the preconditioner is built only using the solution of local problems. This has the undesired consequence that the results are not scalable, it means that the number of iterations needed to reach convergence increases with the number of subdomains. This is the reason why we have also introduced, and tested numerically, two-level preconditioners. Such preconditioners use a coarse space in their construction. We consider two finite element discretisations, namely, the hybrid discontinuous Galerkin and Taylor-Hood discretisations for the nearly incompressible elasticity problems and Stokes equations.Solving the linear elasticity and Stokes equations by an optimal domain decomposition method derived algebraically involves the use of non standard interface conditions whose discretisation is not trivial. For this reason the use of approximation methods such as hybrid discontinuous Galerkin appears as an appropriate strategy: on the one hand they provide the best compromise in terms of the number of degrees of freedom in between standard continuous and discontinuous Galerkin methods, and on the other hand the degrees of freedom used in the non standard interface conditions are naturally defined at the boundary between elements. In this manuscript we present the coupling between a well chosen discretisation method (hybrid discontinuous Galerkin) and a novel and efficient domain decomposition method to solve the Stokes system. An analysis of the boundary value problem with non standard condition is provided as well as the numerical evidence showing the advantages of the new method. Furthermore, we present and analyse a stabilisation method for the presented discretisation that allows the use of the same polynomial degrees for velocity and pressure discrete spaces. The original definition of the domain decomposition preconditioners is one-level, this is, the preconditioner is built only using the solution of local problems. This has the undesired consequence that the results are not scalable, it means that the number of iterations needed to reach convergence increases with the number of subdomains. This is the reason why we have also introduced, and tested numerically, two-level preconditioners. Such preconditioners use a coarse space in their construction. We consider two finite element discretisations, namely, the hybrid discontinuous Galerkin and Taylor-Hood discretisations for the nearly incompressible elasticity problems and Stokes equations
Using high resolution mass spectrometry to profile impurities in drugs from different sources
Get PDFStrathclyde theses - ask staff. Thesis no. : T14726Impurities in active pharmaceutical ingredients (APIs) include volatile and involatile organic compounds and inorganic anions and cations. The impurities in an API are acquired during the manufacturing process and may arise from impurities in reagents, side reactions and may, as in the case of ionic impurities associate with the molecule during purification processes. Impurity levels have to be controlled to conform to pharmacopoeial requirements; although this is less apparent in the case of organic and inorganic counterions. In the work reported in this thesis four applications of impurity profiling in APIs and API intermediates were investigated. In chapter 3 the removal of impurities in lipoic acid prior to crystallisation was investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several impurities of lipoic acid were characterised by using MSn and the success of the purification process in removing impurities was verified. In chapter 4 the organic impurities in chlorpheniramine maleate were investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several new impurities of chlorpheniramine maleate were characterised by using MSn and it was demonstrated that it was possible to distinguish between different manufacturers' batches of chlorpheniramine maleate according to their impurity profiles by using high resolution mass spectrometry data in combination with chemometric modelling. In chapter 5 the anionic impurities in different pharmaceutical bases were investigated by using capillary ion chromatography. The different pharmaceutical bases contained a wide range of trace ions as well as the main counter-anion. Aside from the anions being present as impurities they might have an impact of processing procedures such as crystallisation. In chapter 6 a range of techniques including nuclear magnetic resonance spectroscopy, high resolution LC-MSn, headspace gas chromatography mass spectrometry, anion and cation chromatography were applied to the analysis of 6-aminopenicillanic acid (6-APA) samples, provided by GSK, which had of low to high clarity values. It was not possible to find any direct association between clarity readings and the various impurity profiles although a number of new impurities in 6-APA were characterised.Impurities in active pharmaceutical ingredients (APIs) include volatile and involatile organic compounds and inorganic anions and cations. The impurities in an API are acquired during the manufacturing process and may arise from impurities in reagents, side reactions and may, as in the case of ionic impurities associate with the molecule during purification processes. Impurity levels have to be controlled to conform to pharmacopoeial requirements; although this is less apparent in the case of organic and inorganic counterions. In the work reported in this thesis four applications of impurity profiling in APIs and API intermediates were investigated. In chapter 3 the removal of impurities in lipoic acid prior to crystallisation was investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several impurities of lipoic acid were characterised by using MSn and the success of the purification process in removing impurities was verified. In chapter 4 the organic impurities in chlorpheniramine maleate were investigated using high resolution mass spectrometry in combination with chemometric modelling of the data. Several new impurities of chlorpheniramine maleate were characterised by using MSn and it was demonstrated that it was possible to distinguish between different manufacturers' batches of chlorpheniramine maleate according to their impurity profiles by using high resolution mass spectrometry data in combination with chemometric modelling. In chapter 5 the anionic impurities in different pharmaceutical bases were investigated by using capillary ion chromatography. The different pharmaceutical bases contained a wide range of trace ions as well as the main counter-anion. Aside from the anions being present as impurities they might have an impact of processing procedures such as crystallisation. In chapter 6 a range of techniques including nuclear magnetic resonance spectroscopy, high resolution LC-MSn, headspace gas chromatography mass spectrometry, anion and cation chromatography were applied to the analysis of 6-aminopenicillanic acid (6-APA) samples, provided by GSK, which had of low to high clarity values. It was not possible to find any direct association between clarity readings and the various impurity profiles although a number of new impurities in 6-APA were characterised
Dynamics of quantum many-body systems with long-range interactions
Get PDFConstantly increasing experimental possibilities with strongly correlated systems of ultracold atoms in optical lattices and trapped ions make them one of the most promising candidates for quantum simulation and quantum computation in the near future, and open new opportunities for study many-body physics. Out-of-equilibrium properties of such complex systems present truly fascinating and rich physics, which is yet to be fully understood. This thesis studies many-body dynamics of quantum systems with long-range interactions and addresses a few distinct issues. The first one is related to a growing interest in the use of ultracold atoms in optical lattices to simulate condensed matter systems, in particular to understand their magnetic properties. In our project on tilted optical lattices we map the dynamics of bosonic particles with resonantly enhanced long-range tunnelings onto a spin chain with peculiar interaction terms. We study the novel properties of this system in and out of equilibrium. The second main topic is the dynamical growth of entanglement and spread of correlations between system partitions in quench experiments. Our investigation is based on current experiments with trapped ions, where the range of interactions can be tuned dynamically from almost neighboring to all-to-all. We analyze the role of this interaction range in non-equilibrium dynamics. The third topic we address is a new method of quantum state estimation, certified Matrix Product State (MPS) tomography, which has potential applications in regimes unreachable by full quantum state tomography. The investigation of quantum many-body systems often goes beyond analytically solvable models; that is where numerical simulations become vital. The majority of results in this thesis were obtained via the Density Matrix Renormalization Group (DMRG) methods in the context of the MPS and Matrix Product Operator(MPO) formalism. Further developing and optimizing these methods made it possible to obtain eigenstates and thermal states as well as to calculate the time dependent dynamics in quenches for experimentally relevant regimes.Constantly increasing experimental possibilities with strongly correlated systems of ultracold atoms in optical lattices and trapped ions make them one of the most promising candidates for quantum simulation and quantum computation in the near future, and open new opportunities for study many-body physics. Out-of-equilibrium properties of such complex systems present truly fascinating and rich physics, which is yet to be fully understood. This thesis studies many-body dynamics of quantum systems with long-range interactions and addresses a few distinct issues. The first one is related to a growing interest in the use of ultracold atoms in optical lattices to simulate condensed matter systems, in particular to understand their magnetic properties. In our project on tilted optical lattices we map the dynamics of bosonic particles with resonantly enhanced long-range tunnelings onto a spin chain with peculiar interaction terms. We study the novel properties of this system in and out of equilibrium. The second main topic is the dynamical growth of entanglement and spread of correlations between system partitions in quench experiments. Our investigation is based on current experiments with trapped ions, where the range of interactions can be tuned dynamically from almost neighboring to all-to-all. We analyze the role of this interaction range in non-equilibrium dynamics. The third topic we address is a new method of quantum state estimation, certified Matrix Product State (MPS) tomography, which has potential applications in regimes unreachable by full quantum state tomography. The investigation of quantum many-body systems often goes beyond analytically solvable models; that is where numerical simulations become vital. The majority of results in this thesis were obtained via the Density Matrix Renormalization Group (DMRG) methods in the context of the MPS and Matrix Product Operator(MPO) formalism. Further developing and optimizing these methods made it possible to obtain eigenstates and thermal states as well as to calculate the time dependent dynamics in quenches for experimentally relevant regimes
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