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Novel experimental techniques for biopharmaceutical analysis
Get PDFDrug solubility and dissolution are important attributes controlling the bioavailability (BA) of oral dosage forms and can be determined in vivo, however it is expensive and can generate ethical issues. In vitro tests have been introduced utilising simulated gastrointestinal (GI) fluids, capturing the GI composition and conditions. However, individual variation and food-induced changes of the GI environment affecting drug BA have been recognised and in-depth knowledge is required to understand their effects on drug absorption. A fractional factorial design of experiment (DoE) and a 4-component mixture design (4MD) were used to investigate drug equilibrium solubility in media presenting in different levels of pH, concentration of amphiphiles, buffer, salt and pancreatin. Poorly soluble acidic, basic and neutral drugs with various physiochemical properties were tested. Solubility results correlate well with literature values, indicating they explored the solubility variation in the biorelevant space. Except pancreatin, all factors showed significant impacts on drug solubility. The descending order of average effect magnitude is pH, amphiphiles, buffer and salt, some of which also displayed remarkable drug specific interactions. Changing amphiphile ratios in 4MD further indicated that solubilisation is not a simple accumulative solubilisation of individual amphiphiles, but interactions between amphiphile-amphiphile and drug-amphiphiles. Powder dissolution using various biorelevant media indicates intrinsic dissolution rates (IDR) are positively correlated with equilibrium solubility and the diffusion coefficient of drugs in different ionisation states and interactions with amphiphiles. The above studies illustrate the convoluted nature of the GI fluids and provide a visualisation of how solubility/dissolution map varies within the ranges of GI fluid parameters. Statistical approaches can systematically detect critical factors affecting drug solubility and dissolution, and the output can potentially be applied in physiologically based pharmacokinetic (PBPK) model to achieve better in vivo-in vitro correlation (IVIVC).Drug solubility and dissolution are important attributes controlling the bioavailability (BA) of oral dosage forms and can be determined in vivo, however it is expensive and can generate ethical issues. In vitro tests have been introduced utilising simulated gastrointestinal (GI) fluids, capturing the GI composition and conditions. However, individual variation and food-induced changes of the GI environment affecting drug BA have been recognised and in-depth knowledge is required to understand their effects on drug absorption. A fractional factorial design of experiment (DoE) and a 4-component mixture design (4MD) were used to investigate drug equilibrium solubility in media presenting in different levels of pH, concentration of amphiphiles, buffer, salt and pancreatin. Poorly soluble acidic, basic and neutral drugs with various physiochemical properties were tested. Solubility results correlate well with literature values, indicating they explored the solubility variation in the biorelevant space. Except pancreatin, all factors showed significant impacts on drug solubility. The descending order of average effect magnitude is pH, amphiphiles, buffer and salt, some of which also displayed remarkable drug specific interactions. Changing amphiphile ratios in 4MD further indicated that solubilisation is not a simple accumulative solubilisation of individual amphiphiles, but interactions between amphiphile-amphiphile and drug-amphiphiles. Powder dissolution using various biorelevant media indicates intrinsic dissolution rates (IDR) are positively correlated with equilibrium solubility and the diffusion coefficient of drugs in different ionisation states and interactions with amphiphiles. The above studies illustrate the convoluted nature of the GI fluids and provide a visualisation of how solubility/dissolution map varies within the ranges of GI fluid parameters. Statistical approaches can systematically detect critical factors affecting drug solubility and dissolution, and the output can potentially be applied in physiologically based pharmacokinetic (PBPK) model to achieve better in vivo-in vitro correlation (IVIVC)
Effective exporting : an analysis of contemporary and enduring critical success factors which enable successful exporting performance by UK SME
No full textThe overall aim of this study is to establish CSF (critical success factors) associated with effective export performance through an analysis of successful practice. The research examines and investigates the characteristics of UK small to medium enterprises SME across a multitude of industries that have recently won a highly prestigious Queens Award for International Trade between the year 2014 to 2016. Who better to ask what makes an effective exporter than those firms awarded the highest accolade for their International trade through exporting. The research also serves as a replication of a study undertaken by the Department of Marketing at Strathclyde University in the early 1980s titled 'Successful Exporting'. The massive growth and changes within contemporary global trade and the subsequent significant impact on UK exporting along with a scarcity of relevant replications makes the need for this research timely. This research project was based on a comprehensive review of relevant literature and empirical research in the form of online self completion questionnaires taken and adapted from the most significant previous research.The findings highlight that there are a number of critical success factors for UK exporters including main export markets, "Born Global SME", competitors, antecedents of export performance, export marketing strategy, destination markets and investment in technology. This research makes several recommendations with regard to advancing understanding of key issues in future and providing guidance on both contemporary and enduring critical success factors for firms wishing to initiate or expand their exporting activities. Main recommendations include a collaborative effort by the many researchers in this field to develop and agree upon a conceptual framework which can act as a foundation for all future studies. Additionally, further research into at a tactical level the development of an optimum marketing mix and with particular emphasis on further contemporary research into export promotions, product quality and pricing. Born global firms has emerged from findings as a significant emerging phenomenon which requires further investigation. Finally, more replications of previous accepted export studies are recommended. Thus elucidating guidance on the way forward for future research and practical advice for UK exporters seeking to initiate or expand their current exporting activities.The overall aim of this study is to establish CSF (critical success factors) associated with effective export performance through an analysis of successful practice. The research examines and investigates the characteristics of UK small to medium enterprises SME across a multitude of industries that have recently won a highly prestigious Queens Award for International Trade between the year 2014 to 2016. Who better to ask what makes an effective exporter than those firms awarded the highest accolade for their International trade through exporting. The research also serves as a replication of a study undertaken by the Department of Marketing at Strathclyde University in the early 1980s titled 'Successful Exporting'. The massive growth and changes within contemporary global trade and the subsequent significant impact on UK exporting along with a scarcity of relevant replications makes the need for this research timely. This research project was based on a comprehensive review of relevant literature and empirical research in the form of online self completion questionnaires taken and adapted from the most significant previous research.The findings highlight that there are a number of critical success factors for UK exporters including main export markets, "Born Global SME", competitors, antecedents of export performance, export marketing strategy, destination markets and investment in technology. This research makes several recommendations with regard to advancing understanding of key issues in future and providing guidance on both contemporary and enduring critical success factors for firms wishing to initiate or expand their exporting activities. Main recommendations include a collaborative effort by the many researchers in this field to develop and agree upon a conceptual framework which can act as a foundation for all future studies. Additionally, further research into at a tactical level the development of an optimum marketing mix and with particular emphasis on further contemporary research into export promotions, product quality and pricing. Born global firms has emerged from findings as a significant emerging phenomenon which requires further investigation. Finally, more replications of previous accepted export studies are recommended. Thus elucidating guidance on the way forward for future research and practical advice for UK exporters seeking to initiate or expand their current exporting activities
An analysis of the Committee for the Security of the Kingdom of the Scottish Parliament, 1693-1702
No full textIn 1689, King James VII and II, monarch of England, Scotland and Ireland, was replaced by William III and II. The Revolution, traditionally known as the 'Glorious' Revolution, resulted in constitutional reform in all three kingdoms. William landed in England on 5 November, 1688, and James fled just over a month later. A group of one hundred and ten leading Scottish peers and gentry gathered in Whitehall to discuss the future of their country, inviting William to call a Convention of Estates to meet at Edinburgh, March 14, to settle the government.2 This convention became a parliament which met over ten sessions between 1689 and 1702. As well as creating the Claim of Right and the Articles of Grievance, constitutional reforms which defined the boundaries in which the monarch of Scotland could rule the country, in 1690 the Parliament also passed the 'Act concerning the election of committees of parliament' which abolished the Lords of the Articles, a controversial steering committee considered to be a tool of crown management by contemporaries, particularly those who were members of the parliamentary grouping 'the Club' who drew on the constitutional reforms of the Covenanters.3 This act allowed the Parliament to create committees on an ad-hoc basis to relieve the Parliament of its legislative burden.Committees had long been a feature of the Scottish Parliament. The Lords of the Articles, created in the 1450s, was the longest standing committee although crown interference in its membership in the seventeenth century led to the Covenanters rendering the legislative committee optional. Choosing not to use it, they instead established a series of session committees, to assist Parliament when it was sitting, and interval committees, which managed the country when Parliament was not in session. After the invasion of Scotland, Oliver Cromwell ruled Scotland from London however, when the Stewart monarchy was restored in 1660, Scotland regained its parliament. The Parliament reinstated the Articles although perceived crown management resulted in the Scottish Parliament replacing it with a series of committees after the Revolution.This dissertation will consider the most important committee created after the Revolution, the Committee for the Security of the Kingdom, 1693-1702. Created as one of three standing committees, this committee dealt with a range of issues while also taking part in the Parliament's response to major events unfolding in Scotland such as the Massacre of Glencoe in 1692. To examine the Committee for Security, this dissertation will initially consider the historiography surrounding the Scottish Parliament in the seventeenth century, with specific attention to the years 1689-1702, as well as the Parliament's membership and previous committee systems. The first chapter will then discuss the methodology used to examine the Committee for Security including a brief consideration of the Records of the Parliament of Scotland website and the European research method of prosopography. The second chapter will discuss the committee system created after the Revolution and the formation of the Committee for Security. The third and fourth chapters will consider the Committee for Security's legislative function through contemplation of the issues remitted to it and the acts it produced. As the activities of the Committee and the legislation that it produced were the result of the men who occupied it, the fifth chapter will consider the membership of the Committee for Security, examining their predominance in the committee as well as contemplating other roles they may have had, before concluding with a discussion about factional allegiances.In 1689, King James VII and II, monarch of England, Scotland and Ireland, was replaced by William III and II. The Revolution, traditionally known as the 'Glorious' Revolution, resulted in constitutional reform in all three kingdoms. William landed in England on 5 November, 1688, and James fled just over a month later. A group of one hundred and ten leading Scottish peers and gentry gathered in Whitehall to discuss the future of their country, inviting William to call a Convention of Estates to meet at Edinburgh, March 14, to settle the government.2 This convention became a parliament which met over ten sessions between 1689 and 1702. As well as creating the Claim of Right and the Articles of Grievance, constitutional reforms which defined the boundaries in which the monarch of Scotland could rule the country, in 1690 the Parliament also passed the 'Act concerning the election of committees of parliament' which abolished the Lords of the Articles, a controversial steering committee considered to be a tool of crown management by contemporaries, particularly those who were members of the parliamentary grouping 'the Club' who drew on the constitutional reforms of the Covenanters.3 This act allowed the Parliament to create committees on an ad-hoc basis to relieve the Parliament of its legislative burden.Committees had long been a feature of the Scottish Parliament. The Lords of the Articles, created in the 1450s, was the longest standing committee although crown interference in its membership in the seventeenth century led to the Covenanters rendering the legislative committee optional. Choosing not to use it, they instead established a series of session committees, to assist Parliament when it was sitting, and interval committees, which managed the country when Parliament was not in session. After the invasion of Scotland, Oliver Cromwell ruled Scotland from London however, when the Stewart monarchy was restored in 1660, Scotland regained its parliament. The Parliament reinstated the Articles although perceived crown management resulted in the Scottish Parliament replacing it with a series of committees after the Revolution.This dissertation will consider the most important committee created after the Revolution, the Committee for the Security of the Kingdom, 1693-1702. Created as one of three standing committees, this committee dealt with a range of issues while also taking part in the Parliament's response to major events unfolding in Scotland such as the Massacre of Glencoe in 1692. To examine the Committee for Security, this dissertation will initially consider the historiography surrounding the Scottish Parliament in the seventeenth century, with specific attention to the years 1689-1702, as well as the Parliament's membership and previous committee systems. The first chapter will then discuss the methodology used to examine the Committee for Security including a brief consideration of the Records of the Parliament of Scotland website and the European research method of prosopography. The second chapter will discuss the committee system created after the Revolution and the formation of the Committee for Security. The third and fourth chapters will consider the Committee for Security's legislative function through contemplation of the issues remitted to it and the acts it produced. As the activities of the Committee and the legislation that it produced were the result of the men who occupied it, the fifth chapter will consider the membership of the Committee for Security, examining their predominance in the committee as well as contemplating other roles they may have had, before concluding with a discussion about factional allegiances
SERS-based nanoparticle biodetection using carbohydrate-lectin interactions
Get PDFEndogenous biological processes including cellular recognition, motility and differentiation together with infection often result from carbohydrate-based interactions. Investigation into glycobiological interactions using sugar-coated nanoparticles are the basis for the research described herein.Metallic nanoparticles were coated with a variety of thiol-based linker molecules. Heterobifunctional PEG (carboxyl/thiol) molecules were found to be most successful in preventing non-specific aggregation. The carboxylic acid functionality of the PEG molecules used allowed for subsequent coupling of a variety of carbohydrates to the nanoparticle surface. This resulted in the production of glyconanoparticles with unique surface functionality, for example, glucose or galactose. Additionally, functionalising the particles with Raman reporter molecules (RRMs) resulted in the measurement of surface enhanced Raman scattering (SERS) signals. Aggregation of the glyconanoparticles in the presence of a variety of carbohydrate-binding proteins (lectins) was measured via changes in the extinction profile, size and the SERS response of those particles. Nanoparticle aggregation was used for the sensitive detection of plant lectins, including the Concanavalin A and Jacalin lectin and also bacterial lectins including cholera toxin B subunit (CTB). CTB was detected sensitively, selectively and rapidly by using glyconanoparticles coated in a mixture of different carbohydrates (mixed-monolayers of galactose and N-acetylneuraminic acid). Detection was possible in both buffer and synthetic freshwater conditions, demonstrating the use of these glyconanoparticles in detecting a target in complex samples.By exploiting the reversible nature of carbohydrate-lectin interactions, it was possible to use the glyconanoparticles together with the lectin ConA to develop a glucose sensor. This performed effectively across the physiological range and into the hypo/hyperglycaemic regions in buffer conditions.Finally, the glyconanoparticles were used for the detection of plant and bacterial lectins on glass substrates by initially developing a sandwich SERS assay with a view to eventually creating SERS-based carbohydrate microarrays.Endogenous biological processes including cellular recognition, motility and differentiation together with infection often result from carbohydrate-based interactions. Investigation into glycobiological interactions using sugar-coated nanoparticles are the basis for the research described herein.Metallic nanoparticles were coated with a variety of thiol-based linker molecules. Heterobifunctional PEG (carboxyl/thiol) molecules were found to be most successful in preventing non-specific aggregation. The carboxylic acid functionality of the PEG molecules used allowed for subsequent coupling of a variety of carbohydrates to the nanoparticle surface. This resulted in the production of glyconanoparticles with unique surface functionality, for example, glucose or galactose. Additionally, functionalising the particles with Raman reporter molecules (RRMs) resulted in the measurement of surface enhanced Raman scattering (SERS) signals. Aggregation of the glyconanoparticles in the presence of a variety of carbohydrate-binding proteins (lectins) was measured via changes in the extinction profile, size and the SERS response of those particles. Nanoparticle aggregation was used for the sensitive detection of plant lectins, including the Concanavalin A and Jacalin lectin and also bacterial lectins including cholera toxin B subunit (CTB). CTB was detected sensitively, selectively and rapidly by using glyconanoparticles coated in a mixture of different carbohydrates (mixed-monolayers of galactose and N-acetylneuraminic acid). Detection was possible in both buffer and synthetic freshwater conditions, demonstrating the use of these glyconanoparticles in detecting a target in complex samples.By exploiting the reversible nature of carbohydrate-lectin interactions, it was possible to use the glyconanoparticles together with the lectin ConA to develop a glucose sensor. This performed effectively across the physiological range and into the hypo/hyperglycaemic regions in buffer conditions.Finally, the glyconanoparticles were used for the detection of plant and bacterial lectins on glass substrates by initially developing a sandwich SERS assay with a view to eventually creating SERS-based carbohydrate microarrays
Chiral concepts in s-block metal chemistry
Get PDFGiven the nature of the work undertaken in this project, this thesis will be divided into six chapters. The topics discussed within this thesis primarily focus on the study of chiral bimetallic complexes both from a synthetic and a structural approach. The chemistry of magnesiate complexes will be covered in Chapters 1-3. Chapter 1 focuses on the synthesis and characterisation of five different adducts of the synthetically important lithium tris(n-butyl)magnesiate LiMg(nBu)3 (1). Complex 1 has been co-complexed with different ligands to form the complexes [(TMPDA)·Li(u-nBu)2Mg(u-nBu)]2 (48), [(PMDETA)·Li(u-nBu)(nBu)Mg(u-nBu)]2 (49) [{(R,R)-TMCDA}·Li(u-nBu)2Mg(u-nBu)]2 (51), [(TMEDA)·Li(u-nBu)(u-OnBu)Mg(nBu)]2 (52) and [[(dioxane)·Li(u-nBu)2Mg(u-nBu)]2]∞ (56) In Chapter 2, the reactivity of lithium magnesiates complexes for the asymmetric deprotonation of prochiral ketones is studied. Homoleptic and heteroleptic lithium magnesiate bases have been evaluated and the results highlight that good conversions and enantioselectivities can be achieved when lithium amide LiPEA (lithium (+)-bis-(R)-1-phenylethylamide, Li-57) and a second organometallic reagent are combined. The chemistry of chiral sodium magnesiates is studied in Chapter 3. Solid state and solution structural studies of complexes [NaMg(PEA)2nBu]∞ (103), [TMEDA·Na(PEA)2MgnBu] (104) and inverse crown ether [NaMg(PEA)4O] (105) have been performed. Compounds 103 and 104 have also been tested as deprotonating reagents towards 4-tert-butylcyclohexanone. Chapter 4 focuses on the synthesis of chiral homoleptic and heteroleptic lithium zincates and their applications in enantioselective addition reactions towards ketones. Two new lithium zincates have been fully characterised, TMEDA·Li(u-PEA)(u-Me)ZnMe (147) and (R,R)-TMCDA·Li(u-Me)2ZnMe (149). The alkyl addition to ketones with this monomer is successful although the enantiomeric excess is relatively low. Chapter 5 describes the synthesis, characterization and reactivity studies of a series of mixed alkali-metal complexes: [LiNa(PEA)2]2 (168), [(THF)2LiNaPEA2] (169) and [LiK(PEA)2]2 (170). A preliminary study on the reactivity of these amides as initiators of the asymmetric rearrangement of epoxides has been performed. Each chapter contains a self-contained experimental section where the synthesis and solution characterisation of the complexes are included. Chapter 6 summarises the synthetic procedures for starting materials, as well as a description of general experimental techniques. Finally, an appendix with the crystallographic data for compounds synthesised in this work is included after Chapter 6.Given the nature of the work undertaken in this project, this thesis will be divided into six chapters. The topics discussed within this thesis primarily focus on the study of chiral bimetallic complexes both from a synthetic and a structural approach. The chemistry of magnesiate complexes will be covered in Chapters 1-3. Chapter 1 focuses on the synthesis and characterisation of five different adducts of the synthetically important lithium tris(n-butyl)magnesiate LiMg(nBu)3 (1). Complex 1 has been co-complexed with different ligands to form the complexes [(TMPDA)·Li(u-nBu)2Mg(u-nBu)]2 (48), [(PMDETA)·Li(u-nBu)(nBu)Mg(u-nBu)]2 (49) [{(R,R)-TMCDA}·Li(u-nBu)2Mg(u-nBu)]2 (51), [(TMEDA)·Li(u-nBu)(u-OnBu)Mg(nBu)]2 (52) and [[(dioxane)·Li(u-nBu)2Mg(u-nBu)]2]∞ (56) In Chapter 2, the reactivity of lithium magnesiates complexes for the asymmetric deprotonation of prochiral ketones is studied. Homoleptic and heteroleptic lithium magnesiate bases have been evaluated and the results highlight that good conversions and enantioselectivities can be achieved when lithium amide LiPEA (lithium (+)-bis-(R)-1-phenylethylamide, Li-57) and a second organometallic reagent are combined. The chemistry of chiral sodium magnesiates is studied in Chapter 3. Solid state and solution structural studies of complexes [NaMg(PEA)2nBu]∞ (103), [TMEDA·Na(PEA)2MgnBu] (104) and inverse crown ether [NaMg(PEA)4O] (105) have been performed. Compounds 103 and 104 have also been tested as deprotonating reagents towards 4-tert-butylcyclohexanone. Chapter 4 focuses on the synthesis of chiral homoleptic and heteroleptic lithium zincates and their applications in enantioselective addition reactions towards ketones. Two new lithium zincates have been fully characterised, TMEDA·Li(u-PEA)(u-Me)ZnMe (147) and (R,R)-TMCDA·Li(u-Me)2ZnMe (149). The alkyl addition to ketones with this monomer is successful although the enantiomeric excess is relatively low. Chapter 5 describes the synthesis, characterization and reactivity studies of a series of mixed alkali-metal complexes: [LiNa(PEA)2]2 (168), [(THF)2LiNaPEA2] (169) and [LiK(PEA)2]2 (170). A preliminary study on the reactivity of these amides as initiators of the asymmetric rearrangement of epoxides has been performed. Each chapter contains a self-contained experimental section where the synthesis and solution characterisation of the complexes are included. Chapter 6 summarises the synthetic procedures for starting materials, as well as a description of general experimental techniques. Finally, an appendix with the crystallographic data for compounds synthesised in this work is included after Chapter 6
Application of advanced material analyses for the investigation of the role of nano-mechanical properties in cell - scaffold interactions
Get PDFThis thesis was previously held under moratorium from 20/07/2016 to 21/05/2021.The fate of cells seeded onto a scaffold is determined by a number of factors including chemical, topographical and mechanical stimuli. The combination of these factors regulates a number of cellular functions and ultimately determines the performance of the engineered tissue. In recent years, focus has shifted from investigating bulk scaffold properties to nano-scale properties that are more relevant on the cellular scale. This trend has been partially fuelled by a significant increase in the availability of nano-scale analysis techniques and a general development in scientific investigations on such scales. Standard Euler's principles do not apply on the nano-scale, and a number of previous publications have examined and modelled various strain dependent nano-mechanical properties. Size effect theories predict that the effective modulus of elasticity increases as the length scale of measurement decreases. These changes occur at the length scales of the order of the cell and their effects on cellular mechanotransduction have not yet been investigated. This body of work attempts to lay the foundations and develop techniques that can eventually be used to investigate the influence of nano-mechanical properties on cell mechanotransduction in fibrous scaffolds. Medical grade polyurethanes (Biomer Technology Limited, Runcorn, UK) were chosen for this study because of their wide range of mechanical properties while maintaining similar chemistry. Solvent-cast films fabricated from various grades of these materials were first characterised on both the nano- and macro- scale in order to inform the fabrication of three-dimensional electrospun fibrous scaffolds. Such scaffolds were then fabricated with a variety of nano-mechanical properties by altering fibre diameter distributions. Dual spinning was also used in order to fabricate a scaffold with mixed nano-mechanical properties. The stability of such polymers when stored under physiological conditions over a period of 90 days was then investigated. Thereafter, samples were prepared for use in an initial assessment of cell attachment in order to investigate the extent to which three different cell types were able to adhere and proliferate on both scaffold forms fabricated from two grades of polyurethane with distinct macro- and nano- mechanical properties. The implications that such changes in nano-mechanical properties could have on cell mechanotransduction are discussed. Further experiments are suggested in order to develop a better understanding of these interactions.The fate of cells seeded onto a scaffold is determined by a number of factors including chemical, topographical and mechanical stimuli. The combination of these factors regulates a number of cellular functions and ultimately determines the performance of the engineered tissue. In recent years, focus has shifted from investigating bulk scaffold properties to nano-scale properties that are more relevant on the cellular scale. This trend has been partially fuelled by a significant increase in the availability of nano-scale analysis techniques and a general development in scientific investigations on such scales. Standard Euler's principles do not apply on the nano-scale, and a number of previous publications have examined and modelled various strain dependent nano-mechanical properties. Size effect theories predict that the effective modulus of elasticity increases as the length scale of measurement decreases. These changes occur at the length scales of the order of the cell and their effects on cellular mechanotransduction have not yet been investigated. This body of work attempts to lay the foundations and develop techniques that can eventually be used to investigate the influence of nano-mechanical properties on cell mechanotransduction in fibrous scaffolds. Medical grade polyurethanes (Biomer Technology Limited, Runcorn, UK) were chosen for this study because of their wide range of mechanical properties while maintaining similar chemistry. Solvent-cast films fabricated from various grades of these materials were first characterised on both the nano- and macro- scale in order to inform the fabrication of three-dimensional electrospun fibrous scaffolds. Such scaffolds were then fabricated with a variety of nano-mechanical properties by altering fibre diameter distributions. Dual spinning was also used in order to fabricate a scaffold with mixed nano-mechanical properties. The stability of such polymers when stored under physiological conditions over a period of 90 days was then investigated. Thereafter, samples were prepared for use in an initial assessment of cell attachment in order to investigate the extent to which three different cell types were able to adhere and proliferate on both scaffold forms fabricated from two grades of polyurethane with distinct macro- and nano- mechanical properties. The implications that such changes in nano-mechanical properties could have on cell mechanotransduction are discussed. Further experiments are suggested in order to develop a better understanding of these interactions
Sustainable production of platform chemicals using novel synthetic biology and microbial fermentations
Get PDFFluctuating oil prices and environmental concerns have led to a directed effort by industry to develop sustainable production of high value chemicals. Mesaconate, an industrially relevant platform chemical used in the production of methyl methacrylate, can be synthesised through the L-glutamate degradation pathway present in certain anaerobic organisms. This study investigates the potential of genes derived from this pathway to be expressed in Corynebacterium glutamicum, as a cellular factory to produce mesaconate in the first instance, with future scope to produce methyl methacrylate. C. glutamicum was chosen as a primary organism due to its existing industrial use as a microbial workhorse for the production of Lglutamate. Firstly, as the proposed process incorporated the initial over production of Lglutamate, various induction methods were investigated to establish an optimal process. Genetically engineered strains were then constructed and examined for their ability to produce mesaconate. Further process development was carried out to develop an efficient induction protocol. While the accumulation of mesaconate remains unclear, novel expression of the desired glutamate mutase and methylaspartate ammonia-lyase within C. glutamicum ATCC 13869 was established. A secondary approach where production of desired chemicals under oxygen limited conditions was examined. High cell densities of several mutant strains of C. glutamicum were investigated during a bioconversion process. Significant levels of succinic acid were achieved, however, further conversion to α-ketoglutarate, the precursor to L-glutamate was not observed. Co-factor regeneration appeared to be crucial for successful application of this process. Finally, toxicity of potential products and feedstocks were analysed to identify detrimental or toxic effects. While many of the compounds appeared to have little effect on the organisms examined, presence of methyl methacrylate, methacrylic acid and methanol significantly decreased growth and/or production. Design of future processes will be significant in maintaining these compounds at non-inhibitory levels to ensure efficiency.Fluctuating oil prices and environmental concerns have led to a directed effort by industry to develop sustainable production of high value chemicals. Mesaconate, an industrially relevant platform chemical used in the production of methyl methacrylate, can be synthesised through the L-glutamate degradation pathway present in certain anaerobic organisms. This study investigates the potential of genes derived from this pathway to be expressed in Corynebacterium glutamicum, as a cellular factory to produce mesaconate in the first instance, with future scope to produce methyl methacrylate. C. glutamicum was chosen as a primary organism due to its existing industrial use as a microbial workhorse for the production of Lglutamate. Firstly, as the proposed process incorporated the initial over production of Lglutamate, various induction methods were investigated to establish an optimal process. Genetically engineered strains were then constructed and examined for their ability to produce mesaconate. Further process development was carried out to develop an efficient induction protocol. While the accumulation of mesaconate remains unclear, novel expression of the desired glutamate mutase and methylaspartate ammonia-lyase within C. glutamicum ATCC 13869 was established. A secondary approach where production of desired chemicals under oxygen limited conditions was examined. High cell densities of several mutant strains of C. glutamicum were investigated during a bioconversion process. Significant levels of succinic acid were achieved, however, further conversion to α-ketoglutarate, the precursor to L-glutamate was not observed. Co-factor regeneration appeared to be crucial for successful application of this process. Finally, toxicity of potential products and feedstocks were analysed to identify detrimental or toxic effects. While many of the compounds appeared to have little effect on the organisms examined, presence of methyl methacrylate, methacrylic acid and methanol significantly decreased growth and/or production. Design of future processes will be significant in maintaining these compounds at non-inhibitory levels to ensure efficiency
Types, categories, actions
Get PDFThis thesis explores relational parametricity using fibrations. We present a complementary view of Reynolds's relational parametricity using the relations fibration. This approach allows us to uncover some of the hidden categorical structure present in Reynolds's original definitions and results, leading to new insights in the study of parametricity. In a similar vain we provide an alternative parametric model of System F using group actions, which has some novel differences to the standard relational model. We then alter the type system leading to a general categorical framework for type systems with dimension types. We develop some informative models of this type theory, including a model based on group actions that captures invariance under scaling.This thesis explores relational parametricity using fibrations. We present a complementary view of Reynolds's relational parametricity using the relations fibration. This approach allows us to uncover some of the hidden categorical structure present in Reynolds's original definitions and results, leading to new insights in the study of parametricity. In a similar vain we provide an alternative parametric model of System F using group actions, which has some novel differences to the standard relational model. We then alter the type system leading to a general categorical framework for type systems with dimension types. We develop some informative models of this type theory, including a model based on group actions that captures invariance under scaling
An analysis of resistance to miltefosine and paromomycin in leishmania donovani
Get PDFVisceral leishmaniasis (VL) is estimated to cause over 300,000 deaths annually, with over 90% of these cases attributed to infection by Leishmania donovani. It is therefore a significant global health problem and a major problem in endemic areas such as Nepal and northern India. Drug resistance in the parasite population is reducing the efficacy of clinical drugs, especially antimonials, and new methods to use existing drugs more carefully or develop new drugs are required.In this study, promastigotes of three Nepalese clinical isolates with different inherent susceptibilities to antimony (Sb) based drugs (i.e. sensitive, Sb-S; intermediate, Sb-I; or resistant, Sb-R) were grown in increasing concentrations of drugs until they expressed tolerance to 74 μM MIL (termed MIL-R) or 97 μM PMM (termed PMM-R). The drug resistant parents were then cloned to assess the impact of resistance to miltefosine (MIL) or paromomycin (PMM) on the 'fitness' and metabolomics/lipidomic profile, thereby elucidating the mechanism(s) responsible for drug resistance and potentially the development of screening assays for MIL or PMM resistance. MIL selected resistance gave rise to significant changes in the lipidome (p 75% suppression in parasite burdens compared to controls. One compound, MGB-3-NO, was tested in a murine model of VL. Treatment with MGB-3-NO (50 mg/kg) solution had no antileishmanial activity but treatment with MGB-3-NO encapsulated into non-ionic surfactant vesicles to increase its targeting to macrophages, caused a significant reduction in liver parasite burdens compared to controls (p 75% suppression in parasite burdens compared to controls. One compound, MGB-3-NO, was tested in a murine model of VL. Treatment with MGB-3-NO (50 mg/kg) solution had no antileishmanial activity but treatment with MGB-3-NO encapsulated into non-ionic surfactant vesicles to increase its targeting to macrophages, caused a significant reduction in liver parasite burdens compared to controls (p < 0.05).The results of this study identified similar types of metabolic and lipidomic changes in MIL-R and PMM-R parasites compared to WTs but the changes were clone-specific indicating that there was no clear and predictable mechanism to either MIL or PMM resistance selected in promastigotes
BEMT and CFD-based unsteady aerodynamic analyses of floating offshore wind turbine
Get PDFNowadays the demands for floating offshore wind (FOWT) have exceeded 5MW with the rapidly growing wind market. The aerodynamic environment of FOWT is more complex than onshore or fixed offshore wind turbine due to the large motions of floating platforms. The platform motion, especially pitch and surge motions, increase aerodynamic unsteadiness, wake interactions and other complex flow phenomena. These conditions influence the velocities and accelerations at the rotor sections along the blade. However, a limited simulation and load estimation capability make aerodynamic analysis a challenge. It is questionable whether some industry aerodynamic analysis codes like conventional Blade Element Momentum (BEM) theory and Generalised Dynamic Wake theory are accurate. Results indicate that current methods for predicting the aerodynamic loads may be inadequate.Aerodynamic flow effects cannot be accurately modelled using traditional BEM theory with common corrections in such a complex condition. So compared with traditional potential theory, CFD method provides more physically realistic simulation. The applying and validation of CFD method will be outlined in this dissertation. The commercial multi-purpose CFD solver STAR CCM+ 9.02 is employed for calculation of the flow using Reynolds-Average Navier-Stokes (RANS) equations in conjunction with different turbulent models. Finally, results from CFD simulations of various offshore floating wind turbines under different load conditions will be presented. CFD simulation is accurate, but time consuming. So, an optimization method will be detected to get a more accurate result and saving time. 2D CFD RANS data was instead of commonly 2D data. However, not result in the desired improvements when compared to BEM results. Therefore, a 2D airfoil data obtained by post-processing of 3D CFD computations was used. 3D results were used to estimate 2D airfoil characteristics to modify two important parameters in BEM codes: the axial and the tangential induction factors by applying the reduced axial velocity method by getting the local angle of attack from CFD solutions. This thesis will demonstrate that the aerodynamics of offshore floating wind turbines is sufficiently different from conventional offshore and onshore wind turbines, warranting the use of higher fidelity analysis approaches. It is obvious that thexxiiiplatform motions will have a great effect on unsteady aerodynamic performance of the wind turbine rotor. This thesis will study and explain the rules and reasons of this phenomenon in detail.Future offshore floating wind turbine designs should strive to either minimize platform motions or be complementarily optimized, via higher fidelity aerodynamic analysis techniques, to account for them. It is believed that this dissertation is the first in-depth study of offshore floating wind turbine aerodynamics and the applicability of various analysis methods.Nowadays the demands for floating offshore wind (FOWT) have exceeded 5MW with the rapidly growing wind market. The aerodynamic environment of FOWT is more complex than onshore or fixed offshore wind turbine due to the large motions of floating platforms. The platform motion, especially pitch and surge motions, increase aerodynamic unsteadiness, wake interactions and other complex flow phenomena. These conditions influence the velocities and accelerations at the rotor sections along the blade. However, a limited simulation and load estimation capability make aerodynamic analysis a challenge. It is questionable whether some industry aerodynamic analysis codes like conventional Blade Element Momentum (BEM) theory and Generalised Dynamic Wake theory are accurate. Results indicate that current methods for predicting the aerodynamic loads may be inadequate.Aerodynamic flow effects cannot be accurately modelled using traditional BEM theory with common corrections in such a complex condition. So compared with traditional potential theory, CFD method provides more physically realistic simulation. The applying and validation of CFD method will be outlined in this dissertation. The commercial multi-purpose CFD solver STAR CCM+ 9.02 is employed for calculation of the flow using Reynolds-Average Navier-Stokes (RANS) equations in conjunction with different turbulent models. Finally, results from CFD simulations of various offshore floating wind turbines under different load conditions will be presented. CFD simulation is accurate, but time consuming. So, an optimization method will be detected to get a more accurate result and saving time. 2D CFD RANS data was instead of commonly 2D data. However, not result in the desired improvements when compared to BEM results. Therefore, a 2D airfoil data obtained by post-processing of 3D CFD computations was used. 3D results were used to estimate 2D airfoil characteristics to modify two important parameters in BEM codes: the axial and the tangential induction factors by applying the reduced axial velocity method by getting the local angle of attack from CFD solutions. This thesis will demonstrate that the aerodynamics of offshore floating wind turbines is sufficiently different from conventional offshore and onshore wind turbines, warranting the use of higher fidelity analysis approaches. It is obvious that thexxiiiplatform motions will have a great effect on unsteady aerodynamic performance of the wind turbine rotor. This thesis will study and explain the rules and reasons of this phenomenon in detail.Future offshore floating wind turbine designs should strive to either minimize platform motions or be complementarily optimized, via higher fidelity aerodynamic analysis techniques, to account for them. It is believed that this dissertation is the first in-depth study of offshore floating wind turbine aerodynamics and the applicability of various analysis methods
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