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Formation of optimised particles for formulation and processing
Get PDFThis thesis was previously held under moratorium from 10th September 2018 until 10th September 2023.Pharmaceutical crystals frequently exhibit unfavourable bulk solid properties leading to low downstream processing efficiency and additional unit operations to enhance processing characteristics. Novel particle engineering techniques such as spherical crystallization or spherical agglomeration can be used in order to obtain spherical agglomerates with enhanced properties. Spherical agglomerates are produced through cooling crystallization in ethanol-water mixture under specific process conditions involving liquid-liquid phase separation; hence ternary phase diagrams were determined experimentally. The liquid-liquid phase region was found to increase with increasing temperature, whilst absent at 20°C. Ibuprofen agglomerates crystallised in the presence of liquid-liquid phase separation showed an increased flowability and higher yield compared to the standard cooling crystallization process. Spherical agglomerates of lovastatin were prepared by suspension of crystals in water and agglomeration through the action of another solvent called bridging liquid. All the solvents except alkenes led to the formation of spherical agglomerates as long as a sufficient amount is added. The influence of amount of bridging liquid and agitation rate on the properties of lovastatin spherical agglomerates obtained from methyl isobutyl ketone are investigated. With increasing amount of bridging liquid the particle size increased and the shape became irregular. In a separate chapter, a combined cooling antisolvent seeded crystallization process was monitored using process analytical technologies to investigate the agglomeration under different process conditions. A novel in-house image analysis algorithm coded in MATLAB was used to analyse images of agglomerates recorded by ParticleView V19 probe through descriptors. Images showed that seeds were already aggregated before addition to the reactor indicating an insufficient dispersion. Experiments using the same seed loading led to products with slightly variable particle size distribution but different degree of breakage ranging from moderate to significant breakage. Stronger crystals with larger size were produced when a temperature cycle was applied. Overall this work showed that agglomeration processes can lead to product with enhanced properties, and advanced the scientific understanding of the agglomeration mechanisms through implementation of process analytical technologies hence facilitating the scale-up and selection of control strategies.Pharmaceutical crystals frequently exhibit unfavourable bulk solid properties leading to low downstream processing efficiency and additional unit operations to enhance processing characteristics. Novel particle engineering techniques such as spherical crystallization or spherical agglomeration can be used in order to obtain spherical agglomerates with enhanced properties. Spherical agglomerates are produced through cooling crystallization in ethanol-water mixture under specific process conditions involving liquid-liquid phase separation; hence ternary phase diagrams were determined experimentally. The liquid-liquid phase region was found to increase with increasing temperature, whilst absent at 20°C. Ibuprofen agglomerates crystallised in the presence of liquid-liquid phase separation showed an increased flowability and higher yield compared to the standard cooling crystallization process. Spherical agglomerates of lovastatin were prepared by suspension of crystals in water and agglomeration through the action of another solvent called bridging liquid. All the solvents except alkenes led to the formation of spherical agglomerates as long as a sufficient amount is added. The influence of amount of bridging liquid and agitation rate on the properties of lovastatin spherical agglomerates obtained from methyl isobutyl ketone are investigated. With increasing amount of bridging liquid the particle size increased and the shape became irregular. In a separate chapter, a combined cooling antisolvent seeded crystallization process was monitored using process analytical technologies to investigate the agglomeration under different process conditions. A novel in-house image analysis algorithm coded in MATLAB was used to analyse images of agglomerates recorded by ParticleView V19 probe through descriptors. Images showed that seeds were already aggregated before addition to the reactor indicating an insufficient dispersion. Experiments using the same seed loading led to products with slightly variable particle size distribution but different degree of breakage ranging from moderate to significant breakage. Stronger crystals with larger size were produced when a temperature cycle was applied. Overall this work showed that agglomeration processes can lead to product with enhanced properties, and advanced the scientific understanding of the agglomeration mechanisms through implementation of process analytical technologies hence facilitating the scale-up and selection of control strategies
Biomechanical evaluation of user fatigue during burring with the MAKO RIO surgical system
Get PDFThe MAKO RIO (MAKO Surgical, Stryker, Mahwah, NJ, USA) is an assistive surgical robotic arm system developed to increase the accuracy of bone cuts in joint replacement surgery. A high-speed cutting burr is mounted on the arm and is manoeuvred by the surgeon. The robotic arm allows free movement of the burr through the calculated cutting volume but restricts movement, and hence cutting, outside of this volume.;Localised fatigue anecdotally reported during burring from high output users of the MAKO RIO system is an issue. An ergonomic assessment of the MAKO RIO was carried out to review possible causes of the complaint of discomfort and fatigue. A clinical trial was observed and assessed for typical use of the system. This assessment culminated in a time analysis review of video footage recorded, defining a typical workflow of the surgery and details of its constituent parts. The clinical trial didn't represent a high output use of the system, but a number of users presented discomfort associated with fatigue.;After observing fatigue in users of the system, the project explored the biomechanical reasons for potential causes of this fatigue. A testing protocol of optical tracking, EMG and a force transducer was developed to assess users performing repetitive burring stages of the surgery. The output from the assessment showed high levels of muscle activity, poor posture and large forces that ultimately led to fatiguing of muscles in the lower arm. Specifically, the most significant fatigue was seen in the intrinsic muscles of the hand, with the high grip forces being held for extended periods and a splayed hand over the handle of the robotic arm.;A new prototype handle was also available for assessment to investigate if this would resolve the issues with the current handle. While there were some improvements in some muscles, extension and grip muscles were still presenting fatigue. The manoeuvring of the burr is still shown to take an extended length of time and require large forces from muscles that eventually cannot be met. Within high output users, either this accumulation of demand on these muscles over the day or the increased probability of a patient with sclerotic bone on a surgical list would lead these users to experience fatigue when working with the MAKO RIO system.;Finally, some conceptual ideas for improvements to the system are suggested throughout the thesis. Fundamentally, however, the cutting method of a burr while enabling accurate cuts and ability to create unique shapes in the bone is not suitable for large volume resection of hard, sclerotic bone.The MAKO RIO (MAKO Surgical, Stryker, Mahwah, NJ, USA) is an assistive surgical robotic arm system developed to increase the accuracy of bone cuts in joint replacement surgery. A high-speed cutting burr is mounted on the arm and is manoeuvred by the surgeon. The robotic arm allows free movement of the burr through the calculated cutting volume but restricts movement, and hence cutting, outside of this volume.;Localised fatigue anecdotally reported during burring from high output users of the MAKO RIO system is an issue. An ergonomic assessment of the MAKO RIO was carried out to review possible causes of the complaint of discomfort and fatigue. A clinical trial was observed and assessed for typical use of the system. This assessment culminated in a time analysis review of video footage recorded, defining a typical workflow of the surgery and details of its constituent parts. The clinical trial didn't represent a high output use of the system, but a number of users presented discomfort associated with fatigue.;After observing fatigue in users of the system, the project explored the biomechanical reasons for potential causes of this fatigue. A testing protocol of optical tracking, EMG and a force transducer was developed to assess users performing repetitive burring stages of the surgery. The output from the assessment showed high levels of muscle activity, poor posture and large forces that ultimately led to fatiguing of muscles in the lower arm. Specifically, the most significant fatigue was seen in the intrinsic muscles of the hand, with the high grip forces being held for extended periods and a splayed hand over the handle of the robotic arm.;A new prototype handle was also available for assessment to investigate if this would resolve the issues with the current handle. While there were some improvements in some muscles, extension and grip muscles were still presenting fatigue. The manoeuvring of the burr is still shown to take an extended length of time and require large forces from muscles that eventually cannot be met. Within high output users, either this accumulation of demand on these muscles over the day or the increased probability of a patient with sclerotic bone on a surgical list would lead these users to experience fatigue when working with the MAKO RIO system.;Finally, some conceptual ideas for improvements to the system are suggested throughout the thesis. Fundamentally, however, the cutting method of a burr while enabling accurate cuts and ability to create unique shapes in the bone is not suitable for large volume resection of hard, sclerotic bone
Quantifying AAAs and developing FEA models for stent grafts
No full textAbdominal Aortic Aneurysm (AAA) is an irreversible dilation of the lower section of the aorta that poses lethal threat to the patient. Medical intervention has been conducted for decades via open surgery, yet more recently, the minimally invasive technique of endovascular aneurysm repair (EVAR) is preferred, via the introduction of a stent graft into the aneurysmal region. In this thesis, finite element analysis (FEA) techniques have been developed to model the AnacondaTM stent graft. The aim is to produce the necessary numerical tools to allow for personalized EVAR simulations for mechanical and clinical evaluation. The basic unit of an AnacondaTM is modelled with a novel FEA approach acquiring computationally efficient solutions without sacrificing precision. By taking into account the manufacturing process, the developed strains and forces can be predicted, allowing for fatigue life and anchoring evaluation. The mean strain of the unit is found to be strongly affected by the oversize of the device, yet its radial force is mainly influenced by the friction of the vessel/stent interface. The effects of non-circular aortic cross sections are also examined and mean aortic diameter approximations are shown to be superior. For all analyses, a phenomenological model of the abdominal aorta is created, able to accurately mimic the pressure-radius response of the artery. Furthermore, a separate model of lower fidelity and higher computational efficiency is developed, allowing the simulation of the full AnacondaTM stent graft. The model has the ability to predict the deployed position of the device and demonstrates that inclusion of fabric folds can allow for more insightful hemodynamic studies that capture blood recirculation. Finally, an extensive statistical analysis of 258 patient geometries is conducted and a set of 10 angles is proposed as a way to quantify the AAA shape. No anterior/posterior or lateral symmetries are identified. The measurements of angular and dimensional variables correspond to the most thorough study of the AAA shape available in the literature and allow the identification of average and worst case topologies for future EVAR simulations.Abdominal Aortic Aneurysm (AAA) is an irreversible dilation of the lower section of the aorta that poses lethal threat to the patient. Medical intervention has been conducted for decades via open surgery, yet more recently, the minimally invasive technique of endovascular aneurysm repair (EVAR) is preferred, via the introduction of a stent graft into the aneurysmal region. In this thesis, finite element analysis (FEA) techniques have been developed to model the AnacondaTM stent graft. The aim is to produce the necessary numerical tools to allow for personalized EVAR simulations for mechanical and clinical evaluation. The basic unit of an AnacondaTM is modelled with a novel FEA approach acquiring computationally efficient solutions without sacrificing precision. By taking into account the manufacturing process, the developed strains and forces can be predicted, allowing for fatigue life and anchoring evaluation. The mean strain of the unit is found to be strongly affected by the oversize of the device, yet its radial force is mainly influenced by the friction of the vessel/stent interface. The effects of non-circular aortic cross sections are also examined and mean aortic diameter approximations are shown to be superior. For all analyses, a phenomenological model of the abdominal aorta is created, able to accurately mimic the pressure-radius response of the artery. Furthermore, a separate model of lower fidelity and higher computational efficiency is developed, allowing the simulation of the full AnacondaTM stent graft. The model has the ability to predict the deployed position of the device and demonstrates that inclusion of fabric folds can allow for more insightful hemodynamic studies that capture blood recirculation. Finally, an extensive statistical analysis of 258 patient geometries is conducted and a set of 10 angles is proposed as a way to quantify the AAA shape. No anterior/posterior or lateral symmetries are identified. The measurements of angular and dimensional variables correspond to the most thorough study of the AAA shape available in the literature and allow the identification of average and worst case topologies for future EVAR simulations
Evaluating the application and limitations of bio-based solvents within organic synthesis
Get PDFThe growing sustainability movement within the chemical industries endeavours to forge cleaner manufacturing processes which integrate the key principles of Green Chemistry.At the forefront of these initiatives are solvent replacement strategies, driven, in part, by increasingly stringent regulations surrounding the use of solvents of concern. A group of solvents which have fallen under particular scrutiny are polar aprotic solvents, such as DMF, NMP and DMAc. This solvent class is characterised by high polarity and superior solvating abilities, which has firmly established their use within synthetic organic and medicinal chemistry. However, they are also associated with reproductive toxicity and are regarded as teratogens. As such, their continued use within industry is becoming increasingly discouraged.Direct replacement of polar aprotics using existing solvents often fails and, as such, novel alternatives are required. In this regard, the use of biomass feedstocks in the development of new solvents is an expanding area within Green Chemistry which aims to minimise the dependence on petroleum-based chemicals;Cyrene and dimethyl isosorbide (DMI) are two emerging solvents derived from cellulose. However, their application within organic chemistry is under explored and, as such, their use within industry is currently limited.This research programme aims to investigate the use of these alternative solvents in synthetic transformations commonly utilised within the context of drug discovery in the pharmaceutical industries. Robust and general condition sets have been developed and thoroughly evaluated in the application of Cyrene as a medium for the Sonogashira and Suzuki-Miyaura cross-couplings, and amide bond formation. In addition, the methodology developed for the Sonogashira cross-coupling was extended to enable the efficient synthesis of pharmaceutically relevant heterocycles. Cyrene exhibited a pronounced base sensitivity, the effect and limitations of which were studied within organic reactions.Additionally, the utilisation of DMI as an alternative solvent within prominent Pdcatalysed transformations was also evaluated. Accessible conditions for the Suzuki-Miyaura, Mizoroki-Heck and Sonogashira cross-coupling reactions were developed and the scope of the reactions investigated. Ultimately, it is hoped that exemplifying the use of these solvents within organic synthesis and highlighting their limitations will influence their uptake by industrial practitioners.The growing sustainability movement within the chemical industries endeavours to forge cleaner manufacturing processes which integrate the key principles of Green Chemistry.At the forefront of these initiatives are solvent replacement strategies, driven, in part, by increasingly stringent regulations surrounding the use of solvents of concern. A group of solvents which have fallen under particular scrutiny are polar aprotic solvents, such as DMF, NMP and DMAc. This solvent class is characterised by high polarity and superior solvating abilities, which has firmly established their use within synthetic organic and medicinal chemistry. However, they are also associated with reproductive toxicity and are regarded as teratogens. As such, their continued use within industry is becoming increasingly discouraged.Direct replacement of polar aprotics using existing solvents often fails and, as such, novel alternatives are required. In this regard, the use of biomass feedstocks in the development of new solvents is an expanding area within Green Chemistry which aims to minimise the dependence on petroleum-based chemicals;Cyrene and dimethyl isosorbide (DMI) are two emerging solvents derived from cellulose. However, their application within organic chemistry is under explored and, as such, their use within industry is currently limited.This research programme aims to investigate the use of these alternative solvents in synthetic transformations commonly utilised within the context of drug discovery in the pharmaceutical industries. Robust and general condition sets have been developed and thoroughly evaluated in the application of Cyrene as a medium for the Sonogashira and Suzuki-Miyaura cross-couplings, and amide bond formation. In addition, the methodology developed for the Sonogashira cross-coupling was extended to enable the efficient synthesis of pharmaceutically relevant heterocycles. Cyrene exhibited a pronounced base sensitivity, the effect and limitations of which were studied within organic reactions.Additionally, the utilisation of DMI as an alternative solvent within prominent Pdcatalysed transformations was also evaluated. Accessible conditions for the Suzuki-Miyaura, Mizoroki-Heck and Sonogashira cross-coupling reactions were developed and the scope of the reactions investigated. Ultimately, it is hoped that exemplifying the use of these solvents within organic synthesis and highlighting their limitations will influence their uptake by industrial practitioners
Essays on the economics of information
Get PDFIn three distinct, yet interrelated, essays I examine the effects of asymmetric information and imperfect information on economic decision makers' incentives and behaviour. To do so I employ, and modify, the methodology of Bayesian games.In chapter one, I analyse an unconventional contest inspired by the real world.In this contest, players are ranked by a scoring rule based on both their realised performance and how close this performance is to a target set before the contest,which is private information. I elucidate and analyse the incentive properties of these rules then characterise the equilibrium behaviour of the players.In chapter two, I integrate aspects from adverse selection and moral hazard models to provide a unied theory of securitisation under asymmetric information.I show that introducing skin in the game increases signalling costs for originators who performed sufficient due-diligence yet still improves incentives by making high effort relatively more likely. I relax the conventional assumption of risk neutrality and show that risk-sharing concerns are sufficient for the aforementioned qualitative properties of equilibrium to hold. Finally, I demonstrate that, depending on the severity of the originator's preference for liquidity or need to share risk, each setting may be more conducive for signalling.In chapter three, I propose a simple and intuitive way to transform canonical signalling games with exogenous types into games in which the informed agent endogenously generates her private information through an unobservable costly effort decision. I provide portable results on the differentiability of action functions and existence of equilibrium. I then apply these results to classic models of security design and the job market to demonstrate the practical usefulness of endogenous effort. In particular, my approach in these applications lends theoretical support to stylised facts that cannot be derived from the standard signalling framework.In three distinct, yet interrelated, essays I examine the effects of asymmetric information and imperfect information on economic decision makers' incentives and behaviour. To do so I employ, and modify, the methodology of Bayesian games.In chapter one, I analyse an unconventional contest inspired by the real world.In this contest, players are ranked by a scoring rule based on both their realised performance and how close this performance is to a target set before the contest,which is private information. I elucidate and analyse the incentive properties of these rules then characterise the equilibrium behaviour of the players.In chapter two, I integrate aspects from adverse selection and moral hazard models to provide a unied theory of securitisation under asymmetric information.I show that introducing skin in the game increases signalling costs for originators who performed sufficient due-diligence yet still improves incentives by making high effort relatively more likely. I relax the conventional assumption of risk neutrality and show that risk-sharing concerns are sufficient for the aforementioned qualitative properties of equilibrium to hold. Finally, I demonstrate that, depending on the severity of the originator's preference for liquidity or need to share risk, each setting may be more conducive for signalling.In chapter three, I propose a simple and intuitive way to transform canonical signalling games with exogenous types into games in which the informed agent endogenously generates her private information through an unobservable costly effort decision. I provide portable results on the differentiability of action functions and existence of equilibrium. I then apply these results to classic models of security design and the job market to demonstrate the practical usefulness of endogenous effort. In particular, my approach in these applications lends theoretical support to stylised facts that cannot be derived from the standard signalling framework
Design, synthesis and biological evaluation of sphingosine kinase inhibitors for the treatment of prostate cancer
Get PDFSphingosine is phosphorylated via the action of the enzymes sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) to produce the bioactive signalling molecule sphingosine 1-phosphate (S1P). S1P drives cancer cell proliferation and migration whilst also promoting cell survival. Many studies have demonstrated that SK is a promising target for the treatment of cancer and the development of novel isoform-selective SK inhibitors to treat human cancers is of major interest. To date, inhibitors for this enzyme have either been selective for SK1 or non-selective for both isoforms. However, most SK inhibitors have only weak potency. This project involves the design and synthesis of small molecule inhibitors of SK as potential anti-cancer compounds. In this drug discovery project, a series of potent and selective inhibitors of SK (SK1 or SK2 or SK1/SK2) were developed based on the structure of PF-543, a known potent SK1 selective inhibitor. Analogues of PF-543 were prepared that were potent selective inhibitors of SK1 over SK2 and nM potent SK2 inhibitors with selectivity over SK1. These compounds represent some of the first nM potent SK2 inhibitors with selectivity over SK1. Indeed, the studies identified a structural determinant in the catalytic site of SK1 and SK2 that confers selectivity, with the heel and toe regions of the so-called J-channel in either enzyme providing a means toward selectivity. Exemplars from the series were shown to have potent cellular activity but poor in vitro microsomal stability. Effective target engagement and selectivity for SK1 in prostate cancer cell lines (LNCaP and LNCaP-AI) and proliferating human pulmonary artery smooth muscle cells (hPSMAC) were also established. A variety of biological assays associated with SK inhibition were used to evaluate their ability to induce cancer cell death, which was shown to involve a caspase-3/7-independent mechanism. Our SK1 and SK1/SK2 inhibitors, but not SK2 inhibitors, also reduced expression of dihydroceramide desaturase 1 (Des1) in a dose dependent manner, causing growth arrest and caspase-independent cell death. This project highlighted the importance for combining SK1 with Des1 inhibition in terms of endowing compounds with cytotoxicity against cancer cells.Sphingosine is phosphorylated via the action of the enzymes sphingosine kinase 1 (SK1) and sphingosine kinase 2 (SK2) to produce the bioactive signalling molecule sphingosine 1-phosphate (S1P). S1P drives cancer cell proliferation and migration whilst also promoting cell survival. Many studies have demonstrated that SK is a promising target for the treatment of cancer and the development of novel isoform-selective SK inhibitors to treat human cancers is of major interest. To date, inhibitors for this enzyme have either been selective for SK1 or non-selective for both isoforms. However, most SK inhibitors have only weak potency. This project involves the design and synthesis of small molecule inhibitors of SK as potential anti-cancer compounds. In this drug discovery project, a series of potent and selective inhibitors of SK (SK1 or SK2 or SK1/SK2) were developed based on the structure of PF-543, a known potent SK1 selective inhibitor. Analogues of PF-543 were prepared that were potent selective inhibitors of SK1 over SK2 and nM potent SK2 inhibitors with selectivity over SK1. These compounds represent some of the first nM potent SK2 inhibitors with selectivity over SK1. Indeed, the studies identified a structural determinant in the catalytic site of SK1 and SK2 that confers selectivity, with the heel and toe regions of the so-called J-channel in either enzyme providing a means toward selectivity. Exemplars from the series were shown to have potent cellular activity but poor in vitro microsomal stability. Effective target engagement and selectivity for SK1 in prostate cancer cell lines (LNCaP and LNCaP-AI) and proliferating human pulmonary artery smooth muscle cells (hPSMAC) were also established. A variety of biological assays associated with SK inhibition were used to evaluate their ability to induce cancer cell death, which was shown to involve a caspase-3/7-independent mechanism. Our SK1 and SK1/SK2 inhibitors, but not SK2 inhibitors, also reduced expression of dihydroceramide desaturase 1 (Des1) in a dose dependent manner, causing growth arrest and caspase-independent cell death. This project highlighted the importance for combining SK1 with Des1 inhibition in terms of endowing compounds with cytotoxicity against cancer cells
Spatial and temporal disaggregation of whole system energy models through exemplar local multi-carrier networks
Get PDFDifferent futures of domestic energy use - in particular, considering options in heat provision - are simulated and analysed within characteristic UK local energy systems (urban, suburban, rural) in order to determine the Delivered Cost of Energy, Emissions Intensity, and Abatement Cost for different technology options across multiple carriers, including both options in electrification and the use of alternative gases. This incorporates the costs and efficiencies of domestic technologies, district heating options, and the necessary levels of network reinforcement.;The methodology extends the use of an existing Energy Hub optimisation model into the multi-carrier assessment of domestic heat incorporating high levels of spatial and temporal detail, and determines the respective contributions each technology may make to carbon emissions reduction. The optimal choice of technology is found to differ according to the spatial characteristics of the location, with a greater value for thermal storage and local supply arrangements with renewable energy sources where the per-customer cost of infrastructure reinforcement is higher.;The use of resources with a high emissions intensity may be displaced through time-shifting of demand towards the use of lower-intensity carriers to overcome existing network capacity constraints. The results are used to disaggregate infrastructure costs and technical parameters into the domestic heating sector in the UK TIMES model, showing that recognition of a greater diversity of infrastructure capacities and costs entails a greater diversity in technology selections when seeking a least-cost trajectory towards national emission targets, with increased use of district heating systems and night storage over a non-spatially disaggregated formulation.;There is a strong potential for the coordination of local renewable output in constrained networks with local heat demand, with total abatement costs reduced where this value can be unlocked through investment in domestic low-carbon heating technologies such as heat pumps and thermal stores.Different futures of domestic energy use - in particular, considering options in heat provision - are simulated and analysed within characteristic UK local energy systems (urban, suburban, rural) in order to determine the Delivered Cost of Energy, Emissions Intensity, and Abatement Cost for different technology options across multiple carriers, including both options in electrification and the use of alternative gases. This incorporates the costs and efficiencies of domestic technologies, district heating options, and the necessary levels of network reinforcement.;The methodology extends the use of an existing Energy Hub optimisation model into the multi-carrier assessment of domestic heat incorporating high levels of spatial and temporal detail, and determines the respective contributions each technology may make to carbon emissions reduction. The optimal choice of technology is found to differ according to the spatial characteristics of the location, with a greater value for thermal storage and local supply arrangements with renewable energy sources where the per-customer cost of infrastructure reinforcement is higher.;The use of resources with a high emissions intensity may be displaced through time-shifting of demand towards the use of lower-intensity carriers to overcome existing network capacity constraints. The results are used to disaggregate infrastructure costs and technical parameters into the domestic heating sector in the UK TIMES model, showing that recognition of a greater diversity of infrastructure capacities and costs entails a greater diversity in technology selections when seeking a least-cost trajectory towards national emission targets, with increased use of district heating systems and night storage over a non-spatially disaggregated formulation.;There is a strong potential for the coordination of local renewable output in constrained networks with local heat demand, with total abatement costs reduced where this value can be unlocked through investment in domestic low-carbon heating technologies such as heat pumps and thermal stores
How the solo self-employed mitigate lower income with their personality in order to manifest well-being
Get PDFHow do the world's almost 1 billion 'solos' mitigate lower income with their personality in order to manifest well-being? (Solos are individuals operating non-employer businesses, lower income and classed 'vulnerably-employed' by the UN - over 75% of UK and US businesses in 2013/14). The British Household Panel Survey (BHPS) is utilised in a novel and positivist approach to answering this question in the case of the UK population. Using structural equation modelling (SEM) this thesis simultaneously examines the income, hedonic and eudemonic well-being, and personality of the solo.;Well-being is usually measured in terms of hedonic cognitive responses such as life satisfaction, or happiness, or, less frequently, affect. The thesis emphasizes that well-being has, two components, hedonic and eudemonic - where the functional eudemonic can cause 'healthy' hedonic responses. Modern eudaimonia research includes dimensions such as purpose, relationships or autonomy, seen as critical to high functioning, and the latter in particular, to entrepreneurship. Connecting income to eudaimonia, hedonic and traits lead to a model with 6 direct paths and 4 mediation relationships.;All models were well fit with SRMR of less than 0.08. Solos were found to have the lowest income, highest affect and happiness compared to the employed and self-employed with employees. Solos were shown to derive the most hedonic and eudaimonic well-being from income compared to other employment types. Income was found to be positively associated with all personality traits. The analysis confirmed the relationship between traits and hedonic well-being. Agreeability and extroversion traits were also found to be positively linked to eudaimonia.;Eudaimonia was found to be strongly positively associated with hedonic well-being, and, notably, stronger than both traits and income. The analysis also demonstrated a mediation, not moderation, relationship between income and hedonic well-being and both traits and eudaimonia. Notably, income was shown to be more important than traits or eudaimonia in raising negative affect for those solos who were more conscientious, introverted or disagreeable. Finally, for the positive affect, neuroticism had a large indirect effect, emphasizing that mental health could be more important than income (or even eudaimonia) for raising hedonic well-being for those with neurotic traits.;The findings have important implications for the domains of economic well-being and raises questions regarding a solo's place in the domain of entrepreneurship (less than 20 academics have published on the almost 1 billion solos and none on their well-being). Solos and practitioners supporting solos are provided with a mechanism for examining appropriate personality and eudaimonic responses to changes in income and how these can be utilised to raise 'healthy' hedonic well-being.How do the world's almost 1 billion 'solos' mitigate lower income with their personality in order to manifest well-being? (Solos are individuals operating non-employer businesses, lower income and classed 'vulnerably-employed' by the UN - over 75% of UK and US businesses in 2013/14). The British Household Panel Survey (BHPS) is utilised in a novel and positivist approach to answering this question in the case of the UK population. Using structural equation modelling (SEM) this thesis simultaneously examines the income, hedonic and eudemonic well-being, and personality of the solo.;Well-being is usually measured in terms of hedonic cognitive responses such as life satisfaction, or happiness, or, less frequently, affect. The thesis emphasizes that well-being has, two components, hedonic and eudemonic - where the functional eudemonic can cause 'healthy' hedonic responses. Modern eudaimonia research includes dimensions such as purpose, relationships or autonomy, seen as critical to high functioning, and the latter in particular, to entrepreneurship. Connecting income to eudaimonia, hedonic and traits lead to a model with 6 direct paths and 4 mediation relationships.;All models were well fit with SRMR of less than 0.08. Solos were found to have the lowest income, highest affect and happiness compared to the employed and self-employed with employees. Solos were shown to derive the most hedonic and eudaimonic well-being from income compared to other employment types. Income was found to be positively associated with all personality traits. The analysis confirmed the relationship between traits and hedonic well-being. Agreeability and extroversion traits were also found to be positively linked to eudaimonia.;Eudaimonia was found to be strongly positively associated with hedonic well-being, and, notably, stronger than both traits and income. The analysis also demonstrated a mediation, not moderation, relationship between income and hedonic well-being and both traits and eudaimonia. Notably, income was shown to be more important than traits or eudaimonia in raising negative affect for those solos who were more conscientious, introverted or disagreeable. Finally, for the positive affect, neuroticism had a large indirect effect, emphasizing that mental health could be more important than income (or even eudaimonia) for raising hedonic well-being for those with neurotic traits.;The findings have important implications for the domains of economic well-being and raises questions regarding a solo's place in the domain of entrepreneurship (less than 20 academics have published on the almost 1 billion solos and none on their well-being). Solos and practitioners supporting solos are provided with a mechanism for examining appropriate personality and eudaimonic responses to changes in income and how these can be utilised to raise 'healthy' hedonic well-being
The role of sphingosine kinases and dihydroceramide desaturase in regulating senescence in prostate cancer cells
Get PDFSphingosine kinase 1 and Sphingosine kinase 2 (SK1 and SK2) are lipid kinases which form the bioactive lipid sphingosine-1-phosphate (S1P). SKs have been widely implicated in human cancers and inflammation. This has been demonstrated to be a consequence of the actions of S1P, which acts as a ligand at five G protein-coupled receptors - termed S1P1-5. S1P is also an intracellular effector which binds to proteins such as HDAC1/2 and TRAF2 to elicit cell responses. Recently, other mediators in the pathway have also emerged as important mediators of autophagic, apoptotic, senescent and proliferative cell processes.This study aims to investigate the molecular pathways which link SK1 and SK2 with senescence in order to identify novel signalling networks which could in turn lead to potential therapeutic approaches to cancer treatment. These aims were achieved by down-regulating SK1 and SK2 using a series of SK inhibitors in an advanced stage castrate resistant prostate cancer cell line (LNCaP AI cells). The current study demonstrated that dual inhibition of SK1 and SK2 as well as knockdown of an additional target up stream in the sphingolipid signalling pathway - dihydroceramide desaturase (Des1) - was responsible for promoting a senescent phenotype in LNCaP AI cells. As an adjunct to these findings it is reported here for the first time that the sphingosine kinase 2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide), which is currently in phase 2 clinical trials for renal cancer and B-cell lymphoma, induces the proteasomal degradation of sphingosine kinase 1; therefore ABC294640 cannot be considered an SK2 selective inhibitor in a cellular context. Also as an adjunct to these findings, Des1 was discovered as a novel target for ABC294640. Thus, this study highlights a role of SKs and the sphingolipid signalling pathway in mediating senescence in human cancer cells which could provide novel therapeutic approaches to cancer treatment. In addition, the study challenged a central dogma in the field and provided useful and previously unknown mechanistic information about a drug which is currently in phase 2 clinical trials. Finally, the study identified a common novel target (Des1) of two existing compounds which, in combination with SK1, is responsible for inducing senescence in LNCaP AI cells. Taken together these findings provide novel and useful information not only regarding the role of SKs in senescence but in a more general context with respect to the mechanisms of action of these inhibitors, which are commonly used as tools to investigate SK signalling in vitro and in vivo.Sphingosine kinase 1 and Sphingosine kinase 2 (SK1 and SK2) are lipid kinases which form the bioactive lipid sphingosine-1-phosphate (S1P). SKs have been widely implicated in human cancers and inflammation. This has been demonstrated to be a consequence of the actions of S1P, which acts as a ligand at five G protein-coupled receptors - termed S1P1-5. S1P is also an intracellular effector which binds to proteins such as HDAC1/2 and TRAF2 to elicit cell responses. Recently, other mediators in the pathway have also emerged as important mediators of autophagic, apoptotic, senescent and proliferative cell processes.This study aims to investigate the molecular pathways which link SK1 and SK2 with senescence in order to identify novel signalling networks which could in turn lead to potential therapeutic approaches to cancer treatment. These aims were achieved by down-regulating SK1 and SK2 using a series of SK inhibitors in an advanced stage castrate resistant prostate cancer cell line (LNCaP AI cells). The current study demonstrated that dual inhibition of SK1 and SK2 as well as knockdown of an additional target up stream in the sphingolipid signalling pathway - dihydroceramide desaturase (Des1) - was responsible for promoting a senescent phenotype in LNCaP AI cells. As an adjunct to these findings it is reported here for the first time that the sphingosine kinase 2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide), which is currently in phase 2 clinical trials for renal cancer and B-cell lymphoma, induces the proteasomal degradation of sphingosine kinase 1; therefore ABC294640 cannot be considered an SK2 selective inhibitor in a cellular context. Also as an adjunct to these findings, Des1 was discovered as a novel target for ABC294640. Thus, this study highlights a role of SKs and the sphingolipid signalling pathway in mediating senescence in human cancer cells which could provide novel therapeutic approaches to cancer treatment. In addition, the study challenged a central dogma in the field and provided useful and previously unknown mechanistic information about a drug which is currently in phase 2 clinical trials. Finally, the study identified a common novel target (Des1) of two existing compounds which, in combination with SK1, is responsible for inducing senescence in LNCaP AI cells. Taken together these findings provide novel and useful information not only regarding the role of SKs in senescence but in a more general context with respect to the mechanisms of action of these inhibitors, which are commonly used as tools to investigate SK signalling in vitro and in vivo
Cobalt induced cardiotoxicity : a suspected adverse effect associated with COCR alloy orthopaedic implants
Get PDFCobalt toxicity, arising from the release of metal nanoparticles and ions during wear of Co/Cr metal-on-metal (MoM) hip implants has become a recognised internal source of Co poisoning. Co ions enter the bloodstream during wear and corrosion processes of MoM implants, and then travel throughout the body causing systemic toxicity. Cardiac toxic manifestations have been shown to be among the most prevalent systemic symptoms following exposure.;In this thesis we have investigated the effects of short and/or long term CoCl2 exposure on the Swiss 3T3 fibroblast cell line (3T3s) and primary adult cardiac fibroblasts (CFs) in vitro. We have measured effects on cell viability, morphology, proliferation, assessed intracellular Co uptake, and detected and quantified protein expression by western blotting. Further, we also studied the effects of chronic in vivo CoCl2 treatment (4 weeks of daily 1mg/kg intraperitoneal injections) of rats carrying out echocardiography, and determining the Co distribution into various organs.;The expression of potential transporter proteins, TRPC6, TRPM7, DMT1, and of CAMKIIδ, a serine/threonine kinase with pivotal roles in cardiovascular function through regulation of Ca2+ handling and excitation-contraction coupling, were also investigated. To complete the in vitro and in vivo studies, the molecular mechanism(s) underlying the overall changes were screened by RNA-Seq analysis, and gene expression was subsequently validated by quantitative real-time-PCR (RT-qPCR) and western blotting;In terms of proliferation of 3T3 cells and CFs treated with CoCl2, the CFs were much more sensitive than 3T3 cells with IC50 values for CoCl2 in the range of ~20 μM inCFs and ~250 μM in 3T3 cells. Using phalloidin to stain the actin inside cells showed that in both types of cells actin fibres were disrupted, and the membrane formed blebs at high Co concentrations. Co uptake, evaluated at the cellular level by using inductively coupled plasma mass spectrometry (ICP-MS), revealed 3 to 4-times greater Co uptake into CFs than 3T3 cells at 48 h.;In vivo studies using echocardiography showed evidence of altered cardiac function in Co treated rats after 28 days exposure. Reduction of the percentage of fractional shortening (%FS), from 60.29±0.53%, to 54.01±0.90% n=6, p<0.05, (Co-treated compared to normal rats) occurred. This could imply early indications of cardiac dysfunction.;Co accumulated in the organs of the rats and significant increases in Co ion levels (compared with control untreated animals) were detected in liver, kidney and heart (1,839.86±177.30, 1,536.01±83.95, and 307.82±35.74 μg/L respectively) by ICP-MS after 7 days exposure. Liver and kidney are the primary organs of excretion, and higher concentrations than other organs might be expected. However, these data provide strong evidence that Co accumulates in the hearts of the treated rats and this may result in cardiac dysfunction.;Western blot analysis of CFs, and heart tissue lysates from animals treated with CoCl2 for 28 days, showed a significantly increased level of protein expression for CaMKIIδ, TRPC6 and TRPM7. In contrast, in 3T3 cells, the expression of TRPs was decreased at high concentrations of Co. TRP transport channel proteins are likely to act as ubiquitous metal ion flux pathways, and may play a role in uptake of Co2+ into the heart enabling it to contribute to compromised heart function.;Gene expression analysis of Camkiid, Dmt1, Trpc6, Trpm7, and Trpv1 using RNA-Seq and RT-qPCR, found all had increased expression levels in heart RNA after 28 days exposure. RT-qPCR analysis showed there were increased levels in 4 out of the 5 selected genes (Camkiid, Dmt1, Trpc6, and Trpm7) in CFs after 72 h Co treatment. In contrast, Trpc6 mRNA expression was absent in 3T3 cells using RNA-Seq and RT-qPCR. These results suggest the differential uptake of Co2+ between CFs and 3T3 cells might be mediated through Trpc6.;Sequestration of Co into cardiac cells in vitro and in vivo, suggests that in vivo the metal may accumulate in the hearts of MoM patients with high circulating Co blood levels. This may lead to systemic adverse effects including cardiotoxicity. Inhibition or downregulation of Co uptake mechanisms into cardiac cells may offer a therapeutic intervention to minimise adverse effects of Co in patients with MoM implants. We recommend careful monitoring of cardiac function in MoM patients, in addition to the blood metal ion level monitoring and scans already instigated by MHRA.Cobalt toxicity, arising from the release of metal nanoparticles and ions during wear of Co/Cr metal-on-metal (MoM) hip implants has become a recognised internal source of Co poisoning. Co ions enter the bloodstream during wear and corrosion processes of MoM implants, and then travel throughout the body causing systemic toxicity. Cardiac toxic manifestations have been shown to be among the most prevalent systemic symptoms following exposure.;In this thesis we have investigated the effects of short and/or long term CoCl2 exposure on the Swiss 3T3 fibroblast cell line (3T3s) and primary adult cardiac fibroblasts (CFs) in vitro. We have measured effects on cell viability, morphology, proliferation, assessed intracellular Co uptake, and detected and quantified protein expression by western blotting. Further, we also studied the effects of chronic in vivo CoCl2 treatment (4 weeks of daily 1mg/kg intraperitoneal injections) of rats carrying out echocardiography, and determining the Co distribution into various organs.;The expression of potential transporter proteins, TRPC6, TRPM7, DMT1, and of CAMKIIδ, a serine/threonine kinase with pivotal roles in cardiovascular function through regulation of Ca2+ handling and excitation-contraction coupling, were also investigated. To complete the in vitro and in vivo studies, the molecular mechanism(s) underlying the overall changes were screened by RNA-Seq analysis, and gene expression was subsequently validated by quantitative real-time-PCR (RT-qPCR) and western blotting;In terms of proliferation of 3T3 cells and CFs treated with CoCl2, the CFs were much more sensitive than 3T3 cells with IC50 values for CoCl2 in the range of ~20 μM inCFs and ~250 μM in 3T3 cells. Using phalloidin to stain the actin inside cells showed that in both types of cells actin fibres were disrupted, and the membrane formed blebs at high Co concentrations. Co uptake, evaluated at the cellular level by using inductively coupled plasma mass spectrometry (ICP-MS), revealed 3 to 4-times greater Co uptake into CFs than 3T3 cells at 48 h.;In vivo studies using echocardiography showed evidence of altered cardiac function in Co treated rats after 28 days exposure. Reduction of the percentage of fractional shortening (%FS), from 60.29±0.53%, to 54.01±0.90% n=6, p<0.05, (Co-treated compared to normal rats) occurred. This could imply early indications of cardiac dysfunction.;Co accumulated in the organs of the rats and significant increases in Co ion levels (compared with control untreated animals) were detected in liver, kidney and heart (1,839.86±177.30, 1,536.01±83.95, and 307.82±35.74 μg/L respectively) by ICP-MS after 7 days exposure. Liver and kidney are the primary organs of excretion, and higher concentrations than other organs might be expected. However, these data provide strong evidence that Co accumulates in the hearts of the treated rats and this may result in cardiac dysfunction.;Western blot analysis of CFs, and heart tissue lysates from animals treated with CoCl2 for 28 days, showed a significantly increased level of protein expression for CaMKIIδ, TRPC6 and TRPM7. In contrast, in 3T3 cells, the expression of TRPs was decreased at high concentrations of Co. TRP transport channel proteins are likely to act as ubiquitous metal ion flux pathways, and may play a role in uptake of Co2+ into the heart enabling it to contribute to compromised heart function.;Gene expression analysis of Camkiid, Dmt1, Trpc6, Trpm7, and Trpv1 using RNA-Seq and RT-qPCR, found all had increased expression levels in heart RNA after 28 days exposure. RT-qPCR analysis showed there were increased levels in 4 out of the 5 selected genes (Camkiid, Dmt1, Trpc6, and Trpm7) in CFs after 72 h Co treatment. In contrast, Trpc6 mRNA expression was absent in 3T3 cells using RNA-Seq and RT-qPCR. These results suggest the differential uptake of Co2+ between CFs and 3T3 cells might be mediated through Trpc6.;Sequestration of Co into cardiac cells in vitro and in vivo, suggests that in vivo the metal may accumulate in the hearts of MoM patients with high circulating Co blood levels. This may lead to systemic adverse effects including cardiotoxicity. Inhibition or downregulation of Co uptake mechanisms into cardiac cells may offer a therapeutic intervention to minimise adverse effects of Co in patients with MoM implants. We recommend careful monitoring of cardiac function in MoM patients, in addition to the blood metal ion level monitoring and scans already instigated by MHRA
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