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Formulation of a conceptual framework for maintenance strategies : a case study on UK North Sea oil and gas industries
Get PDFMaintenance has been linked with costs and plant downtime, which makes it thought of as being a necessary evil. In recent times, reliability, availability, and safety in plant production have been more emphasized, particularly in hazardous working environments. Companies are now increasingly replacing fire-fighting maintenance approaches with more proactive maintenance strategies, such as predictive and preventive maintenance, in order to attain world-class performance with huge plant efficiency and high safety performance.This master thesis aims to investigate what the issues are that are hindering North Sea Oil and Gas Companies from achieving a more proactive maintenance approach. The common maintenance strategy in today's North Sea Oil and Gas is a reactive approach, where events and failures dictate pace, although there have been on-going changes that have been put in place to adopt a more preventive and proactive maintenance approach. This master's thesis would serve as a foundation for developing North Sea Oil and Gas' maintenance strategy, which will guide oil and gas companies toward a preventive and proactive maintenance environment.Different research methods have been used in this thesis. These include an extensive literature study, a systematic review of literature, interviews with maintenance personnel, and a review of a case study examining companies' documentation and benchmarking practices. In order to perform an accurate comparison between companies, a benchmarking tool was developed. The tool is called Maintenance Section Review (MSR). The MSR consists of questions within the areas of: maintenance structure, maintenance training programs, work orders, planning and scheduling, preventive maintenance (PM), spares inventory & purchasing, computerized maintenance management system (CMMS), operation, maintenance reporting, predictive maintenance, reliability & breakdown, maintenance - key performance indicators (KPIs), and financial planning. All questions generated are justified according to the published literature.This thesis provides results showing that highly reactive approaches are common in the maintenance department. This is evidenced by the average score from the MSR on predictive maintenance, with a value of 1.2. Some other key aspects identified as lacking or behind include planning and scheduling, maintenance reporting, inventory and purchasing, reliability and breakdown, and maintenance structure. There is also room for improvements in cooperation and communication between the maintenance department and production department, which would contribute to a more proactive working environment. The maintenance department is often left out of projects and is seen as a separate supporting function. The benchmarking has shown that successful companies need to change their approach in communication between departments and should focus on an integrated approach. These findings later formed the basis of the Shareholder Focused Model which has been developed to guide North Sea Oil and Gas in developing a maintenance strategy.The Shareholder Focused Model has been developed as part of this thesis. This is mainly based on the research findings relating to the factors that are impeding the maintenance department from maximizing their productivity. This model was developed as a form of guidance to maximize productivity.Maintenance has been linked with costs and plant downtime, which makes it thought of as being a necessary evil. In recent times, reliability, availability, and safety in plant production have been more emphasized, particularly in hazardous working environments. Companies are now increasingly replacing fire-fighting maintenance approaches with more proactive maintenance strategies, such as predictive and preventive maintenance, in order to attain world-class performance with huge plant efficiency and high safety performance.This master thesis aims to investigate what the issues are that are hindering North Sea Oil and Gas Companies from achieving a more proactive maintenance approach. The common maintenance strategy in today's North Sea Oil and Gas is a reactive approach, where events and failures dictate pace, although there have been on-going changes that have been put in place to adopt a more preventive and proactive maintenance approach. This master's thesis would serve as a foundation for developing North Sea Oil and Gas' maintenance strategy, which will guide oil and gas companies toward a preventive and proactive maintenance environment.Different research methods have been used in this thesis. These include an extensive literature study, a systematic review of literature, interviews with maintenance personnel, and a review of a case study examining companies' documentation and benchmarking practices. In order to perform an accurate comparison between companies, a benchmarking tool was developed. The tool is called Maintenance Section Review (MSR). The MSR consists of questions within the areas of: maintenance structure, maintenance training programs, work orders, planning and scheduling, preventive maintenance (PM), spares inventory & purchasing, computerized maintenance management system (CMMS), operation, maintenance reporting, predictive maintenance, reliability & breakdown, maintenance - key performance indicators (KPIs), and financial planning. All questions generated are justified according to the published literature.This thesis provides results showing that highly reactive approaches are common in the maintenance department. This is evidenced by the average score from the MSR on predictive maintenance, with a value of 1.2. Some other key aspects identified as lacking or behind include planning and scheduling, maintenance reporting, inventory and purchasing, reliability and breakdown, and maintenance structure. There is also room for improvements in cooperation and communication between the maintenance department and production department, which would contribute to a more proactive working environment. The maintenance department is often left out of projects and is seen as a separate supporting function. The benchmarking has shown that successful companies need to change their approach in communication between departments and should focus on an integrated approach. These findings later formed the basis of the Shareholder Focused Model which has been developed to guide North Sea Oil and Gas in developing a maintenance strategy.The Shareholder Focused Model has been developed as part of this thesis. This is mainly based on the research findings relating to the factors that are impeding the maintenance department from maximizing their productivity. This model was developed as a form of guidance to maximize productivity
Exploring the use of seaweed biopolymers in composite construction products
Get PDFThe ambition of this research was to develop composite building products which utilise a locally sourced, natural material in the form of alginate - a biopolymer derived from macro-algae. Two case study materials were included as part of the project: unfired clay bricks, where the alginate was used as a stabilising additive, and an alginate-based insulation, which was proposed as an alternative to petrochemical-based foams or silica aerogels. For both materials, a series of prototypes were produced and characterised in order to investigate the role of the alginate source and chemical composition on the properties of the final material.The results demonstrated that the source and composition of the alginate can have an important influence on the properties of the two proposed products. For the clay bricks, improvements in mechanical strength were found to be dependent upon the alginate source and the composition of the soil. The greatest increase in compressive strength equated to 2.5 times that of the equivalent control specimen and was achieved using an alginate sourced from the Laminaria Hyperborea seaweed. Increases in the alginate dosage did not necessarily lead to an increase in strength suggesting that there is an optimum concentration at which strength improvement is most effective. For the aerogel product, whilst all of the biopolymers tested offered an improvement over the control sample, again the results confirmed that the type of alginate used has a significant influence on the physical properties of the composites. Although alginate variables are not typically considered in the existing literature, this study has demonstrated that there may be significant variations in the quality of specimens produced using alginate from different sources. It was also concluded that, for both of the proposed products, larger prototypes should be analysed in order to facilitate direct comparison with other buildings materials.The ambition of this research was to develop composite building products which utilise a locally sourced, natural material in the form of alginate - a biopolymer derived from macro-algae. Two case study materials were included as part of the project: unfired clay bricks, where the alginate was used as a stabilising additive, and an alginate-based insulation, which was proposed as an alternative to petrochemical-based foams or silica aerogels. For both materials, a series of prototypes were produced and characterised in order to investigate the role of the alginate source and chemical composition on the properties of the final material.The results demonstrated that the source and composition of the alginate can have an important influence on the properties of the two proposed products. For the clay bricks, improvements in mechanical strength were found to be dependent upon the alginate source and the composition of the soil. The greatest increase in compressive strength equated to 2.5 times that of the equivalent control specimen and was achieved using an alginate sourced from the Laminaria Hyperborea seaweed. Increases in the alginate dosage did not necessarily lead to an increase in strength suggesting that there is an optimum concentration at which strength improvement is most effective. For the aerogel product, whilst all of the biopolymers tested offered an improvement over the control sample, again the results confirmed that the type of alginate used has a significant influence on the physical properties of the composites. Although alginate variables are not typically considered in the existing literature, this study has demonstrated that there may be significant variations in the quality of specimens produced using alginate from different sources. It was also concluded that, for both of the proposed products, larger prototypes should be analysed in order to facilitate direct comparison with other buildings materials
Radiosensitisation of glioma cells through development of a gold nanoparticle delivery system to inhibit Ataxia telangiectasia mutated (ATM)
No full textPatients with brain cancers like glioma have a very poor survival rate and although there are various treatment options, there is still no cure for the disease. Better more effective treatments are therefore needed. Current treatment options include: chemotherapy, radiotherapy, immunotherapy, surgery and a variety of drugs. Recent research has allowed a better understanding of the disease, with more specific, targeted treatments being developed. The ATM repair pathway, responds to radiation induced DNA damage, activating a pathway to repair DNA double stranded breaks (DSBs). Small molecule ATM inhibitors were developed in order to prevent the repair of these radiation induced DNA DSBs, in turn preventing the tumour from repairing itself and thus increasing tumour cell death. There have been numerous studies demonstrated the radiosensitisation potential of ATM kinase inhibitors thus suggesting ATM inhibition has great potential as a cancer therapy in combination with radiotherapy. Until recently due to poor solubility ATM kinase inhibitors had not progressed into clinical trials however an orally administered ATM tyrosine kinase inhibitor was recently developed by AstraZenca and patients are being recruited for a phase 1 clinical trial. There are however concerns of potential side effects and it is thought that ATP-competitive ATM inhibitors may cause severe side effects in vivo than a loss of ATM protein expression. Therefore, we aimed to develop a tumour specific delivery system delivering complementary oligonucleotides specific for ATM to silence ATM protein expression. Gold nanoparticles have been shown to not only acquire at the sites of tumours through their leaky, immature vasculature but also enhance the radiosensitisation potential, making the glioma cells more sensitive to radiation. This study will look at the use of gold nanoparticles as a delivery system of ATM inhibition, in order to prevent radiation induced upregulation of ATM as well as assessing the potential radioenhancement by the gold nanoparticles themselves.Patients with brain cancers like glioma have a very poor survival rate and although there are various treatment options, there is still no cure for the disease. Better more effective treatments are therefore needed. Current treatment options include: chemotherapy, radiotherapy, immunotherapy, surgery and a variety of drugs. Recent research has allowed a better understanding of the disease, with more specific, targeted treatments being developed. The ATM repair pathway, responds to radiation induced DNA damage, activating a pathway to repair DNA double stranded breaks (DSBs). Small molecule ATM inhibitors were developed in order to prevent the repair of these radiation induced DNA DSBs, in turn preventing the tumour from repairing itself and thus increasing tumour cell death. There have been numerous studies demonstrated the radiosensitisation potential of ATM kinase inhibitors thus suggesting ATM inhibition has great potential as a cancer therapy in combination with radiotherapy. Until recently due to poor solubility ATM kinase inhibitors had not progressed into clinical trials however an orally administered ATM tyrosine kinase inhibitor was recently developed by AstraZenca and patients are being recruited for a phase 1 clinical trial. There are however concerns of potential side effects and it is thought that ATP-competitive ATM inhibitors may cause severe side effects in vivo than a loss of ATM protein expression. Therefore, we aimed to develop a tumour specific delivery system delivering complementary oligonucleotides specific for ATM to silence ATM protein expression. Gold nanoparticles have been shown to not only acquire at the sites of tumours through their leaky, immature vasculature but also enhance the radiosensitisation potential, making the glioma cells more sensitive to radiation. This study will look at the use of gold nanoparticles as a delivery system of ATM inhibition, in order to prevent radiation induced upregulation of ATM as well as assessing the potential radioenhancement by the gold nanoparticles themselves
Use of direct oral anticoagulants in Scotland
Get PDFPatients with atrial fibrillation (AF), a common arrhythmic disorder, are treated long-term with oral anticoagulants in order to prevent strokes. As warfarin treatment is associated with several problems, the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban, apixaban and edoxaban have been introduced. However, real-world information regarding the utilisation of DOACs as well as their clinical effectiveness and safety is still scarce. Hence, the aim of this project was to increase the evidence from clinical practice regarding the use of DOACs in patients with AF in Scotland. Methods: This study has been designed as a retrospective cohort study (study period 2009 - 2015), using routinely collected administrative data. Three databases - the Prescribing Information System (PIS); Scottish Morbidity records (SMR); and National Records of Scotland (NRS) - covering prescriptions dispensed in primary care, hospital episodes and death records, respectively, have been linked using Community Health Index (CHI) numbers, a unique patient identifier in Scotland. Based on this data, three analyses have been conducted: a description of DOAC prescribing over time; an evaluation of patients' adherence to DOAC treatment; and an analysis of the comparative clinical effectiveness and safety of DOACs. Results: In Scotland, the number of patients being treated with DOACs has steadily been increasing, and in 2015, the number of incident DOAC patients exceeded those of warfarin. During the study period, 14,811 AF patients with a mean age of 74.1 years [SD 11.3] initiated DOAC treatment. Adherence to treatment was good overall, with a median Medication Refill Adherence (MRA) of 102.3% [IQR 90.1% - 112.5%]; discontinuation rates were however variable, ranging from 24.9% (apixaban) to 63.3% (dabigatran). Persistence rates 12 months after treatment initiation were 61.8%, 78.6%, and 83.6% among patients initiating treatment with dabigatran, rivaroxaban, and apixaban, respectively. All DOACs were similarly effective in preventing strokes and systemic embolisms - nevertheless, the overall bleeding risk was higher with rivaroxaban as compared to apixaban [HR 1.52, 95% CI 1.21 - 1.91]. Conclusion: DOACs have swiftly been accepted into clinical practice, and adherence to treatment is generally good. As all DOACs are similarly effective, decisions for or against a specific drug should be made based on a wider risk assessment, with a focus on bleeding risks.Patients with atrial fibrillation (AF), a common arrhythmic disorder, are treated long-term with oral anticoagulants in order to prevent strokes. As warfarin treatment is associated with several problems, the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban, apixaban and edoxaban have been introduced. However, real-world information regarding the utilisation of DOACs as well as their clinical effectiveness and safety is still scarce. Hence, the aim of this project was to increase the evidence from clinical practice regarding the use of DOACs in patients with AF in Scotland. Methods: This study has been designed as a retrospective cohort study (study period 2009 - 2015), using routinely collected administrative data. Three databases - the Prescribing Information System (PIS); Scottish Morbidity records (SMR); and National Records of Scotland (NRS) - covering prescriptions dispensed in primary care, hospital episodes and death records, respectively, have been linked using Community Health Index (CHI) numbers, a unique patient identifier in Scotland. Based on this data, three analyses have been conducted: a description of DOAC prescribing over time; an evaluation of patients' adherence to DOAC treatment; and an analysis of the comparative clinical effectiveness and safety of DOACs. Results: In Scotland, the number of patients being treated with DOACs has steadily been increasing, and in 2015, the number of incident DOAC patients exceeded those of warfarin. During the study period, 14,811 AF patients with a mean age of 74.1 years [SD 11.3] initiated DOAC treatment. Adherence to treatment was good overall, with a median Medication Refill Adherence (MRA) of 102.3% [IQR 90.1% - 112.5%]; discontinuation rates were however variable, ranging from 24.9% (apixaban) to 63.3% (dabigatran). Persistence rates 12 months after treatment initiation were 61.8%, 78.6%, and 83.6% among patients initiating treatment with dabigatran, rivaroxaban, and apixaban, respectively. All DOACs were similarly effective in preventing strokes and systemic embolisms - nevertheless, the overall bleeding risk was higher with rivaroxaban as compared to apixaban [HR 1.52, 95% CI 1.21 - 1.91]. Conclusion: DOACs have swiftly been accepted into clinical practice, and adherence to treatment is generally good. As all DOACs are similarly effective, decisions for or against a specific drug should be made based on a wider risk assessment, with a focus on bleeding risks
The informal funding market for new businesses in the United Kingdom
Get PDFInformal funding is a part of the informal venture capital market, provided by individuals who are not professional investors, such as family and friends. Despite being a widespread source of small-scale finance for starting businesses, it has not been investigated holistically both from the demand and supply perspectives. This thesis brings the two sides together at four levels of analysis. Individual experiences of both entrepreneurs and their informal funders are explored, and further integrated at the dyadic level. The relationship is then embedded into the context of local communities, and macroeconomic environment.The exploratory part of the research draws on seven case studies of informal funding deals in Scotland. Both entrepreneurs and their informal funders were interviewed separately between July 2012 and September 2013. Further information from secondary sources was collected to complement the case material. Using a thematic analysis method, the perspectives were reconciled, and propositions about the nature of informal funding relationship were developed. The embeddedness effects were subsequently empirically validated at the local and macroeconomic levels using the UK Global Entrepreneurship Monitor data, and Indices of Multiple Deprivation from Official Statistics for the 2007-2012 period.This thesis contributes to the entrepreneurial finance literature, distinguishing three types of informal capital users who implicitly initiate a deal (demand factor): bootstrappers, discouraged, and rejected borrowers/investees. Non-pecuniary motives are important for funders, but are restrained by income factor. The interaction of the demand and supply leads to an equilibrium at the local level for the communities which are neither deprived, nor munificent. However during a macroeconomic downturn, the demand factor dominates, resulting in double equilibria - both for the least and most munificent areas. The findings also lead to implications for policy makers (regarding the formalisation of informal cash flows), and for practitioners - around structuring the funding process.Informal funding is a part of the informal venture capital market, provided by individuals who are not professional investors, such as family and friends. Despite being a widespread source of small-scale finance for starting businesses, it has not been investigated holistically both from the demand and supply perspectives. This thesis brings the two sides together at four levels of analysis. Individual experiences of both entrepreneurs and their informal funders are explored, and further integrated at the dyadic level. The relationship is then embedded into the context of local communities, and macroeconomic environment.The exploratory part of the research draws on seven case studies of informal funding deals in Scotland. Both entrepreneurs and their informal funders were interviewed separately between July 2012 and September 2013. Further information from secondary sources was collected to complement the case material. Using a thematic analysis method, the perspectives were reconciled, and propositions about the nature of informal funding relationship were developed. The embeddedness effects were subsequently empirically validated at the local and macroeconomic levels using the UK Global Entrepreneurship Monitor data, and Indices of Multiple Deprivation from Official Statistics for the 2007-2012 period.This thesis contributes to the entrepreneurial finance literature, distinguishing three types of informal capital users who implicitly initiate a deal (demand factor): bootstrappers, discouraged, and rejected borrowers/investees. Non-pecuniary motives are important for funders, but are restrained by income factor. The interaction of the demand and supply leads to an equilibrium at the local level for the communities which are neither deprived, nor munificent. However during a macroeconomic downturn, the demand factor dominates, resulting in double equilibria - both for the least and most munificent areas. The findings also lead to implications for policy makers (regarding the formalisation of informal cash flows), and for practitioners - around structuring the funding process
Multi-technology offshore wind power systems : control and dynamic performance assessment
Get PDFThis thesis presents a comprehensive study on the operation, principles and theory of wind farms consisting of doubly-fed induction (DFIG) and fully-rated converter (FRC) wind generators working together in a hybrid arrangement. The main objective of this study is to develop control strategies for the hybrid arrangement of wind turbines in order to improve the grid code compliance of the overall wind farm by exploiting the unique characteristics of both technologies to support each other in case of a fault happening. As a result, this thesis presents a novel control strategy for fully rated converter wind generators to improve the fault ride through capabilities of DFIG wind turbines during an AC voltage sag. The developed controller enables the creation of an environment where the FRC and DFIG technologies coexist for the purpose of compliance of grid code requirements. This type of environment can be created in both new wind farm developments and in already deployed DFIG-based wind farms where the addition of FRCs results in the overall improvement of the grid code compliance of the wind farm.The novel controller developed in this thesis uses the FRC to supply reactive power to the hybrid wind farm network during faults with the objective of reducing the magnitude of the voltage dip. This has positive effects in DFIG rotor speed and DC voltage variables during and after the fault period. These variables, as explained in the thesis, play a crucial role in stabilising the dynamic fault ride through capabilities of the turbine. Additionally, the novel controller developed in this thesis does not compromise the integrity of the FRC system.This thesis also contributes to the investigation of hybrid wind farms connected to the main grid using voltage source converter high-voltage direct current (VSC-HVDC) as a mean to increase renewable energy penetration and transmission capacity without affecting voltage stability or power quality of the specific case of the Great Britain's (GB) network. One main control approach was investigated on the sending-end converter to integrate offshore wind power from hybrid network where all generated power is injected to the point-to-point DC link with a stiff AC bus at the wind farm network. Additionally, two possible connection topologies of future VSC-HVDC were investigated for steady state and transient conditions. The operation of a multi terminal DC network (MTDC) for hybrid offshore wind farms is analysed with power flow studies of a 5-terminal MTDC model regulated by droop control.Finally, this thesis investigates three VSC-HVDC connections schemes designed to transfer 2.4GW of power from two separate Dogger Bank wind farms to the GB grid, in terms of the investment costs, controllability and reliability against expected scenarios. The benefits and drawbacks of all three scenarios are highlighted. These include the benefits of auxiliary cables on AC and DC site of the multi-terminal connections.This thesis presents a comprehensive study on the operation, principles and theory of wind farms consisting of doubly-fed induction (DFIG) and fully-rated converter (FRC) wind generators working together in a hybrid arrangement. The main objective of this study is to develop control strategies for the hybrid arrangement of wind turbines in order to improve the grid code compliance of the overall wind farm by exploiting the unique characteristics of both technologies to support each other in case of a fault happening. As a result, this thesis presents a novel control strategy for fully rated converter wind generators to improve the fault ride through capabilities of DFIG wind turbines during an AC voltage sag. The developed controller enables the creation of an environment where the FRC and DFIG technologies coexist for the purpose of compliance of grid code requirements. This type of environment can be created in both new wind farm developments and in already deployed DFIG-based wind farms where the addition of FRCs results in the overall improvement of the grid code compliance of the wind farm.The novel controller developed in this thesis uses the FRC to supply reactive power to the hybrid wind farm network during faults with the objective of reducing the magnitude of the voltage dip. This has positive effects in DFIG rotor speed and DC voltage variables during and after the fault period. These variables, as explained in the thesis, play a crucial role in stabilising the dynamic fault ride through capabilities of the turbine. Additionally, the novel controller developed in this thesis does not compromise the integrity of the FRC system.This thesis also contributes to the investigation of hybrid wind farms connected to the main grid using voltage source converter high-voltage direct current (VSC-HVDC) as a mean to increase renewable energy penetration and transmission capacity without affecting voltage stability or power quality of the specific case of the Great Britain's (GB) network. One main control approach was investigated on the sending-end converter to integrate offshore wind power from hybrid network where all generated power is injected to the point-to-point DC link with a stiff AC bus at the wind farm network. Additionally, two possible connection topologies of future VSC-HVDC were investigated for steady state and transient conditions. The operation of a multi terminal DC network (MTDC) for hybrid offshore wind farms is analysed with power flow studies of a 5-terminal MTDC model regulated by droop control.Finally, this thesis investigates three VSC-HVDC connections schemes designed to transfer 2.4GW of power from two separate Dogger Bank wind farms to the GB grid, in terms of the investment costs, controllability and reliability against expected scenarios. The benefits and drawbacks of all three scenarios are highlighted. These include the benefits of auxiliary cables on AC and DC site of the multi-terminal connections
Intra-pulse dynamics of laser-driven ion acceleration in ultra-thin foils
Get PDFThis thesis reports on experimental and numerical investigations of ion acceler-ation driven by the interaction of short, intense laser pulses with ultra-thin, solid targets in which relativistic transparency is induced. In particular, it explores the multiple laser-ion acceleration mechanisms that take place over the duration of the laser pulse. Investigating these acceleration mechanisms is important for understanding the underlying physical dynamics and optimising laser-driven ion acceleration.;The investigations featured in this thesis result from intense laser-solid in-teractions conducted at the Rutherford Appleton Laboratory, using the Vulcan Petawatt laser system. The first investigation explores the spatial-intensity profile of the proton beam accelerated from thin (tens of nanometre) aluminium targets.The beam of accelerated protons displayed a variety of features, including a low-energy annular profile, a high energy component with a small divergence and Rayleigh-Taylor-like instabilities. A particularly interesting observation is the low-energy annular profile, which is shown to be sensitive to target thickness and proton energy.;Numerical investigations using particle-in-cell (PIC) simulations exhibit the same trends and demonstrate that the radiation pressure from the laser pulse drives an expansion of the target ions within the spatial extent of the laser focal spot. This induces a radial deection of relatively low energy sheath-accelerated protons to form an annular distribution.;Through variation of the target foil thickness, the opening angle of the ring is shown to be correlated to the point in time during the laser pulse interaction at which the target becomes transparent to the laser (in a process termed relativistic induced transparency). The ring is largest when transparency occurs close to the peak of the laser intensity.;The second investigation focuses on the rising edge profile of the laser pulse and the correlation between its temporal width and the resultant maximum proton energy. An important parameter to consider when irradiating nanometre-thick foils is the laser contrast. However, the effect of the temporal width of the laser pulse at 1% of the peak, where the intensity is ~1018 Wcm-2, has not been previously explored. Using CH targets with a fixed thickness, a range of proton energies, from 20-70 MeV, are measured experimentally.;The temporal width ofthe laser pulse is measured using a second order autocorrelator and is used to model the rising edge of the laser pulse on target. The temporal width at 50%, 10% and 1%, of the peak of the pulse, is measured. The measured proton energies are found to strongly correlate with the temporal width at the 1% level, and as the duration at this pulse width increased the maximum proton energy decreased.;Using particle-in-cell simulations, a detailed numerical investigation is carried out to understand the effect the rising edge of the laser pulse has on proton energies. By increasing the temporal width at 1%, the expansion of the target increased, resulting in a less efficient acceleration of protons. Furthermore, by inducing a small expansion in the target before the peak of the pulse arrives, the hole boring mechanism of RPA can be optimised along the laser axis.;However, in the case where the temporal width at 1% is relatively larger, the hole boring mechanism no longer dominates the interaction, as the target undergoes relativis-tic induced transparency on the rising edge of the pulse, limiting the effect of hole boring. Improving the laser contrast on the picosecond time-scale could result in higher and stable proton energy.This thesis reports on experimental and numerical investigations of ion acceler-ation driven by the interaction of short, intense laser pulses with ultra-thin, solid targets in which relativistic transparency is induced. In particular, it explores the multiple laser-ion acceleration mechanisms that take place over the duration of the laser pulse. Investigating these acceleration mechanisms is important for understanding the underlying physical dynamics and optimising laser-driven ion acceleration.;The investigations featured in this thesis result from intense laser-solid in-teractions conducted at the Rutherford Appleton Laboratory, using the Vulcan Petawatt laser system. The first investigation explores the spatial-intensity profile of the proton beam accelerated from thin (tens of nanometre) aluminium targets.The beam of accelerated protons displayed a variety of features, including a low-energy annular profile, a high energy component with a small divergence and Rayleigh-Taylor-like instabilities. A particularly interesting observation is the low-energy annular profile, which is shown to be sensitive to target thickness and proton energy.;Numerical investigations using particle-in-cell (PIC) simulations exhibit the same trends and demonstrate that the radiation pressure from the laser pulse drives an expansion of the target ions within the spatial extent of the laser focal spot. This induces a radial deection of relatively low energy sheath-accelerated protons to form an annular distribution.;Through variation of the target foil thickness, the opening angle of the ring is shown to be correlated to the point in time during the laser pulse interaction at which the target becomes transparent to the laser (in a process termed relativistic induced transparency). The ring is largest when transparency occurs close to the peak of the laser intensity.;The second investigation focuses on the rising edge profile of the laser pulse and the correlation between its temporal width and the resultant maximum proton energy. An important parameter to consider when irradiating nanometre-thick foils is the laser contrast. However, the effect of the temporal width of the laser pulse at 1% of the peak, where the intensity is ~1018 Wcm-2, has not been previously explored. Using CH targets with a fixed thickness, a range of proton energies, from 20-70 MeV, are measured experimentally.;The temporal width ofthe laser pulse is measured using a second order autocorrelator and is used to model the rising edge of the laser pulse on target. The temporal width at 50%, 10% and 1%, of the peak of the pulse, is measured. The measured proton energies are found to strongly correlate with the temporal width at the 1% level, and as the duration at this pulse width increased the maximum proton energy decreased.;Using particle-in-cell simulations, a detailed numerical investigation is carried out to understand the effect the rising edge of the laser pulse has on proton energies. By increasing the temporal width at 1%, the expansion of the target increased, resulting in a less efficient acceleration of protons. Furthermore, by inducing a small expansion in the target before the peak of the pulse arrives, the hole boring mechanism of RPA can be optimised along the laser axis.;However, in the case where the temporal width at 1% is relatively larger, the hole boring mechanism no longer dominates the interaction, as the target undergoes relativis-tic induced transparency on the rising edge of the pulse, limiting the effect of hole boring. Improving the laser contrast on the picosecond time-scale could result in higher and stable proton energy
Understanding the independent and combinatory effects of radiation therapy and doxorubicin on endothelial cell function : the role of JNK
Get PDFA number of epidemiological studies have associated anticancer therapy with an increased risk of cardiovascular disease in later life, a concern for patient long-term survival. Survivors of childhood cancer, previously administered radiotherapy, display chronic arterial damage including endothelial cell dysfunction, a defining feature of atherosclerosis (Brouwer et al., 2013). This thesis aimed to characterise the effects of radiation therapy (X-rays) and the cardiotoxic chemotherapeutic drug doxorubicin, alone or in combination, on coronary artery endothelial cell viability and function. The role of stress-activated c-Jun N-terminal kinase (JNK) in therapy-mediated endothelial cell dysfunction was also elucidated. Survival assays, employed to assess the effects of single-agent therapy, demonstrated that doxorubicin causes concentration-dependent death of human coronary artery endothelial cells (HCAECs) and X-irradiation inhibits HCAEC clonogenic survival dose-dependently. Using fluorescence-activated cell sorting (FACS), the ability of doxorubicin to arrest HCAECs in the radiosensitive G2/M phase of the cell cycle after a period of 24 hours was identified. Nonetheless, when doxorubicin and X-rays were used in combination, synergy between the two agents was not observed, an additive effect on HCAEC clonogenic survival was detected at the specific concentration (1 μM doxorubicin) and dose (1 Gy X-rays) studied. JNK was moderately activated by doxorubicin and played a partial role in the G2/M arrest of HCAECs by doxorubicin. Surprisingly, X-irradiation poorly activated JNK, thus JNK does not appear to play a major role in endothelial cell dysfunction post-therapy with these anticancer agents. The data collated in this thesis provides an insight into the endothelial cell dysfunction and death elicited by anticancer agents, doxorubicin and X-rays, contributing to vascular wall destruction and development of atherosclerosis post-cancer therapy.A number of epidemiological studies have associated anticancer therapy with an increased risk of cardiovascular disease in later life, a concern for patient long-term survival. Survivors of childhood cancer, previously administered radiotherapy, display chronic arterial damage including endothelial cell dysfunction, a defining feature of atherosclerosis (Brouwer et al., 2013). This thesis aimed to characterise the effects of radiation therapy (X-rays) and the cardiotoxic chemotherapeutic drug doxorubicin, alone or in combination, on coronary artery endothelial cell viability and function. The role of stress-activated c-Jun N-terminal kinase (JNK) in therapy-mediated endothelial cell dysfunction was also elucidated. Survival assays, employed to assess the effects of single-agent therapy, demonstrated that doxorubicin causes concentration-dependent death of human coronary artery endothelial cells (HCAECs) and X-irradiation inhibits HCAEC clonogenic survival dose-dependently. Using fluorescence-activated cell sorting (FACS), the ability of doxorubicin to arrest HCAECs in the radiosensitive G2/M phase of the cell cycle after a period of 24 hours was identified. Nonetheless, when doxorubicin and X-rays were used in combination, synergy between the two agents was not observed, an additive effect on HCAEC clonogenic survival was detected at the specific concentration (1 μM doxorubicin) and dose (1 Gy X-rays) studied. JNK was moderately activated by doxorubicin and played a partial role in the G2/M arrest of HCAECs by doxorubicin. Surprisingly, X-irradiation poorly activated JNK, thus JNK does not appear to play a major role in endothelial cell dysfunction post-therapy with these anticancer agents. The data collated in this thesis provides an insight into the endothelial cell dysfunction and death elicited by anticancer agents, doxorubicin and X-rays, contributing to vascular wall destruction and development of atherosclerosis post-cancer therapy
Investigation of the use of electro active polymer as a paediatric VAD driver
Get PDFBackground : Heart failure is one of the principal causes of death and disability. The causes of heart failure are many, and a number of technologies have been developed to address this issue by providing support to the failing heart, both as a permanent solution and as a bridge to recovery. These options are called Mechanical Circulatory Support Devices, a particular branch of these devices is the Ventricular Assist Devices, which have been under intense development over the recent years offering a promising solution for this major problem.;However, these devices are still bulky, and heavy designed to support failing hearts in the adult population. On the other hand, little has been done in recent times on the development of implantable solutions for heart failure or insufficiency in children. There are many reasons for this, but primarily the relatively small number of children requiring these procedures, the challenges associated with growth, and the lack of physical space for such implantable circulatory support technologies in children are fundamental limitations to the development and deployment of these technologies.;Aims of the project : The primary purpose of this project was to investigate the development of a new miniaturised self-power VAD that is suitable for paediatrics implantation. This project suggested the use of the newly developed Artificial Muscles to create a mesh that envelops the heart and works as an external assisting circulation mechanism. The same materials could be used to generate electricity when deformed, which can be used to power the proposed device. Critically, the project was to focus on optimising the materials with regard to their operating efficiency to ascertain whether they represent a viable option for VAD production.;Materials and Methods : A full review of the current available Artificial Muscles was performed to choose the most suitable type for this project. Then different fabrication protocols were developed to make IPMC Artificial Muscles using platinum and palladium coatings. A series of characterization tests were conducted on the fabricated Ionic Polymeric Metal Composites (IPMC) to ensure their quality. Finally, the mechanical and electrical properties were tested and compared with the proposed device requirements.;Results : The review of Artificial Muscles showed that IPMC would be the best candidate to use in this application. The characterisation tests showed as well that the produced IPMC Artificial Muscles were fabricated to the same standards as those commercially available, and the reported by other investigators. However, these materials showed very low mechanical output with high electrical power consumption, which made them far from practical and not suitable for the proposed application. On the other hand, IPMCs showed promising results as an option to generate electricity to power low consumption implantable devices.Background : Heart failure is one of the principal causes of death and disability. The causes of heart failure are many, and a number of technologies have been developed to address this issue by providing support to the failing heart, both as a permanent solution and as a bridge to recovery. These options are called Mechanical Circulatory Support Devices, a particular branch of these devices is the Ventricular Assist Devices, which have been under intense development over the recent years offering a promising solution for this major problem.;However, these devices are still bulky, and heavy designed to support failing hearts in the adult population. On the other hand, little has been done in recent times on the development of implantable solutions for heart failure or insufficiency in children. There are many reasons for this, but primarily the relatively small number of children requiring these procedures, the challenges associated with growth, and the lack of physical space for such implantable circulatory support technologies in children are fundamental limitations to the development and deployment of these technologies.;Aims of the project : The primary purpose of this project was to investigate the development of a new miniaturised self-power VAD that is suitable for paediatrics implantation. This project suggested the use of the newly developed Artificial Muscles to create a mesh that envelops the heart and works as an external assisting circulation mechanism. The same materials could be used to generate electricity when deformed, which can be used to power the proposed device. Critically, the project was to focus on optimising the materials with regard to their operating efficiency to ascertain whether they represent a viable option for VAD production.;Materials and Methods : A full review of the current available Artificial Muscles was performed to choose the most suitable type for this project. Then different fabrication protocols were developed to make IPMC Artificial Muscles using platinum and palladium coatings. A series of characterization tests were conducted on the fabricated Ionic Polymeric Metal Composites (IPMC) to ensure their quality. Finally, the mechanical and electrical properties were tested and compared with the proposed device requirements.;Results : The review of Artificial Muscles showed that IPMC would be the best candidate to use in this application. The characterisation tests showed as well that the produced IPMC Artificial Muscles were fabricated to the same standards as those commercially available, and the reported by other investigators. However, these materials showed very low mechanical output with high electrical power consumption, which made them far from practical and not suitable for the proposed application. On the other hand, IPMCs showed promising results as an option to generate electricity to power low consumption implantable devices
Analogues of BH4 and nitric oxide synthase activators
Get PDFNitric oxide synthase (NOS) is an enzyme that catalyses the synthesis of nitric oxide (NO)from L-arginine. There are three kinds of nitric oxide synthase enzymes: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Nitric oxide is a biological messenger molecule and a potent vasodilator which controls many biological processes, such as hypertension, stroke, memory, learning disorders and many more. The Nobel Prize in Physiology and Medicine was granted for the discovery and identification of the endothelium-derived relaxing factor as nitric oxide. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs) and presumably is present in every cell or tissue of higher organisms. Oxidation of BH4, in diabetes and in different chronic vasoinflammatory diseases can produce cofactor deficiency. This decreased level of BH4 can result in uncoupling of endothelial nitric oxide synthase where this enzyme produces superoxide and thus nitric oxide production is suppressed. BH4 in its active, reduced form is highly unstable and therefore not suitable for oral administration. BH4 does not readily pass across the blood brain barrier; also it cannot be utilized to improve the central neurotransmitter insufficiency in case of BH4 deficiency. This defect of BH4 owes to its hydrophilic nature; however, lipophilic particles can readily pass this brain barrier. If we can have a molecule that is not easily oxidized, and is more lipophilic so that it can cross the blood brain barrier and is also a nitric oxide synthase activator, we can treat all diseases which are caused due to deficiency of nitric oxide especially in old age, when the body starts producing less of nitric oxide. In other words, we can find a cure for diseases which are caused by nitric oxide deficiency. When I started my PhD, Prof Suckling group has already discovered an active pteridine called as WSG1002 1.2 which is more stable to oxidation and has greater solubility than BH41.1. It was an improvement but still not an ideal molecule; both stability and solubility needed to improve. We worked to develop an oxidatively stable and lipophilic pteridine molecule which can act as a cofactor for nitric oxide synthase (NOS) and can correct BH4 deficiency in selected diseases. The following substitutions at WSG1002 (1.2) were considered for my research project. i) N8-deaza ii) C6-unsubstituted iii) 2H at C7 instead of methyl groups. iv) At C6 methyl, hydroxymethyl, acetoxymethyl, acetyl and 1, 2-dihydroxypropyl. This research project provided 8-alkyl and 8-deaza analogues for for nitric oxide synthase enzyme essay, the biological assays for these compounds will be discussed Chapter 3. The investigation of these compounds also made possible studies of the mechanism of action of NOS. Chapter 1 describes nitric oxide and how it is formed from NOS enzymes along with NOS structures and mechanism. It also describes the role of BH4 and its drawbacks. The stucture of the cofactor plays an important role for binding and NOS activity which has been discussed with examples along with requirements for a better molecule. Chapter 2 is about synthesis of important molecules which can help us to understand the mechanism of NO formation and the possibility of finding an ideal drug with better medicinal properties. Although the reactions were challenging, we have prepared many new molecules, many them have been evaluated, and some of them were found to be active and oxidatively stable which is one of the problems with these molecules. 8-Alkyl and 8-deaza analogues have been successfully synthesized. Chapter 3 describes biological results of our compounds which were screened for nitric oxide synthase assays in collaboration with Dr. Simon Daff at the University of Edinburgh. In addition to NOS activity, a number of molecues were also submitted for antibacterial and microbial activity in SIPBS and some of them were found to be active. Chapter 4 describes the experiments for the synthesis of our desired compounds. The methods for the preparation and their characterisation have been given in detail. The last Chapter lists the references.Nitric oxide synthase (NOS) is an enzyme that catalyses the synthesis of nitric oxide (NO)from L-arginine. There are three kinds of nitric oxide synthase enzymes: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Nitric oxide is a biological messenger molecule and a potent vasodilator which controls many biological processes, such as hypertension, stroke, memory, learning disorders and many more. The Nobel Prize in Physiology and Medicine was granted for the discovery and identification of the endothelium-derived relaxing factor as nitric oxide. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs) and presumably is present in every cell or tissue of higher organisms. Oxidation of BH4, in diabetes and in different chronic vasoinflammatory diseases can produce cofactor deficiency. This decreased level of BH4 can result in uncoupling of endothelial nitric oxide synthase where this enzyme produces superoxide and thus nitric oxide production is suppressed. BH4 in its active, reduced form is highly unstable and therefore not suitable for oral administration. BH4 does not readily pass across the blood brain barrier; also it cannot be utilized to improve the central neurotransmitter insufficiency in case of BH4 deficiency. This defect of BH4 owes to its hydrophilic nature; however, lipophilic particles can readily pass this brain barrier. If we can have a molecule that is not easily oxidized, and is more lipophilic so that it can cross the blood brain barrier and is also a nitric oxide synthase activator, we can treat all diseases which are caused due to deficiency of nitric oxide especially in old age, when the body starts producing less of nitric oxide. In other words, we can find a cure for diseases which are caused by nitric oxide deficiency. When I started my PhD, Prof Suckling group has already discovered an active pteridine called as WSG1002 1.2 which is more stable to oxidation and has greater solubility than BH41.1. It was an improvement but still not an ideal molecule; both stability and solubility needed to improve. We worked to develop an oxidatively stable and lipophilic pteridine molecule which can act as a cofactor for nitric oxide synthase (NOS) and can correct BH4 deficiency in selected diseases. The following substitutions at WSG1002 (1.2) were considered for my research project. i) N8-deaza ii) C6-unsubstituted iii) 2H at C7 instead of methyl groups. iv) At C6 methyl, hydroxymethyl, acetoxymethyl, acetyl and 1, 2-dihydroxypropyl. This research project provided 8-alkyl and 8-deaza analogues for for nitric oxide synthase enzyme essay, the biological assays for these compounds will be discussed Chapter 3. The investigation of these compounds also made possible studies of the mechanism of action of NOS. Chapter 1 describes nitric oxide and how it is formed from NOS enzymes along with NOS structures and mechanism. It also describes the role of BH4 and its drawbacks. The stucture of the cofactor plays an important role for binding and NOS activity which has been discussed with examples along with requirements for a better molecule. Chapter 2 is about synthesis of important molecules which can help us to understand the mechanism of NO formation and the possibility of finding an ideal drug with better medicinal properties. Although the reactions were challenging, we have prepared many new molecules, many them have been evaluated, and some of them were found to be active and oxidatively stable which is one of the problems with these molecules. 8-Alkyl and 8-deaza analogues have been successfully synthesized. Chapter 3 describes biological results of our compounds which were screened for nitric oxide synthase assays in collaboration with Dr. Simon Daff at the University of Edinburgh. In addition to NOS activity, a number of molecues were also submitted for antibacterial and microbial activity in SIPBS and some of them were found to be active. Chapter 4 describes the experiments for the synthesis of our desired compounds. The methods for the preparation and their characterisation have been given in detail. The last Chapter lists the references
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