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Victims' participation in proceedings before the International Criminal Court : developing an expressivist function of the trial
Get PDFThis thesis was previously held under moratorium from 22nd August 2019 until 21st November 2024.The International Criminal Court (ICC) is the first international criminal tribunal that allows victims to participate in their own rights in criminal proceedings. The ICC Statute offers an opportunity for the meaningful entrenchment of the interests of victims in the international criminal process. However, the provisions of the ICC Statute address only the general principles of victims’ participation regime. It is deliberate since the drafters failed to recognise a procedural system that dominates international criminal justice as a full answer to the concerns with victims. The two procedural systems envisaged, mainly the adversarial and inquisitorial procedures, conceive the role of victims in two diametrically opposed ways. A response to the central question as how to frame a victims’ participatory model in proceedings before the ICC, which aim to achieve the goal of giving victims a voice, depends on what framework of justice the ICC adopts. The view taken is that the ICC criminal justice paradigm is a real sui generis system. Due to the extensive and serious nature of the atrocities committed the existing theories of criminal justice – retributive, utilitarian and restorative justice models – are not adequate to meet the need for justice of victims, as recognised by the provisions on victims’ participation of the ICC Statute. This thesis suggests that the ICC should adopt an expressivist paradigm in order to give meaningful effect to the victims’ participatory rights, alongside the defendants’ right and the law enforcement functions of the Court and Prosecutor. The adoption of the expressivist framework to the ICC criminal justice contributes to establish a common grammar to bridge the gap in the languages of the civil law and common law systems. The novelty of this idea of common language is that it is critical and fundamental to move forward the goal of victims’ participation and reshape the rights of victims, defendants, judges and prosecutor, going beyond the conflicting languages of the adversarial and inquisitorial systems and allowing to all the provisions to coherently fit together.The International Criminal Court (ICC) is the first international criminal tribunal that allows victims to participate in their own rights in criminal proceedings. The ICC Statute offers an opportunity for the meaningful entrenchment of the interests of victims in the international criminal process. However, the provisions of the ICC Statute address only the general principles of victims’ participation regime. It is deliberate since the drafters failed to recognise a procedural system that dominates international criminal justice as a full answer to the concerns with victims. The two procedural systems envisaged, mainly the adversarial and inquisitorial procedures, conceive the role of victims in two diametrically opposed ways. A response to the central question as how to frame a victims’ participatory model in proceedings before the ICC, which aim to achieve the goal of giving victims a voice, depends on what framework of justice the ICC adopts. The view taken is that the ICC criminal justice paradigm is a real sui generis system. Due to the extensive and serious nature of the atrocities committed the existing theories of criminal justice – retributive, utilitarian and restorative justice models – are not adequate to meet the need for justice of victims, as recognised by the provisions on victims’ participation of the ICC Statute. This thesis suggests that the ICC should adopt an expressivist paradigm in order to give meaningful effect to the victims’ participatory rights, alongside the defendants’ right and the law enforcement functions of the Court and Prosecutor. The adoption of the expressivist framework to the ICC criminal justice contributes to establish a common grammar to bridge the gap in the languages of the civil law and common law systems. The novelty of this idea of common language is that it is critical and fundamental to move forward the goal of victims’ participation and reshape the rights of victims, defendants, judges and prosecutor, going beyond the conflicting languages of the adversarial and inquisitorial systems and allowing to all the provisions to coherently fit together
Employment, work organization and employee experiences of work in post-crisis Indian business process outsourcing (BPO) industry
Get PDFPreviously held under moratorium from 19th December 2019 until 6th January 2025.The dynamics of change within and across economies have led to restructuring of business activities globally impacting work organization and employees’ experiences of work and employment. Externalization and outsourcing of service functions has resulted in firms subcontracting part of work to third-party firms in remote locations. As a result increasing number of workers are no longer directly employed by the organization where and/or whom they work for but are employed by the third-party firms giving rise to “fragmented employment relations and working conditions” (Flecker, 2010). Literature documents the negative consequences of such business arrangements (Taylor and Bain, 2005; Russell, 2009; Vidal and Hauptmeier, 2014).
In the context of the globalization of business services from 2000, the business process outsourcing (BPO) industry witnessed significant growth. BPO is a subset of outsourcing that involves the contracting of the operations and responsibilities of a specific business process to a third-party service provider or to an in-house service provider located elsewhere. BPO is typically categorized into back office outsourcing, which includes internal business functions such as human resources or finance and accounting, and front office outsourcing, which includes customer-related services such as contact centre services. BPO that is contracted outside a company's country is called offshore outsourcing. BPO that is contracted to a company's neighboring (or nearby) country is called nearshore outsourcing. Such dimensions allow for diverse inter-firm arrangements and delivery modes, ranging from complete ownership and control to third-party provision. Often the business processes outsourced are information technology-based, and are referred to as ITeS-BPO, where ITeS stands for Information Technology enabled Service.
With regards to BPO-ITeS services, most attention focused on the high-profile offshoring of call centres from the developed economies of the global North (United State, United Kingdom, Canada) to the developing economies of the global South, particularly India (e.g. Dossani and Kenney, 2007). Contrasting but complementary challenges confronted labour and labour markets effecting work and employment at both nodes of capital’s transnational servicing chains (Taylor and Bain, 2008).
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However, these important debates rested exclusively on evidence derived from the period preceding the crisis of 2008.
A re-evaluation was required based on the re-configured political economy of Business Process Outsourcing (BPO) characterized by shifting customer demands, changing markets and rapidly shifting technology needs. Given the lacuna of published work on post-crisis Indian BPO, this thesis cuts new ground. It examines the dynamics of work and employment across capital’s three contrasting servicing chain relationships (Indian third-party, global third-party provider, and an in-house operation), that span the spectrum of offshoring. Evidence from in-depth interviews with senior managers, middle managers and, crucially, agents engaged on ‘voice’ and back-office services indicate that market driven intensification, strategic reorientation and people management practices adopted post crisis exposed workers much more directly to market pressures giving rise to greater intensification and extensification of work, job insecurity and well-being issues manifesting in different ways in the three case study organisations. In evaluating the empirical evidence of the contrasting case studies, GVC, GPN concepts have been employed to inform analysis and explain developments and differences thereby contributing to the scant literature (pace Taylor, 2010) that applies these analytical frameworks through the concept of the service delivery chain in the ‘Indian BPO sector’.The dynamics of change within and across economies have led to restructuring of business activities globally impacting work organization and employees’ experiences of work and employment. Externalization and outsourcing of service functions has resulted in firms subcontracting part of work to third-party firms in remote locations. As a result increasing number of workers are no longer directly employed by the organization where and/or whom they work for but are employed by the third-party firms giving rise to “fragmented employment relations and working conditions” (Flecker, 2010). Literature documents the negative consequences of such business arrangements (Taylor and Bain, 2005; Russell, 2009; Vidal and Hauptmeier, 2014).
In the context of the globalization of business services from 2000, the business process outsourcing (BPO) industry witnessed significant growth. BPO is a subset of outsourcing that involves the contracting of the operations and responsibilities of a specific business process to a third-party service provider or to an in-house service provider located elsewhere. BPO is typically categorized into back office outsourcing, which includes internal business functions such as human resources or finance and accounting, and front office outsourcing, which includes customer-related services such as contact centre services. BPO that is contracted outside a company's country is called offshore outsourcing. BPO that is contracted to a company's neighboring (or nearby) country is called nearshore outsourcing. Such dimensions allow for diverse inter-firm arrangements and delivery modes, ranging from complete ownership and control to third-party provision. Often the business processes outsourced are information technology-based, and are referred to as ITeS-BPO, where ITeS stands for Information Technology enabled Service.
With regards to BPO-ITeS services, most attention focused on the high-profile offshoring of call centres from the developed economies of the global North (United State, United Kingdom, Canada) to the developing economies of the global South, particularly India (e.g. Dossani and Kenney, 2007). Contrasting but complementary challenges confronted labour and labour markets effecting work and employment at both nodes of capital’s transnational servicing chains (Taylor and Bain, 2008).
xi
However, these important debates rested exclusively on evidence derived from the period preceding the crisis of 2008.
A re-evaluation was required based on the re-configured political economy of Business Process Outsourcing (BPO) characterized by shifting customer demands, changing markets and rapidly shifting technology needs. Given the lacuna of published work on post-crisis Indian BPO, this thesis cuts new ground. It examines the dynamics of work and employment across capital’s three contrasting servicing chain relationships (Indian third-party, global third-party provider, and an in-house operation), that span the spectrum of offshoring. Evidence from in-depth interviews with senior managers, middle managers and, crucially, agents engaged on ‘voice’ and back-office services indicate that market driven intensification, strategic reorientation and people management practices adopted post crisis exposed workers much more directly to market pressures giving rise to greater intensification and extensification of work, job insecurity and well-being issues manifesting in different ways in the three case study organisations. In evaluating the empirical evidence of the contrasting case studies, GVC, GPN concepts have been employed to inform analysis and explain developments and differences thereby contributing to the scant literature (pace Taylor, 2010) that applies these analytical frameworks through the concept of the service delivery chain in the ‘Indian BPO sector’
Investigating effects of Ampakines in cortical neurons : implications for cognitive enhancement and brain doping
No full textThe dysfunction of glutamatergic receptors, particularly α-amino-3-hydroxyl-5-methyl-4-isoxazepolepropoanic acid (AMPA) receptors, has been observed in a broad spectrum of neurological diseases ranging from dementia to schizophrenia. The involvement of AMPA receptors in several disorders explains their attention in the pharmaceutical industry. Positive allosteric modulators, termed Ampakines, have been synthesised based on the hypothesis that synaptic receptors could be modulated to alleviate cognitive deficits present in disease. In this study, utilizing electrophysiological recordings the Ampakines CX614 and CMPDA were used to test whether they modulate synaptic transmission in two different types of neurons, excitatory pyramidal neurons and GABAergic NDNF (Neuron-derived neurotrophic factor)-positive neurons, in the medial prefrontal cortex (mPFC), an area of the brain associated with cognitive ability. NDNF-positive neurons were identified unambiguously in transgenic mice expressing fluorescent protein under the control of the NDNF promoter. Spontaneous excitatory post-synaptic currents (sEPSC) were recorded before and after the application of CX614 andCMPDA. CX614 increased the frequency, as well as tau and the half duration of the sEPSCs in layer 2/3 cortical pyramidal neurons. The decay time constant tau, however, was the only measured parameter found to be significantly enhanced in NDNF-expressing interneurons located in superficial layers of the mPFC. The amplitude of sEPSCs was inconsistently increased in both cell types. Intriguingly, it has been shown that Ampakines do not only demonstrate an AMPA receptor subunit selectively, but also show different efficacy depending on the AMPA receptor auxiliary subunit expression. The data suggests that non-responding neurons may either lack specific AMPA receptor subunits or AMPA receptor auxiliary subunits preferentially modulated by Ampakines. It is concluded that CX614 has a more potent effect on AMPA receptor-mediated synaptic transmission in pyramidal neurons compared to NDNF-expressing interneurons in the mPFC. Future studies testing Ampakines should pair electrophysiological recordings with a sophisticated analysis of expression pattern of both AMPA receptor subunits and auxiliary subunits of the AMPA receptor.The dysfunction of glutamatergic receptors, particularly α-amino-3-hydroxyl-5-methyl-4-isoxazepolepropoanic acid (AMPA) receptors, has been observed in a broad spectrum of neurological diseases ranging from dementia to schizophrenia. The involvement of AMPA receptors in several disorders explains their attention in the pharmaceutical industry. Positive allosteric modulators, termed Ampakines, have been synthesised based on the hypothesis that synaptic receptors could be modulated to alleviate cognitive deficits present in disease. In this study, utilizing electrophysiological recordings the Ampakines CX614 and CMPDA were used to test whether they modulate synaptic transmission in two different types of neurons, excitatory pyramidal neurons and GABAergic NDNF (Neuron-derived neurotrophic factor)-positive neurons, in the medial prefrontal cortex (mPFC), an area of the brain associated with cognitive ability. NDNF-positive neurons were identified unambiguously in transgenic mice expressing fluorescent protein under the control of the NDNF promoter. Spontaneous excitatory post-synaptic currents (sEPSC) were recorded before and after the application of CX614 andCMPDA. CX614 increased the frequency, as well as tau and the half duration of the sEPSCs in layer 2/3 cortical pyramidal neurons. The decay time constant tau, however, was the only measured parameter found to be significantly enhanced in NDNF-expressing interneurons located in superficial layers of the mPFC. The amplitude of sEPSCs was inconsistently increased in both cell types. Intriguingly, it has been shown that Ampakines do not only demonstrate an AMPA receptor subunit selectively, but also show different efficacy depending on the AMPA receptor auxiliary subunit expression. The data suggests that non-responding neurons may either lack specific AMPA receptor subunits or AMPA receptor auxiliary subunits preferentially modulated by Ampakines. It is concluded that CX614 has a more potent effect on AMPA receptor-mediated synaptic transmission in pyramidal neurons compared to NDNF-expressing interneurons in the mPFC. Future studies testing Ampakines should pair electrophysiological recordings with a sophisticated analysis of expression pattern of both AMPA receptor subunits and auxiliary subunits of the AMPA receptor
Applications of surface plasmon resonance effect based on gold nanoparticles
Get PDFSurface plasmon resonance is a photophysical phenomenon, which attracts broad interest with possible applications in sensing, nanolasers and electrochemical reaction catalysis. Meanwhile, gold nanoparticles are excellent candidates among all plasmonic noble metals, showing good and controllable plasmonic features. The aim of this thesis is to study the unique optical properties of gold nanoparticles and gold composites and demonstrate the energy transfer in plasmon enhanced fluorescence, SPASER and oxygen evolution reaction (OER) catalysis via microscopic and spectroscopic techniques.;Firstly, synthesis of colloid gold nanoparticles was introduced in Chapter 3. Surface modifications of gold with silica and polymers were also discussed in this part as well as 2D MnO2 nanosheets fabrication. In addition, the function of each reaction regents was also explained as well as the development background of each synthetic method.;Then in Chapter 4, the surface plasmon effect on the energy transfer towards SPASER was investigated with a Rh 800 doped polystyrene-gold nanorod core-shell structure. The steady state and time-resolved fluorescence spectroscopy study disclosed an enhanced energy transfer when the longitudinal surface plasmon mode of the gold nanorods overlapped with the absorption and emission of Rh 800.;Further study was performed on the metal enhanced fluorescence employing Mega 520 dye loaded mesoporous silica coated gold nanorods in Chapter 5. Fluorescence enhancement was found arising from both increased excitation rate as the transverse surface plasmon mode of gold nanorods overlapped with the excitation wavelength and enhanced quantum yield when the emission of the dye was not coincident with the longitudinal plasmon mode. Furthermore, this study revealed the distance dependence of the enhancement effect.;Finally in Chapter 6, a gold-MnO2 catalyst was designed and prepared with excellent OER catalytic performance. It is believed that the plasmon-induced Mnn+ species provide active sites to extract electrons from OH- to facilitate the oxygen evolution. By tuning the laser intensity from 100 to 200 mW, the overpotential was decreased from 0.38 to 0.32 V, which was comparable to IrO2 and RuO2 catalysts.Surface plasmon resonance is a photophysical phenomenon, which attracts broad interest with possible applications in sensing, nanolasers and electrochemical reaction catalysis. Meanwhile, gold nanoparticles are excellent candidates among all plasmonic noble metals, showing good and controllable plasmonic features. The aim of this thesis is to study the unique optical properties of gold nanoparticles and gold composites and demonstrate the energy transfer in plasmon enhanced fluorescence, SPASER and oxygen evolution reaction (OER) catalysis via microscopic and spectroscopic techniques.;Firstly, synthesis of colloid gold nanoparticles was introduced in Chapter 3. Surface modifications of gold with silica and polymers were also discussed in this part as well as 2D MnO2 nanosheets fabrication. In addition, the function of each reaction regents was also explained as well as the development background of each synthetic method.;Then in Chapter 4, the surface plasmon effect on the energy transfer towards SPASER was investigated with a Rh 800 doped polystyrene-gold nanorod core-shell structure. The steady state and time-resolved fluorescence spectroscopy study disclosed an enhanced energy transfer when the longitudinal surface plasmon mode of the gold nanorods overlapped with the absorption and emission of Rh 800.;Further study was performed on the metal enhanced fluorescence employing Mega 520 dye loaded mesoporous silica coated gold nanorods in Chapter 5. Fluorescence enhancement was found arising from both increased excitation rate as the transverse surface plasmon mode of gold nanorods overlapped with the excitation wavelength and enhanced quantum yield when the emission of the dye was not coincident with the longitudinal plasmon mode. Furthermore, this study revealed the distance dependence of the enhancement effect.;Finally in Chapter 6, a gold-MnO2 catalyst was designed and prepared with excellent OER catalytic performance. It is believed that the plasmon-induced Mnn+ species provide active sites to extract electrons from OH- to facilitate the oxygen evolution. By tuning the laser intensity from 100 to 200 mW, the overpotential was decreased from 0.38 to 0.32 V, which was comparable to IrO2 and RuO2 catalysts
Walking to occupational activities in Basra city : developing and testing an ecological model to support evidence-based feedback in neighbourhood planning
No full textPlease note: the CD along with its files for Appendix (4) p. 295 has not been submitted with this thesis - neither are these files included in the digital copy.The widespread pattern of urban sprawl, consistent with many modern urban developments, is considered in contemporary planning literature as anti-pedestrian. Conversely, the 'traditional neighbourhood' is widely considered by those in the field as offering a pedestrian-friendly environment. Recent research interests in the potential walkability of traditional neighbourhoods conform to the neo-traditional approach in urban planning, design, and development, and have influenced the emergence of New Urbanism. The transformation of Basra City's urban form during the 20th Century (from traditional to modern) remains unexplored in terms of its impact on the walking behaviour of residents, and therefore, this research develops and tests an ecological model of walking to occupational activities at a neighbourhood scale within Basra City, and generates evidence-based feedback to guide further master planning in the region. The thesis comparatively applies the ecological model to the neighbourhood scale in order to shift the walking-neighbourhood relationship from a correlational approach to a casual and multilevel approach, examining socio-demographic factors, urban planning and design measures, the perceived environment, and social cognition factors based on the construct of the Theory of Planned Behaviour (TPB). Walking behaviour was modelled on three types of influence by the neighbourhood environment on walking outcomes, namely mediation, moderation, and determination (or prediction), in order to address research questions and generate evidence-based feedback. Each model combines and tests several variables to address research questions and statistically evaluate the significance of individual walking outcomes. The mediation model combines the objectively measured walkability index (X: predictor), perceived environment factors, or belief-based measures of walking from the TPB (M: mediators), and a walking outcome (Y: dependent variable) in order to evaluate the extent to which M mediates the direct effect of X on Y. The moderation model combines the objectively measured walkability index (X: predictor), socio-demographic factors (Mo: moderators), and a walking outcome (Y: dependent variable) to establish whether the interaction between X and Mo have a significant effect on Y; in other words, to establish the extent to which Mo moderates the direct effect of X on Y. The determination model tests the extent to which the objective measures of the physical environment can predict the walking outcomes; in this respect, the objective measures of urban design and urban form morphology are tested. The objective measures of the physical environment indicate the high to moderate predictability of walking outcomes. Meanwhile, the subjective measures (socio-demographic factors, perceived environment factors, and belief based measures of walking) indicate a moderate to weak predictability of walking outcomes. Moreover, the results indicate that meeting the recommended ≥150-minutes walking per week is largely determined by spatial factors within the neighbourhood typology constituent of traditional and modern neighbourhood classifications. Subsequently, feedback to the master planning of Basra city is generated, and general guidance on neighbourhood design is proposed.The widespread pattern of urban sprawl, consistent with many modern urban developments, is considered in contemporary planning literature as anti-pedestrian. Conversely, the 'traditional neighbourhood' is widely considered by those in the field as offering a pedestrian-friendly environment. Recent research interests in the potential walkability of traditional neighbourhoods conform to the neo-traditional approach in urban planning, design, and development, and have influenced the emergence of New Urbanism. The transformation of Basra City's urban form during the 20th Century (from traditional to modern) remains unexplored in terms of its impact on the walking behaviour of residents, and therefore, this research develops and tests an ecological model of walking to occupational activities at a neighbourhood scale within Basra City, and generates evidence-based feedback to guide further master planning in the region. The thesis comparatively applies the ecological model to the neighbourhood scale in order to shift the walking-neighbourhood relationship from a correlational approach to a casual and multilevel approach, examining socio-demographic factors, urban planning and design measures, the perceived environment, and social cognition factors based on the construct of the Theory of Planned Behaviour (TPB). Walking behaviour was modelled on three types of influence by the neighbourhood environment on walking outcomes, namely mediation, moderation, and determination (or prediction), in order to address research questions and generate evidence-based feedback. Each model combines and tests several variables to address research questions and statistically evaluate the significance of individual walking outcomes. The mediation model combines the objectively measured walkability index (X: predictor), perceived environment factors, or belief-based measures of walking from the TPB (M: mediators), and a walking outcome (Y: dependent variable) in order to evaluate the extent to which M mediates the direct effect of X on Y. The moderation model combines the objectively measured walkability index (X: predictor), socio-demographic factors (Mo: moderators), and a walking outcome (Y: dependent variable) to establish whether the interaction between X and Mo have a significant effect on Y; in other words, to establish the extent to which Mo moderates the direct effect of X on Y. The determination model tests the extent to which the objective measures of the physical environment can predict the walking outcomes; in this respect, the objective measures of urban design and urban form morphology are tested. The objective measures of the physical environment indicate the high to moderate predictability of walking outcomes. Meanwhile, the subjective measures (socio-demographic factors, perceived environment factors, and belief based measures of walking) indicate a moderate to weak predictability of walking outcomes. Moreover, the results indicate that meeting the recommended ≥150-minutes walking per week is largely determined by spatial factors within the neighbourhood typology constituent of traditional and modern neighbourhood classifications. Subsequently, feedback to the master planning of Basra city is generated, and general guidance on neighbourhood design is proposed
Framework for assessing stability challenges in future converter-dominated power networks
Get PDFWith requirements to deal with ageing infrastructure and to meet environmental targets, the installed capacity of converters, including converter-interfaced generation and back-to-back converters, is expected to experience a continued growth. In traditional power networks, synchronous generators provided the overwhelming majority of electrical power, with some induction generators providing the remaining electrical power.;The dynamics of operation of both machines are well understood, including potential stability issues. With the introduction of converter-interfaced generation, power networks are becoming diverse systems, associated with which is an increased number of stability issues to consider.;The majority of modern converters employ dq-axis current injection control (or vector current control) in which a phase-locked loop is used to synchronise with the voltage at the point of common coupling where the converter is connected with the network. In recent years, potential issues with performance of PLL when the AC network it is connected to is weak have been reported. Poor performance of PLL under such circumstances will lead to a cascade of errors in the control system, culminating in an unstable system.;This thesis investigates the stability of the power system when large quantities of converter-based generation are present. The stability thresholds, termed as system tipping points in this work, are evaluated for both small and large disturbances. A time-domain analytical method to assess the tipping points, the tipping point search method, is introduced. This can be applied to any network model. Additionally, a network frequency perturbation tool, which can also be applied in time-domain model, is introduced to visualise the response of individual generators to network frequency fluctuation and predict potential interactions among the generators.;Following the identification of the limitations of vector current control, alternative control strategies which emulate synchronous generators, some more so than others, are investigated. Based on these studies, recommendations for power system engineers are made to ensure that the transition from a generator-dominated network to a converter-dominated network is as smooth as possible.With requirements to deal with ageing infrastructure and to meet environmental targets, the installed capacity of converters, including converter-interfaced generation and back-to-back converters, is expected to experience a continued growth. In traditional power networks, synchronous generators provided the overwhelming majority of electrical power, with some induction generators providing the remaining electrical power.;The dynamics of operation of both machines are well understood, including potential stability issues. With the introduction of converter-interfaced generation, power networks are becoming diverse systems, associated with which is an increased number of stability issues to consider.;The majority of modern converters employ dq-axis current injection control (or vector current control) in which a phase-locked loop is used to synchronise with the voltage at the point of common coupling where the converter is connected with the network. In recent years, potential issues with performance of PLL when the AC network it is connected to is weak have been reported. Poor performance of PLL under such circumstances will lead to a cascade of errors in the control system, culminating in an unstable system.;This thesis investigates the stability of the power system when large quantities of converter-based generation are present. The stability thresholds, termed as system tipping points in this work, are evaluated for both small and large disturbances. A time-domain analytical method to assess the tipping points, the tipping point search method, is introduced. This can be applied to any network model. Additionally, a network frequency perturbation tool, which can also be applied in time-domain model, is introduced to visualise the response of individual generators to network frequency fluctuation and predict potential interactions among the generators.;Following the identification of the limitations of vector current control, alternative control strategies which emulate synchronous generators, some more so than others, are investigated. Based on these studies, recommendations for power system engineers are made to ensure that the transition from a generator-dominated network to a converter-dominated network is as smooth as possible
Synthesis and evaluation of novel non-viral gene delivery systems for prostate cancer targeting
Get PDFThis thesis was previously held under moratorium from 18th May 2018 until 18th May 2023Prostate cancer is the second most widespread cancer in men worldwide. Treatment choices are limited to prostatectomy, hormonal and radiotherapy that commonly have deleterious side effects and vary in their efficacy, depending on the stage of the disease. Among novel experimental strategies, gene therapy holds great promise for the treatment ofcancer, but its use is currently limited by the lack of delivery systems able to selectively deliver the therapeutic genes to the tumours after intravenous administration without major drawbacks. Given that lactoferrin receptors, prostate specific membrane antigen (PSMA) and integrins areoverexpressed on prostate cancer cells, the purpose of this study is to determine whether lactoferrin, Peptide2 (CWQPDTAHHWATL) and Peptide4 (CPRPRGDNPPLTCGGKKK) bearing diaminobutyric polypropylenimine (DAB) based dendriplexs would improve thetargeting of therapeutic genes in vitro and in vivo. The chemical and physical characteristics of the synthesised dendrimers were first determined, followed by various in vitro experiments, to assess the improvement in the transfection and cellular uptake of the modified dendriplexes in PC-3, DU145 and LNCaP prostate cancer cell lines. Finally, in vivo studies were carried out using BALB/c nude mice to investigate the anticancer effects of the Lf-bearing dendriplexes encoding TNFα, TRAIL, or IL-12. DAB-Lf significantly increased the cellular uptake of the DNA in all prostate cancer cells. The highest DNA uptake, observed in PC-3 cells, was double than that observed in cells treated with non-targeted dendriplex. The anti-proliferative efficacy of DAB-Lf dendriplex encodingTNFα, TRAIL, or IL-12 was significantly improved compared with unmodified DAB dendriplex. In vivo, intravenous injections of DAB-Lf dendrimer complexed with plasmid DNA encoding TNFα and TRAIL have resulted in complete regression in 70% and 40% of tumours respectively at the end of the experiment in tumour-bearing mice. DAB-PEG2k-Pep2 significantly improved the cellular uptake in LNCaP and DU145 cells, butnot in PC-3 cells compared with the non-targeted dendriplex. The therapeutic DNA encoding TNFα was successfully transfected after complexation with DAB-PEG2k-Pep2 in all three cell lines, with significant variance in the cytokine concentration between cell lines. The IC50 ofDAB-PEG2k-Pep2 dendriplex encoding TNFα was significantly improved compared with untargeted DAB-PEG dendriplex in LNCaP cells. In conclusion, DAB-Lf is a promising DNA carrier for targeting prostate cancer. This study is one of few showing significant tumour regression after intravenous administration of gene therapy using non-viral vectors as a single therapy approach. Peptide2 was also found to be an effective ligand for PSMA, however more improvement in the formulation is still required toobtain an enhanced therapeutic effect.Prostate cancer is the second most widespread cancer in men worldwide. Treatment choices are limited to prostatectomy, hormonal and radiotherapy that commonly have deleterious side effects and vary in their efficacy, depending on the stage of the disease. Among novel experimental strategies, gene therapy holds great promise for the treatment ofcancer, but its use is currently limited by the lack of delivery systems able to selectively deliver the therapeutic genes to the tumours after intravenous administration without major drawbacks. Given that lactoferrin receptors, prostate specific membrane antigen (PSMA) and integrins areoverexpressed on prostate cancer cells, the purpose of this study is to determine whether lactoferrin, Peptide2 (CWQPDTAHHWATL) and Peptide4 (CPRPRGDNPPLTCGGKKK) bearing diaminobutyric polypropylenimine (DAB) based dendriplexs would improve thetargeting of therapeutic genes in vitro and in vivo. The chemical and physical characteristics of the synthesised dendrimers were first determined, followed by various in vitro experiments, to assess the improvement in the transfection and cellular uptake of the modified dendriplexes in PC-3, DU145 and LNCaP prostate cancer cell lines. Finally, in vivo studies were carried out using BALB/c nude mice to investigate the anticancer effects of the Lf-bearing dendriplexes encoding TNFα, TRAIL, or IL-12. DAB-Lf significantly increased the cellular uptake of the DNA in all prostate cancer cells. The highest DNA uptake, observed in PC-3 cells, was double than that observed in cells treated with non-targeted dendriplex. The anti-proliferative efficacy of DAB-Lf dendriplex encodingTNFα, TRAIL, or IL-12 was significantly improved compared with unmodified DAB dendriplex. In vivo, intravenous injections of DAB-Lf dendrimer complexed with plasmid DNA encoding TNFα and TRAIL have resulted in complete regression in 70% and 40% of tumours respectively at the end of the experiment in tumour-bearing mice. DAB-PEG2k-Pep2 significantly improved the cellular uptake in LNCaP and DU145 cells, butnot in PC-3 cells compared with the non-targeted dendriplex. The therapeutic DNA encoding TNFα was successfully transfected after complexation with DAB-PEG2k-Pep2 in all three cell lines, with significant variance in the cytokine concentration between cell lines. The IC50 ofDAB-PEG2k-Pep2 dendriplex encoding TNFα was significantly improved compared with untargeted DAB-PEG dendriplex in LNCaP cells. In conclusion, DAB-Lf is a promising DNA carrier for targeting prostate cancer. This study is one of few showing significant tumour regression after intravenous administration of gene therapy using non-viral vectors as a single therapy approach. Peptide2 was also found to be an effective ligand for PSMA, however more improvement in the formulation is still required toobtain an enhanced therapeutic effect
Expanding the DNA binding repertoire of pyrrole-imidazole polyamids
Get PDFPyrrole-Imidazole (Py-Im) hairpin polyamides are a programmable class of compounds that bind in the minor groove of double-stranded DNA (dsDNA). The hairpin conformationenables sufficient flexibility to form a side-by-side arrangement within the minor groove of target dsDNA sequences. An Im-Py pair discriminates G over C, A and T, whereas a Py-Pypair binds A and T over C and G. The possibility to target specific dsDNA sequences enables polyamides to modulate gene expression by the disruption of transcription factors such as the androgen receptor, over expressed in prostate cancer. A current limitation of the biological applications of Py-Im polyamides is their variable cell permeability profile. Im-richpolyamides tend to have reduced cellular and nuclear uptake in eukaryotic cells. Although modifications to the periphery of the polyamide scaffold have been explored at length, there has been limited studies on tuning the physicochemical properties of the G-recognising Imunit. This thesis describes the preparation and the evaluation of the binding mode of hairpin polyamides with Im units replaced by a series of 5-substituted 2-amino-4-carboxylic thiazole(Nt) building blocks. Chapter 1 introduces the endogenous and exogenous DNA recognition by protein and small molecules, the modulation of gene expression using Py-Im polyamides and the limitations of this approach. Chapter 2 describes the preparation of the building blocks and the optimisation of the solid phase synthesis of hairpin polyamides containing Nt units. These optimised conditions were used for the preparation of a suite of 8-ring polyamides incorporating Nt in different positions of the polyamide scaffold. Expanding the DNA binding repertoire of Pyrrole-Imidazole polyamides Chapter 3 describes the evaluation of the binding mode of Nt-containing polyamides using a combination of biophysical and biochemical methods. The 5-isopropyl substituted Nt (iPrNt) building block was identified as an alternative to Im for targeting G when incorporated at theN-terminus of the polyamide scaffold. Chapter 4 describes the structural characterisation of three selected polyamides binding to their dsDNA target sequence using NMR spectroscopy and molecular dynamics. This study reveals that the polyamide containing iPrNt at the N-terminus induces a greater compression of the major groove compared to the Im-containing analogue. Finally, Chapter 5 reflects on the work of this thesis and offers some perspective of the future development of Py-Im polyamides as gene expression modulators.Pyrrole-Imidazole (Py-Im) hairpin polyamides are a programmable class of compounds that bind in the minor groove of double-stranded DNA (dsDNA). The hairpin conformationenables sufficient flexibility to form a side-by-side arrangement within the minor groove of target dsDNA sequences. An Im-Py pair discriminates G over C, A and T, whereas a Py-Pypair binds A and T over C and G. The possibility to target specific dsDNA sequences enables polyamides to modulate gene expression by the disruption of transcription factors such as the androgen receptor, over expressed in prostate cancer. A current limitation of the biological applications of Py-Im polyamides is their variable cell permeability profile. Im-richpolyamides tend to have reduced cellular and nuclear uptake in eukaryotic cells. Although modifications to the periphery of the polyamide scaffold have been explored at length, there has been limited studies on tuning the physicochemical properties of the G-recognising Imunit. This thesis describes the preparation and the evaluation of the binding mode of hairpin polyamides with Im units replaced by a series of 5-substituted 2-amino-4-carboxylic thiazole(Nt) building blocks. Chapter 1 introduces the endogenous and exogenous DNA recognition by protein and small molecules, the modulation of gene expression using Py-Im polyamides and the limitations of this approach. Chapter 2 describes the preparation of the building blocks and the optimisation of the solid phase synthesis of hairpin polyamides containing Nt units. These optimised conditions were used for the preparation of a suite of 8-ring polyamides incorporating Nt in different positions of the polyamide scaffold. Expanding the DNA binding repertoire of Pyrrole-Imidazole polyamides Chapter 3 describes the evaluation of the binding mode of Nt-containing polyamides using a combination of biophysical and biochemical methods. The 5-isopropyl substituted Nt (iPrNt) building block was identified as an alternative to Im for targeting G when incorporated at theN-terminus of the polyamide scaffold. Chapter 4 describes the structural characterisation of three selected polyamides binding to their dsDNA target sequence using NMR spectroscopy and molecular dynamics. This study reveals that the polyamide containing iPrNt at the N-terminus induces a greater compression of the major groove compared to the Im-containing analogue. Finally, Chapter 5 reflects on the work of this thesis and offers some perspective of the future development of Py-Im polyamides as gene expression modulators
Identity change and the entrepreneurial journey : a case of Art-School graduates
Get PDFWhilst many have addressed the question, it is still not clearly known how identity influences entrepreneurial behaviour. There is a need for research to look at the formation of entrepreneurial identity as a process - an important contribution considering identities and ventures both take time to form. This thesis will address this research demand by looking at entrepreneurship as a journey that individuals undertake and explore how this interplays with their identity. Therefore, this thesis has 3 objectives: (1) to understand if and how the entrepreneurial identity changes throughout the entrepreneurial process and what triggers change; (2) to understand how entrepreneurs manage the performance of multiple identities and the relationship this has with the venture; and (3) to understand the temporal and processual development of identity and the relationship this has with venture development. By exploring these objectives this thesis aims to understand what the entrepreneurial identity is and how it is formed and enacted. This will advance the understanding of what drives entrepreneurs to develop ventures. To achieve this, a longitudinal study on seven arts entrepreneurs was conducted, with data collection lasting between 12 and 18 months. Data was triangulated with media articles and participant diagrams. In total, 21 interviews were conducted, 61 media articles reviewed and 20 participant diagrams formed which allowed insights to emerge on the entirety of the entrepreneurial journey. Data was systematically analysed using an inductive approach, where aggregate themes emerged from the raw interview data by way of a data structure (Gioia, Corley, & Hamilton, 2012). Visual mapping strategies were also used to help generate theory from the raw data (interviews and participant diagrams) by way of venture timelines and process diagrams (Langley, 1999). This research makes contributions to existing work on entrepreneurial identities. The concepts of role naivety and role defiance are introduced which can add to existing explanations on the challenges that entrepreneurs face during identity transition. Insight is also offered to literature debate on how identities effect entrepreneurial behaviour by introducing a model which shows identity as both influencing and being influenced by venture development. This conceptual model of identity change for arts entrepreneurs is presented and fundamentally sees a process of identity disruption, reconciliation and affirmation which is mediated by venture activity and moderated by community identity forces. Additionally, insights are offered that contribute to wider entrepreneurship literature by showing how identity influences and forms different venture pursuits, namely arts-focused ventures and commercial-focused ventures. By looking at entrepreneurial identity construction as a process, this thesis has offered an explanation as to why some ventures scale and grow and why some do not.Whilst many have addressed the question, it is still not clearly known how identity influences entrepreneurial behaviour. There is a need for research to look at the formation of entrepreneurial identity as a process - an important contribution considering identities and ventures both take time to form. This thesis will address this research demand by looking at entrepreneurship as a journey that individuals undertake and explore how this interplays with their identity. Therefore, this thesis has 3 objectives: (1) to understand if and how the entrepreneurial identity changes throughout the entrepreneurial process and what triggers change; (2) to understand how entrepreneurs manage the performance of multiple identities and the relationship this has with the venture; and (3) to understand the temporal and processual development of identity and the relationship this has with venture development. By exploring these objectives this thesis aims to understand what the entrepreneurial identity is and how it is formed and enacted. This will advance the understanding of what drives entrepreneurs to develop ventures. To achieve this, a longitudinal study on seven arts entrepreneurs was conducted, with data collection lasting between 12 and 18 months. Data was triangulated with media articles and participant diagrams. In total, 21 interviews were conducted, 61 media articles reviewed and 20 participant diagrams formed which allowed insights to emerge on the entirety of the entrepreneurial journey. Data was systematically analysed using an inductive approach, where aggregate themes emerged from the raw interview data by way of a data structure (Gioia, Corley, & Hamilton, 2012). Visual mapping strategies were also used to help generate theory from the raw data (interviews and participant diagrams) by way of venture timelines and process diagrams (Langley, 1999). This research makes contributions to existing work on entrepreneurial identities. The concepts of role naivety and role defiance are introduced which can add to existing explanations on the challenges that entrepreneurs face during identity transition. Insight is also offered to literature debate on how identities effect entrepreneurial behaviour by introducing a model which shows identity as both influencing and being influenced by venture development. This conceptual model of identity change for arts entrepreneurs is presented and fundamentally sees a process of identity disruption, reconciliation and affirmation which is mediated by venture activity and moderated by community identity forces. Additionally, insights are offered that contribute to wider entrepreneurship literature by showing how identity influences and forms different venture pursuits, namely arts-focused ventures and commercial-focused ventures. By looking at entrepreneurial identity construction as a process, this thesis has offered an explanation as to why some ventures scale and grow and why some do not
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