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Using implementation intentions to reduce self-harm
Full text linkImplementation intentions (IMPs) are IF-THEN plans that require people to specify critical situations (e.g., situations that tempt a behaviour, such as self-harm) and link those situations with goal-directed responses (e.g., coping strategies). This research tested the effectiveness of an intervention technique (a volitional help sheet) designed to encourage the formation of IMPs to avoid self-harm thoughts and behaviour in the wider community. Chapter 1 discusses the prevalence and detrimental impact of self-harm behaviour and thoughts, and existing interventions. Chapter 2 introduces the concept of IMPs and reviews evidence suggesting that IMP interventions are likely to reduce self-harm. Potential motivational, volitional, and cognitive moderators of IMPs are also considered.Following a consideration of key methodological issues relating to the design of the present research (chapter 3), study 1 is presented in chapter 4. Study 1 showed that an IMP intervention reduced self-harm behaviour in the critical situations specified in participants’ plans. In line with expectations, this effect was observed only when individuals were motivated to reduce self-harm and experienced high levels of self-harm and suicide-related mental imagery. No effects were observed on other measured outcomes: self-harm in unspecified critical situations, suicidality, anxiety, and depression. Exposure to self-harm by friends and family did not moderate the effects of the intervention on any outcome measure.Study 2 (chapter 5) showed that the IMP intervention reduced self-harm thoughts in the participants’ specified critical situations. Consistent with study 1, this effect was observed only when individuals were motivated to stop thinking about self-harm. No effects of the intervention were largely observed on other outcome measures. Cognitive abilities (attention, and prospective and retrospective memory) did not moderate the effects of the intervention on self-harm thoughts, suicidality, anxiety or depression. However, there was evidence that they moderated the effects of the intervention on self-harm behaviour.Chapter 6 presents a pilot study for a clinical trial to test the effects of IMPs, and the moderators investigated in this thesis, on patients admitted to hospital for self-harm. A reflection on the pilot’s methods and results is presented with a view to a future, full-scale clinical trial.The overall findings across the three studies are discussed in chapter 7. Implications for practice and future research are presented.Implementation intentions (IMPs) are IF-THEN plans that require people to specify critical situations (e.g., situations that tempt a behaviour, such as self-harm) and link those situations with goal-directed responses (e.g., coping strategies). This research tested the effectiveness of an intervention technique (a volitional help sheet) designed to encourage the formation of IMPs to avoid self-harm thoughts and behaviour in the wider community. Chapter 1 discusses the prevalence and detrimental impact of self-harm behaviour and thoughts, and existing interventions. Chapter 2 introduces the concept of IMPs and reviews evidence suggesting that IMP interventions are likely to reduce self-harm. Potential motivational, volitional, and cognitive moderators of IMPs are also considered.Following a consideration of key methodological issues relating to the design of the present research (chapter 3), study 1 is presented in chapter 4. Study 1 showed that an IMP intervention reduced self-harm behaviour in the critical situations specified in participants’ plans. In line with expectations, this effect was observed only when individuals were motivated to reduce self-harm and experienced high levels of self-harm and suicide-related mental imagery. No effects were observed on other measured outcomes: self-harm in unspecified critical situations, suicidality, anxiety, and depression. Exposure to self-harm by friends and family did not moderate the effects of the intervention on any outcome measure.Study 2 (chapter 5) showed that the IMP intervention reduced self-harm thoughts in the participants’ specified critical situations. Consistent with study 1, this effect was observed only when individuals were motivated to stop thinking about self-harm. No effects of the intervention were largely observed on other outcome measures. Cognitive abilities (attention, and prospective and retrospective memory) did not moderate the effects of the intervention on self-harm thoughts, suicidality, anxiety or depression. However, there was evidence that they moderated the effects of the intervention on self-harm behaviour.Chapter 6 presents a pilot study for a clinical trial to test the effects of IMPs, and the moderators investigated in this thesis, on patients admitted to hospital for self-harm. A reflection on the pilot’s methods and results is presented with a view to a future, full-scale clinical trial.The overall findings across the three studies are discussed in chapter 7. Implications for practice and future research are presented
Organising obscenity : a three-part exploration into the architecture of adult sites from the western world, their intimate interactions and lusty language when searching for sex
Full text linkVideo-streaming porn websites made porn media more widespread and commonplace to the everyday internet user. This study takes a multi-disciplinary approach to exploring porn by treating it as information and viewing it through the lens of Information Science. It updates the idea of porn, the user’s journey and the interaction found on porn websites. The thesis comprises three parts using a scientific approach that experiments, morphs and builds on each study to build a narrative of exploratory discovery within this lesser-studied field. The first part of the study expands on the definitions of porn sites. Using concepts and frameworks from Information Architecture, it breaks down the many types of porn sites and focuses specifically on video-streaming sites. Video streaming sites are then broken down into defining characteristics that are compared to other sites to show the overlapping features and how they straddle different site categories; allowing them to simultaneously fit within the internet yet stand out from these sites. By also applying the video streaming porn site characteristics to a sample of porn sites to test, it draws out further nuances and questions. The second part, applies the new characteristics to the interactive elements found on the sample sites. Primary and secondary data builds a quantitative and qualitative picture of the user's journey. This chapter illustrates the breakdown of interactions and viewership, making correlations between the two and comparing them across the sites. A list of interactions are broken into two types, Simple and Complex, and the site's areas for interaction into two layers, Basic and Involved. Information Seeking concepts like Berrypicking and Information Foraging are used as a framework to create speculations and hypotheses, possible reasons, and searching methods that inform the site's usability. The third part focuses on Pornhub as an example and descriptively explains the changes to its categories over time by using resources like the Wayback Machine for data collection. It takes an exploratory approach to the changing categories and use of tags to supplement the information-seeking speculations made in the previous chapter. Focusing on the links betweencategories as Controlled Vocabularies and tags as Folksonomies informs how the sites morph and change to suit the content creators commercially and the users communally. Anecdotal evidence closes this chapter with speculations from industry professionals about their opinions on the site changes and future predictions. The thesis concludes with contributions that include new definitions, terminology, methods and applications. The definition of porn expands by employing information science that encompasses the nuances of the internet. The various interactions and options create new terminology. New methods explore frameworks for future studies to collect data in new ways. Applying Information Architecture and information-seeking behaviours to porn sites provides a novel way of viewing and speculations about porn sites for future interest and application.Video-streaming porn websites made porn media more widespread and commonplace to the everyday internet user. This study takes a multi-disciplinary approach to exploring porn by treating it as information and viewing it through the lens of Information Science. It updates the idea of porn, the user’s journey and the interaction found on porn websites. The thesis comprises three parts using a scientific approach that experiments, morphs and builds on each study to build a narrative of exploratory discovery within this lesser-studied field. The first part of the study expands on the definitions of porn sites. Using concepts and frameworks from Information Architecture, it breaks down the many types of porn sites and focuses specifically on video-streaming sites. Video streaming sites are then broken down into defining characteristics that are compared to other sites to show the overlapping features and how they straddle different site categories; allowing them to simultaneously fit within the internet yet stand out from these sites. By also applying the video streaming porn site characteristics to a sample of porn sites to test, it draws out further nuances and questions. The second part, applies the new characteristics to the interactive elements found on the sample sites. Primary and secondary data builds a quantitative and qualitative picture of the user's journey. This chapter illustrates the breakdown of interactions and viewership, making correlations between the two and comparing them across the sites. A list of interactions are broken into two types, Simple and Complex, and the site's areas for interaction into two layers, Basic and Involved. Information Seeking concepts like Berrypicking and Information Foraging are used as a framework to create speculations and hypotheses, possible reasons, and searching methods that inform the site's usability. The third part focuses on Pornhub as an example and descriptively explains the changes to its categories over time by using resources like the Wayback Machine for data collection. It takes an exploratory approach to the changing categories and use of tags to supplement the information-seeking speculations made in the previous chapter. Focusing on the links betweencategories as Controlled Vocabularies and tags as Folksonomies informs how the sites morph and change to suit the content creators commercially and the users communally. Anecdotal evidence closes this chapter with speculations from industry professionals about their opinions on the site changes and future predictions. The thesis concludes with contributions that include new definitions, terminology, methods and applications. The definition of porn expands by employing information science that encompasses the nuances of the internet. The various interactions and options create new terminology. New methods explore frameworks for future studies to collect data in new ways. Applying Information Architecture and information-seeking behaviours to porn sites provides a novel way of viewing and speculations about porn sites for future interest and application
The development of an adaptive and reactive interface system for lower limb prosthetic application
Full text linkDeep tissue injury (DTI) is a known problem correlating to the use of a prosthetic by a transtibial amputee (TTA), causing ulcer-like wounds on the residual limb caused by stress-induced cell necrosis. The magnitude of these stresses at the bone tissue interface has been identified computationally, far exceeding those measured at the skin's surface. Limited technology is available to directly target and reduce such cellular loading and actively reduce the risk of DTI from below-knee use. The primary aim of this project was to identify whether a bespoke prosthetic socket system could actively stiffen the tissues of the lower limb. Stabilising the residual tibia during ambulation and reducing stress concentrations on the cells. To achieve this, a proof-of-concept device was designed and manufactured, a system that allowed the change in displacement of a magnet to be responded to by counterbalancing load. The device was evaluated through experimentation on an able-bodied subject wearing an orthotic device designed to replicate the environment of a prosthetic socket. The chosen sensor effector system was validated against vector data generated by the Motek Medical Computer Assisted Rehabilitation Environment (CAREN.) The project explored a new concept of reactive loading of a below-knee prosthesis to reduce tibial/socket oscillation. The evaluation of the device indicated that external loading of the residual limb in such a manner could reduce the magnitude of rotation about the tibia and therefore minimise the conditions by which DTIs are known to occur. Efforts were made to move the design to the next iteration, focusing on implementing the target demographic.Deep tissue injury (DTI) is a known problem correlating to the use of a prosthetic by a transtibial amputee (TTA), causing ulcer-like wounds on the residual limb caused by stress-induced cell necrosis. The magnitude of these stresses at the bone tissue interface has been identified computationally, far exceeding those measured at the skin's surface. Limited technology is available to directly target and reduce such cellular loading and actively reduce the risk of DTI from below-knee use. The primary aim of this project was to identify whether a bespoke prosthetic socket system could actively stiffen the tissues of the lower limb. Stabilising the residual tibia during ambulation and reducing stress concentrations on the cells. To achieve this, a proof-of-concept device was designed and manufactured, a system that allowed the change in displacement of a magnet to be responded to by counterbalancing load. The device was evaluated through experimentation on an able-bodied subject wearing an orthotic device designed to replicate the environment of a prosthetic socket. The chosen sensor effector system was validated against vector data generated by the Motek Medical Computer Assisted Rehabilitation Environment (CAREN.) The project explored a new concept of reactive loading of a below-knee prosthesis to reduce tibial/socket oscillation. The evaluation of the device indicated that external loading of the residual limb in such a manner could reduce the magnitude of rotation about the tibia and therefore minimise the conditions by which DTIs are known to occur. Efforts were made to move the design to the next iteration, focusing on implementing the target demographic
Analysis of the chemistry and microbiology of urban stormwater and its treatment by rain gardens
No full textSustainable urban drainage systems (SUDS) are designed to both lower the quantity and increase the quality of urban runoff that is released to surface water bodies, reducing flood risk and minimising environmental damage. Little is currently known about the microbial communities within SUDS, despite the important role that bacteria play in pollutant removal. Optimising the water treatment potential of SUDS will require a better understanding of how water treatment and microbial community composition are affected by factors such as design and local pollutant concentrations.This thesis examined the chemical and microbial variation in stormwater from Glasgow, Scotland and Florianópolis, Brazil, as well as in influent, effluent, and soil from Glaswegian rain gardens. Concentrations of contaminants were generally higher in Glasgow than in Florianópolis, with several potentially toxic elements (PTEs) exceeding local freshwater standards. Taxonomic and functional microbial diversity were significantly impacted by country of origin, suggesting that geographical factors such as climate are affecting the stormwater community.The Glaswegian rain gardens’ design differed only in soil particle size distribution. All four gardens were able to lower pollutant concentrations, but no clear trend in removal efficiency based on soil type was observed. Influent microbial communities differed significantly from those of the effluent, while the four effluent communities resembled one another and varied based on sampling date, suggesting that seasonal factors or community maturation have a greater impact on water microbiology than soil particle size.Some variation in hydrocarbon and PTE concentrations was seen in the rain garden soil, but the overall level of contamination was low. Taxonomy of the soil microbial communities was similar between gardens, with several common hydrocarbon degraders identified. Differences in taxonomic and functional diversity caused by soil chemistry and morphology were found, suggesting that the choice of soil should be taken into account to maximise community stability.Sustainable urban drainage systems (SUDS) are designed to both lower the quantity and increase the quality of urban runoff that is released to surface water bodies, reducing flood risk and minimising environmental damage. Little is currently known about the microbial communities within SUDS, despite the important role that bacteria play in pollutant removal. Optimising the water treatment potential of SUDS will require a better understanding of how water treatment and microbial community composition are affected by factors such as design and local pollutant concentrations.This thesis examined the chemical and microbial variation in stormwater from Glasgow, Scotland and Florianópolis, Brazil, as well as in influent, effluent, and soil from Glaswegian rain gardens. Concentrations of contaminants were generally higher in Glasgow than in Florianópolis, with several potentially toxic elements (PTEs) exceeding local freshwater standards. Taxonomic and functional microbial diversity were significantly impacted by country of origin, suggesting that geographical factors such as climate are affecting the stormwater community.The Glaswegian rain gardens’ design differed only in soil particle size distribution. All four gardens were able to lower pollutant concentrations, but no clear trend in removal efficiency based on soil type was observed. Influent microbial communities differed significantly from those of the effluent, while the four effluent communities resembled one another and varied based on sampling date, suggesting that seasonal factors or community maturation have a greater impact on water microbiology than soil particle size.Some variation in hydrocarbon and PTE concentrations was seen in the rain garden soil, but the overall level of contamination was low. Taxonomy of the soil microbial communities was similar between gardens, with several common hydrocarbon degraders identified. Differences in taxonomic and functional diversity caused by soil chemistry and morphology were found, suggesting that the choice of soil should be taken into account to maximise community stability
Marine Engineering Systems and Control NM346 Exam Papers
No full textAccess restricted to staff and registered students of the University of Strathclyde.PAST EXAM PAPERS ARE NO LONGER BEING ADDED TO STAX. PLEASE VISIT SUPRIMO TO ACCESS AN UP-TO-DATE COLLECTION OF PAST EXAM PAPERS: https://suprimo.lib.strath.ac.uk
IBML 5 Spanish: Research and productive skills annotated translation R4902 exam papers
No full textNo papers available.PAST EXAM PAPERS ARE NO LONGER BEING ADDED TO STAX. PLEASE VISIT SUPRIMO TO ACCESS AN UP-TO-DATE COLLECTION OF PAST EXAM PAPERS: https://suprimo.lib.strath.ac.uk
Hypergravitational stimulation of cell differentiation
No full textMechanobiology is an emerging field within biophysics which encapsulates cellular responses to mechanical stimuli. Mechanotransduction is the highly dynamic and varied downstream cellular signalling which is activated through many different modes of mechanical stimulation. Control of stem cell differentiation has been controlled in the past via mechanical stimulation. A plethora of studies have been conducted within this field documenting the effects of many mechanical stimuli such as vibration or compression. Despite this, in vitro compression of cells via hypergravity has received less attention than other applied forces of material properties, considering the availability of suitable centrifuges to the average biomedical scientist. Hypergravity is defined as any level of acceleration due to gravity which is above the level experienced on Earth (>1 g). MG63 osteosarcoma and mesenchymal stem cells were subjected to prolonged intermittent periods of hypergravity stimulation between 10-50 g. Hypergravity stimulation was applied to test the impact on osteogenic marker expression. A marked response both in cell viability, F-actin polymerisation, and nuclear area were observed among both cell types. MG63 osteosarcoma cells displayed a detrimental response towards stimulation. Mesenchymal stem cells showed similar sensitivity, yet heightened viability. Overall, the protocol of hypergravity stimulation applied was not sufficient to induce osteogenesis in MG63 cells.Mechanobiology is an emerging field within biophysics which encapsulates cellular responses to mechanical stimuli. Mechanotransduction is the highly dynamic and varied downstream cellular signalling which is activated through many different modes of mechanical stimulation. Control of stem cell differentiation has been controlled in the past via mechanical stimulation. A plethora of studies have been conducted within this field documenting the effects of many mechanical stimuli such as vibration or compression. Despite this, in vitro compression of cells via hypergravity has received less attention than other applied forces of material properties, considering the availability of suitable centrifuges to the average biomedical scientist. Hypergravity is defined as any level of acceleration due to gravity which is above the level experienced on Earth (>1 g). MG63 osteosarcoma and mesenchymal stem cells were subjected to prolonged intermittent periods of hypergravity stimulation between 10-50 g. Hypergravity stimulation was applied to test the impact on osteogenic marker expression. A marked response both in cell viability, F-actin polymerisation, and nuclear area were observed among both cell types. MG63 osteosarcoma cells displayed a detrimental response towards stimulation. Mesenchymal stem cells showed similar sensitivity, yet heightened viability. Overall, the protocol of hypergravity stimulation applied was not sufficient to induce osteogenesis in MG63 cells
A novel faulted section location technique for future active distribution networks
Full text linkDistribution Network Operators (DNOs) face increasingly higher challenges to preserve quality and continuity of supply due to the widespread penetration of Distributed Energy Resources (DER) [1–8]. In parallel, more advanced technologies are being introduced into secondary substations for better observability and controllability. These features provided via instrumented substation assets and Information Communication Technologies (ICT) present opportunities for the development and implementation of new functions aiming to the effective operation and monitoring of active distribution networks [9–14]. This thesis focuses on one of these functionalities – that is, leveraging the ability of Low Voltage (LV) sensors to locate 11 kV unsymmetrical faults by monitoring and processing the network voltage profile during fault conditions. In particular, a novel technique has been developed which identifies the Faulted Section (FS) of the Medium Voltage (MV) feeder after a fault has occurred. The proposed algorithm, of which the successful operation depends solely on distributed LV voltage monitoring devices, represents the main contribution of the research work. A key characteristic is that, although the LV sensors connected at the secondary side of MV/LV step-down transformers require communication to transmit the data to a central point, they do not require time synchronisation. The technique facilitates the fault location procedure,which is of major importance as it accelerates restoration, reduces the system downtime, minimises repair cost, and hence, increases the overall availability and reliability of the distribution network. Moreover, the thesis deals with the challenges related to the complexity of modern distribution networks, taking into account ring topologies, MV lateral connections, pre-fault load unbalance and the presence of DERs. In this sense, the empirical characterisation of grid connection stability and fault response of small scale commercially available LV PV inverters was realised. The purpose was twofold: 1) highlight the diversity among the inverters’ responses as observed during the testing and indicate the risk of loss of PV generation during typical MV and HV level faults and 2) develop a dynamic model representing the behaviour of a real inverter under the applied physical testing conditions. The particular model was deployed in the power system studies conducted, aiding the evaluation of the FS location technique. Laboratory investigation was also carried out at the facilities of the Power Networks Demonstration Centre (PNDC) to further examine the performance of the developed faulted section location algorithm. The tests were performed in both MV radial and ring PNDC network configurations and measurements were acquired from various LV test-bays. It was demonstrated that the scheme can reliably identify the faulted section of the line while consistently maintaining high accuracy across a wide range of fault scenarios. Further sensitivity analysis demonstrates that the proposed scheme is robust against partial loss of communications and noise interference. The thesis concludes with an overview of future work that is required to further advance the concepts demonstrated.Distribution Network Operators (DNOs) face increasingly higher challenges to preserve quality and continuity of supply due to the widespread penetration of Distributed Energy Resources (DER) [1–8]. In parallel, more advanced technologies are being introduced into secondary substations for better observability and controllability. These features provided via instrumented substation assets and Information Communication Technologies (ICT) present opportunities for the development and implementation of new functions aiming to the effective operation and monitoring of active distribution networks [9–14]. This thesis focuses on one of these functionalities – that is, leveraging the ability of Low Voltage (LV) sensors to locate 11 kV unsymmetrical faults by monitoring and processing the network voltage profile during fault conditions. In particular, a novel technique has been developed which identifies the Faulted Section (FS) of the Medium Voltage (MV) feeder after a fault has occurred. The proposed algorithm, of which the successful operation depends solely on distributed LV voltage monitoring devices, represents the main contribution of the research work. A key characteristic is that, although the LV sensors connected at the secondary side of MV/LV step-down transformers require communication to transmit the data to a central point, they do not require time synchronisation. The technique facilitates the fault location procedure,which is of major importance as it accelerates restoration, reduces the system downtime, minimises repair cost, and hence, increases the overall availability and reliability of the distribution network. Moreover, the thesis deals with the challenges related to the complexity of modern distribution networks, taking into account ring topologies, MV lateral connections, pre-fault load unbalance and the presence of DERs. In this sense, the empirical characterisation of grid connection stability and fault response of small scale commercially available LV PV inverters was realised. The purpose was twofold: 1) highlight the diversity among the inverters’ responses as observed during the testing and indicate the risk of loss of PV generation during typical MV and HV level faults and 2) develop a dynamic model representing the behaviour of a real inverter under the applied physical testing conditions. The particular model was deployed in the power system studies conducted, aiding the evaluation of the FS location technique. Laboratory investigation was also carried out at the facilities of the Power Networks Demonstration Centre (PNDC) to further examine the performance of the developed faulted section location algorithm. The tests were performed in both MV radial and ring PNDC network configurations and measurements were acquired from various LV test-bays. It was demonstrated that the scheme can reliably identify the faulted section of the line while consistently maintaining high accuracy across a wide range of fault scenarios. Further sensitivity analysis demonstrates that the proposed scheme is robust against partial loss of communications and noise interference. The thesis concludes with an overview of future work that is required to further advance the concepts demonstrated
Earnings management, stakeholders and the impact of competition and political representation
Full text linkThis PhD thesis is comprised of three individual research papers, examines
issues around earnings management and its implications for firms and
stakeholders, and provides new insights on factors that drive or mitigate the
accounting practice of earnings management. In the second chapter, I examine
whether earnings management and managerial overconfidence are factors that
affect the relationship of the firm with its customers and employees.
Furthermore, I examine the incremental effect of managerial overconfidence
on the association between earnings management and stakeholder
relationships, focusing on customers and employees. I find that both earnings
management and managerial overconfidence improve the relationship between
the firm and its customers, while I find some evidence that they deteriorate the
relationship of the firm with its employees. I do not find evidence to suggest
that managerial overconfidence acts as a factor amplifying the association
between earnings management stakeholder relationships. The results remain
consistent in various robustness tests, including alternative measures,
instrumental variable regressions, and difference in differences approach. In
the third chapter, I assess whether product market competition amplifies the
negative relationship between ESG and earnings management. ESG
engagement on its own is effective in mitigating earnings management.
However, engagement in ESG practices is more important in limiting earnings
management by the firm when competition is high. Disclosing ESG related
information, irrespective of the actual ESG performance of the firm, also
reduces earnings management when competition is high as managers
voluntarily provide more information about the firm’s operations. In the fourth
chapter, I assess whether political representation amplifies the negative
relationship between ESG engagement and earnings management. I find that
when Democrats are in power as elected state governors, ESG engagement is
effective in mitigating earnings management, as the Democratic party places
more emphasis on ESG policies. A one standard deviation increase in ESG
score leads to a 0.79% reduction in firms’ earnings management when Democrats are in power. Moreover, engagement in ESG practices is a better hedge against earnings management for firms incorporated in states with governors from the Democratic party compared to Republican states. Results remain consistent when using the control of the Senate suggesting that political representation has a persistent effect on ESG practices across different government levels.This PhD thesis is comprised of three individual research papers, examines
issues around earnings management and its implications for firms and
stakeholders, and provides new insights on factors that drive or mitigate the
accounting practice of earnings management. In the second chapter, I examine
whether earnings management and managerial overconfidence are factors that
affect the relationship of the firm with its customers and employees.
Furthermore, I examine the incremental effect of managerial overconfidence
on the association between earnings management and stakeholder
relationships, focusing on customers and employees. I find that both earnings
management and managerial overconfidence improve the relationship between
the firm and its customers, while I find some evidence that they deteriorate the
relationship of the firm with its employees. I do not find evidence to suggest
that managerial overconfidence acts as a factor amplifying the association
between earnings management stakeholder relationships. The results remain
consistent in various robustness tests, including alternative measures,
instrumental variable regressions, and difference in differences approach. In
the third chapter, I assess whether product market competition amplifies the
negative relationship between ESG and earnings management. ESG
engagement on its own is effective in mitigating earnings management.
However, engagement in ESG practices is more important in limiting earnings
management by the firm when competition is high. Disclosing ESG related
information, irrespective of the actual ESG performance of the firm, also
reduces earnings management when competition is high as managers
voluntarily provide more information about the firm’s operations. In the fourth
chapter, I assess whether political representation amplifies the negative
relationship between ESG engagement and earnings management. I find that
when Democrats are in power as elected state governors, ESG engagement is
effective in mitigating earnings management, as the Democratic party places
more emphasis on ESG policies. A one standard deviation increase in ESG
score leads to a 0.79% reduction in firms’ earnings management when Democrats are in power. Moreover, engagement in ESG practices is a better hedge against earnings management for firms incorporated in states with governors from the Democratic party compared to Republican states. Results remain consistent when using the control of the Senate suggesting that political representation has a persistent effect on ESG practices across different government levels
The design, synthesis and optimisation of small molecule ERAP1 inhibitors
No full textPreviously held under moratorium in the Chemistry Department (GSK) from 1st February 2023 until 4th March 2025.
The confidentiality statement in this thesis does not apply.Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular
aminopeptidase based in the endoplasmic reticulum. Peptides are cleaved by ERAP1
then subsequently presented on the cell surface for signalling with the immune system.
Inhibition of ERAP1 modulates the adaptive immune response and therefore has
indications as a target for cancer or autoimmune diseases.
Described herein is the design and syntheses of three distinct chemical series, within
the hit to lead drug discovery stage, which inhibit ERAP1: the Benzazepine series,
Cyclohexyl Acid series and Proline series [see Table 1 in thesis]. These series were optimised in
terms of potency, physicochemical properties and ligand efficiencies. Structure-based
drug design, based on ERAP1 X-ray crystallography, was used as the primary tool to
optimise potency by achieving new protein-ligand interactions with ERAP1.
Physicochemical property optimisation was guided by literature best practices to
reduce the probability of developability risks such as poor solubility and high
metabolic clearance.
For the Benzazepine Series, although progress was achieved in terms of ERAP1
potency and physicochemical property optimisation, a data-driven decision was made
to pause the chemistry on the series due to the shortcomings of murine Endoplasmic
Reticulum Aminopeptidase Associated with Antigen Processing (ERAAP1) activity.
Progress was also made in the Proline series in terms of biochemical potency, but the
series generally showed poor cellular activity. For the Cyclohexyl Acid series, highly
ligand efficient examples in a desirable physicochemical property space were
developed, with several examples exhibiting subnanomolar cellular potency. Several
Cyclohexyl Acid compounds were tested against closely related enzymes Endoplasmic
Reticulum Aminopeptidase 2 (ERAP2) and Insulin-Regulated Aminopeptidase
(IRAP), and were found to be highly selective for ERAP1 over these other enzymes.
As a result of satisfying all project objectives, the Cyclohexyl Acid series transitioned
into Lead Optimisation for further development.Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular
aminopeptidase based in the endoplasmic reticulum. Peptides are cleaved by ERAP1
then subsequently presented on the cell surface for signalling with the immune system.
Inhibition of ERAP1 modulates the adaptive immune response and therefore has
indications as a target for cancer or autoimmune diseases.
Described herein is the design and syntheses of three distinct chemical series, within
the hit to lead drug discovery stage, which inhibit ERAP1: the Benzazepine series,
Cyclohexyl Acid series and Proline series [see Table 1 in thesis]. These series were optimised in
terms of potency, physicochemical properties and ligand efficiencies. Structure-based
drug design, based on ERAP1 X-ray crystallography, was used as the primary tool to
optimise potency by achieving new protein-ligand interactions with ERAP1.
Physicochemical property optimisation was guided by literature best practices to
reduce the probability of developability risks such as poor solubility and high
metabolic clearance.
For the Benzazepine Series, although progress was achieved in terms of ERAP1
potency and physicochemical property optimisation, a data-driven decision was made
to pause the chemistry on the series due to the shortcomings of murine Endoplasmic
Reticulum Aminopeptidase Associated with Antigen Processing (ERAAP1) activity.
Progress was also made in the Proline series in terms of biochemical potency, but the
series generally showed poor cellular activity. For the Cyclohexyl Acid series, highly
ligand efficient examples in a desirable physicochemical property space were
developed, with several examples exhibiting subnanomolar cellular potency. Several
Cyclohexyl Acid compounds were tested against closely related enzymes Endoplasmic
Reticulum Aminopeptidase 2 (ERAP2) and Insulin-Regulated Aminopeptidase
(IRAP), and were found to be highly selective for ERAP1 over these other enzymes.
As a result of satisfying all project objectives, the Cyclohexyl Acid series transitioned
into Lead Optimisation for further development
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