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Metabolomic modelling and applications in inflammatory bowel diseases
Get PDFBackground: Metabolomics experiments typically produce high dimensional data and its handling is an extremely important step in data pre-treatment. Metabolomics is an indispensable research tool for the identification and tracking of biomarkers in biological systems. In a typical metabolomics study, complex extracts or body fluids are analysed and compared by various methods to generate metabolic fingerprints. Crohn's Disease (CD) and ulcerative colitis (UC) are major components of Inflammatory Bowel Disease (IBD), a multifactorial disorder most likely resulting from altered immune response to commensal or pathogenic gut microbes under the influence of environmental factors, such as diet. Exclusive Enteral Nutrition (EEN) is the most common treatment for paediatric CD in the UK and the rest of Europe. Non-invasive metabolomics approaches could be used to diagnose and differentiate between related diseases. This could enhance disease control, management and patient compliance. It is known that gut microbiota may discriminate IBD subtypes from each other, therefore, metabolomics of faecal extracts was used to examine metabolites in faeces many of which result from the activity of gut microbiota and thus to differentiate between IBD subtypes and healthy controls as well as within IBD subtypes.;Methodology: This study investigated the effect of pre-treatment strategies on data set derived from LC-MS based metabolomics experiments. Different methods of imputing missing values were examined in conjugation with various scaling and transformation methods. SIMCA-P 14 was used to evaluate the model parameters for each pre-treatment method.In this thesis, metabolomics was employed in various studies to assess metabolite biomarkers associated with healthy controls and IBD diseases. All the studies employed liquid chromatography-mass spectrometry (LC-MS) on an Orbitrap Exactive mass analyser, and using ZIC-pHILIC or/and C18 analytical columns. Data was acquired using XCalibur software and metabolite identification was ascertained based on accurate mass detection, retention time comparisons with authentic external standards, and database searching. The acquired data was analysed using both unsupervised (PCA-X) and supervised (OPLS-DA) models in SIMCA in order to determine discriminating metabolite biomarkers responsible for the observed clustering patterns.;Results: Compared to the various imputation methods used in this study, NIPALS algorithm along with suitable transformation and scaling was significantly better according to the model parameter evaluation Pareto (Par) as scaling and Log transformation were better able to explain the data. The OPLS-DA model was able to discriminate the CD samples from the controls at different time points after the commencement of treatment .The models were not able to differentiate the CD samples from one another at the different time points during treatment with exclusive enteral nutrition. The metabolites identified in the CD samples which varied between CD samples and controls included tyrosine, an ornithine isomer, arachidonic acid, eicosatrienoic acid, docosatetraenoic acid, a sphingomyelin, a ceramide, and dimethylsphinganine. Similarly, the OPLS-DA model was able to discriminate the CD samples from the UC. Based on VIP values, the top 10 metabolites were used in the OPLS-DA model, and there was a clear separation between CD and UC with p CV-ANOVA = 5.30541e-007.Conclusion: The SIMCA-P 14's (NIPALS) default logarithm was the only imputation methodology that generated a valid model according to valid criteria (R2-Q2<0.3). This was in conjugation with Pareto scaling in conjugation with Log transformation were the best data pre-treatment methodology. Despite successful treatment, underlying differences remained in the metabolome of the CD patients. Untargeted metabolomics analysis was also performed to classify the faecal extracts from patients suffering from different inflammatory bowel diseases to evaluate the use of this technique as a diagnostic tool and categorize specific metabolites in the faecal extract of participants with specific types of inflammation.Background: Metabolomics experiments typically produce high dimensional data and its handling is an extremely important step in data pre-treatment. Metabolomics is an indispensable research tool for the identification and tracking of biomarkers in biological systems. In a typical metabolomics study, complex extracts or body fluids are analysed and compared by various methods to generate metabolic fingerprints. Crohn's Disease (CD) and ulcerative colitis (UC) are major components of Inflammatory Bowel Disease (IBD), a multifactorial disorder most likely resulting from altered immune response to commensal or pathogenic gut microbes under the influence of environmental factors, such as diet. Exclusive Enteral Nutrition (EEN) is the most common treatment for paediatric CD in the UK and the rest of Europe. Non-invasive metabolomics approaches could be used to diagnose and differentiate between related diseases. This could enhance disease control, management and patient compliance. It is known that gut microbiota may discriminate IBD subtypes from each other, therefore, metabolomics of faecal extracts was used to examine metabolites in faeces many of which result from the activity of gut microbiota and thus to differentiate between IBD subtypes and healthy controls as well as within IBD subtypes.;Methodology: This study investigated the effect of pre-treatment strategies on data set derived from LC-MS based metabolomics experiments. Different methods of imputing missing values were examined in conjugation with various scaling and transformation methods. SIMCA-P 14 was used to evaluate the model parameters for each pre-treatment method.In this thesis, metabolomics was employed in various studies to assess metabolite biomarkers associated with healthy controls and IBD diseases. All the studies employed liquid chromatography-mass spectrometry (LC-MS) on an Orbitrap Exactive mass analyser, and using ZIC-pHILIC or/and C18 analytical columns. Data was acquired using XCalibur software and metabolite identification was ascertained based on accurate mass detection, retention time comparisons with authentic external standards, and database searching. The acquired data was analysed using both unsupervised (PCA-X) and supervised (OPLS-DA) models in SIMCA in order to determine discriminating metabolite biomarkers responsible for the observed clustering patterns.;Results: Compared to the various imputation methods used in this study, NIPALS algorithm along with suitable transformation and scaling was significantly better according to the model parameter evaluation Pareto (Par) as scaling and Log transformation were better able to explain the data. The OPLS-DA model was able to discriminate the CD samples from the controls at different time points after the commencement of treatment .The models were not able to differentiate the CD samples from one another at the different time points during treatment with exclusive enteral nutrition. The metabolites identified in the CD samples which varied between CD samples and controls included tyrosine, an ornithine isomer, arachidonic acid, eicosatrienoic acid, docosatetraenoic acid, a sphingomyelin, a ceramide, and dimethylsphinganine. Similarly, the OPLS-DA model was able to discriminate the CD samples from the UC. Based on VIP values, the top 10 metabolites were used in the OPLS-DA model, and there was a clear separation between CD and UC with p CV-ANOVA = 5.30541e-007.Conclusion: The SIMCA-P 14's (NIPALS) default logarithm was the only imputation methodology that generated a valid model according to valid criteria (R2-Q2<0.3). This was in conjugation with Pareto scaling in conjugation with Log transformation were the best data pre-treatment methodology. Despite successful treatment, underlying differences remained in the metabolome of the CD patients. Untargeted metabolomics analysis was also performed to classify the faecal extracts from patients suffering from different inflammatory bowel diseases to evaluate the use of this technique as a diagnostic tool and categorize specific metabolites in the faecal extract of participants with specific types of inflammation
Understanding teachers' attitudes towards students with immigrant backgrounds in Italy : identities, policies and pedagogies
Get PDFThis thesis was previously held under moratorium from 28th November 2019 until 28th November 2024.This qualitative study analyses how teachers’ and head teachers’ identities shape their dispositions towards pupils with immigrant backgrounds in Italy, and how their understanding of Italian education policies inform their beliefs about pedagogical practices for pupils with immigrant backgrounds. In considering identity, this study takes an intersectional approach, focusing on social class, gender and ethnicity as aspects that interact and shape life experiences. Bourdieu’s concepts of habitus, field and capital, together with Butler’s concept of performativity, help theorise how teachers and head teachers take up and understand classed, gendered, and ethnicised identities. Data collection is based on semi-structured interviews with 23 participants, 9 males and 14 females, with ages ranging from 36 to 65. The findings highlight a general lack of explicit reflection on class, gender and ethnicity by teachers and head teachers. An unequivocal link between their identity and how they position their students cannot be straightforwardly established. However, notions of (not)belonging circulate around and are attached to students with immigrant backgrounds. Such circulations coalesce around values and practices linked to gendered, ethnic majority middle class habitus norms, through which difference is positioned and opposed in hierarchical terms. The background neoliberal ideology is normalised and permeates the educational environment. This study aims to analyse the relationship between teachers’ identities and their attitudes and pedagogic dispositions towards students with immigrant backgrounds in the Italian context, showing how these contribute to their state of (non)belonging in the educational setting and indeed in the wider society. This investigation also highlights the difficulties and subtleties of talking about ethnicity and cultural difference alongside professional identities. This research considers teachers’ pedagogic dispositions and highlights some practical consequences and implications. Such considerations are extended to recommendations and suggestions for future research.This qualitative study analyses how teachers’ and head teachers’ identities shape their dispositions towards pupils with immigrant backgrounds in Italy, and how their understanding of Italian education policies inform their beliefs about pedagogical practices for pupils with immigrant backgrounds. In considering identity, this study takes an intersectional approach, focusing on social class, gender and ethnicity as aspects that interact and shape life experiences. Bourdieu’s concepts of habitus, field and capital, together with Butler’s concept of performativity, help theorise how teachers and head teachers take up and understand classed, gendered, and ethnicised identities. Data collection is based on semi-structured interviews with 23 participants, 9 males and 14 females, with ages ranging from 36 to 65. The findings highlight a general lack of explicit reflection on class, gender and ethnicity by teachers and head teachers. An unequivocal link between their identity and how they position their students cannot be straightforwardly established. However, notions of (not)belonging circulate around and are attached to students with immigrant backgrounds. Such circulations coalesce around values and practices linked to gendered, ethnic majority middle class habitus norms, through which difference is positioned and opposed in hierarchical terms. The background neoliberal ideology is normalised and permeates the educational environment. This study aims to analyse the relationship between teachers’ identities and their attitudes and pedagogic dispositions towards students with immigrant backgrounds in the Italian context, showing how these contribute to their state of (non)belonging in the educational setting and indeed in the wider society. This investigation also highlights the difficulties and subtleties of talking about ethnicity and cultural difference alongside professional identities. This research considers teachers’ pedagogic dispositions and highlights some practical consequences and implications. Such considerations are extended to recommendations and suggestions for future research
Ultra-slow dynamics of localised modes in the discrete nonlinear Schrödinger equation
Get PDFThe work presented in this thesis focuses on the ultra-slow dynamics of localised modes (breathers) for the Discrete Nonlinear Schrödinger Equation (DNLSE), and on the mechanisms which trigger their astronomically slow decays.The thesis starts with a literature review of breathers and the DNLSE, giving information about the theoretical background of the project. It then continues with a description of the numerical methods used throughout the project, and of the general behaviour of the DNLSE under numerical integration.Discrete breathers in Bose-Einstein Condensates in optical lattices or in arrays of optical wave-guides oscillate with frequencies which are much higher than those present in the spectrum of the background. Hence, the interaction between localized breathers and their surroundings is extremely weak, allowing the development of a multiple-time scale perturbation expansion, which is presented in Chapter 4. This analysis will predict a lower bound of the breather drift times and will explain the topological differences between breathers in dimers, trimers and in spatially extended one-dimensional lattices even in the presence of transport from boundary heat baths.These analytical boundaries hold true for lattices of any length, due to the highly localised nature of breathers.We later look closer at the exceedingly slow thermalisation occurring in the DNLSE.We provide evidence that the breather norm is an adiabatic invariant, and this freezes the dynamics of a tall breather. Consequently, relaxation proceeds via rare events,where energy is suddenly released towards the background. A more detailed investigation of these events is provided in Chapter 5.In Chapter 6, a Heterogeneous Multiscale Method is introduced. We take advantage of the fast frequency of the breather oscillation to perform averaging, and to build a numerical integrator which behaves similarly to a predictor-corrector propagator,speeding up the running times by a factor of at least 5.The work presented in this thesis focuses on the ultra-slow dynamics of localised modes (breathers) for the Discrete Nonlinear Schrödinger Equation (DNLSE), and on the mechanisms which trigger their astronomically slow decays.The thesis starts with a literature review of breathers and the DNLSE, giving information about the theoretical background of the project. It then continues with a description of the numerical methods used throughout the project, and of the general behaviour of the DNLSE under numerical integration.Discrete breathers in Bose-Einstein Condensates in optical lattices or in arrays of optical wave-guides oscillate with frequencies which are much higher than those present in the spectrum of the background. Hence, the interaction between localized breathers and their surroundings is extremely weak, allowing the development of a multiple-time scale perturbation expansion, which is presented in Chapter 4. This analysis will predict a lower bound of the breather drift times and will explain the topological differences between breathers in dimers, trimers and in spatially extended one-dimensional lattices even in the presence of transport from boundary heat baths.These analytical boundaries hold true for lattices of any length, due to the highly localised nature of breathers.We later look closer at the exceedingly slow thermalisation occurring in the DNLSE.We provide evidence that the breather norm is an adiabatic invariant, and this freezes the dynamics of a tall breather. Consequently, relaxation proceeds via rare events,where energy is suddenly released towards the background. A more detailed investigation of these events is provided in Chapter 5.In Chapter 6, a Heterogeneous Multiscale Method is introduced. We take advantage of the fast frequency of the breather oscillation to perform averaging, and to build a numerical integrator which behaves similarly to a predictor-corrector propagator,speeding up the running times by a factor of at least 5
Exploring leadership as it is expressed within professional rugby : the application of Merleau-Ponty's sensual ontology of flesh to organisational practice
No full textThis thesis centres on the practice turn, specifically leadership-as-practice (LAP). It draws on a phenomenological lineage in order to expand LAP's ambition to grasp leadership empirically. The thesis argues that to ward off regurgitating realist assumptions as we conduct our methodology, it may be useful to direct our philosophical endeavours at how the body is understood during empirical inquiries. The body, however, is a problematic concept within the social sciences, often depicted as a distinct, bounded, entity with the result a 'disembodied' gaze onto leadership. The research questions therefore whether an alternative philosophy of the body may better inform how researchers get a feel for leadership in practice.To embrace this alternative, the thesis turns to Maurice Merleau-Ponty's reversible ontology of flesh. This philosophy illustrates how body and world continually co-create each other. Furthermore, such corporeality paves the way for an epistemology of sensual expression which identifies knowledge as emerging from this reversible creation. In order to elaborate on this 'fleshy'frame, the research draws on sociological and anthropological literature to sensually 'reawaken' the scholar's body within the 'thick' of practice. The thesis utilises this framework to re-envisage ethnography from a realist,bounded, perspective to a sensory, emplaced, affair. The ethnography culminates by providing six sensual depictions of leadership within Hibernia, a professional rugby team. Through these depictions we can empirically understand LAP as a 'sensuous intoxication',displayed through three corporeal lenses that explore leadership: the situated body; the emotional body; and the physical body. These lenses respectively inform the expression of leadership as: coproduced through lines of site/sight; a deeply felt (e)motional engagement; and as a manner of communal orientation. The thesis closes by detailing the key empirical features of such sensuous intoxication and how it contributes towards a practice approach.This thesis centres on the practice turn, specifically leadership-as-practice (LAP). It draws on a phenomenological lineage in order to expand LAP's ambition to grasp leadership empirically. The thesis argues that to ward off regurgitating realist assumptions as we conduct our methodology, it may be useful to direct our philosophical endeavours at how the body is understood during empirical inquiries. The body, however, is a problematic concept within the social sciences, often depicted as a distinct, bounded, entity with the result a 'disembodied' gaze onto leadership. The research questions therefore whether an alternative philosophy of the body may better inform how researchers get a feel for leadership in practice.To embrace this alternative, the thesis turns to Maurice Merleau-Ponty's reversible ontology of flesh. This philosophy illustrates how body and world continually co-create each other. Furthermore, such corporeality paves the way for an epistemology of sensual expression which identifies knowledge as emerging from this reversible creation. In order to elaborate on this 'fleshy'frame, the research draws on sociological and anthropological literature to sensually 'reawaken' the scholar's body within the 'thick' of practice. The thesis utilises this framework to re-envisage ethnography from a realist,bounded, perspective to a sensory, emplaced, affair. The ethnography culminates by providing six sensual depictions of leadership within Hibernia, a professional rugby team. Through these depictions we can empirically understand LAP as a 'sensuous intoxication',displayed through three corporeal lenses that explore leadership: the situated body; the emotional body; and the physical body. These lenses respectively inform the expression of leadership as: coproduced through lines of site/sight; a deeply felt (e)motional engagement; and as a manner of communal orientation. The thesis closes by detailing the key empirical features of such sensuous intoxication and how it contributes towards a practice approach
Structural vibration control of fixed offshore wind foundations
Get PDFDue to the high flexibility of new offshore wind turbines (OWT) and dynamic content of the loading from wind, wave and earthquake applied to OWT systems, they are prone to excessive vibrations and this may result in serviceability issues as well as low fatigue lives of structural members. Therefore, control systems capable of mitigating undesired vibrations can help to reduce serviceability issues and increase fatigue lives. In this research, numerical models of jacket and monopile OWTs are developed and the effect of different types of vibration control devices such as Tuned Mass Dampers (TMDs) and Tuned Liquid Columns Dampers (TLCDs) on the dynamic responses of OWTs under various loadings is investigated. The dynamic responses are compared with those of the baseline system in which no vibration control device is used. Then, fragility analysis based on Multiple Stripe Analysis is performed to estimate the fragility reduction due to the implementation of vibration control devices. Different limit states for different equipment inside the nacelle are considered in the fragility analysis. The results show that the fragility reduction offered by the tuned liquid column dampers is higher for low-intensity earthquakes. In addition, the corresponding values for the parked condition are greater due to the lack of aerodynamic damping in this condition.;Therefore, the implementation of an optimal TLCD can increase the overall reliability of the system, especially for parked conditions under low-intensity earthquake motions. Then a model for offshore wind turbine systems equipped with a semi-active time-variant tuned mass damper is developed considering nonlinear soil-pile interaction phenomenon and time-variant damage conditions. The adaptive concept of this tuned mass damper assumes a slow change in its structural properties. Stochastic wind and wave loadings in conjunction with ground motions are applied to the system. Damages to soil and tower caused by earthquake strokes are considered and the semi-active control device is retuned to the instantaneous frequency of the system using short-time Fourier transformation (STFT). The performance of semi-active time-variant vibration control is compared with its passive counterpart in operational and parked conditions. The results show that a semi-active mass damper with a mass ratio of 1% performs significantly better than a passive tuned mass damper with a mass ratio of 4%.Due to the high flexibility of new offshore wind turbines (OWT) and dynamic content of the loading from wind, wave and earthquake applied to OWT systems, they are prone to excessive vibrations and this may result in serviceability issues as well as low fatigue lives of structural members. Therefore, control systems capable of mitigating undesired vibrations can help to reduce serviceability issues and increase fatigue lives. In this research, numerical models of jacket and monopile OWTs are developed and the effect of different types of vibration control devices such as Tuned Mass Dampers (TMDs) and Tuned Liquid Columns Dampers (TLCDs) on the dynamic responses of OWTs under various loadings is investigated. The dynamic responses are compared with those of the baseline system in which no vibration control device is used. Then, fragility analysis based on Multiple Stripe Analysis is performed to estimate the fragility reduction due to the implementation of vibration control devices. Different limit states for different equipment inside the nacelle are considered in the fragility analysis. The results show that the fragility reduction offered by the tuned liquid column dampers is higher for low-intensity earthquakes. In addition, the corresponding values for the parked condition are greater due to the lack of aerodynamic damping in this condition.;Therefore, the implementation of an optimal TLCD can increase the overall reliability of the system, especially for parked conditions under low-intensity earthquake motions. Then a model for offshore wind turbine systems equipped with a semi-active time-variant tuned mass damper is developed considering nonlinear soil-pile interaction phenomenon and time-variant damage conditions. The adaptive concept of this tuned mass damper assumes a slow change in its structural properties. Stochastic wind and wave loadings in conjunction with ground motions are applied to the system. Damages to soil and tower caused by earthquake strokes are considered and the semi-active control device is retuned to the instantaneous frequency of the system using short-time Fourier transformation (STFT). The performance of semi-active time-variant vibration control is compared with its passive counterpart in operational and parked conditions. The results show that a semi-active mass damper with a mass ratio of 1% performs significantly better than a passive tuned mass damper with a mass ratio of 4%
Multi-objective robust early stage ship design optimisation under uncertainty
Get PDFShipping industry has become very competitive, while a lot of research is carried out in the shipbuilding world to investigate possible ways to improve ship design and create efficient and economical ships. Technological improvements allow the detailed exploration of design space and assist the theory of optimisation in becoming a vital part of ship design. Advanced software tools are available to designers and researchers to expand their design optimisation methodologies and introduce not only more efficient techniques, but also more robust approaches to ship design.The topic of ship design optimisation has been investigated by numerous researchers, who have established structured methodologies which can be applied to real case studies and produce efficient solutions to the ship design problem. However, the definition of the ship design problem changes often due to the introduction of new ship types, international regulations and technological improvements.This thesis contributes to the aforementioned developments with regard to the ship design optimisation problem. The mission is to develop a methodology for a multi-objective robust early stage ship design optimisation under uncertainty. Several aspects of ship design are incorporated, taking into account the holistic ship design model. Various performance indicators are used as measures of merit to evaluate the response of possible solutions to the problem. New regulations are incorporated to the optimisation problem, investigating their impact on its solution. In addition, uncertainty quantification is applied throughout the proposed methodology, while its effect on the ship design optimisation problem is examined.Shipping industry has become very competitive, while a lot of research is carried out in the shipbuilding world to investigate possible ways to improve ship design and create efficient and economical ships. Technological improvements allow the detailed exploration of design space and assist the theory of optimisation in becoming a vital part of ship design. Advanced software tools are available to designers and researchers to expand their design optimisation methodologies and introduce not only more efficient techniques, but also more robust approaches to ship design.The topic of ship design optimisation has been investigated by numerous researchers, who have established structured methodologies which can be applied to real case studies and produce efficient solutions to the ship design problem. However, the definition of the ship design problem changes often due to the introduction of new ship types, international regulations and technological improvements.This thesis contributes to the aforementioned developments with regard to the ship design optimisation problem. The mission is to develop a methodology for a multi-objective robust early stage ship design optimisation under uncertainty. Several aspects of ship design are incorporated, taking into account the holistic ship design model. Various performance indicators are used as measures of merit to evaluate the response of possible solutions to the problem. New regulations are incorporated to the optimisation problem, investigating their impact on its solution. In addition, uncertainty quantification is applied throughout the proposed methodology, while its effect on the ship design optimisation problem is examined
A chemical probe for TIGAR
Get PDFThe University of Strathclyde has established a partnership with the Beatson Institute to initiate this multidisciplinary project, bringing together three academic researchers; Prof. Nick Tomkinson (Chemistry), Dr Blair Johnston (Modelling) and Prof. Karen Vousden (Biology). The project primarily applied a standard SAR approach following the design, target synthesis, biological evaluation and data analysis cycle, to develop a chemical probe for the emerging tumour suppression target, TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR). Upon optimisation, these tool compounds were then used to dissect the fundamental biology associated with this target, specifically in cancer models developed within the Vousden laboratory.The phosphatase TIGAR plays a key role in the flow of metabolites within two key biological pathways; glycolysis and the pentose phosphate pathway (PPP). The regulation of these pathways is crucial for the stability and growth of cancer cells,which highlighted TIGAR as a potential therapeutic target. Currently, there are no chemical tools for the interrogation of TIGAR, and its downstream functional effects.Here, a novel series of 2-amino thiophene-3-cabomate benzoic acid derivatives were designed, synthesised, and biologically evaluated, as potential TIGAR inhibitors. A summary of the optimisation achieved during the SAR studies is highlighted in Figure 1, from initial hit compound 58 to lead compound 338. Ligand 338 exhibited a half-maximal inhibitory concentration in the nanomolar range. Pharmacokinetic studies demonstrated that 338 possessed a sufficiently robust PK profile for potential use within in vivo studies. The selectivity and cellular activity of lead compound 338 has yet to be tested, however, compound 184 exhibited a promising selectivity profile and phenocopied the effects of siRNA in cell based studies.The University of Strathclyde has established a partnership with the Beatson Institute to initiate this multidisciplinary project, bringing together three academic researchers; Prof. Nick Tomkinson (Chemistry), Dr Blair Johnston (Modelling) and Prof. Karen Vousden (Biology). The project primarily applied a standard SAR approach following the design, target synthesis, biological evaluation and data analysis cycle, to develop a chemical probe for the emerging tumour suppression target, TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR). Upon optimisation, these tool compounds were then used to dissect the fundamental biology associated with this target, specifically in cancer models developed within the Vousden laboratory.The phosphatase TIGAR plays a key role in the flow of metabolites within two key biological pathways; glycolysis and the pentose phosphate pathway (PPP). The regulation of these pathways is crucial for the stability and growth of cancer cells,which highlighted TIGAR as a potential therapeutic target. Currently, there are no chemical tools for the interrogation of TIGAR, and its downstream functional effects.Here, a novel series of 2-amino thiophene-3-cabomate benzoic acid derivatives were designed, synthesised, and biologically evaluated, as potential TIGAR inhibitors. A summary of the optimisation achieved during the SAR studies is highlighted in Figure 1, from initial hit compound 58 to lead compound 338. Ligand 338 exhibited a half-maximal inhibitory concentration in the nanomolar range. Pharmacokinetic studies demonstrated that 338 possessed a sufficiently robust PK profile for potential use within in vivo studies. The selectivity and cellular activity of lead compound 338 has yet to be tested, however, compound 184 exhibited a promising selectivity profile and phenocopied the effects of siRNA in cell based studies
Structural integrity assessment of engineering components under cyclic loading at high temperature
Get PDFStructural integrity assessment is essential for many industries, especially for industries which have machinery components and structures in operation at high temperature. Nuclear power plant industry is one of a good example, and they have planned to introduce the very high temperature reactor to increase efficiency. The high temperature operations may improve power productions but cause severe structural problems due to creep, fatigue, creep-fatigue failure mechanisms. Hence, performing structural integrity assessment accurately and developing effective assessment methods are vital tasks in these industries.;In order to contribute to the research field of the high temperature industries, this thesis have achieved the following three main objectives:;Firstly, this thesis provides insights into cyclic plasticity and creep-cyclic plasticity behaviours of high temperature engineering problems which have not been explored in the past. A numerical study investigates cyclic plasticity behaviours of 90° back-to-back pipe bends under cyclic thermo-mechanical load and constant pressure. Another numerical study investigates creep-cyclic plasticity behaviours of Particle Reinforced Titanium Matrix Composites (PRTMCs), which is a futuristic engineering material, subjected to a cyclic thermo-mechanical load. Both numerical studies are carried out using a novel direct method called The LMM Framework;Secondly, this thesis has enhanced the LMM Framework allowing to evaluate the structural response in non-isothermal condition and multiple dwell periods. In order to demonstrate this, the extended method is applied to analyse creep-cyclic plasticity behaviour of a superheater outlet tube plate subjected to a cyclic thermo-mechanical load, and to evaluate creep-fatigue damage endurance;Finally, this thesis introduces a critical high temperature failure mechanism, named as Structural Creep Recovery Mechanism (SCRM), utilising a numerical technique involving cyclic creep and plastic behaviours. This study identifies the cause of this critical failure mechanism and defines factors that have substantial influences on the structural integrity in the presence of SCRM. Chaboche nonlinear kinematic hardening model and temperature dependent material parameters are employed to demonstrate the effectiveness of SCRM in practical problems.Structural integrity assessment is essential for many industries, especially for industries which have machinery components and structures in operation at high temperature. Nuclear power plant industry is one of a good example, and they have planned to introduce the very high temperature reactor to increase efficiency. The high temperature operations may improve power productions but cause severe structural problems due to creep, fatigue, creep-fatigue failure mechanisms. Hence, performing structural integrity assessment accurately and developing effective assessment methods are vital tasks in these industries.;In order to contribute to the research field of the high temperature industries, this thesis have achieved the following three main objectives:;Firstly, this thesis provides insights into cyclic plasticity and creep-cyclic plasticity behaviours of high temperature engineering problems which have not been explored in the past. A numerical study investigates cyclic plasticity behaviours of 90° back-to-back pipe bends under cyclic thermo-mechanical load and constant pressure. Another numerical study investigates creep-cyclic plasticity behaviours of Particle Reinforced Titanium Matrix Composites (PRTMCs), which is a futuristic engineering material, subjected to a cyclic thermo-mechanical load. Both numerical studies are carried out using a novel direct method called The LMM Framework;Secondly, this thesis has enhanced the LMM Framework allowing to evaluate the structural response in non-isothermal condition and multiple dwell periods. In order to demonstrate this, the extended method is applied to analyse creep-cyclic plasticity behaviour of a superheater outlet tube plate subjected to a cyclic thermo-mechanical load, and to evaluate creep-fatigue damage endurance;Finally, this thesis introduces a critical high temperature failure mechanism, named as Structural Creep Recovery Mechanism (SCRM), utilising a numerical technique involving cyclic creep and plastic behaviours. This study identifies the cause of this critical failure mechanism and defines factors that have substantial influences on the structural integrity in the presence of SCRM. Chaboche nonlinear kinematic hardening model and temperature dependent material parameters are employed to demonstrate the effectiveness of SCRM in practical problems
Should the misappropriation of trade secrets be a criminal offence in Oman? : a comparative analysis with England and the United States
Get PDFThis thesis was previously held under moratorium from 27th November 2019 until 27th November 2024.This study considers the criminalisation of the misappropriation of trade secrets, which is conceptualised primarily as the dishonest acquisition, disclosure or use of the confidential commercial information of another. This consideration of the criminalisation question is generated mainly by the situation in Oman, the case in point. While the economic importance of trade secrets is substantial and the threat of misappropriation is serious, the Omani legal system currently provides only very limited civil protection for individuals and enterprises against the very real problem of the misappropriation of industrial and commercial information. An examination of the present civil remedies relating to the protection of trade secrets leads to the conclusion that these civil solutions are not adequate for Oman because of either the economic efficiency of the civil law itself, or its application and enforcement in Oman. It would remain inappropriate even if remedies were made widely available because Oman lacks sufficient deterrents for less affluent defendants and wealthy corporations. Arguably, a criminal law intervention could overcome many of the deficiencies in the civil law and could provide the necessary deterrent. However, the criminalisation solution still provokes significant academic and political controversy. Certainly, the criminal law is not an alternative tool that could be used lightly; rather its possible use requires plausible justifications. This study examines the case for criminalising trade secret misappropriation based on the interference with proprietary information, economic harm, and commercial immorality. This three-fold normative paradigm contributes to the scant literature on the criminalisation of trade secret misappropriation. Equally, the study is an original contribution to the development of an effective trade secrecy law in Oman, as it presents a new proposal for reform that is based on a comparative analysis with England and the United States. More importantly, the proposed criminal reform is Sharia-compliant and consistent with the social and economic conditions of Oman.This study considers the criminalisation of the misappropriation of trade secrets, which is conceptualised primarily as the dishonest acquisition, disclosure or use of the confidential commercial information of another. This consideration of the criminalisation question is generated mainly by the situation in Oman, the case in point. While the economic importance of trade secrets is substantial and the threat of misappropriation is serious, the Omani legal system currently provides only very limited civil protection for individuals and enterprises against the very real problem of the misappropriation of industrial and commercial information. An examination of the present civil remedies relating to the protection of trade secrets leads to the conclusion that these civil solutions are not adequate for Oman because of either the economic efficiency of the civil law itself, or its application and enforcement in Oman. It would remain inappropriate even if remedies were made widely available because Oman lacks sufficient deterrents for less affluent defendants and wealthy corporations. Arguably, a criminal law intervention could overcome many of the deficiencies in the civil law and could provide the necessary deterrent. However, the criminalisation solution still provokes significant academic and political controversy. Certainly, the criminal law is not an alternative tool that could be used lightly; rather its possible use requires plausible justifications. This study examines the case for criminalising trade secret misappropriation based on the interference with proprietary information, economic harm, and commercial immorality. This three-fold normative paradigm contributes to the scant literature on the criminalisation of trade secret misappropriation. Equally, the study is an original contribution to the development of an effective trade secrecy law in Oman, as it presents a new proposal for reform that is based on a comparative analysis with England and the United States. More importantly, the proposed criminal reform is Sharia-compliant and consistent with the social and economic conditions of Oman
Exploring the extent and nature of principal-agent theory in charitable organisations
Get PDFThis thesis was previously held under moratorium from 13/06/2019 to 13/06/2024The non-profit sector is seeing increased attention in academic accounting literature. Recent papers have sought to examine the relevance of principal-agent theory to the sector, in contrast to its more traditional, for-profit context. Here, this dialogue is continued with an examination of principal-agent theory in Scottish charitable organisations. Agency, stewardship and stakeholder theories, together with social entrepreneurship and entrepreneurial orientation are examined, in order to gain greater understanding of charitable organisations.This study is comprised of two interview stages held with representatives from traditional charities. The first, unstructured stage, along with the literature review, serves to determine the key issues facing the sector. From this, four research questions are outlined. These research questions are considered in relation to the second, semi-structured interview stage. The developed research questions address the balancing of social and financial objectives, charity accountability, the extent and nature of social entrepreneurship and the usefulness of entrepreneurial thinking.The subsequent analysis takes four separate ‘components’ of principal-agent theory and social entrepreneurship, each corresponding to one of the four developed research questions. The analysis from this research finds conflicting evidence relating to the relevance, or importance, of agency and stewardship towards social entrepreneurship. Key concepts of social entrepreneurship, including risk, innovation and personal ambition, are found to be strengths of agency orientated individuals. By contrast, blended value and a heightened sense of accountability are found to be strengths of stewardship orientated individuals. This study takes inspiration from this previous research in order to develop a unique analytical framework that incorporates a number of existing concepts and theories. The conclusion that can be drawn from is that principal-agent theory can offer insight into the charity sector and can act as a facilitating framework through which we can examine the individuals and relationships that exist.The non-profit sector is seeing increased attention in academic accounting literature. Recent papers have sought to examine the relevance of principal-agent theory to the sector, in contrast to its more traditional, for-profit context. Here, this dialogue is continued with an examination of principal-agent theory in Scottish charitable organisations. Agency, stewardship and stakeholder theories, together with social entrepreneurship and entrepreneurial orientation are examined, in order to gain greater understanding of charitable organisations.This study is comprised of two interview stages held with representatives from traditional charities. The first, unstructured stage, along with the literature review, serves to determine the key issues facing the sector. From this, four research questions are outlined. These research questions are considered in relation to the second, semi-structured interview stage. The developed research questions address the balancing of social and financial objectives, charity accountability, the extent and nature of social entrepreneurship and the usefulness of entrepreneurial thinking.The subsequent analysis takes four separate ‘components’ of principal-agent theory and social entrepreneurship, each corresponding to one of the four developed research questions. The analysis from this research finds conflicting evidence relating to the relevance, or importance, of agency and stewardship towards social entrepreneurship. Key concepts of social entrepreneurship, including risk, innovation and personal ambition, are found to be strengths of agency orientated individuals. By contrast, blended value and a heightened sense of accountability are found to be strengths of stewardship orientated individuals. This study takes inspiration from this previous research in order to develop a unique analytical framework that incorporates a number of existing concepts and theories. The conclusion that can be drawn from is that principal-agent theory can offer insight into the charity sector and can act as a facilitating framework through which we can examine the individuals and relationships that exist
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