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Giving back or fighting back? A transatlantic, qualitative study exploring citizenship, social movement learning and mental health
Get PDFThis transatlantic, qualitative study privileges how people with lived experience of mental health issues conceptualise the intersections between mental health, citizenship, and education. Using a Mad Studies lens and drawing from the bricolage tradition of emancipatory research, this study aims to understand what role social movement learning has in facilitating collective or political agency. A range of qualitative and collaborative methods were used, including oral history interviews and arts-based methods. Thematic analysis and NVivo software were used to analyse the qualitative material.;Findings suggest two very different types of social movement learning occurring as well as contrasting journeys towards collective, or political agency. In Scotland, there was evidence of a directive and intentional form of social movement learning. In the US, a new pedagogical space was identified, through contact with social movement activities and actors, resulting in a more situated form of learning through action or learning in the struggle. Themes of the relational, validation and love are identified as important for developing collective identity as well as collective and political agency. Findings also linked validation to theories of epistemic justice, suggesting that in Scotland validation came not just from the relational but from contact with counter hegemonic understandings of mental illness.;This thesis concludes by making recommendations at a research, pedagogical and policy level. These include moving towards genuine participation in "participatory" research, increased academic and institutional support for service user or survivor led research, the inclusion of Mad Studies curricula in mainstream mental health professional education and the significance of social movement or critical pedagogies in progressing a genuinely human rights paradigm in mental health.;This thesis makes an original contribution to knowledge by fusing theories of social movement learning and epistemic justice; demonstrating the key role of social movement learning and Mad Studies critical pedagogies in strengthening the agency and ability of people with experience of mental health issues to collectively enact and claim their citizenship or human rights.This transatlantic, qualitative study privileges how people with lived experience of mental health issues conceptualise the intersections between mental health, citizenship, and education. Using a Mad Studies lens and drawing from the bricolage tradition of emancipatory research, this study aims to understand what role social movement learning has in facilitating collective or political agency. A range of qualitative and collaborative methods were used, including oral history interviews and arts-based methods. Thematic analysis and NVivo software were used to analyse the qualitative material.;Findings suggest two very different types of social movement learning occurring as well as contrasting journeys towards collective, or political agency. In Scotland, there was evidence of a directive and intentional form of social movement learning. In the US, a new pedagogical space was identified, through contact with social movement activities and actors, resulting in a more situated form of learning through action or learning in the struggle. Themes of the relational, validation and love are identified as important for developing collective identity as well as collective and political agency. Findings also linked validation to theories of epistemic justice, suggesting that in Scotland validation came not just from the relational but from contact with counter hegemonic understandings of mental illness.;This thesis concludes by making recommendations at a research, pedagogical and policy level. These include moving towards genuine participation in "participatory" research, increased academic and institutional support for service user or survivor led research, the inclusion of Mad Studies curricula in mainstream mental health professional education and the significance of social movement or critical pedagogies in progressing a genuinely human rights paradigm in mental health.;This thesis makes an original contribution to knowledge by fusing theories of social movement learning and epistemic justice; demonstrating the key role of social movement learning and Mad Studies critical pedagogies in strengthening the agency and ability of people with experience of mental health issues to collectively enact and claim their citizenship or human rights
The Strathclyde inventory as a measure of outcome in person-centred therapy
Get PDFPerson-centred therapy, like other humanistic therapies, proposes a potentiality model in which psychological growth, not simply the reduction of symptoms, is the anticipated outcome of therapy. Although substantial evidence of the effectiveness of person-centred therapy using medical model concepts exists, there is a need to develop measures that test outcome in therapy according to the person-centred theory of change. The Strathclyde Inventory (SI) is a brief self-report instrument designed to measure congruent functioning (described elsewhere as Rogers' fully functioning person, or congruence) for use as an outcome measure in therapy. The main purpose of this innovative three-part mixed method study was to investigate the validity of the SI as an outcome measure from multiple perspectives using data collected from a large UK-based clinical population. The first study evaluated the internal structure and reliability/precision of the instrument using the Rasch model. The second study investigated patterns of change in SI scores over the course of therapy seeking evidence of sensitivity to change, as well as convergent and construct validity. The third study tested the validity of change in SI scores as a measure of congruent functioning via a meta-synthesis of a series of eight systematic case studies examining client improvement and deterioration in therapy identified by pre-post change in SI scores. The results supported the validity of the SI as an internally consistent and precise unidimensional instrument that is able to identify meaningful change in congruent functioning within a UK-based clinical population. A brief 12-item version of the instrument was produced. An evidence-based, theoretically coherent, developmental pathway for congruent functioning was proposed, identifying self-acceptance as a pivot point. Overall, the results of this three-part study established that change in participants' scores during therapy demonstrated a high degree of variation and proposed an explanation for different post-therapy outcomes in congruent functioning.Person-centred therapy, like other humanistic therapies, proposes a potentiality model in which psychological growth, not simply the reduction of symptoms, is the anticipated outcome of therapy. Although substantial evidence of the effectiveness of person-centred therapy using medical model concepts exists, there is a need to develop measures that test outcome in therapy according to the person-centred theory of change. The Strathclyde Inventory (SI) is a brief self-report instrument designed to measure congruent functioning (described elsewhere as Rogers' fully functioning person, or congruence) for use as an outcome measure in therapy. The main purpose of this innovative three-part mixed method study was to investigate the validity of the SI as an outcome measure from multiple perspectives using data collected from a large UK-based clinical population. The first study evaluated the internal structure and reliability/precision of the instrument using the Rasch model. The second study investigated patterns of change in SI scores over the course of therapy seeking evidence of sensitivity to change, as well as convergent and construct validity. The third study tested the validity of change in SI scores as a measure of congruent functioning via a meta-synthesis of a series of eight systematic case studies examining client improvement and deterioration in therapy identified by pre-post change in SI scores. The results supported the validity of the SI as an internally consistent and precise unidimensional instrument that is able to identify meaningful change in congruent functioning within a UK-based clinical population. A brief 12-item version of the instrument was produced. An evidence-based, theoretically coherent, developmental pathway for congruent functioning was proposed, identifying self-acceptance as a pivot point. Overall, the results of this three-part study established that change in participants' scores during therapy demonstrated a high degree of variation and proposed an explanation for different post-therapy outcomes in congruent functioning
Pharmacological studies of bioactive compounds from medicinal mushrooms in Northeast of Thailand
Get PDFIn north-eastern Thailand, there are many varieties of mushrooms that the local people consume in high quantities annually; some of which are used for medicinal purposes. The local people use them for treatment by boiling with water and drinking the liquor, while some people finely grate the mushrooms, mould them into a bolusand eat it like a tablet as an anti-cancer and anti-diabetic treatment. In the present study, the compounds from three mushrooms P. everhartii, P. laevigatus and F.cajanderi were extracted with ethanol and biological evaluation such as anti-cancer, anti-Alzheimers, anti-microbial and anti-inflammatory activity carried out. An ethanol crude extract of F. cajanderi showed cytotoxicity against ovarian carcinoma (A2780), prostate carcinoma (LNCap) and breast carcinoma (ZR75-1)with IC50 of 149.70 µg/ml, 125.60 µg/ml and more than 150 µg/ml, respectively. While EtOH crude extracts of P. everhartii and P. laevigatus showed cytotoxicity against LNCap at IC50 80.46 µg/ml and 125.90 µg/ml, respectively and againstZR75-1 at IC50 of more than 150 µg/ml. An ethanol crude extract of F. cajanderi showed antimicrobial activity against three gram-positive bacteria (Bacillus subtillis, Staphylococcus aureus, and Listeria monocytogenes) and one gram-negative strain(Pseudomonas aeruginosa) at a concentration of 1 mg/ml. Three ethanol crude extracts of mushroom F. cajanderi, P. everhartii and P. laevigatus showed antiinflammatory activity in THP-1 cells stimulated with lipopolysaccharide at concentrations of 31.25μg/ml, 7.81μg/ml and 1.76μg/ml, respectively. In terms of compound elucidation, 7-methoxyindole-3-carboxylic acid methyl ester, an alkaloid compound, was isolated for the first time from P. everhartii and an ester of malonic acid of a lanostanoid type triterpene was isolated for the first time from F.cajanderi. The pure compound 7-methoxyindole-3-carboxylic acid methyl ester purchased (P) from a commercial source and extracted (E) of P. everhartii showed significant anti-inflammatory activity at concentrations of 20 µg/ml and 30 µg/ml inTHP-1 cells and at a concentration of 30 µg/ml in NCTC cells. The highest percentage of acetylcholinesterase inhibitory activity was 70% at 150 μg/ml for P and E. All six genes (Ccl2, Cxcl10, Cxcl13, Tnfsf10, Il6, and Tnf-α) showed downregulation in all samples. RNA-Seq of P and E showed the cytokine-cytokine receptor interaction pathway was affected in almost all treatment samples. RT-qPCR showed that TNFα, IL6 and CCL2 were up-regulated in three samples (sample E 10μg/ml, sample E 30 μg/ml and sample P 30 μg/ml) with a 1-2 fold increase andCXCL13, CXCL10 and TNFS10 showed down-regulation with a 1-2 fold change. These findings suggest that 7-methoxyindole-3-carboxylic acid methyl ester from P.everhartii could be developed as a potential anti-inflammatory therapy in the future according to the in vitro results. The ethanol crude extract from F. cajanderi could be considered for further anti-cancer and anti-microbial study.In north-eastern Thailand, there are many varieties of mushrooms that the local people consume in high quantities annually; some of which are used for medicinal purposes. The local people use them for treatment by boiling with water and drinking the liquor, while some people finely grate the mushrooms, mould them into a bolusand eat it like a tablet as an anti-cancer and anti-diabetic treatment. In the present study, the compounds from three mushrooms P. everhartii, P. laevigatus and F.cajanderi were extracted with ethanol and biological evaluation such as anti-cancer, anti-Alzheimers, anti-microbial and anti-inflammatory activity carried out. An ethanol crude extract of F. cajanderi showed cytotoxicity against ovarian carcinoma (A2780), prostate carcinoma (LNCap) and breast carcinoma (ZR75-1)with IC50 of 149.70 µg/ml, 125.60 µg/ml and more than 150 µg/ml, respectively. While EtOH crude extracts of P. everhartii and P. laevigatus showed cytotoxicity against LNCap at IC50 80.46 µg/ml and 125.90 µg/ml, respectively and againstZR75-1 at IC50 of more than 150 µg/ml. An ethanol crude extract of F. cajanderi showed antimicrobial activity against three gram-positive bacteria (Bacillus subtillis, Staphylococcus aureus, and Listeria monocytogenes) and one gram-negative strain(Pseudomonas aeruginosa) at a concentration of 1 mg/ml. Three ethanol crude extracts of mushroom F. cajanderi, P. everhartii and P. laevigatus showed antiinflammatory activity in THP-1 cells stimulated with lipopolysaccharide at concentrations of 31.25μg/ml, 7.81μg/ml and 1.76μg/ml, respectively. In terms of compound elucidation, 7-methoxyindole-3-carboxylic acid methyl ester, an alkaloid compound, was isolated for the first time from P. everhartii and an ester of malonic acid of a lanostanoid type triterpene was isolated for the first time from F.cajanderi. The pure compound 7-methoxyindole-3-carboxylic acid methyl ester purchased (P) from a commercial source and extracted (E) of P. everhartii showed significant anti-inflammatory activity at concentrations of 20 µg/ml and 30 µg/ml inTHP-1 cells and at a concentration of 30 µg/ml in NCTC cells. The highest percentage of acetylcholinesterase inhibitory activity was 70% at 150 μg/ml for P and E. All six genes (Ccl2, Cxcl10, Cxcl13, Tnfsf10, Il6, and Tnf-α) showed downregulation in all samples. RNA-Seq of P and E showed the cytokine-cytokine receptor interaction pathway was affected in almost all treatment samples. RT-qPCR showed that TNFα, IL6 and CCL2 were up-regulated in three samples (sample E 10μg/ml, sample E 30 μg/ml and sample P 30 μg/ml) with a 1-2 fold increase andCXCL13, CXCL10 and TNFS10 showed down-regulation with a 1-2 fold change. These findings suggest that 7-methoxyindole-3-carboxylic acid methyl ester from P.everhartii could be developed as a potential anti-inflammatory therapy in the future according to the in vitro results. The ethanol crude extract from F. cajanderi could be considered for further anti-cancer and anti-microbial study
Exploring the impact of conversational strategies on user search experience in goal-oriented tasks in a voice-only domain
Get PDFConversational search has recently become established as a new information search paradigm. Increasing numbers of people are using smart speakers and virtual personal assistants to access information online. Given the substantial increase in the usage of devices that feature conversational agents, it is timely to explore the implications that they have on user search behaviour.;This thesis explores how conversational search agents impact on user search experience and outcomes for goal-oriented tasks. Our enquiry is inspired by the premise that a fully conversational agent equipped with memory could lead to a better user search experience than an agent that is based on a slot-filling paradigm which represents the current state of the art. This dissertation presents three Wizard of Oz, lab-based studies that explore a series of conversational agents that differ in their ability to preserve conversational state and employ a different degree of conversational initiative. The goal of this research is to get a better understanding of how different ways of presenting information impact on user search experience in terms of cognitive load, satisfaction with the agent, time required to complete the task and overall performance.;In the first study, we address the problem of an agent's statefulness, which is the ability to preserve and account for the information presented by the user without the need to repeat it. Specifically, through a series of interactive search tasks, we evaluate how agent's memory improves user search experience. In the second study, we focus on mixed-initiative in conversation, by evaluating how different ways of eliciting information and presenting it back to the user (revealment) impact upon user search experience. In the third study, we further explore the role of mixed initiative by evaluating agent's 'proactivity' (i.e. the search involvement that goes beyond the original scope of the query) on user search experience. Finally, we compare the insights from all of the three studies and assess how differences in search task design and the mode of delivering the studies (lab-based vs. deployed online) impact upon experimental outcomes.;Overall, the contribution of the research presented in the current thesis is threefold. Firstly, it provides a validation of theoretical frameworks of conversational search by empirically investigating the impact of agent's memory and mixed initiative on user search experience. Secondly, it provides insights into the efficacy of alternative ways of eliciting information and presenting search results during conversational search. Thirdly, it contributes towards a more robust evaluation of conversational agents by developing a spectrum of conversational strategies and reflecting on the impact of the design of goal-oriented search tasks.Conversational search has recently become established as a new information search paradigm. Increasing numbers of people are using smart speakers and virtual personal assistants to access information online. Given the substantial increase in the usage of devices that feature conversational agents, it is timely to explore the implications that they have on user search behaviour.;This thesis explores how conversational search agents impact on user search experience and outcomes for goal-oriented tasks. Our enquiry is inspired by the premise that a fully conversational agent equipped with memory could lead to a better user search experience than an agent that is based on a slot-filling paradigm which represents the current state of the art. This dissertation presents three Wizard of Oz, lab-based studies that explore a series of conversational agents that differ in their ability to preserve conversational state and employ a different degree of conversational initiative. The goal of this research is to get a better understanding of how different ways of presenting information impact on user search experience in terms of cognitive load, satisfaction with the agent, time required to complete the task and overall performance.;In the first study, we address the problem of an agent's statefulness, which is the ability to preserve and account for the information presented by the user without the need to repeat it. Specifically, through a series of interactive search tasks, we evaluate how agent's memory improves user search experience. In the second study, we focus on mixed-initiative in conversation, by evaluating how different ways of eliciting information and presenting it back to the user (revealment) impact upon user search experience. In the third study, we further explore the role of mixed initiative by evaluating agent's 'proactivity' (i.e. the search involvement that goes beyond the original scope of the query) on user search experience. Finally, we compare the insights from all of the three studies and assess how differences in search task design and the mode of delivering the studies (lab-based vs. deployed online) impact upon experimental outcomes.;Overall, the contribution of the research presented in the current thesis is threefold. Firstly, it provides a validation of theoretical frameworks of conversational search by empirically investigating the impact of agent's memory and mixed initiative on user search experience. Secondly, it provides insights into the efficacy of alternative ways of eliciting information and presenting search results during conversational search. Thirdly, it contributes towards a more robust evaluation of conversational agents by developing a spectrum of conversational strategies and reflecting on the impact of the design of goal-oriented search tasks
Creating an automated analysis toolbox for ultrafast 2D-IR spectroscopy
Get PDFUnderstanding protein structure is intrinsic to understanding their biological mechanisms. The technique of infrared (IR) spectroscopy can be used to analyse secondary structure of proteins using the amide I vibrational mode. However, the broad peak associated with this mode can be convoluted and extracting structural information can be difficult. The technique of two-dimensional infrared (2D-IR) spectroscopy can assist by spreading the spectral content across two frequency axes. It is a time-resolved method based on a series of sub-picosecond laser pulses that allows for ultrafast dynamics to be probed providing an advantage over more established structural analysis techniques, such as circular dichroism (CD) spectroscopy and X-ray crystallography.;The aims of this thesis are to assess the ability of 2D-IR spectroscopy to extract information pertaining to changes in structure of proteins in tandem with the multivariate analysis method of principal component analysis (PCA). This has been performed as a means to understand the spectral features of structure change in proteins upon perturbation and provides the basis for analysing protein dynamics using time-resolved infrared (TRIR) spectroscopy. As a testbed for this analysis, the previously well-characterised protein calmodulin (CaM) has been studied. CaM is a calcium binding messenger protein that is predominantly α-helical in structure. Ca2+ free CaM (apo) can bind up to four Ca2+ ions (holo) which produces a change in structure and α-helical content.;Thermal studies on both apo- and holo-CaM were performed and the quantitative results from 2D-IR spectroscopy produced good agreement with CD spectroscopy with a reduction in α-helix structure by 13% (CD) and 15% (2D-IR) observed for apo-CaM. Accurate differentiation between melting transitions and generic heating effects was achieved using the thermally stable holo-CaM as a reference.;A temperature-jump (T-jump) TRIR experiment was then established. The system was calibrated and determined to induce a 9 °C temperature rise in the sample. Comparison of non-equilibrium relaxations of apo-CaM and holo-CaM showed domain melting of apo-CaM begins on microsecond timescales with α-helix destabilisation. These observations enable the assignment of previously reported dynamics of CaM on hundreds of microsecond timescales to thermally activated melting, producing a complete mechanism for thermal unfolding of CaM.;CaM-drug binding studies were performed using IR and 2D-IR spectroscopy and small changes in structure and electrostatic properties were extracted utilising PCA. Separation into groups of ligand binding was achieved for IR spectroscopy with 2D-IR spectroscopy providing spectral evidence for the changes occurring.;The limitations of 2D-IR data processing for elucidating the small spectral changes and the developments made to ensure accurate extraction of spectral features are discussed.Understanding protein structure is intrinsic to understanding their biological mechanisms. The technique of infrared (IR) spectroscopy can be used to analyse secondary structure of proteins using the amide I vibrational mode. However, the broad peak associated with this mode can be convoluted and extracting structural information can be difficult. The technique of two-dimensional infrared (2D-IR) spectroscopy can assist by spreading the spectral content across two frequency axes. It is a time-resolved method based on a series of sub-picosecond laser pulses that allows for ultrafast dynamics to be probed providing an advantage over more established structural analysis techniques, such as circular dichroism (CD) spectroscopy and X-ray crystallography.;The aims of this thesis are to assess the ability of 2D-IR spectroscopy to extract information pertaining to changes in structure of proteins in tandem with the multivariate analysis method of principal component analysis (PCA). This has been performed as a means to understand the spectral features of structure change in proteins upon perturbation and provides the basis for analysing protein dynamics using time-resolved infrared (TRIR) spectroscopy. As a testbed for this analysis, the previously well-characterised protein calmodulin (CaM) has been studied. CaM is a calcium binding messenger protein that is predominantly α-helical in structure. Ca2+ free CaM (apo) can bind up to four Ca2+ ions (holo) which produces a change in structure and α-helical content.;Thermal studies on both apo- and holo-CaM were performed and the quantitative results from 2D-IR spectroscopy produced good agreement with CD spectroscopy with a reduction in α-helix structure by 13% (CD) and 15% (2D-IR) observed for apo-CaM. Accurate differentiation between melting transitions and generic heating effects was achieved using the thermally stable holo-CaM as a reference.;A temperature-jump (T-jump) TRIR experiment was then established. The system was calibrated and determined to induce a 9 °C temperature rise in the sample. Comparison of non-equilibrium relaxations of apo-CaM and holo-CaM showed domain melting of apo-CaM begins on microsecond timescales with α-helix destabilisation. These observations enable the assignment of previously reported dynamics of CaM on hundreds of microsecond timescales to thermally activated melting, producing a complete mechanism for thermal unfolding of CaM.;CaM-drug binding studies were performed using IR and 2D-IR spectroscopy and small changes in structure and electrostatic properties were extracted utilising PCA. Separation into groups of ligand binding was achieved for IR spectroscopy with 2D-IR spectroscopy providing spectral evidence for the changes occurring.;The limitations of 2D-IR data processing for elucidating the small spectral changes and the developments made to ensure accurate extraction of spectral features are discussed
Plasma-water interface reactions caused by positive corona and glow discharges
Get PDFPlasma in and in contact with water has drawn extensive attention in the field of advanced oxidation processes, due to its advantages of producing various reactive species such as O, OH, HO2, H2O2 and O3 in water. Plasma-water interface reactions are one of the core challenges in this field since it involves multiple physical and chemical processes leading to complex mechanism of mass/energy transfer and reactive species production at interface. Exploration of the plasma-water interface reactions would promote the wide application of plasma in environmental remediation and plasma medicine.;The objective of this research is to investigate the interface reactions between water cathode and positive plasma produced by two types of gas discharges: corona discharge producing low energy drift positive ions and glow discharge producing energetic positive ions. A nine-needle electrode was developed to initiate d.c. corona discharge in nitrogen and oxygen. The experiments with a mesh cathode above water and a water cathode were conducted to explore the effects of ions and reactive neutral species. Glow discharge was generated between a single-needle anode and water cathode in nitrogen, oxygen and helium. The electrical characteristics of the discharges have been studied. The treated solutions have been investigated, including hydrogen peroxide (H2O2) production, pH and conductivity change. The effects of gas flow rate, gas pressure and hydroxyl radical (OH) scavengers on H2O2 production were studied.;In corona discharges, the contribution of positive ions and reactive neutral species to H2O2 production has been quantified. An analytical model that describes interface processes has been developed. The drift positive ions accumulated on water surface acted as ion-anode, on which the adsorbed hydroxyl radical (•OH) and oxygen radical (•O) were formed. The H2O2 production under both nitrogen corona discharge and oxygen corona discharge was proved not from the OH dimerization.;In glow discharge, the amount of hydrogen peroxide (H2O2) produced by each positive ion has been proved higher than that in corona discharge, which is thought caused by the large kinetic energy of positive ions. In nitrogen and helium glow discharge, the majority of H2O2 production was found to be from OH dimerization. Oxygen glow discharge did not produce OH in water. The effects of ions' kinetic energy and potential energy on the interface reactions were discussed.Plasma in and in contact with water has drawn extensive attention in the field of advanced oxidation processes, due to its advantages of producing various reactive species such as O, OH, HO2, H2O2 and O3 in water. Plasma-water interface reactions are one of the core challenges in this field since it involves multiple physical and chemical processes leading to complex mechanism of mass/energy transfer and reactive species production at interface. Exploration of the plasma-water interface reactions would promote the wide application of plasma in environmental remediation and plasma medicine.;The objective of this research is to investigate the interface reactions between water cathode and positive plasma produced by two types of gas discharges: corona discharge producing low energy drift positive ions and glow discharge producing energetic positive ions. A nine-needle electrode was developed to initiate d.c. corona discharge in nitrogen and oxygen. The experiments with a mesh cathode above water and a water cathode were conducted to explore the effects of ions and reactive neutral species. Glow discharge was generated between a single-needle anode and water cathode in nitrogen, oxygen and helium. The electrical characteristics of the discharges have been studied. The treated solutions have been investigated, including hydrogen peroxide (H2O2) production, pH and conductivity change. The effects of gas flow rate, gas pressure and hydroxyl radical (OH) scavengers on H2O2 production were studied.;In corona discharges, the contribution of positive ions and reactive neutral species to H2O2 production has been quantified. An analytical model that describes interface processes has been developed. The drift positive ions accumulated on water surface acted as ion-anode, on which the adsorbed hydroxyl radical (•OH) and oxygen radical (•O) were formed. The H2O2 production under both nitrogen corona discharge and oxygen corona discharge was proved not from the OH dimerization.;In glow discharge, the amount of hydrogen peroxide (H2O2) produced by each positive ion has been proved higher than that in corona discharge, which is thought caused by the large kinetic energy of positive ions. In nitrogen and helium glow discharge, the majority of H2O2 production was found to be from OH dimerization. Oxygen glow discharge did not produce OH in water. The effects of ions' kinetic energy and potential energy on the interface reactions were discussed
Nonlinear network vector autoregression
Get PDFAs we all know, the time series model is one of the most important aspects of modern econometric analysis. The autoregressive model is the theoretical basis of time series. The classic autoregressive model has two features that can be improved, linear, and one-dimensional. Economic theory shows that many important macroeconomic time series exhibit nonlinear characteristics. If this non-linear feature is ignored, the conclusion is likely to be wrong by only using linear analysis. Therefore, it is necessary to expand the linear model and propose nonlinear methods. Economic theory also shows that there is a mutual influence between individuals, and it is also necessary to consider it as a network.;In this dissertation, we consider three nonlinear autoregressive models for timeseries with network structure: The Threshold Network autoregressive (TNAR) model, the Threshold Network quantile autoregressive (TNQAR) model and the Markov Switching Network autoregressive (MS-NAR) model. For the TNAR model, we provide the parameter conditions for the stationary of the time series. Under this parameter condition, the TNAR process can be approximated by the geometrically ergodic process. Under these conditions, we discuss the statistical inference (estimation and test) of the TNAR model and give the asymptotic theory on the inference. The test for nonlinearity is applied. Simulation results and modeling for Twitter data were applied to support our methodology for TNAR models.;For the TNQAR model, we also provide the parameter conditions for the stationary of the time series. Under these parameter conditions, the TNQAR process can be approximated by the geometric traversal process. Under these condition, we discuss the statistical inference (estimation and test) of the TNQAR model and give the asymptotic theory on the inference. A normality test is applied on the data and a Hill estimator is provided to check whether the conditional distribution of the historical information is a thick tail or not. Simulation results and modeling of hedge fund data were used to support our methodology for TNQAR models. The Markovian Switching model is provided and its maximum likelihood estimation method is discussed. Finally, the techniques and the process in collecting Twitter data are presented.As we all know, the time series model is one of the most important aspects of modern econometric analysis. The autoregressive model is the theoretical basis of time series. The classic autoregressive model has two features that can be improved, linear, and one-dimensional. Economic theory shows that many important macroeconomic time series exhibit nonlinear characteristics. If this non-linear feature is ignored, the conclusion is likely to be wrong by only using linear analysis. Therefore, it is necessary to expand the linear model and propose nonlinear methods. Economic theory also shows that there is a mutual influence between individuals, and it is also necessary to consider it as a network.;In this dissertation, we consider three nonlinear autoregressive models for timeseries with network structure: The Threshold Network autoregressive (TNAR) model, the Threshold Network quantile autoregressive (TNQAR) model and the Markov Switching Network autoregressive (MS-NAR) model. For the TNAR model, we provide the parameter conditions for the stationary of the time series. Under this parameter condition, the TNAR process can be approximated by the geometrically ergodic process. Under these conditions, we discuss the statistical inference (estimation and test) of the TNAR model and give the asymptotic theory on the inference. The test for nonlinearity is applied. Simulation results and modeling for Twitter data were applied to support our methodology for TNAR models.;For the TNQAR model, we also provide the parameter conditions for the stationary of the time series. Under these parameter conditions, the TNQAR process can be approximated by the geometric traversal process. Under these condition, we discuss the statistical inference (estimation and test) of the TNQAR model and give the asymptotic theory on the inference. A normality test is applied on the data and a Hill estimator is provided to check whether the conditional distribution of the historical information is a thick tail or not. Simulation results and modeling of hedge fund data were used to support our methodology for TNQAR models. The Markovian Switching model is provided and its maximum likelihood estimation method is discussed. Finally, the techniques and the process in collecting Twitter data are presented
Investigations into the generation and pleiotropic reactivity modes of the nitrile imine 1,3-dipole
No full textThe nitrile imine 1,3-dipole is a versatile intermediate with a diverse range of applications from chemical biology to materials chemistry. In the 60 years since its initial discovery, this system has been found to undergo 1,3-dipolar cyclo addition with numerous dipolarophiles, while also engaging with various conventional heteroatomic nucleophiles through anelectrophilic addition mechanism. This pleiotropic reactivity profile makes the nitrile iminean especially unique motif within 1,3-dipole chemistry. The research detailed within this thesis relates to the manipulation of the nitrile imine 1,3-dipole and its role in the discovery of novel chemical transformations and works towards methods of harnessing its complex reactivity profile with the ultimate goal of improving the understanding of the species in its continued application within ligation chemistry. As aninitial investigation, a novel approach towards the popular 2,5-tetrazole nitrile imine precursor was developed. Employing robust Suzuki-hydrogenation methodology previously established within our laboratory, this protocol demonstrates a facile means of accessing abroad palette of 2,5-diaryl tetrazoles for application as a source of nitrile imines (Scheme0.1). Scheme 0.1: The development of a novel route towards 2,5-diaryltetrazoles employing Suzuki-debenzylation methodology [Scheme available in print and digital copies];With efficient access to the 1,3-dipole demonstrated, the extensive reactivity of the nitrileimine was investigated through its combination with arylboronic acids. Drawing mechanistic inspiration from the Petasis-Mannich reaction, a novel and metal-free approach towards C-C bond formation was developed, forming an array of aryl ketone hydrazone compounds (Scheme 0.2). The scope of the procedure was further expanded through the introduction of hydrazonyl chlorides as an alternative source of the nitrile imine. Exemplification of the transformation was accomplished through the metal-free synthesis of hypolipidemic agent fenofibrate, the adaption of the methodology to incorporate the nitrile oxide 1,3-dipole, and the integration of 2,5-tetrazole photolysis within a flow-chemistry manifold. ii Scheme 0.2: The development of a metal-free C-C bond-formation through the combination of nitrile imines and arylboronic acids [Scheme available in print and digital copies ];Finally, following extensive experience with the promiscuous reaction profile of nitrileimines, a series of competition experiments were undertaken to develop a comprehensive guide to the relative reactivity of the pleiotropic dipole (Scheme 0.3). The study investigated numerous potential substrates, spanning a selection of biomolecular residues, potent nucleophiles and bespoke dipolarophiles. Particular attention was paid to common NI bioorthogonal ligation agents that have been previously reported. Based on this, a definitive roadmap of NI reactivity was developed towards the more informed application of the versatile dipole within the field of chemical biology. Scheme 0.3: Quantitative investigations into the reactivity profile of the nitrile imine 1,3-dipole. [Scheme available in print and digital copies ]The nitrile imine 1,3-dipole is a versatile intermediate with a diverse range of applications from chemical biology to materials chemistry. In the 60 years since its initial discovery, this system has been found to undergo 1,3-dipolar cyclo addition with numerous dipolarophiles, while also engaging with various conventional heteroatomic nucleophiles through anelectrophilic addition mechanism. This pleiotropic reactivity profile makes the nitrile iminean especially unique motif within 1,3-dipole chemistry. The research detailed within this thesis relates to the manipulation of the nitrile imine 1,3-dipole and its role in the discovery of novel chemical transformations and works towards methods of harnessing its complex reactivity profile with the ultimate goal of improving the understanding of the species in its continued application within ligation chemistry. As aninitial investigation, a novel approach towards the popular 2,5-tetrazole nitrile imine precursor was developed. Employing robust Suzuki-hydrogenation methodology previously established within our laboratory, this protocol demonstrates a facile means of accessing abroad palette of 2,5-diaryl tetrazoles for application as a source of nitrile imines (Scheme0.1). Scheme 0.1: The development of a novel route towards 2,5-diaryltetrazoles employing Suzuki-debenzylation methodology [Scheme available in print and digital copies];With efficient access to the 1,3-dipole demonstrated, the extensive reactivity of the nitrileimine was investigated through its combination with arylboronic acids. Drawing mechanistic inspiration from the Petasis-Mannich reaction, a novel and metal-free approach towards C-C bond formation was developed, forming an array of aryl ketone hydrazone compounds (Scheme 0.2). The scope of the procedure was further expanded through the introduction of hydrazonyl chlorides as an alternative source of the nitrile imine. Exemplification of the transformation was accomplished through the metal-free synthesis of hypolipidemic agent fenofibrate, the adaption of the methodology to incorporate the nitrile oxide 1,3-dipole, and the integration of 2,5-tetrazole photolysis within a flow-chemistry manifold. ii Scheme 0.2: The development of a metal-free C-C bond-formation through the combination of nitrile imines and arylboronic acids [Scheme available in print and digital copies ];Finally, following extensive experience with the promiscuous reaction profile of nitrileimines, a series of competition experiments were undertaken to develop a comprehensive guide to the relative reactivity of the pleiotropic dipole (Scheme 0.3). The study investigated numerous potential substrates, spanning a selection of biomolecular residues, potent nucleophiles and bespoke dipolarophiles. Particular attention was paid to common NI bioorthogonal ligation agents that have been previously reported. Based on this, a definitive roadmap of NI reactivity was developed towards the more informed application of the versatile dipole within the field of chemical biology. Scheme 0.3: Quantitative investigations into the reactivity profile of the nitrile imine 1,3-dipole. [Scheme available in print and digital copies
Fluid-structure interaction simulations on skeleton-reinforced biomimetic fin propulsion
Get PDFThis study is inspired by the key features possessed by the fins of ray-finned fish (e.g.,soft membrane supported by bony rays, anisotropic flexibility, individual actuation of fin rays, active curvature and stiffness control). A better understanding of the effects of these characteristics will provide inspirations and guidelines for the design ofbio-inspired underwater locomotion systems, which are playing an increasingly important role as the growing activities in ocean engineering.Due to the complicated structures of fish fins, it is of great challenge to numerically model such bio-membrane systems, which involve the fluid-structure interaction (FSI)between the flexible fin and the surrounding flow, and the modelling and active control of individual fin rays. It is therefore preferable to develop a compact and handy FSI solver, which allows to be tailored for specific problems, rather than using commercial software, which have no direct model capable of handling skeleton-strengthened bio-membrane systems and provides little freedom to betailored. To elucidate the effects of the aforementioned main characteristics on the performance of biomimetic fin propulsion, a fully coupled FSI solver capable of simulating the dynamics of skeleton-reinforced bio-membranes is established in thepresent work. Specifically, a flow model, which solves the 3D unsteady compressible Navier-Stokes equations on an overset, multi-block, structured grid system with a finite-volume method, is coupled with a structural model, which solves a nonlinear Euler-Bernoulli beam equation with a finite-difference method, within a partitioned framework. The developed FSI solver is thoroughly validated against benchmark cases available in literature and good agreements are obtained.Firstly, the established FSI model is applied to investigate the effects of different spanwise deformations on the propulsion performance of a simplified 3D ray-supported caudal fin. The rays are modelled as nonlinear beams. Kinematically,the leading edge of the fin undergoes a sinusoidal sway motion while the rest part deforms passively. Our numerical results show that with specific ray stiffness distributions, certain caudal fin deformation patterns observed in real fish (e.g., the cupping deformation) can be reproduced through passive structural deformations.Among the four different stiffness distributions (uniform, cupping, W-shape and heterocercal) considered here, we find that the cupping distribution requires the least power expenditure. The uniform distribution, on the other hand, performs the best interms of thrust generation and efficiency. The uniform stiffness distribution, per se,also leads to 'cupping' deformation patterns with relatively smaller phase differences between various rays.;Subsequently, the effect of active curvature control on the performance of aray-strengthened caudal fin is examined. Kinematically, the fin is activated by a uniform sway motion at the basal ends of the rays, and distributed time-varying forces along each ray individually, which imitate effects of tendons that actively change the curvatures of the rays. The dynamics of the fin is closely associated with the exact distribution of phase lags (between the sway motion and external forces) among the rays. We find that the fin's performance can be significantly enhanced by active control when the mean phase lag is less than 90 degree. Among different deformation patterns,the cupping deformation (C-mode) produces the best propulsion performance. The underlying physical mechanism is found to be areas with increased pressure attributed to three-dimensional fin deformations. W-shape deformations (W-mode) have a similar(yet less pronounced) effect. In addition to symmetric fin deformations, asymmetric deformations such as heterocercal mode (H-mode) and undulation mode (S-mode) are reproduced in the present work. Both of which are able to generate vertical forces.Compared with the H-mode, the S-mode creates less thrust force but it significantly reduces the transverse force, making it more suitable in cases when there is no other mechanism to balance the transverse force (e.g. during the braking maneuver).Finally, the propulsion performance of a skate-inspired underwater robot with a pair of ray-supported undulating pectoral fins is numerically investigated with the fully coupled FSI solver. Each pectoral fin is activated independently via individually distributed time-varying forces along each fin ray, which imitate effects of tendons that can actively curve the fin rays. We find that the propulsion performance of the bio-inspired robot is closely associated with the phase difference between the leading edge ray and the trailing edge ray of the pectoral fin. The results show that with asymmetrical kinematics, the highest thrust is created when the phase difference is 90 degree while the point maximizing the propulsion efficiency varies with the motion frequency. It is also found that there is a minimum frequency of generating net thrust for a specific parameter setup, which rises as the increase of phase difference.Compared with the symmetrical kinematics, the non-symmetrical kinematics generates more complicated hydrodynamic forces and moments which may be beneficial for maneuvering.This study is inspired by the key features possessed by the fins of ray-finned fish (e.g.,soft membrane supported by bony rays, anisotropic flexibility, individual actuation of fin rays, active curvature and stiffness control). A better understanding of the effects of these characteristics will provide inspirations and guidelines for the design ofbio-inspired underwater locomotion systems, which are playing an increasingly important role as the growing activities in ocean engineering.Due to the complicated structures of fish fins, it is of great challenge to numerically model such bio-membrane systems, which involve the fluid-structure interaction (FSI)between the flexible fin and the surrounding flow, and the modelling and active control of individual fin rays. It is therefore preferable to develop a compact and handy FSI solver, which allows to be tailored for specific problems, rather than using commercial software, which have no direct model capable of handling skeleton-strengthened bio-membrane systems and provides little freedom to betailored. To elucidate the effects of the aforementioned main characteristics on the performance of biomimetic fin propulsion, a fully coupled FSI solver capable of simulating the dynamics of skeleton-reinforced bio-membranes is established in thepresent work. Specifically, a flow model, which solves the 3D unsteady compressible Navier-Stokes equations on an overset, multi-block, structured grid system with a finite-volume method, is coupled with a structural model, which solves a nonlinear Euler-Bernoulli beam equation with a finite-difference method, within a partitioned framework. The developed FSI solver is thoroughly validated against benchmark cases available in literature and good agreements are obtained.Firstly, the established FSI model is applied to investigate the effects of different spanwise deformations on the propulsion performance of a simplified 3D ray-supported caudal fin. The rays are modelled as nonlinear beams. Kinematically,the leading edge of the fin undergoes a sinusoidal sway motion while the rest part deforms passively. Our numerical results show that with specific ray stiffness distributions, certain caudal fin deformation patterns observed in real fish (e.g., the cupping deformation) can be reproduced through passive structural deformations.Among the four different stiffness distributions (uniform, cupping, W-shape and heterocercal) considered here, we find that the cupping distribution requires the least power expenditure. The uniform distribution, on the other hand, performs the best interms of thrust generation and efficiency. The uniform stiffness distribution, per se,also leads to 'cupping' deformation patterns with relatively smaller phase differences between various rays.;Subsequently, the effect of active curvature control on the performance of aray-strengthened caudal fin is examined. Kinematically, the fin is activated by a uniform sway motion at the basal ends of the rays, and distributed time-varying forces along each ray individually, which imitate effects of tendons that actively change the curvatures of the rays. The dynamics of the fin is closely associated with the exact distribution of phase lags (between the sway motion and external forces) among the rays. We find that the fin's performance can be significantly enhanced by active control when the mean phase lag is less than 90 degree. Among different deformation patterns,the cupping deformation (C-mode) produces the best propulsion performance. The underlying physical mechanism is found to be areas with increased pressure attributed to three-dimensional fin deformations. W-shape deformations (W-mode) have a similar(yet less pronounced) effect. In addition to symmetric fin deformations, asymmetric deformations such as heterocercal mode (H-mode) and undulation mode (S-mode) are reproduced in the present work. Both of which are able to generate vertical forces.Compared with the H-mode, the S-mode creates less thrust force but it significantly reduces the transverse force, making it more suitable in cases when there is no other mechanism to balance the transverse force (e.g. during the braking maneuver).Finally, the propulsion performance of a skate-inspired underwater robot with a pair of ray-supported undulating pectoral fins is numerically investigated with the fully coupled FSI solver. Each pectoral fin is activated independently via individually distributed time-varying forces along each fin ray, which imitate effects of tendons that can actively curve the fin rays. We find that the propulsion performance of the bio-inspired robot is closely associated with the phase difference between the leading edge ray and the trailing edge ray of the pectoral fin. The results show that with asymmetrical kinematics, the highest thrust is created when the phase difference is 90 degree while the point maximizing the propulsion efficiency varies with the motion frequency. It is also found that there is a minimum frequency of generating net thrust for a specific parameter setup, which rises as the increase of phase difference.Compared with the symmetrical kinematics, the non-symmetrical kinematics generates more complicated hydrodynamic forces and moments which may be beneficial for maneuvering
A microfluidic platform for functional assays on tumour biopsy-derived spheroids for precision medicine
Get PDFPrecision medicine aims to determine the ideal treatment for each cancer patient through the use of genomic and molecular diagnostics, as well as functional chemo-sensitivity screening assays. In recent years, the use and development of physiologically relevant patient-derived 3D in vitro cancer models has increased, since 3D ex vivo and in vitro models can replicate many aspects of the tumour microenvironment closely. These aim to provide more predictive tools than cell line-derived models for testing anticancer drug efficacy, particularly in the context of precision medicine in oncology. However, the small number of cells contained in many biopsies, especially in fine needle aspirates, is a major barrier to the use of patient biopsy tissue in 3D functional assays for precision medicine.;Microfluidic technologies have extensive miniaturisation capabilities, which offer increased data throughput while using very small amounts of cells. Therefore, this technology is a good candidate to perform 3D functional assays using patient-derived tissue. However, microfluidic devices frequently require an experienced handler or the use of dedicated fluid actuation equipment, which can create obstacles to its widespread adoption for precision medicine applications.;This PhD aimed to address these issues by creating a microfluidic platform and protocols for medium-throughput screening of tumour biopsy-derived spheroids. The microfluidic system developed in this PhD was used to generate thousands of spheroids from single cell suspensions, which could be cultured in the device for a prolonged period of time. Subsequently, as a proof-of-concept application, prostate biopsy-derived spheroids were exposed to drug concentration gradients, which allowed the establishment of one concentration-response curve per chip, and up to 21 concentration-response curves per patient. This platform offers a novel solution for the functional chemosensitivity testing of biopsy-derived spheroids, maximising the number of conditions that can be tested on patient-derived tissue for the purpose of precision medicine.Precision medicine aims to determine the ideal treatment for each cancer patient through the use of genomic and molecular diagnostics, as well as functional chemo-sensitivity screening assays. In recent years, the use and development of physiologically relevant patient-derived 3D in vitro cancer models has increased, since 3D ex vivo and in vitro models can replicate many aspects of the tumour microenvironment closely. These aim to provide more predictive tools than cell line-derived models for testing anticancer drug efficacy, particularly in the context of precision medicine in oncology. However, the small number of cells contained in many biopsies, especially in fine needle aspirates, is a major barrier to the use of patient biopsy tissue in 3D functional assays for precision medicine.;Microfluidic technologies have extensive miniaturisation capabilities, which offer increased data throughput while using very small amounts of cells. Therefore, this technology is a good candidate to perform 3D functional assays using patient-derived tissue. However, microfluidic devices frequently require an experienced handler or the use of dedicated fluid actuation equipment, which can create obstacles to its widespread adoption for precision medicine applications.;This PhD aimed to address these issues by creating a microfluidic platform and protocols for medium-throughput screening of tumour biopsy-derived spheroids. The microfluidic system developed in this PhD was used to generate thousands of spheroids from single cell suspensions, which could be cultured in the device for a prolonged period of time. Subsequently, as a proof-of-concept application, prostate biopsy-derived spheroids were exposed to drug concentration gradients, which allowed the establishment of one concentration-response curve per chip, and up to 21 concentration-response curves per patient. This platform offers a novel solution for the functional chemosensitivity testing of biopsy-derived spheroids, maximising the number of conditions that can be tested on patient-derived tissue for the purpose of precision medicine
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