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Development of computational methods for standing wave microscopy
Get PDFThis thesis was previously held under moratorium from 27th November 2019 until 27th November 2024.Optical microscopy is an important tool in biomedical sciences and allows for the imaging of single cells, and has become vital and versatile tool for understanding cellular and subcellular processes. However, due to the wave nature of light, the spatial resolution is limited. As a result, most of the important biological process of a cell take place below 200 nm, which is beyond the resolution capabilities of conventional optical microscopy techniques. In this work, I used multi-planar standing wave microscopy, an axial super resolution technique, where incident and reflected light from a mirror surface, create a standing wave. Multiple planes of lights are generated with a spacing of λ/2n, with an axial resolution of λ/4n, where λ is the excitation wavelength of light and n is the refractive index. When the multiple planes of light intersect a fluorescently labelled specimen, the result is an image with 3D information encoded in a 2D image. I showed that multi-planar standing wave images of healthy and Plasmodium berghei infected red blood cells had clear morphological deformations in the cell membrane. Furthermore, by applying a combination of noise filtering and segmentation techniques, 2D anti-nodal plane information was extracted. Next, I applied a priori knowledge to the standing wave red blood cells images to create a 3D reconstruction of the bottom concave surface. To overcome, the limitations of single-wavelength standing wave (SW) microscopy a new method, which we call TartanSW multi-excitation, was applied to biological specimens. This reduced the modulation gap when compared with the use of a single-excitation wavelength. Furthermore, TartanSW multi-excitation and multi-emission both showed a unique spectral signature that reduced the ambiguity in the geometry of the specimen. Lastly, by utilising the phase difference between the different TartanSW multi-excitation wavelengths, I showed that in principle, the phase difference could be used to determine the axial height information from a 2D encoded standing wave pattern.Optical microscopy is an important tool in biomedical sciences and allows for the imaging of single cells, and has become vital and versatile tool for understanding cellular and subcellular processes. However, due to the wave nature of light, the spatial resolution is limited. As a result, most of the important biological process of a cell take place below 200 nm, which is beyond the resolution capabilities of conventional optical microscopy techniques. In this work, I used multi-planar standing wave microscopy, an axial super resolution technique, where incident and reflected light from a mirror surface, create a standing wave. Multiple planes of lights are generated with a spacing of λ/2n, with an axial resolution of λ/4n, where λ is the excitation wavelength of light and n is the refractive index. When the multiple planes of light intersect a fluorescently labelled specimen, the result is an image with 3D information encoded in a 2D image. I showed that multi-planar standing wave images of healthy and Plasmodium berghei infected red blood cells had clear morphological deformations in the cell membrane. Furthermore, by applying a combination of noise filtering and segmentation techniques, 2D anti-nodal plane information was extracted. Next, I applied a priori knowledge to the standing wave red blood cells images to create a 3D reconstruction of the bottom concave surface. To overcome, the limitations of single-wavelength standing wave (SW) microscopy a new method, which we call TartanSW multi-excitation, was applied to biological specimens. This reduced the modulation gap when compared with the use of a single-excitation wavelength. Furthermore, TartanSW multi-excitation and multi-emission both showed a unique spectral signature that reduced the ambiguity in the geometry of the specimen. Lastly, by utilising the phase difference between the different TartanSW multi-excitation wavelengths, I showed that in principle, the phase difference could be used to determine the axial height information from a 2D encoded standing wave pattern
The role of emotion in decision making when information is framed positively and negatively
No full textHuman decision-making is subject to a number of cognitive biases. One of the first biases to be identified is the way information in a decision problem is framed. It is now widely recognized that when information is framed positively (i.e. in terms of gains), people make risk-averse choices, whereas when information is framed negatively (i.e. in terms of losses), people make risk-seeking choices. Information framing is one of the most studied cognitive biases and its effects have been observed in decision problems ranging from medicine and finance to terrorism. More recently, researchers have focused on the role of emotion in the decision-making process. The purpose of this research was to investigate the role of emotion on the effects of information framing. To do this, I developed a technology-related information-framing problem about the reliability of internet service providers. Having observed strong information framing effects in my technology-related problem, I used Lerner et al.'s (2015) Emotion Imbued Choice (EIC) model to investigate the effects of integral and incidental emotions. Contrary to the predictions of the EIC, I found that the characteristics of options (in this case, positively framed or negatively framed information) did not affect integral emotions. In order to investigate the effects of incidental emotions, I developed a method to induce participants with fear and happiness by using the International Affective Picture System (IAPS). Consistent with the predictions of the EIC, I found that incidental emotions can moderate the effects of information framing (e.g.higher levels of incidental fear can lead participants to make risk-averse choices when information is framed negatively, even though negatively framed information usually leads to risk-seeking choices). The main theoretical contribution in this thesis comes from an amended EIC model that takes into consideration the effects of information framing. Other researchers could also use the method I used to induce emotions using the IAPS. This method was found to induce emotions more reliably than some existing methods, and as it does not involve language production, can be used with mixed-cultural and cross-cultural samples. There are also several practical implications of my research, which I consider in this thesis.Human decision-making is subject to a number of cognitive biases. One of the first biases to be identified is the way information in a decision problem is framed. It is now widely recognized that when information is framed positively (i.e. in terms of gains), people make risk-averse choices, whereas when information is framed negatively (i.e. in terms of losses), people make risk-seeking choices. Information framing is one of the most studied cognitive biases and its effects have been observed in decision problems ranging from medicine and finance to terrorism. More recently, researchers have focused on the role of emotion in the decision-making process. The purpose of this research was to investigate the role of emotion on the effects of information framing. To do this, I developed a technology-related information-framing problem about the reliability of internet service providers. Having observed strong information framing effects in my technology-related problem, I used Lerner et al.'s (2015) Emotion Imbued Choice (EIC) model to investigate the effects of integral and incidental emotions. Contrary to the predictions of the EIC, I found that the characteristics of options (in this case, positively framed or negatively framed information) did not affect integral emotions. In order to investigate the effects of incidental emotions, I developed a method to induce participants with fear and happiness by using the International Affective Picture System (IAPS). Consistent with the predictions of the EIC, I found that incidental emotions can moderate the effects of information framing (e.g.higher levels of incidental fear can lead participants to make risk-averse choices when information is framed negatively, even though negatively framed information usually leads to risk-seeking choices). The main theoretical contribution in this thesis comes from an amended EIC model that takes into consideration the effects of information framing. Other researchers could also use the method I used to induce emotions using the IAPS. This method was found to induce emotions more reliably than some existing methods, and as it does not involve language production, can be used with mixed-cultural and cross-cultural samples. There are also several practical implications of my research, which I consider in this thesis
Phytochemical and pharmacological studies on Hibiscus sabdariffa and Polygonum salicifolium
Get PDFMedicinal plants are an important resource for the discovery of new and potent therapeutic compounds. Hibiscus sabdariffa (Malvaceae) is a plant that is widely recognised for its antihypertensive properties; however the constituent(s) responsible for this biological activity are presently unknown. The aim of this study was to identify the potential compounds that are responsible for the vasorelaxant activity of Hibiscus sabdariffa. A second aim was to determine whether the aquatic plant, Polygonum salicifolium (Polygonaceae) has vasorelaxant activity. Thereafter, the mechanisms involved in producing the vasorelaxation were investigated. The plants were subjected to hot solvent extraction in a sequential manner (72 h each) with n-hexane, ethyl acetate and methanol using a Soxhlet apparatus. The methanolic extract was subjected to bioassay-guided fractionation in order to isolate pure compounds and determine their vasorelaxant activity. The vascular effects of the crude methanolic extracts, sub-fractions, and pure compounds were studied on the rat aorta in vitro using myography techniques. In this study, hibiscus acid has been isolated as one of the main organic acids of Hibiscus sabdariffa. Parallel studies were also carried out with garcinia acid, which is a diastereoisomer of hibiscus acid and is commercially available. Hibiscus acid produced a concentration-dependent relaxation of the aorta pre-contracted with either phenylephrine (3 μM) or KCl (60 mM), irrespective of the presence or absence of the endothelium. When the tissue was pre-contracted with phenylephrine, the concentration required to produce 50% relaxation (IC50), was 0.09 ± 0.01 mg/ml. Moreover, garcinia acid was found to have an almost identical vasorelaxant effect. When the aorta was pre-contracted with the Ca2+ channel activator Bay K8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3-carboxylic acid methyl ester or FPL 64176 (2,5-dimethyl-4-[2-(phenylmethyl) benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester), both hibiscus and garcinia acid were able to produce almost complete relaxation. Hibiscus acid had no effect on the phasic contraction induced by phenylephrine in Ca2+-free physiological solution; but it did affect the component of the contraction that is due to Ca2+ influx. Previous studies have showed that the crude extracts of H. sabdariffa have negative inotropic activity and relaxant effects on the tracheal tissues. Therefore, it was plausible to determine whether hibiscus acid has similar effects. Both hibiscus and garcinia acid, at a concentration of 0.6 mg/ml almost completely relaxed the electrically evoked contraction of the rat atria. Furthermore, both organic acids produced a concentration-dependent relaxation of the rat trachea, pre-contracted with either carbachol (1 μM) or KCl (60 mM). The vasorelaxant action of both compounds appears to be through inhibition of extracellular calcium influx, most likely by inhibition of voltage-dependent Ca2+ channels. There may be a slight modulatory role of the endothelium in the action of these substances; but the endothelium is not essential for the vasorelaxant response. With regard to the activity of Polygonum salicifolium, the crude methanolic extract of this plant produced a concentration-dependent relaxation of the aorta pre-contracted with phenylephrine. The IC50 was 0.04 ± 0.007 mg/ml and the extract caused complete relaxation of the aorta. The vasorelaxant activity of the crude extract was completely inhibited upon removal of the endothelium. Also, the crude extract was unable to relax the aorta when it was pre-contracted with KCl (60 mM). In conclusion, the diastereomers, hibiscus acid and garcinia acid were demonstrated to cause vasorelaxation in a similar manner. This thesis also reported for the first time the vasorelaxant activity of the medicinal plant Polygonum salicifolium, and the vasorelaxant action of this plant appears to be mediated through an endothelium-dependent mechanism.Medicinal plants are an important resource for the discovery of new and potent therapeutic compounds. Hibiscus sabdariffa (Malvaceae) is a plant that is widely recognised for its antihypertensive properties; however the constituent(s) responsible for this biological activity are presently unknown. The aim of this study was to identify the potential compounds that are responsible for the vasorelaxant activity of Hibiscus sabdariffa. A second aim was to determine whether the aquatic plant, Polygonum salicifolium (Polygonaceae) has vasorelaxant activity. Thereafter, the mechanisms involved in producing the vasorelaxation were investigated. The plants were subjected to hot solvent extraction in a sequential manner (72 h each) with n-hexane, ethyl acetate and methanol using a Soxhlet apparatus. The methanolic extract was subjected to bioassay-guided fractionation in order to isolate pure compounds and determine their vasorelaxant activity. The vascular effects of the crude methanolic extracts, sub-fractions, and pure compounds were studied on the rat aorta in vitro using myography techniques. In this study, hibiscus acid has been isolated as one of the main organic acids of Hibiscus sabdariffa. Parallel studies were also carried out with garcinia acid, which is a diastereoisomer of hibiscus acid and is commercially available. Hibiscus acid produced a concentration-dependent relaxation of the aorta pre-contracted with either phenylephrine (3 μM) or KCl (60 mM), irrespective of the presence or absence of the endothelium. When the tissue was pre-contracted with phenylephrine, the concentration required to produce 50% relaxation (IC50), was 0.09 ± 0.01 mg/ml. Moreover, garcinia acid was found to have an almost identical vasorelaxant effect. When the aorta was pre-contracted with the Ca2+ channel activator Bay K8644 (1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3-carboxylic acid methyl ester or FPL 64176 (2,5-dimethyl-4-[2-(phenylmethyl) benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester), both hibiscus and garcinia acid were able to produce almost complete relaxation. Hibiscus acid had no effect on the phasic contraction induced by phenylephrine in Ca2+-free physiological solution; but it did affect the component of the contraction that is due to Ca2+ influx. Previous studies have showed that the crude extracts of H. sabdariffa have negative inotropic activity and relaxant effects on the tracheal tissues. Therefore, it was plausible to determine whether hibiscus acid has similar effects. Both hibiscus and garcinia acid, at a concentration of 0.6 mg/ml almost completely relaxed the electrically evoked contraction of the rat atria. Furthermore, both organic acids produced a concentration-dependent relaxation of the rat trachea, pre-contracted with either carbachol (1 μM) or KCl (60 mM). The vasorelaxant action of both compounds appears to be through inhibition of extracellular calcium influx, most likely by inhibition of voltage-dependent Ca2+ channels. There may be a slight modulatory role of the endothelium in the action of these substances; but the endothelium is not essential for the vasorelaxant response. With regard to the activity of Polygonum salicifolium, the crude methanolic extract of this plant produced a concentration-dependent relaxation of the aorta pre-contracted with phenylephrine. The IC50 was 0.04 ± 0.007 mg/ml and the extract caused complete relaxation of the aorta. The vasorelaxant activity of the crude extract was completely inhibited upon removal of the endothelium. Also, the crude extract was unable to relax the aorta when it was pre-contracted with KCl (60 mM). In conclusion, the diastereomers, hibiscus acid and garcinia acid were demonstrated to cause vasorelaxation in a similar manner. This thesis also reported for the first time the vasorelaxant activity of the medicinal plant Polygonum salicifolium, and the vasorelaxant action of this plant appears to be mediated through an endothelium-dependent mechanism
A categorical approach to the foundations of Quantum theory
Get PDFIn this work we pursue two goals: the first is to bridge a gap between various projects within the field of categorical quantum theory, namely: topos quantum theory as initiated by Butterfield and Isham; monoidal quantum theory, as initiated by Abramsky and Coecke; and the sheaf theoretic approach to contextuality and non-locality, as initiated by Abramsky and Brandenburger. We show connections between these projects on the level of mathematical formalisms, and also on the level of physical interpretations. The central element is a generalisation of the topos theoretic structures of Butterfield and Isham, which incorporates the categorical structures considered within monoidal quantum theory, resulting in structures that can be embedded into the general sheaf-formalism of Abramsky and Brandenburger. The second main thrust of this work is in providing a framework within which to consider the foundations of quantum theory, specifically within the context of a pragmatic metaphysical interpretation. This is done using similar mathematical structures as topos quantum theory, but using quite different metaphysical presuppositions. In particular, we consider presheaves on posets of commutative subsemialgebras which can be naturally associated with a physical system as represented in categorical quantum mechanics. The main distinction between our work and topos quantum theory is that we do not pursue a realist metaphysical interpretation of these structures. Rather we pursue a pragmatic interpretation of metaphysics which is consistent with the sheaf-formalism of Abramsky and Brandenburger. From this categorical perspective, we consider some of the fundamental features of quantum foundations, including a derivation of the Born rule, contextuality/non-locality, the meaning of quantum probabilities, and model toy quantum-like theories. We also present a new outlook on quantum metaphysics which seeks to lend clarity to some of the conceptual problems which exist in quantum foundations and which draws a connection with the Bohrification programme of Heunen, Spitters and Landsman.In this work we pursue two goals: the first is to bridge a gap between various projects within the field of categorical quantum theory, namely: topos quantum theory as initiated by Butterfield and Isham; monoidal quantum theory, as initiated by Abramsky and Coecke; and the sheaf theoretic approach to contextuality and non-locality, as initiated by Abramsky and Brandenburger. We show connections between these projects on the level of mathematical formalisms, and also on the level of physical interpretations. The central element is a generalisation of the topos theoretic structures of Butterfield and Isham, which incorporates the categorical structures considered within monoidal quantum theory, resulting in structures that can be embedded into the general sheaf-formalism of Abramsky and Brandenburger. The second main thrust of this work is in providing a framework within which to consider the foundations of quantum theory, specifically within the context of a pragmatic metaphysical interpretation. This is done using similar mathematical structures as topos quantum theory, but using quite different metaphysical presuppositions. In particular, we consider presheaves on posets of commutative subsemialgebras which can be naturally associated with a physical system as represented in categorical quantum mechanics. The main distinction between our work and topos quantum theory is that we do not pursue a realist metaphysical interpretation of these structures. Rather we pursue a pragmatic interpretation of metaphysics which is consistent with the sheaf-formalism of Abramsky and Brandenburger. From this categorical perspective, we consider some of the fundamental features of quantum foundations, including a derivation of the Born rule, contextuality/non-locality, the meaning of quantum probabilities, and model toy quantum-like theories. We also present a new outlook on quantum metaphysics which seeks to lend clarity to some of the conceptual problems which exist in quantum foundations and which draws a connection with the Bohrification programme of Heunen, Spitters and Landsman
The meaning of mandates : party competition and the programme-to-policy linkage
Get PDFThe connection between political parties' campaign promises and government actions -known as the programme-to-policy linkage - has been a topic of scholarly interest for nearly half a century. Indeed, the degree to which governments follow up on their campaign pledges represents an important question for representative democracies as political systems in which regular elections serve as the mechanism for the enactment of public priorities.Despite voter cynicism, it has become well-established that election winners tend to redeem a healthy share of their pledges in office. However, studies of this linkage focused overwhelmingly on straightforward empirical assessments. This research has primarily examined the extent to which specific manifesto promises are enacted across countries and the institutional constraints which explain variation. Yet, serious questions persist about the origins and format of manifesto documents, the conceptualisation and measurement of the linkage and its significance for democracy in theory and practice. My doctoral thesis contributes to the programme-to-policy literature by shedding light on these gaps in current scholarly understanding.Through a series of sequential chapters, I address these questions. I first focus on the conceptualisation and measurement of linkage. In particular, I re-evaluate an influential alternative approach focused on the connection between issue emphasis and government spending by reassessing a canonical work in the literature and applying new tests. Having established the validity of an adapted version of this approach, finding that the party mandate extends to the government policy agenda in a UK context, I investigate the relationship between parties' issue emphasis and pledge-making strategies, introducing the concept of manifesto \composition" as distinct from policy content to examine its impact on pledge fulfilment. Finally, I turn to the idea of the responsible electorate, investigating the extent to which voters retrospectively reward parties for fulfilling pledges, identifying the first evidence that governments are punished for breaking their promises. By questioning established wisdom and innovating to offer a more comprehensive account of mandates,my thesis contributes greatly to the scholarly understanding of the meaning of the linkage and reaffirms the centrality of the oft-overlooked party manifesto to party competition, the policy agenda and public opinion.The connection between political parties' campaign promises and government actions -known as the programme-to-policy linkage - has been a topic of scholarly interest for nearly half a century. Indeed, the degree to which governments follow up on their campaign pledges represents an important question for representative democracies as political systems in which regular elections serve as the mechanism for the enactment of public priorities.Despite voter cynicism, it has become well-established that election winners tend to redeem a healthy share of their pledges in office. However, studies of this linkage focused overwhelmingly on straightforward empirical assessments. This research has primarily examined the extent to which specific manifesto promises are enacted across countries and the institutional constraints which explain variation. Yet, serious questions persist about the origins and format of manifesto documents, the conceptualisation and measurement of the linkage and its significance for democracy in theory and practice. My doctoral thesis contributes to the programme-to-policy literature by shedding light on these gaps in current scholarly understanding.Through a series of sequential chapters, I address these questions. I first focus on the conceptualisation and measurement of linkage. In particular, I re-evaluate an influential alternative approach focused on the connection between issue emphasis and government spending by reassessing a canonical work in the literature and applying new tests. Having established the validity of an adapted version of this approach, finding that the party mandate extends to the government policy agenda in a UK context, I investigate the relationship between parties' issue emphasis and pledge-making strategies, introducing the concept of manifesto \composition" as distinct from policy content to examine its impact on pledge fulfilment. Finally, I turn to the idea of the responsible electorate, investigating the extent to which voters retrospectively reward parties for fulfilling pledges, identifying the first evidence that governments are punished for breaking their promises. By questioning established wisdom and innovating to offer a more comprehensive account of mandates,my thesis contributes greatly to the scholarly understanding of the meaning of the linkage and reaffirms the centrality of the oft-overlooked party manifesto to party competition, the policy agenda and public opinion
Study on the effects of bitter taste receptor on the rat pulmonary artery
No full textBitter taste receptors (TAS2Rs) have been implicated in roles other than taste perception. TAS2R agonists exert vasorelaxant effects in vascular smooth muscle from guinea pig, mouse and humans. We hypothesis that bitter taste agonists could modulate the pulmonary artery vascular tone. The mechanisms of action of bitter taste agonists, which are used to investigate the functions of TAS2Rs, are unclear. The purpose of this study was to pharmacologically characterise the effects of three common bitter taste agonists in the rat pulmonary artery in vitro to elucidate their mechanisms of action. In addition, this study sought to investigate which TAS2R subunits are expressed in the rat pulmonary artery. Myographic studies were conducted in rat pulmonary artery rings pre-contracted with phenylephrine or U46619 to study the pharmacological effect of bitter taste agonists as well as to investigate the possible mechanisms involved in their effects. The calcium fluorescence dye Cal-520 AM was used to measure the intracellular calcium levels in freshly isolated pulmonary artery SMCs. RNA sequencing analysis was conducted to determine the mRNA expression of the Tas2r subunits in the rat pulmonary artery. In addition, RT-qPCR was conducted using Tas2r-specific primers to validate the results from the RNA sequencing analysis.PCR-based genotyping was also carried out to examine the presence of any potential variations on rat TAS2R genes. Quinine, denatonium, and dextromethorphan caused a concentration-dependent relaxation of the pulmonary artery pre-contracted with phenylephrine. Removal of endothelium had no effect in the concentration-response curves for quinine, denatonium, and dextromethorphan, indicating that the effect of these agonists appears to be endothelium-independent in the rat pulmonary artery. Moreover, BKCa channels and the βγ subunit did not appear to be involved in the mechanism of action of bitter taste agonists on the rat pulmonary artery, as blocking these did not result in an overall significant change in the vasorelaxation. In summary, the results from this in vitro study shows that quinine, denatonium, and dextromethorphan have vasorelaxant activities in the rat pulmonary artery. The vasorelaxant action of quinine and denatonium appears to be through inhibition of extracellular calcium influx, most likely through inhibition of ROCC in pulmonary artery SMCs. Dextromethorphan-induced increases in [Ca2+]i in the rat pulmonary artery isolated SMCs. Dextromethorphan seems to has dual actions; involving the extracellular in nature in addition to inhibition of ROCC, partially via VDCC, and mostly from intracellular Ca2+ stores via the PLC-IP3 pathway in pulmonary artery SMCs. The molecular biology studies have showed that Tas2r108 and Tas2r139 were expressed in the rat pulmonary artery. These findings suggest that these bitter taste agonists are effective vasorelaxant that might be used in pulmonary hypertension.Bitter taste receptors (TAS2Rs) have been implicated in roles other than taste perception. TAS2R agonists exert vasorelaxant effects in vascular smooth muscle from guinea pig, mouse and humans. We hypothesis that bitter taste agonists could modulate the pulmonary artery vascular tone. The mechanisms of action of bitter taste agonists, which are used to investigate the functions of TAS2Rs, are unclear. The purpose of this study was to pharmacologically characterise the effects of three common bitter taste agonists in the rat pulmonary artery in vitro to elucidate their mechanisms of action. In addition, this study sought to investigate which TAS2R subunits are expressed in the rat pulmonary artery. Myographic studies were conducted in rat pulmonary artery rings pre-contracted with phenylephrine or U46619 to study the pharmacological effect of bitter taste agonists as well as to investigate the possible mechanisms involved in their effects. The calcium fluorescence dye Cal-520 AM was used to measure the intracellular calcium levels in freshly isolated pulmonary artery SMCs. RNA sequencing analysis was conducted to determine the mRNA expression of the Tas2r subunits in the rat pulmonary artery. In addition, RT-qPCR was conducted using Tas2r-specific primers to validate the results from the RNA sequencing analysis.PCR-based genotyping was also carried out to examine the presence of any potential variations on rat TAS2R genes. Quinine, denatonium, and dextromethorphan caused a concentration-dependent relaxation of the pulmonary artery pre-contracted with phenylephrine. Removal of endothelium had no effect in the concentration-response curves for quinine, denatonium, and dextromethorphan, indicating that the effect of these agonists appears to be endothelium-independent in the rat pulmonary artery. Moreover, BKCa channels and the βγ subunit did not appear to be involved in the mechanism of action of bitter taste agonists on the rat pulmonary artery, as blocking these did not result in an overall significant change in the vasorelaxation. In summary, the results from this in vitro study shows that quinine, denatonium, and dextromethorphan have vasorelaxant activities in the rat pulmonary artery. The vasorelaxant action of quinine and denatonium appears to be through inhibition of extracellular calcium influx, most likely through inhibition of ROCC in pulmonary artery SMCs. Dextromethorphan-induced increases in [Ca2+]i in the rat pulmonary artery isolated SMCs. Dextromethorphan seems to has dual actions; involving the extracellular in nature in addition to inhibition of ROCC, partially via VDCC, and mostly from intracellular Ca2+ stores via the PLC-IP3 pathway in pulmonary artery SMCs. The molecular biology studies have showed that Tas2r108 and Tas2r139 were expressed in the rat pulmonary artery. These findings suggest that these bitter taste agonists are effective vasorelaxant that might be used in pulmonary hypertension
Evaluating the opportunity that could be provided by underutilised non-agricultural land as a source of bioenergy
No full textGiven concerns regarding food security and land use changes, both direct and indirect, resulting from bioenergy production on agricultural land, a better understanding of the alternative land resources that may exist is required. The potential of 'marginal' land for bioenergy provision has been the subject of increasing research efforts. However, the marginal land discourse is problematically framed. One of the main issues pertains to the ambiguity of the terminology which has led to uncertainty regarding the sustainability of land found. Moreover, it is unclear to what extent non-agricultural land resources have been fully included by marginal land studies and what potential role they could play in providing bioenergy without impacting on agricultural production.;An extended understanding of locality and distribution is especially important when assessing potential sites for bioenergy provision. With this in mind, a bottom-up GIS methodology was developed to assess the opportunity that may be provided by underutilised non-agricultural land. The methodology adapted categorisations of bioenergy potential used by Voivontas et al. (2001) and Slade et al. (2010) to focus on the non-agricultural landbank that is available in Scotland.;Initially the theoretical landbank, the hypothetical maximum amount of land available, took the form of a spatial database of non-agricultural land. This involved the compilation of detailed datasets representing boundaries of brownfield, licensed landfills, historic landfill and abandoned mine land. This was followed by the application of a multicriteria evaluation which resulted in the technical landbank, the proportion ofthe theoretical landbank that could be more realistically considered for bioenergy provision based on a range of technical constraints. Further exploratory spatial data analysis was also undertaken to provide an insight into the distribution of clusters of this landbank and the relationship that may exist with heat demand.;This research led to the identification of 24,862 hectares of underutilised non-agricultural land in Scotland in the theoretical landbank. This is the first attempt to produce a detailed spatial database of brownfield land at a national scale and the first quantification of the area of both licensed and historic landfill sites in Scotland. The 17,404 hectares of technical landbank represents the first time an assessment of non-agricultural land has been undertaken at this level of detail with the consideration of technical constraints, providing a better understanding of the role this land resource could play for a range of purposes.;The work presented in this thesis provides the foundation for further research regarding the potential energy crop yields on this land resource, and, therefore, the contribution it could make towards Scotland's ambitious renewable heat targets.Given concerns regarding food security and land use changes, both direct and indirect, resulting from bioenergy production on agricultural land, a better understanding of the alternative land resources that may exist is required. The potential of 'marginal' land for bioenergy provision has been the subject of increasing research efforts. However, the marginal land discourse is problematically framed. One of the main issues pertains to the ambiguity of the terminology which has led to uncertainty regarding the sustainability of land found. Moreover, it is unclear to what extent non-agricultural land resources have been fully included by marginal land studies and what potential role they could play in providing bioenergy without impacting on agricultural production.;An extended understanding of locality and distribution is especially important when assessing potential sites for bioenergy provision. With this in mind, a bottom-up GIS methodology was developed to assess the opportunity that may be provided by underutilised non-agricultural land. The methodology adapted categorisations of bioenergy potential used by Voivontas et al. (2001) and Slade et al. (2010) to focus on the non-agricultural landbank that is available in Scotland.;Initially the theoretical landbank, the hypothetical maximum amount of land available, took the form of a spatial database of non-agricultural land. This involved the compilation of detailed datasets representing boundaries of brownfield, licensed landfills, historic landfill and abandoned mine land. This was followed by the application of a multicriteria evaluation which resulted in the technical landbank, the proportion ofthe theoretical landbank that could be more realistically considered for bioenergy provision based on a range of technical constraints. Further exploratory spatial data analysis was also undertaken to provide an insight into the distribution of clusters of this landbank and the relationship that may exist with heat demand.;This research led to the identification of 24,862 hectares of underutilised non-agricultural land in Scotland in the theoretical landbank. This is the first attempt to produce a detailed spatial database of brownfield land at a national scale and the first quantification of the area of both licensed and historic landfill sites in Scotland. The 17,404 hectares of technical landbank represents the first time an assessment of non-agricultural land has been undertaken at this level of detail with the consideration of technical constraints, providing a better understanding of the role this land resource could play for a range of purposes.;The work presented in this thesis provides the foundation for further research regarding the potential energy crop yields on this land resource, and, therefore, the contribution it could make towards Scotland's ambitious renewable heat targets
From sentiment analysis to choreography of emotions : social media analysis for improved customer relationship management (CRM) in the Omani telecom sector
Get PDFAcross the globe telecom firms are facing fierce competition amidst rapid technological advancements; thus, in order to succeed in the telecom business and remain profitable, satisfying and retaining loyal customers is vital. The process of providing superior services to customers who are socially interconnected has changed the landscape of customer relationship management (CRM). Following a detailed review of CRM, this study has identified the constructs that are critical for customer satisfaction in the Omani telecom sector.The literature review established that the primary reasons for organizations to implement CRM are to improve customer satisfaction, retain their customer base, obtain strategic information and enhance the value of the customer. It was also established that by collecting pertinent information on customers, such as their interests, habits and interactions, this enables organizations to provide a superior service which is specifically tailored to meet the individual needs of each customer.The sentiment analysis (SA) is particularly useful for CRM data collection. It is an efficient tool that has evolved through machine learning algorithms to provide an efficient and robust mechanism to observe customer sentiment in real-time. This research has demonstrated that such data will help to enhance CRM in Omani telecom firms because positive, negative and neutral sentiments alone cannot be used by firms to make strategic marketing decisions; therefore, sentiment analysis has been extended to include emotional analysis. To my knowledge, this is the first time that a novel visualisation tool has been used to demonstrate the choreographic emotion of tweets in real-time. With the recent push towards Marketing 3.0 where customers are considered to be multidimensional entities, emotional scores, more than sentiment scores, can play an active role in firms' decision-making processes.;Questionnaires were developed for customers and social media managers based on the constructs identified during the literature review. Qualitative data was also collected through semi-structured interviews conducted with social media managers. Sentiment and emotional analysis were then applied to social media data pertaining to 83,981 tweets collected over one year in the Omani telecom sector. The data collected from social media managers, customers and findings of literature review were triangulated in order to arrive at meaningful conclusions. Based on this, a series of recommendations designed to enhance CRM in Omani telecom firms have been provided. Whilst 80% of the managers interviewed confirmed that they offer interactive online customer support, customers' responses relating to their level of satisfaction with the support they received remained neutral. This shows that the effectiveness of customer support remains questionable. Female customers indicated that they were satisfied with the support they received; however, male customers were not. Similarly, younger respondents (less than 19 years of age and between 20 to 30 years of age) responded with lower satisfaction scores than the other age groups. This information has to be taken into consideration during resolution management; the implication being that telecom firms should not only implement customer-centric CRM but also enable segment-focused service delivery.;Students and government employees also provided lower scores for their satisfaction regarding the level of customer support they received. I have identified that the emotional scores of live social media data can play a big role in CRM processes, and when these data were visualised as a choreography of emotions using Plutchik's Wheel of Emotion, it was observed that the customers who received better customer service may have experienced feelings such as "surprise" and "happiness". Conversely, when customers were not satisfied, the emotions shown included "disappointment", "anger", "irritation" and/or "anxiety". These findings have been mapped on the Wheel of Emotion.This study, therefore, led to developing a model that integrates the SA of social media data along with the CRM processes of telecom firms in real-time. This involves horizontal and vertical integration of the outcomes of emotional analyses to be shared across the organisation. I recommended the implementation of a 7-step approach to capitalise on the robustness of machine learning algorithms by choreographing emotions from live stream social media data. This can equip firms with better tools as they strive to prosper in a world of competitors and rapidly advancing technology.Across the globe telecom firms are facing fierce competition amidst rapid technological advancements; thus, in order to succeed in the telecom business and remain profitable, satisfying and retaining loyal customers is vital. The process of providing superior services to customers who are socially interconnected has changed the landscape of customer relationship management (CRM). Following a detailed review of CRM, this study has identified the constructs that are critical for customer satisfaction in the Omani telecom sector.The literature review established that the primary reasons for organizations to implement CRM are to improve customer satisfaction, retain their customer base, obtain strategic information and enhance the value of the customer. It was also established that by collecting pertinent information on customers, such as their interests, habits and interactions, this enables organizations to provide a superior service which is specifically tailored to meet the individual needs of each customer.The sentiment analysis (SA) is particularly useful for CRM data collection. It is an efficient tool that has evolved through machine learning algorithms to provide an efficient and robust mechanism to observe customer sentiment in real-time. This research has demonstrated that such data will help to enhance CRM in Omani telecom firms because positive, negative and neutral sentiments alone cannot be used by firms to make strategic marketing decisions; therefore, sentiment analysis has been extended to include emotional analysis. To my knowledge, this is the first time that a novel visualisation tool has been used to demonstrate the choreographic emotion of tweets in real-time. With the recent push towards Marketing 3.0 where customers are considered to be multidimensional entities, emotional scores, more than sentiment scores, can play an active role in firms' decision-making processes.;Questionnaires were developed for customers and social media managers based on the constructs identified during the literature review. Qualitative data was also collected through semi-structured interviews conducted with social media managers. Sentiment and emotional analysis were then applied to social media data pertaining to 83,981 tweets collected over one year in the Omani telecom sector. The data collected from social media managers, customers and findings of literature review were triangulated in order to arrive at meaningful conclusions. Based on this, a series of recommendations designed to enhance CRM in Omani telecom firms have been provided. Whilst 80% of the managers interviewed confirmed that they offer interactive online customer support, customers' responses relating to their level of satisfaction with the support they received remained neutral. This shows that the effectiveness of customer support remains questionable. Female customers indicated that they were satisfied with the support they received; however, male customers were not. Similarly, younger respondents (less than 19 years of age and between 20 to 30 years of age) responded with lower satisfaction scores than the other age groups. This information has to be taken into consideration during resolution management; the implication being that telecom firms should not only implement customer-centric CRM but also enable segment-focused service delivery.;Students and government employees also provided lower scores for their satisfaction regarding the level of customer support they received. I have identified that the emotional scores of live social media data can play a big role in CRM processes, and when these data were visualised as a choreography of emotions using Plutchik's Wheel of Emotion, it was observed that the customers who received better customer service may have experienced feelings such as "surprise" and "happiness". Conversely, when customers were not satisfied, the emotions shown included "disappointment", "anger", "irritation" and/or "anxiety". These findings have been mapped on the Wheel of Emotion.This study, therefore, led to developing a model that integrates the SA of social media data along with the CRM processes of telecom firms in real-time. This involves horizontal and vertical integration of the outcomes of emotional analyses to be shared across the organisation. I recommended the implementation of a 7-step approach to capitalise on the robustness of machine learning algorithms by choreographing emotions from live stream social media data. This can equip firms with better tools as they strive to prosper in a world of competitors and rapidly advancing technology
High-brightness plasma-based Compton backscattering source for high energy physics
No full textExciting, probing and manipulating the quantum states of nuclei is crucial to many scientific, industrial, medical and defence applications of high energy physics. Inverse Compton scattering (ICS) offers the necessary MeV-level photon energies along with highly directed and collimated pulse profiles. However, respective facilities are scarce as the large underlying particle accelerators cause high costs. Plasma accelerators, in contrast, offer orders of magnitude higher accelerating fields and can operate sensibly priced in considerably smaller laboratories. State-of-the-art experiments have routinely shown generation of dense electron beams suitable for MeV-photon pulses with extremely high peak brilliance. Yet, plasma accelerators suffer from large energy spread and emittance that cause spectral broadening impractical for many nuclear applications.This work investigates the prospects of plasma photocathode wakefield accelerators generating low-emittance, high-quality electron beams for ICS. An important component is the experimental demonstration of a novel, plasma-based diagnostic for spatiotemporal synchronisation and alignment of electron and laser beams.This multi-shot method yields absolute time-of-arrival accuracy of ~16 fs and alignment accuracy of 4 μm. It has facilitated the word's first experimental realisation of a plasma photocathode and the plasma torch injection method. These experiments represent milestones towards highest-quality electron beam production, and are fundamental to plasma-based generation of brilliant, narrow-bandwidth and MeV-level-ray sources. Extensive simulations investigate their production and reveal unprecedented single-shot peak brilliance of ~1 1025 photons s-1 mm-2 mrad-2 0.1%BWat 0.4MeV to 9MeV.This work further outlines the generation of inherently synchronised and brilliant-ray pairs, which constitute temporally and spectrally fully separable multi-colour radiation. The underlying effect can further minimise electron beam energy spread.This is shown to shrink the relative -ray bandwidth to 2.3% at 2.4MeV, and overcomes one of the major problems in plasma accelerators and ICS sources. Each part of this work advances its respective research area, yet combined they promise the highest-quality photon sources for nuclear physics applications.Exciting, probing and manipulating the quantum states of nuclei is crucial to many scientific, industrial, medical and defence applications of high energy physics. Inverse Compton scattering (ICS) offers the necessary MeV-level photon energies along with highly directed and collimated pulse profiles. However, respective facilities are scarce as the large underlying particle accelerators cause high costs. Plasma accelerators, in contrast, offer orders of magnitude higher accelerating fields and can operate sensibly priced in considerably smaller laboratories. State-of-the-art experiments have routinely shown generation of dense electron beams suitable for MeV-photon pulses with extremely high peak brilliance. Yet, plasma accelerators suffer from large energy spread and emittance that cause spectral broadening impractical for many nuclear applications.This work investigates the prospects of plasma photocathode wakefield accelerators generating low-emittance, high-quality electron beams for ICS. An important component is the experimental demonstration of a novel, plasma-based diagnostic for spatiotemporal synchronisation and alignment of electron and laser beams.This multi-shot method yields absolute time-of-arrival accuracy of ~16 fs and alignment accuracy of 4 μm. It has facilitated the word's first experimental realisation of a plasma photocathode and the plasma torch injection method. These experiments represent milestones towards highest-quality electron beam production, and are fundamental to plasma-based generation of brilliant, narrow-bandwidth and MeV-level-ray sources. Extensive simulations investigate their production and reveal unprecedented single-shot peak brilliance of ~1 1025 photons s-1 mm-2 mrad-2 0.1%BWat 0.4MeV to 9MeV.This work further outlines the generation of inherently synchronised and brilliant-ray pairs, which constitute temporally and spectrally fully separable multi-colour radiation. The underlying effect can further minimise electron beam energy spread.This is shown to shrink the relative -ray bandwidth to 2.3% at 2.4MeV, and overcomes one of the major problems in plasma accelerators and ICS sources. Each part of this work advances its respective research area, yet combined they promise the highest-quality photon sources for nuclear physics applications
Expanding the heterocyclic repertoire of DNA minor groove binding polyamides
Get PDFExogenous control of gene expression is an essential goal to better understand and ultimately treat diseases which involve dysregulation of transcription. In this effort, Pyrrole-Imidazole (Py-Im) hairpin polyamides (PAs) are minor groove binding (MGB) organic small molecules that demonstrate a versatile capability to recognize, bind, and alter transcription in vitro and, more recently, in vivo.[1] Despite their utility for distinguishing G-C/C-G base pairs, there are several limitations which impede the utilization of polyamides on scale, a major hurdle being that current monomeric pairings do not distinguish a T-A base pair from an A-T. To break this degeneracy, novel building blocks have been sought after to both improve selectivity as well as tune the pharmacokinetic properties of polyamides. Using an 8-ring hairpin scaffold that has demonstrated activity against prostate cancer, the impact of an N-isopropylimidazole monomer (iPr-Im) in the terminal position is reported and a comparison made with the N-methylimidazole (Im) analogue, along with thiazole analogues studied by Padroni et al. (isopropyl thiazole, iPr-Nt, and methyl thiazole, Me-Nt)[²]. UV absorption / fluorescence melt analyses and detailed interrogation of the binding kinetics suggest a strong affinity of hairpin polyamides incorporating the terminal iPr-Im unit, comparable with Im. The data gathered further suggest that the iPr-Im unit itself maintains specificity for G over C, A, or T. The switchSENSE® data also provided insight into the kinetic basis of the selectivity differences, showing a difference between the imidazole analogues and the thiazole analogues. A three-dimensional NMR structure of the iPr-Im-containing polyamide in complex with a 12-mer sequence of double-stranded DNA containing the targeted androgen response element 5'-WWGWWCW-3' (W = A/T) revealed an enhanced major groove compression over the previously reported Im analogue, but also a deeper minor groove penetration than previously reported iPr-Nt polyamide.[²];Chapter 1 introduces the regulation of gene expression using MGB small molecules.Chapter 2 describes the synthesis of hairpin polyamides, starting with the building blocks and then the solid phase synthetic protocol for constructing 8-ring hairpin polyamides.Chapter 3 showcases the thermal UV melt data, and examines the polyamide binding kinetics with DNA duplexes. Further insight into the binding was obtained with switchSENSE® technology, which allowed the generation of kinetic rate maps. The data outlined in this chapter enabled the profiling of the kinetic parameters that govern PA-dsDNA binding.Chapter 4 provides a structural view of a novel iPr-Im-containing polyamide-DNA complex, highlighting the closer proximity of the N-terminal iPr-Im N2 to the exocyclic amine of G5 compared with the N-terminal iPr-Nt analogue. Furthermore, the 3D NMR-restrained molecular dynamics (MD) structure indicated the major groove compression was greater for polyamide with the terminal iPr-Im monomer compared with the Me-Im analogue, highlighting the importance of a seemingly subtle change in steric bulk facing away from the minor groove for augmenting structural distortion of the DNA duplex.Chapter 5 takes the key findings of this thesis and uses them as a lens for looking to the future direction that this research may take. Namely, the potential of this novel iPr-Im monomer unit to replace imidazole as a G-selective residue that can induce greater structural distortion of the DNA duplex by polyamides.Exogenous control of gene expression is an essential goal to better understand and ultimately treat diseases which involve dysregulation of transcription. In this effort, Pyrrole-Imidazole (Py-Im) hairpin polyamides (PAs) are minor groove binding (MGB) organic small molecules that demonstrate a versatile capability to recognize, bind, and alter transcription in vitro and, more recently, in vivo.[1] Despite their utility for distinguishing G-C/C-G base pairs, there are several limitations which impede the utilization of polyamides on scale, a major hurdle being that current monomeric pairings do not distinguish a T-A base pair from an A-T. To break this degeneracy, novel building blocks have been sought after to both improve selectivity as well as tune the pharmacokinetic properties of polyamides. Using an 8-ring hairpin scaffold that has demonstrated activity against prostate cancer, the impact of an N-isopropylimidazole monomer (iPr-Im) in the terminal position is reported and a comparison made with the N-methylimidazole (Im) analogue, along with thiazole analogues studied by Padroni et al. (isopropyl thiazole, iPr-Nt, and methyl thiazole, Me-Nt)[²]. UV absorption / fluorescence melt analyses and detailed interrogation of the binding kinetics suggest a strong affinity of hairpin polyamides incorporating the terminal iPr-Im unit, comparable with Im. The data gathered further suggest that the iPr-Im unit itself maintains specificity for G over C, A, or T. The switchSENSE® data also provided insight into the kinetic basis of the selectivity differences, showing a difference between the imidazole analogues and the thiazole analogues. A three-dimensional NMR structure of the iPr-Im-containing polyamide in complex with a 12-mer sequence of double-stranded DNA containing the targeted androgen response element 5'-WWGWWCW-3' (W = A/T) revealed an enhanced major groove compression over the previously reported Im analogue, but also a deeper minor groove penetration than previously reported iPr-Nt polyamide.[²];Chapter 1 introduces the regulation of gene expression using MGB small molecules.Chapter 2 describes the synthesis of hairpin polyamides, starting with the building blocks and then the solid phase synthetic protocol for constructing 8-ring hairpin polyamides.Chapter 3 showcases the thermal UV melt data, and examines the polyamide binding kinetics with DNA duplexes. Further insight into the binding was obtained with switchSENSE® technology, which allowed the generation of kinetic rate maps. The data outlined in this chapter enabled the profiling of the kinetic parameters that govern PA-dsDNA binding.Chapter 4 provides a structural view of a novel iPr-Im-containing polyamide-DNA complex, highlighting the closer proximity of the N-terminal iPr-Im N2 to the exocyclic amine of G5 compared with the N-terminal iPr-Nt analogue. Furthermore, the 3D NMR-restrained molecular dynamics (MD) structure indicated the major groove compression was greater for polyamide with the terminal iPr-Im monomer compared with the Me-Im analogue, highlighting the importance of a seemingly subtle change in steric bulk facing away from the minor groove for augmenting structural distortion of the DNA duplex.Chapter 5 takes the key findings of this thesis and uses them as a lens for looking to the future direction that this research may take. Namely, the potential of this novel iPr-Im monomer unit to replace imidazole as a G-selective residue that can induce greater structural distortion of the DNA duplex by polyamides
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