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Investigation and optimisation of pulsed 405nm LEDs and their use in a blended environmental decontamination system
Get PDFWith the rise in strains of antibiotic resistant bacteria, and with that, the rising rates of hospital infection, there is a drive for new antimicrobial infection control technologies. One such technology is the use of narrow spectrum light with a central wavelength in the region of 405 nm - henceforth referred to as '405 nm light' - which has been developed for continuous environmental decontamination applications. This study investigates the use of this pulsed 405 nm light, to evaluate potential operational advantages that this delivery method may provide when compared with continuous 405 nm light.;The initial part of the study investigates the fundamental effects of pulsed operation of light emitting diodes (LEDs), by altering a range of parameters including the frequency of the pulsing, the peak irradiance, the duty cycle and the exposure time, and the resulting effects on the antimicrobial action. Results using pulsed 405 nm light demonstrated more efficient bacterial inactivation, yielding a higher electrical energy efficiency and optical efficiency, suggesting beneficial results in using pulsed 405 nm light over continuous 405 nm light.;The study then investigates, more specifically, the application of pulsed 405 nm light to the area of continuous environmental decontamination. The study documents the design, build and testing of a prototype blended pulsed antimicrobial white light based on pulsed 405 nm LEDs - supplemented by red, green and yellow/amber wavelengths to produce the blended white light. The pulsed blended white light prototype demonstrated an improved colour quality with the supplementary colours when compared with the 405 nm light alone whilst demonstrating effective antimicrobial action.;Overall, this study provides the first evidence of the use of pulsed 405 nm LEDs and the operational advantages over continuously run 405 nm LEDs in terms of antimicrobial action. The study then utilises this pulsed delivery system to develop a pulsed blended white light prototype system, a possible viable future design option for continuous environmental decontamination systems.With the rise in strains of antibiotic resistant bacteria, and with that, the rising rates of hospital infection, there is a drive for new antimicrobial infection control technologies. One such technology is the use of narrow spectrum light with a central wavelength in the region of 405 nm - henceforth referred to as '405 nm light' - which has been developed for continuous environmental decontamination applications. This study investigates the use of this pulsed 405 nm light, to evaluate potential operational advantages that this delivery method may provide when compared with continuous 405 nm light.;The initial part of the study investigates the fundamental effects of pulsed operation of light emitting diodes (LEDs), by altering a range of parameters including the frequency of the pulsing, the peak irradiance, the duty cycle and the exposure time, and the resulting effects on the antimicrobial action. Results using pulsed 405 nm light demonstrated more efficient bacterial inactivation, yielding a higher electrical energy efficiency and optical efficiency, suggesting beneficial results in using pulsed 405 nm light over continuous 405 nm light.;The study then investigates, more specifically, the application of pulsed 405 nm light to the area of continuous environmental decontamination. The study documents the design, build and testing of a prototype blended pulsed antimicrobial white light based on pulsed 405 nm LEDs - supplemented by red, green and yellow/amber wavelengths to produce the blended white light. The pulsed blended white light prototype demonstrated an improved colour quality with the supplementary colours when compared with the 405 nm light alone whilst demonstrating effective antimicrobial action.;Overall, this study provides the first evidence of the use of pulsed 405 nm LEDs and the operational advantages over continuously run 405 nm LEDs in terms of antimicrobial action. The study then utilises this pulsed delivery system to develop a pulsed blended white light prototype system, a possible viable future design option for continuous environmental decontamination systems
Development and evaluation of open-ended learning activities to support chemical engineering students' development
Get PDFThere are myriad challenges in developing a stimulating yet supportive curriculum in many subject areas, and recent shifts in course entry demographics and employer expectations have made this especially challenging in chemical engineering. As a discipline, there has been a gender shift in recent years towards greater women student representation at undergraduate level and an increase in global industry sector demand for chemical engineering graduates. This has raised issues of inclusion, to allow women students to participate equally in learning activities and wider opportunities, as well as those of graduate skills development, tempered by reports from the Confederation of Business Industry, which indicate that employers are dissatisfied with the skill sets offered by graduates.;This work sets out to address these concerns through evaluation of active learning and makes recommendations regarding integrated learning, where group work is used to develop students' professional competencies in tandem with their transferable skills. Engineering education has developed over the years to include many instances of group based working that focusses on problem based learning, however, the full extent of the impact that this may have on students' development is little understood or studied. This thesis explores the role of problem-based learning in facilitating students' engagement with specific components of a chemical engineering degree within UK Higher Education, including surveys of staff and student perceptions of group working and skills development, statistical evaluation of student attainment and appraisal of course (re)design.;Despite significant group work and problem based learning focussed on developing openended working, teaching staff identified issues with students' abilities to deal with such problems in chemical engineering and to accept open-endedness itself. By identifying openendedness as a threshold concept, it has been possible to study the impact that the timeline of teaching has on student development and achievement. This work presents a strategy for vertical alignment of teaching within the chemical engineering degree to support student development and foster student confidence and autonomy.;Within this context, the use of group working is key and the thesis also investigates the role of tutors within this educational framework and how such activities impact on the inclusion of women in engineering subjects. Additional work to redevelop early years teaching to address the identified threshold concept and, specifically, its role in the capstone design project is reported and students' perceptions of skills development has been investigated to understand the impact that working in such an environment has on the transferable skill sets of these cohorts.;The insights gained show that tutor supported problem based learning can be key in nurturing critical evaluation skills in students, often requiring them to explain their reasoning and work with unknown quantities. The role of women students in group working changes with their increased awareness of social expectations to adapt to normalised views of women's roles; this happens early in their University career and sets working parameters for the remainder of their degrees, so addresses the early imbalance in role assignment that may be observed. The successful incorporation of problem based learning activities in early years helps students overcome the liminality that results from open-ended working, with wider impact, beyond the classroom, in providing advanced skill sets and working practices that will enhance employability.;Students demonstrate increased engagement, mitigated stress, bolstered confidence and reduced confusion, while student retention is also improved. By surveying current students and graduates, a link between experiential practice and high skills confidence is observed; hence, it is recommended that students are encouraged to reflect on their learning experiences and that integrated learning be promoted to develop all skills effectively. The work also indicates that using problem based learning in early year classes, to underpin advanced project working in later years, is worthy of consideration for chemical engineering teaching as well as the wider engineering discipline.There are myriad challenges in developing a stimulating yet supportive curriculum in many subject areas, and recent shifts in course entry demographics and employer expectations have made this especially challenging in chemical engineering. As a discipline, there has been a gender shift in recent years towards greater women student representation at undergraduate level and an increase in global industry sector demand for chemical engineering graduates. This has raised issues of inclusion, to allow women students to participate equally in learning activities and wider opportunities, as well as those of graduate skills development, tempered by reports from the Confederation of Business Industry, which indicate that employers are dissatisfied with the skill sets offered by graduates.;This work sets out to address these concerns through evaluation of active learning and makes recommendations regarding integrated learning, where group work is used to develop students' professional competencies in tandem with their transferable skills. Engineering education has developed over the years to include many instances of group based working that focusses on problem based learning, however, the full extent of the impact that this may have on students' development is little understood or studied. This thesis explores the role of problem-based learning in facilitating students' engagement with specific components of a chemical engineering degree within UK Higher Education, including surveys of staff and student perceptions of group working and skills development, statistical evaluation of student attainment and appraisal of course (re)design.;Despite significant group work and problem based learning focussed on developing openended working, teaching staff identified issues with students' abilities to deal with such problems in chemical engineering and to accept open-endedness itself. By identifying openendedness as a threshold concept, it has been possible to study the impact that the timeline of teaching has on student development and achievement. This work presents a strategy for vertical alignment of teaching within the chemical engineering degree to support student development and foster student confidence and autonomy.;Within this context, the use of group working is key and the thesis also investigates the role of tutors within this educational framework and how such activities impact on the inclusion of women in engineering subjects. Additional work to redevelop early years teaching to address the identified threshold concept and, specifically, its role in the capstone design project is reported and students' perceptions of skills development has been investigated to understand the impact that working in such an environment has on the transferable skill sets of these cohorts.;The insights gained show that tutor supported problem based learning can be key in nurturing critical evaluation skills in students, often requiring them to explain their reasoning and work with unknown quantities. The role of women students in group working changes with their increased awareness of social expectations to adapt to normalised views of women's roles; this happens early in their University career and sets working parameters for the remainder of their degrees, so addresses the early imbalance in role assignment that may be observed. The successful incorporation of problem based learning activities in early years helps students overcome the liminality that results from open-ended working, with wider impact, beyond the classroom, in providing advanced skill sets and working practices that will enhance employability.;Students demonstrate increased engagement, mitigated stress, bolstered confidence and reduced confusion, while student retention is also improved. By surveying current students and graduates, a link between experiential practice and high skills confidence is observed; hence, it is recommended that students are encouraged to reflect on their learning experiences and that integrated learning be promoted to develop all skills effectively. The work also indicates that using problem based learning in early year classes, to underpin advanced project working in later years, is worthy of consideration for chemical engineering teaching as well as the wider engineering discipline
An empirical evaluation of fixed income fund performance : new evidence across alternative methods
Get PDFWith a wealth of research directed at fund performance evaluation, that which is specific to bond funds is relatively minimal. This thesis aims to shed further light on this topic using a new sample of UK data. To most effectively judge the merits of active management the specification of a reliable benchmark model is paramount. The first empirical chapter involves testing a range of single and multi-factor models to determine which of these can be considered the most suitable for evaluation of the funds in question. The Gibbons, Ross, and Shanken (1989) test of mean-variance efficiency is first applied as an absolute test, with further alpha test statistics used for a relative evaluation of the candidate models. Overall, the results show that a five-factor model (named Maturity 5) that includes adjustment for both term and credit is the most reliable. This is primarily indicated by the lowest absolute alphas and corresponding goodness of fit statistics, i.e., low standard errors and high (adj)R2. A multi-period analysis is conducted to determine the extent to which this varies over time. The results are consistent, with the same model performing the best in each case. The second empirical chapter builds upon these findings and uses Maturity 5 to evaluate the sample of UK bond funds. The results over the whole period from January 1999 until July 2016 are consistent with much of the academic literature; the funds are found to underperform on a risk-adjusted basis by approximately a magnitude of costs. However, during the recent subsample from September 2009 the performance is neutral. The use of dummy variables and Wald tests indicates that the Government, Corporate, and Diversified funds perform significantly better here. Having identified during testing that minimal bias is likely to be induced by the Maturity 5 model, it can be inferred that the performance is not just a result of exposure to passive portfolios (as represented by the test assets). Instead, there appears to be some ability beyond this being employed by the active funds. The measure of Treynor and Mazuy (1966) has been used to identify if market timing makes a positive contribution to performance. Evidence is minimal when the Barclays Sterling Aggregate Index is used as a proxy, however, 25% of Corporate bond funds exhibit positive ability relative to the category-specific benchmark as assigned by Morningstar. The third and final empirical chapter seeks to shed some light as to whether the active managers are lucky with respect to alpha generation or indeed exhibit true outperformance. A bootstrap procedure is first applied to the individual funds to do so. The method used here is known as entire-cases resampling (Fama and French 2010), whereby the time-ordering is maintained across the sample. This differs from the approach of KTWW (2006), which is used prevalently throughout the fund performance literature. To date, the entire-cases method has not yet been applied to a sample of bond funds. The initial results in this chapter support superior performance in the low-rate environment; this being evident across all funds from the 97h percentile, and Corporate from the 95th. To add further robustness, two variations of the false discovery rate method have been used to adjust for luck. The “classical” approach of BSW (2010) also finds positive alpha, isolated to the post-crisis period. Lower expenses characterise these funds, along with a higher number of observations per fund, and the average alpha is approx. 1.68% p.a. Recent literature has proposed many refinements to the methods used to address multiple hypothesis testing issues. The Ferson and Chen (2019) approach expands upon the entire cases method already used in this chapter, allowing for not only a lucky distribution to be considered, but also simulates those defined as both “good” and “bad”, incorporating power and confusion parameters. The results here are the most positive yet. At 10% 10% level, the proportion of outperforming funds is 11% and 33% across the whole and recent periods respectively. This is again driven primarily by the Corporate category of funds.With a wealth of research directed at fund performance evaluation, that which is specific to bond funds is relatively minimal. This thesis aims to shed further light on this topic using a new sample of UK data. To most effectively judge the merits of active management the specification of a reliable benchmark model is paramount. The first empirical chapter involves testing a range of single and multi-factor models to determine which of these can be considered the most suitable for evaluation of the funds in question. The Gibbons, Ross, and Shanken (1989) test of mean-variance efficiency is first applied as an absolute test, with further alpha test statistics used for a relative evaluation of the candidate models. Overall, the results show that a five-factor model (named Maturity 5) that includes adjustment for both term and credit is the most reliable. This is primarily indicated by the lowest absolute alphas and corresponding goodness of fit statistics, i.e., low standard errors and high (adj)R2. A multi-period analysis is conducted to determine the extent to which this varies over time. The results are consistent, with the same model performing the best in each case. The second empirical chapter builds upon these findings and uses Maturity 5 to evaluate the sample of UK bond funds. The results over the whole period from January 1999 until July 2016 are consistent with much of the academic literature; the funds are found to underperform on a risk-adjusted basis by approximately a magnitude of costs. However, during the recent subsample from September 2009 the performance is neutral. The use of dummy variables and Wald tests indicates that the Government, Corporate, and Diversified funds perform significantly better here. Having identified during testing that minimal bias is likely to be induced by the Maturity 5 model, it can be inferred that the performance is not just a result of exposure to passive portfolios (as represented by the test assets). Instead, there appears to be some ability beyond this being employed by the active funds. The measure of Treynor and Mazuy (1966) has been used to identify if market timing makes a positive contribution to performance. Evidence is minimal when the Barclays Sterling Aggregate Index is used as a proxy, however, 25% of Corporate bond funds exhibit positive ability relative to the category-specific benchmark as assigned by Morningstar. The third and final empirical chapter seeks to shed some light as to whether the active managers are lucky with respect to alpha generation or indeed exhibit true outperformance. A bootstrap procedure is first applied to the individual funds to do so. The method used here is known as entire-cases resampling (Fama and French 2010), whereby the time-ordering is maintained across the sample. This differs from the approach of KTWW (2006), which is used prevalently throughout the fund performance literature. To date, the entire-cases method has not yet been applied to a sample of bond funds. The initial results in this chapter support superior performance in the low-rate environment; this being evident across all funds from the 97h percentile, and Corporate from the 95th. To add further robustness, two variations of the false discovery rate method have been used to adjust for luck. The “classical” approach of BSW (2010) also finds positive alpha, isolated to the post-crisis period. Lower expenses characterise these funds, along with a higher number of observations per fund, and the average alpha is approx. 1.68% p.a. Recent literature has proposed many refinements to the methods used to address multiple hypothesis testing issues. The Ferson and Chen (2019) approach expands upon the entire cases method already used in this chapter, allowing for not only a lucky distribution to be considered, but also simulates those defined as both “good” and “bad”, incorporating power and confusion parameters. The results here are the most positive yet. At 10% 10% level, the proportion of outperforming funds is 11% and 33% across the whole and recent periods respectively. This is again driven primarily by the Corporate category of funds
The role of sphingosine kinases and dihydroceramide desaturase in cell survival/apoptosis and inflammation pathways
No full textThe literature details significant controversy regarding the role of dihydroceramide desaturase (Degs1) in regulating cell survival/apoptosis and therefore this study primarily examined the molecular basis of the reported opposing roles of Degs1. The sphingosine kinase inhibitor SKi [2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole] or the Degs1 inhibitor fenretinide promoted the polyubiquitination of Degs1 (Mr = 40-140 kDa) through a mechanism involving p38 mitogen-activated protein kinase (MAPK), oxidative stress, and Mdm2 (E3 ligase) in HEK293T cells.;The polyubiquitinated forms of Degs1 acquire a 'gain of function' and activate pro-survival pathways, p38 MAPK/c-Jun N-terminal kinase (JNK), and X-box protein 1s (XBP-1s) in HEK293T cells. In contrast, the sphingosine kinase inhibitor, ABC294640 [3-(4- chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide] (25 to 50 μM), did not promote formation of polyubiquitinated Degs1 forms and induced apoptosis of HEK293T cells via a mechanism involving native Degs1. Native Degs1 appears to function in this context via substrate induction to increase de novo synthesis of apoptotic ceramides.;These results were achieved using siRNA transfections, western protein analysis of protein expression, immunoprecipitation, [3H]-Thymidine incorporation assay, and mass spectrometry. These novel findings are the first to reveal that the polyubiquitinated forms of Degs1 exhibit opposing function compared with the native form, which could explain the controversy concerning the role of this enzyme in apoptosis versus cell survival described within literature.;The study next investigated the role of sphingosine kinases (SK1, SK2) in regulating p53, stress activated protein kinases, and XBP-1s in HEK293T cells since SK inhibitors are known to promote p53-dependent cell death. SKi stimulated polyubquitination of p53 to form two higher molecular mass proteins (63 and 90 kDa), which might represent inactive forms of p53. The formation of p63/p90 in response to SKi was enhanced by completely eliminating SK1 from HEK293T cells using a combination of SK1 siRNA and SKi.;In addition, sphingolipids measurements showed a decrease in the levels of S1P and increase in the levels of sphingosine under these conditions. However, SK2 or Degs1 had no role in regulating the formation of p63/p90. In addition, the complete elimination of SK1 enhanced the activation of p38 MAPK/JNK pro-survival pathways in response to SKi.;Taken together with the effect on p53, these findings suggest that SK1 opposes pro-survival signalling pathways in HEK293T cells. The proteasome inhibitor, MG132 also induced expression of the pro-survival protein XBP-1s and this was enhanced when HEK293T cells were treated with SKi. SK2 siRNA reduced XBP-1s levels in response to MG132/SKi while p53 siRNA promoted this effect. These findings were achieved using siRNA and transient plasmid transfections, western protein analysis of protein expression, immunoprecipitation, [3H]-Thymidine incorporation assay, mass spectrometry, and immunofluorescence microscopy which suggest that SK2 opposes the death promoting function of p53.;Lastly, the role of SK1 and SK2 in regulating inflammation-based transcriptional factors in keratinocytes was investigated using western protein analysis of protein expression and luciferase reporter assays. SK2 inhibitors, such as ABC294640 or SKi or K145 or (R)-methylether FTY720 (ROMe) were shown to reverse the degradation of inhibitor kappa B (IκB) and transcriptional regulation of nuclear factor kappa B (NF-κB) in response to TNFα. In contrast, the potent SK1 inhibitor, PF-543 did not reverse IκB degradation and only weakly inhibited transcriptional regulation of NF-κB at a concentration that is 50-fold higher than the Ki for inhibition of SK1 activity.;Thus SK2 and not SK1 is proposed to regulate NF-κB signalling and transcription. The effect of the sphingosine kinases on transcriptional regulation of Activator Protein-1 (AP-1) was also investigated. SK2 inhibitors, ABC294640 or K145 reduced phorbol myristate acetate (PMA) stimulated phosphorylation of JNK and ERK-1/2 and transcriptional activity of AP-1. In contrast, other SK inhibitors including PF-543, SKi and ROMe did not inhibit JNK and ERK-1/2 signalling and only produced a minimal reduction in AP-1 transcriptional activity, thereby suggesting that the effects of SK2 inhibitors on JNK/ERK signalling and AP-1 transcriptional activity are likely to be 'off-target'.;These novel significant findings provide improved understanding of the role of Degs1, SK1 and SK2 in regulating cell survival and inflammation and this might ultimately aid in the identification of novel signalling networks and therapeutic targets for treatment of various diseases, including cancer.The literature details significant controversy regarding the role of dihydroceramide desaturase (Degs1) in regulating cell survival/apoptosis and therefore this study primarily examined the molecular basis of the reported opposing roles of Degs1. The sphingosine kinase inhibitor SKi [2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole] or the Degs1 inhibitor fenretinide promoted the polyubiquitination of Degs1 (Mr = 40-140 kDa) through a mechanism involving p38 mitogen-activated protein kinase (MAPK), oxidative stress, and Mdm2 (E3 ligase) in HEK293T cells.;The polyubiquitinated forms of Degs1 acquire a 'gain of function' and activate pro-survival pathways, p38 MAPK/c-Jun N-terminal kinase (JNK), and X-box protein 1s (XBP-1s) in HEK293T cells. In contrast, the sphingosine kinase inhibitor, ABC294640 [3-(4- chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide] (25 to 50 μM), did not promote formation of polyubiquitinated Degs1 forms and induced apoptosis of HEK293T cells via a mechanism involving native Degs1. Native Degs1 appears to function in this context via substrate induction to increase de novo synthesis of apoptotic ceramides.;These results were achieved using siRNA transfections, western protein analysis of protein expression, immunoprecipitation, [3H]-Thymidine incorporation assay, and mass spectrometry. These novel findings are the first to reveal that the polyubiquitinated forms of Degs1 exhibit opposing function compared with the native form, which could explain the controversy concerning the role of this enzyme in apoptosis versus cell survival described within literature.;The study next investigated the role of sphingosine kinases (SK1, SK2) in regulating p53, stress activated protein kinases, and XBP-1s in HEK293T cells since SK inhibitors are known to promote p53-dependent cell death. SKi stimulated polyubquitination of p53 to form two higher molecular mass proteins (63 and 90 kDa), which might represent inactive forms of p53. The formation of p63/p90 in response to SKi was enhanced by completely eliminating SK1 from HEK293T cells using a combination of SK1 siRNA and SKi.;In addition, sphingolipids measurements showed a decrease in the levels of S1P and increase in the levels of sphingosine under these conditions. However, SK2 or Degs1 had no role in regulating the formation of p63/p90. In addition, the complete elimination of SK1 enhanced the activation of p38 MAPK/JNK pro-survival pathways in response to SKi.;Taken together with the effect on p53, these findings suggest that SK1 opposes pro-survival signalling pathways in HEK293T cells. The proteasome inhibitor, MG132 also induced expression of the pro-survival protein XBP-1s and this was enhanced when HEK293T cells were treated with SKi. SK2 siRNA reduced XBP-1s levels in response to MG132/SKi while p53 siRNA promoted this effect. These findings were achieved using siRNA and transient plasmid transfections, western protein analysis of protein expression, immunoprecipitation, [3H]-Thymidine incorporation assay, mass spectrometry, and immunofluorescence microscopy which suggest that SK2 opposes the death promoting function of p53.;Lastly, the role of SK1 and SK2 in regulating inflammation-based transcriptional factors in keratinocytes was investigated using western protein analysis of protein expression and luciferase reporter assays. SK2 inhibitors, such as ABC294640 or SKi or K145 or (R)-methylether FTY720 (ROMe) were shown to reverse the degradation of inhibitor kappa B (IκB) and transcriptional regulation of nuclear factor kappa B (NF-κB) in response to TNFα. In contrast, the potent SK1 inhibitor, PF-543 did not reverse IκB degradation and only weakly inhibited transcriptional regulation of NF-κB at a concentration that is 50-fold higher than the Ki for inhibition of SK1 activity.;Thus SK2 and not SK1 is proposed to regulate NF-κB signalling and transcription. The effect of the sphingosine kinases on transcriptional regulation of Activator Protein-1 (AP-1) was also investigated. SK2 inhibitors, ABC294640 or K145 reduced phorbol myristate acetate (PMA) stimulated phosphorylation of JNK and ERK-1/2 and transcriptional activity of AP-1. In contrast, other SK inhibitors including PF-543, SKi and ROMe did not inhibit JNK and ERK-1/2 signalling and only produced a minimal reduction in AP-1 transcriptional activity, thereby suggesting that the effects of SK2 inhibitors on JNK/ERK signalling and AP-1 transcriptional activity are likely to be 'off-target'.;These novel significant findings provide improved understanding of the role of Degs1, SK1 and SK2 in regulating cell survival and inflammation and this might ultimately aid in the identification of novel signalling networks and therapeutic targets for treatment of various diseases, including cancer
Registration of pre-operative lung cancer PET/CT scans with post-operative histopathology images
Get PDFNon-invasive imaging modalities used in the diagnosis of lung cancer, such as Positron Emission Tomography (PET) or Computed Tomography (CT), currently provide insuffcient information about the cellular make-up of the lesion microenvironment, unless they are compared against the gold standard of histopathology.The aim of this retrospective study was to build a robust imaging framework for registering in vivo and post-operative scans from lung cancer patients, in order to have a global, pathology-validated multimodality map of the tumour and its surroundings.;Initial experiments were performed on tissue-mimicking phantoms, to test different shape reconstruction methods. The choice of interpolator and slice thickness were found to affect the algorithm's output, in terms of overall volume and local feature recovery. In the second phase of the study, nine lung cancer patients referred for radical lobectomy were recruited. Resected specimens were inflated with agar, sliced at 5 mm intervals, and each cross-section was photographed. The tumour area was delineated on the block-face pathology images and on the preoperative PET/CT scans.;Airway segments were also added to the reconstructed models, to act as anatomical fiducials. Binary shapes were pre-registered by aligning their minimal bounding box axes, and subsequently transformed using rigid registration. In addition, histopathology slides were matched to the block-face photographs using moving least squares algorithm.;A two-step validation process was used to evaluate the performance of the proposed method against manual registration carried out by experienced consultants. In two out of three cases, experts rated the results generated by the algorithm as the best output, suggesting that the developed framework outperforms the current standard practice.Non-invasive imaging modalities used in the diagnosis of lung cancer, such as Positron Emission Tomography (PET) or Computed Tomography (CT), currently provide insuffcient information about the cellular make-up of the lesion microenvironment, unless they are compared against the gold standard of histopathology.The aim of this retrospective study was to build a robust imaging framework for registering in vivo and post-operative scans from lung cancer patients, in order to have a global, pathology-validated multimodality map of the tumour and its surroundings.;Initial experiments were performed on tissue-mimicking phantoms, to test different shape reconstruction methods. The choice of interpolator and slice thickness were found to affect the algorithm's output, in terms of overall volume and local feature recovery. In the second phase of the study, nine lung cancer patients referred for radical lobectomy were recruited. Resected specimens were inflated with agar, sliced at 5 mm intervals, and each cross-section was photographed. The tumour area was delineated on the block-face pathology images and on the preoperative PET/CT scans.;Airway segments were also added to the reconstructed models, to act as anatomical fiducials. Binary shapes were pre-registered by aligning their minimal bounding box axes, and subsequently transformed using rigid registration. In addition, histopathology slides were matched to the block-face photographs using moving least squares algorithm.;A two-step validation process was used to evaluate the performance of the proposed method against manual registration carried out by experienced consultants. In two out of three cases, experts rated the results generated by the algorithm as the best output, suggesting that the developed framework outperforms the current standard practice
Does the N-terminally truncated sphingosine-1-phosphate receptor 2 promote extracellular regulated Kinase-1/2, c-Jun N-Terminus Kinase and p38 Mitogen-activated protein Kinase activation in breast cancer cells, fibroblasts and embryonic kidney cells?
No full textThe reciprocal relationship shared between breast cancer cells and cells of the tumour microenvironment is crucial in relation to metastasis. MDA-MB-231 breast cancer cells have been shown to release the S1P2 receptor in exosomes, where it is taken up by fibroblasts and N-Terminally processed to a shorter, constitutively active form. The aim of the investigation was to examine the effect of truncated S1P2 on the activation of the ERK-1/2 pathway in various cell lines. Indeed, using truncated (1x and 2x HA tagged) S1P2 receptor constructs we have demonstrated constitutive activation of the ERK-1/2 pathway in HEK293 cells, MEFs but not MDA-MB-231 cells. Sustained ERK-1/2 activation could facilitate expansion of the fibroblast population and may prove an important step in the metastatic cascade. Indeed, our results have shown the 2x HA-tagged truncated S1P2 to promote DNA synthesis in HEK293 cells and MEFs but not MDA-MB-231 cells. This would suggest that ERK-1/2 activated by the truncated receptor is responsible for promoting DNA synthesis. The S1P2 receptor sub-type selective agonist, CYM5520, was shown to inhibit DNA synthesis in HEK293 cells (p = 0.1), MEFs (p = 0.01) and MDA-MB-231 cells (p < 0.05). Similarly, the S1P4 selective agonist CYM50308 was also shown to significantly inhibit DNA synthesis in HEK293 cells (p < 0.01), MEFs (p < 0.001) and MDA-MB-231 cells (p < 0.05). Since these agonists were shown to induce ERK-1/2 activation in HEK293 cells, there is a correlation between activation of this kinase pathway and inhibition of DNA synthesis in these cells. However, there was no activation of ERK-1/2 by these agonists in MEFs or MDA-MB-231 cells which indicates there may be activation or inhibition of alternative pathways to achieve this response. The inhibition of DNA synthesis by CYM5520 and CYM50308 could be explained by the agonists promoting the migration of these cells. Migrating cells require growth arrest and therefore DNA synthesis would be inhibited. Indeed, we have shown CYM5520 to induce migration of MDA-MB-231 cells (p < 0.05). Therefore, we speculate here that MDA-MB-231 cells may release the S1P2 receptor early in the metastatic cascade so as to increase DNA synthesis and subsequent proliferation. When taken together, our results show a clear function for this unique form of GPCR signalling in breast cancer tumorigenesis.The reciprocal relationship shared between breast cancer cells and cells of the tumour microenvironment is crucial in relation to metastasis. MDA-MB-231 breast cancer cells have been shown to release the S1P2 receptor in exosomes, where it is taken up by fibroblasts and N-Terminally processed to a shorter, constitutively active form. The aim of the investigation was to examine the effect of truncated S1P2 on the activation of the ERK-1/2 pathway in various cell lines. Indeed, using truncated (1x and 2x HA tagged) S1P2 receptor constructs we have demonstrated constitutive activation of the ERK-1/2 pathway in HEK293 cells, MEFs but not MDA-MB-231 cells. Sustained ERK-1/2 activation could facilitate expansion of the fibroblast population and may prove an important step in the metastatic cascade. Indeed, our results have shown the 2x HA-tagged truncated S1P2 to promote DNA synthesis in HEK293 cells and MEFs but not MDA-MB-231 cells. This would suggest that ERK-1/2 activated by the truncated receptor is responsible for promoting DNA synthesis. The S1P2 receptor sub-type selective agonist, CYM5520, was shown to inhibit DNA synthesis in HEK293 cells (p = 0.1), MEFs (p = 0.01) and MDA-MB-231 cells (p < 0.05). Similarly, the S1P4 selective agonist CYM50308 was also shown to significantly inhibit DNA synthesis in HEK293 cells (p < 0.01), MEFs (p < 0.001) and MDA-MB-231 cells (p < 0.05). Since these agonists were shown to induce ERK-1/2 activation in HEK293 cells, there is a correlation between activation of this kinase pathway and inhibition of DNA synthesis in these cells. However, there was no activation of ERK-1/2 by these agonists in MEFs or MDA-MB-231 cells which indicates there may be activation or inhibition of alternative pathways to achieve this response. The inhibition of DNA synthesis by CYM5520 and CYM50308 could be explained by the agonists promoting the migration of these cells. Migrating cells require growth arrest and therefore DNA synthesis would be inhibited. Indeed, we have shown CYM5520 to induce migration of MDA-MB-231 cells (p < 0.05). Therefore, we speculate here that MDA-MB-231 cells may release the S1P2 receptor early in the metastatic cascade so as to increase DNA synthesis and subsequent proliferation. When taken together, our results show a clear function for this unique form of GPCR signalling in breast cancer tumorigenesis
Not just a joke : rape culture in Internet memes about #MeToo
Get PDFThis thesis provides a critical account of the discursive construction of sexual violence in humorous Internet memes about #MeToo. Applying an interdisciplinary lens, the thesis combines feminist scholarship on discourse, affect, humour, rape culture and online misogyny in order to provide a contribution to the field of feminist digital media studies.;I employ a case study approach to my data set of 866 Internet memes collected from three social media platforms, 9gag, Reddit and Imgur, between October and December 2017 using the four search terms: #MeToo, Harvey Weinstein, Kevin Spacey, and Louis C.K.;Applying discourse analysis to Internet memes generated by these specific search terms enables me to investigate how sexual violence is portrayed in different ways depending on who the perpetrators and the victims are. The three social media platforms have been chosen as they encourage users to upload humorous content enabling me to investigate how humorous content constructs sexual violence in specific ways. The thesis demonstrates how certain notions about gender and sexuality are discursively reproduced in online spaces that privilege heterosexual men and exclude women and homosexual men.;The thesis aims to contribute to existing research in feminist media studies by investigating the backlash against #MeToo on specifically humorous discursive spaces thus gaining insight into how sexual violence is discursively constructed in spaces that otherwise might often be overlooked and disregarded as meaningless and harmless. By taking humour seriously the thesis contends this 'just-a-joke' discourse.This thesis provides a critical account of the discursive construction of sexual violence in humorous Internet memes about #MeToo. Applying an interdisciplinary lens, the thesis combines feminist scholarship on discourse, affect, humour, rape culture and online misogyny in order to provide a contribution to the field of feminist digital media studies.;I employ a case study approach to my data set of 866 Internet memes collected from three social media platforms, 9gag, Reddit and Imgur, between October and December 2017 using the four search terms: #MeToo, Harvey Weinstein, Kevin Spacey, and Louis C.K.;Applying discourse analysis to Internet memes generated by these specific search terms enables me to investigate how sexual violence is portrayed in different ways depending on who the perpetrators and the victims are. The three social media platforms have been chosen as they encourage users to upload humorous content enabling me to investigate how humorous content constructs sexual violence in specific ways. The thesis demonstrates how certain notions about gender and sexuality are discursively reproduced in online spaces that privilege heterosexual men and exclude women and homosexual men.;The thesis aims to contribute to existing research in feminist media studies by investigating the backlash against #MeToo on specifically humorous discursive spaces thus gaining insight into how sexual violence is discursively constructed in spaces that otherwise might often be overlooked and disregarded as meaningless and harmless. By taking humour seriously the thesis contends this 'just-a-joke' discourse
The performance and perception of authenticity in contemporary U.K. spoken word poetry
Get PDFThis thesis was previously held under moratorium from 1st December 2020 until 1st December 2021Contemporary spoken word poetry events are often described as a platform for ‘authentic’ expression: emotionally charged spaces at which poets viscerally, honestly share their personal experiences directly with the audience. Scholarship into this genre generally concurs that ‘authenticity’ functions as an aesthetic and moral quality within the genre: that poems and poets perceived as ‘authentic’ achieve more success. However, ‘authenticity’ is not a singular, static trait but rather a rapidly evolving, culturally conditional, and subjective process relying on the dialogic exchange of performance and perception. This thesis seeks to clarify the discourse regarding authenticity within contemporary U.K. spoken word poetry by proposing a genre-specific taxonomy of ten strains of authenticity which are commonly performed, framed, and perceived in this sphere. These distinct, though interlacing, strains are the authenticities of origin, autobiographical self, narrative, persona, temporal state, emotion, voice, identity, motivation, and engagement. The thesis draws upon social scientific methodology, including interviews with 70 U.K.-based poets, to examine how each of these strains functions as an aesthetic and moral quality within the genre. It considers how individual poets may perform these authenticities as well as how the conventions of spoken word spaces encourage the perception of poets as ‘real’ people (rather than actors playing characters) sharing autobiographical narratives while fully co-present with their audiences. Ultimately, this thesis emphasises the constructed, subjective nature of authenticity by revealing the extent to which spoken word performances are pre-composed, rehearsed, and otherwise artistically wrought. It concludes by analysing the commonality of descriptions of spoken word poetry as ‘authentic’ in academic scholarship and popular media and argues that this rhetoric is rooted in stereotype and downplays the skill and craft required in this multidisciplinary art form.Contemporary spoken word poetry events are often described as a platform for ‘authentic’ expression: emotionally charged spaces at which poets viscerally, honestly share their personal experiences directly with the audience. Scholarship into this genre generally concurs that ‘authenticity’ functions as an aesthetic and moral quality within the genre: that poems and poets perceived as ‘authentic’ achieve more success. However, ‘authenticity’ is not a singular, static trait but rather a rapidly evolving, culturally conditional, and subjective process relying on the dialogic exchange of performance and perception. This thesis seeks to clarify the discourse regarding authenticity within contemporary U.K. spoken word poetry by proposing a genre-specific taxonomy of ten strains of authenticity which are commonly performed, framed, and perceived in this sphere. These distinct, though interlacing, strains are the authenticities of origin, autobiographical self, narrative, persona, temporal state, emotion, voice, identity, motivation, and engagement. The thesis draws upon social scientific methodology, including interviews with 70 U.K.-based poets, to examine how each of these strains functions as an aesthetic and moral quality within the genre. It considers how individual poets may perform these authenticities as well as how the conventions of spoken word spaces encourage the perception of poets as ‘real’ people (rather than actors playing characters) sharing autobiographical narratives while fully co-present with their audiences. Ultimately, this thesis emphasises the constructed, subjective nature of authenticity by revealing the extent to which spoken word performances are pre-composed, rehearsed, and otherwise artistically wrought. It concludes by analysing the commonality of descriptions of spoken word poetry as ‘authentic’ in academic scholarship and popular media and argues that this rhetoric is rooted in stereotype and downplays the skill and craft required in this multidisciplinary art form
A multi-level exploration of academic intentions to participate in academic entrepreneurship
Get PDFThis thesis was previously held under moratorium from 7th April 2021 to 11th April 2023.Academic entrepreneurship is playing an increasingly important role in many governments national and regional growth strategies. Drawing on the academic entrepreneurship and regulatory focus theory literature, and applying a multilevel perspective, this thesis explores why university academics intend to engage in commercialisation (spin-off or start-up companies and licensing university research) or engagement (collaborative research, contract research, continuous professional development and contract consulting) activities, and the role contextual factors play in the entrepreneurial process.Using a mixed methods research design, this research explores academic entrepreneurship through a sequential-exploratory, multi-study approach. The first study is exploratory and qualitative, with results highlighting the importance that actors in an academic’s local contextual play in the entrepreneurial process. The findings allowed a testable conceptual model, hypotheses and a survey to be developed. The second study tests the conceptual model using hierarchical regression, based on a survey of 818 academics working in 14 Scottish universities. The results reveal that the stronger an individual’s chronic promotion focus, the stronger their intentions to participate in commercialisation and engagement activities. The stronger their chronic prevention focus, the weaker their intentions to participate in engagement activities. When local contextual direct and indirect effects are considered, leaders and work group colleagues have different influences on an academic’s entrepreneurial intent.The third study explores whether the contextual factors identified affect academics working in STEM and non-STEM disciplines differently. The findings suggest that the individual and local contextual factors are broadly similar for both disciplines. This thesis contributes to a greater understanding of academic entrepreneurship, by drawing on regulatory focus theory to explain how academic leaders and work group colleagues can affect an academic’s entrepreneurial intentions. Finally, the thesis contributes to the regulatory focus theory literature and argues that multi-level research is required to better understand different forms of entrepreneurship.Academic entrepreneurship is playing an increasingly important role in many governments national and regional growth strategies. Drawing on the academic entrepreneurship and regulatory focus theory literature, and applying a multilevel perspective, this thesis explores why university academics intend to engage in commercialisation (spin-off or start-up companies and licensing university research) or engagement (collaborative research, contract research, continuous professional development and contract consulting) activities, and the role contextual factors play in the entrepreneurial process.Using a mixed methods research design, this research explores academic entrepreneurship through a sequential-exploratory, multi-study approach. The first study is exploratory and qualitative, with results highlighting the importance that actors in an academic’s local contextual play in the entrepreneurial process. The findings allowed a testable conceptual model, hypotheses and a survey to be developed. The second study tests the conceptual model using hierarchical regression, based on a survey of 818 academics working in 14 Scottish universities. The results reveal that the stronger an individual’s chronic promotion focus, the stronger their intentions to participate in commercialisation and engagement activities. The stronger their chronic prevention focus, the weaker their intentions to participate in engagement activities. When local contextual direct and indirect effects are considered, leaders and work group colleagues have different influences on an academic’s entrepreneurial intent.The third study explores whether the contextual factors identified affect academics working in STEM and non-STEM disciplines differently. The findings suggest that the individual and local contextual factors are broadly similar for both disciplines. This thesis contributes to a greater understanding of academic entrepreneurship, by drawing on regulatory focus theory to explain how academic leaders and work group colleagues can affect an academic’s entrepreneurial intentions. Finally, the thesis contributes to the regulatory focus theory literature and argues that multi-level research is required to better understand different forms of entrepreneurship
Organisational rhetoric and leadership in agile : a Wittgensteinian inquiry.
Get PDFThe focal point of this research has been the unpicking of reported experience versus rhetoric around a neo-bureaucratic approach to project management, referred to as “Agile”. This monolithic entity consists of many distinct methodologies, with an overlapping conceptual core. An understanding of Agile discourse is established through the data analysed as an object of comparison. The research findings speak to the space of legitimated expression and action, the depth grammar, of Agile organisation. The research was undertaken from a perspective of leadership agnosticism, in that the term was sceptically treated and included only in an emic capacity. The research is a coding-based analysis which runs across three strands of linguistic “metafunction”, as defined by Michael Halliday’s “Systemic Functional Grammar”. A total of 35 Agile experience reports were analysed through this process. The codes derived in this first pass were aggregated into groupings based on the perceived relation of events captured, termed manifestations. These manifestations were then themselves aggregated into a smaller set of categories. In practice, this meant a reduction from 138 codes, grouping similar exemplars, to 16 manifestations and then 6 categories. These categories establish the core concepts around which the depth grammar is presented through the first discussion chapter. This research has two primary contributions to Agile and another relating to leadership. In leadership studies, this research stands as an early empirical demonstration of the value in leadership agnosticism. Relating to Agile, a much needed description of the focal points of organisational talk in Agile practice is provided. Furthermore, it is argued that concepts of leadership had a significant role to play in disguising the continued operation of power in Agile contexts. This thesis, then, represents a contribution to Agile literature by providing a fuller exploration of the empirical challenges facing Agile’s idealised “Santa’s workshop” or “Hollywood/Disneyland” template.The focal point of this research has been the unpicking of reported experience versus rhetoric around a neo-bureaucratic approach to project management, referred to as “Agile”. This monolithic entity consists of many distinct methodologies, with an overlapping conceptual core. An understanding of Agile discourse is established through the data analysed as an object of comparison. The research findings speak to the space of legitimated expression and action, the depth grammar, of Agile organisation. The research was undertaken from a perspective of leadership agnosticism, in that the term was sceptically treated and included only in an emic capacity. The research is a coding-based analysis which runs across three strands of linguistic “metafunction”, as defined by Michael Halliday’s “Systemic Functional Grammar”. A total of 35 Agile experience reports were analysed through this process. The codes derived in this first pass were aggregated into groupings based on the perceived relation of events captured, termed manifestations. These manifestations were then themselves aggregated into a smaller set of categories. In practice, this meant a reduction from 138 codes, grouping similar exemplars, to 16 manifestations and then 6 categories. These categories establish the core concepts around which the depth grammar is presented through the first discussion chapter. This research has two primary contributions to Agile and another relating to leadership. In leadership studies, this research stands as an early empirical demonstration of the value in leadership agnosticism. Relating to Agile, a much needed description of the focal points of organisational talk in Agile practice is provided. Furthermore, it is argued that concepts of leadership had a significant role to play in disguising the continued operation of power in Agile contexts. This thesis, then, represents a contribution to Agile literature by providing a fuller exploration of the empirical challenges facing Agile’s idealised “Santa’s workshop” or “Hollywood/Disneyland” template
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