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A resilience assessment framework for shipping companies which learns from past accidents by using a Fuzzy Cognitive Maps-based approach
Get PDFThe maritime sector has strived to reduce accidents and their consequences since its beginning, by addressing safety as the priority from the design stage to decommissioning of any vessel. Previous accident studies are focused on identifying Human Factors (HFs) in past maritime accidents. However, these studies have failed to identify deeper relations amongst the aforementioned HFs. Then, there has been a lack of detailed technique, which is capable of modelling the complex interrelations between these factors.;In addition, the maritime sector has traditionally presented a reactive approach to accidents, as regulations are generally developed to prevent reoccurrence rather than to avoid accident scenarios. However, a higher percentage of the time the system is safe, so it is possible to obtain additional useful information when focusing on the positive events and by learning from them.;The aim of this research study is to develop a theoretical understanding and a practical framework to describe how HFs in maritime accidents can more cleverly be identified and linked to the resilience engineering abilities, which will allow assessing the resilience level within a shipping company. Thus, by achieving the aforementioned aim, it is expected to improve overall safety within the maritime domain.;Therefore, in this research study, a new technique for Marine Accident Learning with Fuzzy Cognitive Maps (MALFCMs) is introduced and explained. The novelty of MALFCMs is the application of fuzzy cognitive maps (FCMs) to model the relationships of accident contributors by utilizing information directly from an accident database with the ability to combine expert opinion. Therefore, a key aspect to consider in this approach is the data selection, as a qualitative database will increase the success of the aforementioned MALFCMs technique.;In addition, as each fuzzy cognitive map will be derived from real occurrences, the results can be considered more objective, and MALFCMs may overcome the main disadvantage of fuzzy cognitive maps by eliminating or controlling the subjectivity in results.;Moreover, in this research study, the resilience assessment framework that was developed in EU funded FP7 SEAHORSE project is modified to incorporate additional resilience abilities, and applied to a shipping company. The modified resilience assessment framework, which consists of six phases, is proposed with the aim to assess the resilience level in a shipping company, based on how the company performs on certain resilience abilities, which are linked to common human causes of accidents.;Thus, the resilience assessment framework allows first to measure the resilience level in a shipping company by providing a resilience score, which can be benchmarked with other shipping companies. Second, it allows identifying areas for improvement to increase the company resilience level. Finally, it provides a set of recommendations for resilience improvement that may serve the company for future research.The maritime sector has strived to reduce accidents and their consequences since its beginning, by addressing safety as the priority from the design stage to decommissioning of any vessel. Previous accident studies are focused on identifying Human Factors (HFs) in past maritime accidents. However, these studies have failed to identify deeper relations amongst the aforementioned HFs. Then, there has been a lack of detailed technique, which is capable of modelling the complex interrelations between these factors.;In addition, the maritime sector has traditionally presented a reactive approach to accidents, as regulations are generally developed to prevent reoccurrence rather than to avoid accident scenarios. However, a higher percentage of the time the system is safe, so it is possible to obtain additional useful information when focusing on the positive events and by learning from them.;The aim of this research study is to develop a theoretical understanding and a practical framework to describe how HFs in maritime accidents can more cleverly be identified and linked to the resilience engineering abilities, which will allow assessing the resilience level within a shipping company. Thus, by achieving the aforementioned aim, it is expected to improve overall safety within the maritime domain.;Therefore, in this research study, a new technique for Marine Accident Learning with Fuzzy Cognitive Maps (MALFCMs) is introduced and explained. The novelty of MALFCMs is the application of fuzzy cognitive maps (FCMs) to model the relationships of accident contributors by utilizing information directly from an accident database with the ability to combine expert opinion. Therefore, a key aspect to consider in this approach is the data selection, as a qualitative database will increase the success of the aforementioned MALFCMs technique.;In addition, as each fuzzy cognitive map will be derived from real occurrences, the results can be considered more objective, and MALFCMs may overcome the main disadvantage of fuzzy cognitive maps by eliminating or controlling the subjectivity in results.;Moreover, in this research study, the resilience assessment framework that was developed in EU funded FP7 SEAHORSE project is modified to incorporate additional resilience abilities, and applied to a shipping company. The modified resilience assessment framework, which consists of six phases, is proposed with the aim to assess the resilience level in a shipping company, based on how the company performs on certain resilience abilities, which are linked to common human causes of accidents.;Thus, the resilience assessment framework allows first to measure the resilience level in a shipping company by providing a resilience score, which can be benchmarked with other shipping companies. Second, it allows identifying areas for improvement to increase the company resilience level. Finally, it provides a set of recommendations for resilience improvement that may serve the company for future research
A holistic two-step decision-making process to optimise multiple objectives over various remanufacturing activities for automotive products
Get PDFRemanufacturing is the process which used products are reworked to at least to as new condition and are given at least the same guaranty as equivalent new products. Remanufacturing is the most effective process among other recovery options because it can bring economic benefits and positive environmental impacts. Decision-making in the remanufacturing industry is more complicated than conventional manufacturing due to uncertainties of quality, quantities and return time of used components. Previous studies have developed numerous strategies for optimising remanufacturing outcomes. However, there is a lack of research to study integrated decision-making over multiple remanufacturing activities with consideration of under-studied factors. A decision made at one remanufacturing activity would significantly impact the decisions made in subsequent activities, which will affect remanufacturing outcomes. Also, tacit knowledge is not enough for making decisions since companies always have new threats or opportunities.;Therefore, this study developed a systematic and holistic way to integrate different decisions over multiple remanufacturing activities to make better decision-making and improvere manufacturing outcomes. This research studied the two-step decision-making to select the best recovery options and to find the optimal number of components/products in each remanufacturing activity. This study used case studies and mathematical modelling to enhance the ability to research various perspectives. This can lead to a higher quality of the decision model which is the research output. This first step of the decision model revealed whether additive manufacturing is a suitable recovery option in several scenarios by considering four objectives: maximising profit, minimising time, maximising recovered mass and maximising the reliability of components. This enhanced effectiveness of decision making because of the ability to assess a greater number of options properly.;This research finding will help remanufacturers to find new business opportunities by increasing the ability to recover automotive components such as crankshafts. The second step of the decision model can provide remanufacturing companies with material planning. The optimisation objectives of the model are maximising profit, minimising time or both. The findings from the sensitivity analysis contribute to the literature and real practice by quantifying and controlling the impact of component commonality on the objectives under various reworking scenarios defined by the percentage of reworked components, reworking time, and reworking cost.Remanufacturing is the process which used products are reworked to at least to as new condition and are given at least the same guaranty as equivalent new products. Remanufacturing is the most effective process among other recovery options because it can bring economic benefits and positive environmental impacts. Decision-making in the remanufacturing industry is more complicated than conventional manufacturing due to uncertainties of quality, quantities and return time of used components. Previous studies have developed numerous strategies for optimising remanufacturing outcomes. However, there is a lack of research to study integrated decision-making over multiple remanufacturing activities with consideration of under-studied factors. A decision made at one remanufacturing activity would significantly impact the decisions made in subsequent activities, which will affect remanufacturing outcomes. Also, tacit knowledge is not enough for making decisions since companies always have new threats or opportunities.;Therefore, this study developed a systematic and holistic way to integrate different decisions over multiple remanufacturing activities to make better decision-making and improvere manufacturing outcomes. This research studied the two-step decision-making to select the best recovery options and to find the optimal number of components/products in each remanufacturing activity. This study used case studies and mathematical modelling to enhance the ability to research various perspectives. This can lead to a higher quality of the decision model which is the research output. This first step of the decision model revealed whether additive manufacturing is a suitable recovery option in several scenarios by considering four objectives: maximising profit, minimising time, maximising recovered mass and maximising the reliability of components. This enhanced effectiveness of decision making because of the ability to assess a greater number of options properly.;This research finding will help remanufacturers to find new business opportunities by increasing the ability to recover automotive components such as crankshafts. The second step of the decision model can provide remanufacturing companies with material planning. The optimisation objectives of the model are maximising profit, minimising time or both. The findings from the sensitivity analysis contribute to the literature and real practice by quantifying and controlling the impact of component commonality on the objectives under various reworking scenarios defined by the percentage of reworked components, reworking time, and reworking cost
Raman imaging to assess the risk of disease using a targeted nanoparticle-DNA reporter system
No full textThe aim of this work was to develop a novel method for detecting mRNA in cells using gold nanoparticles and surface enhanced Raman spectroscopy (SERS), with the ultimate goal of early detection of cardiovascular disease. Three different methods to detect mRNA in cells using Raman spectroscopy were investigated. The first approach used a method analogous to fluorescence in situ hybridisation (FISH), named Raman in situ hybridisation. An oligonucleotide complementary to the mRNA target was attached to gold nanoparticles and labelled with a Raman reporter.;When incubated with cells it was hoped that the probe would hybridise to the target mRNA and allow visualisation using Raman mapping. Despite utilisation of various probe designs, no significant discrimination could be seen between the target oligonucleotide and a random control oligonucleotide. The second approach made use of a molecular beacon. Gold nanoparticles were functionalised with a dye and a dye-labelled hairpin loop oligonucleotide. In the closed position SERS signal was obtained from both dyes due to close proximity with the nanoparticles. In the presence of the target oligonucleotide, a change in the spectra was observed due to an increase in distance between the oligonucleotide dye and the nanoparticle.;This allowed ratiometric detection of the target. For the final approach nanoparticles were coated with a Raman active dye and anoligonucleotide. Two batches of nanoparticles were prepared, each with oligonucleotides complementary to half of the target sequence. When combined with the target sequence, the oligonucleotides should both hybridise, bringing the nanoparticles closer together and enhancing the Raman signal. These probes could be detected in cells, however it was not possible to determine whether or not they were hybridised to the target mRNA meaning further work is required. Overall, each method had its own limitations and further development would be required to create a feasible assay.The aim of this work was to develop a novel method for detecting mRNA in cells using gold nanoparticles and surface enhanced Raman spectroscopy (SERS), with the ultimate goal of early detection of cardiovascular disease. Three different methods to detect mRNA in cells using Raman spectroscopy were investigated. The first approach used a method analogous to fluorescence in situ hybridisation (FISH), named Raman in situ hybridisation. An oligonucleotide complementary to the mRNA target was attached to gold nanoparticles and labelled with a Raman reporter.;When incubated with cells it was hoped that the probe would hybridise to the target mRNA and allow visualisation using Raman mapping. Despite utilisation of various probe designs, no significant discrimination could be seen between the target oligonucleotide and a random control oligonucleotide. The second approach made use of a molecular beacon. Gold nanoparticles were functionalised with a dye and a dye-labelled hairpin loop oligonucleotide. In the closed position SERS signal was obtained from both dyes due to close proximity with the nanoparticles. In the presence of the target oligonucleotide, a change in the spectra was observed due to an increase in distance between the oligonucleotide dye and the nanoparticle.;This allowed ratiometric detection of the target. For the final approach nanoparticles were coated with a Raman active dye and anoligonucleotide. Two batches of nanoparticles were prepared, each with oligonucleotides complementary to half of the target sequence. When combined with the target sequence, the oligonucleotides should both hybridise, bringing the nanoparticles closer together and enhancing the Raman signal. These probes could be detected in cells, however it was not possible to determine whether or not they were hybridised to the target mRNA meaning further work is required. Overall, each method had its own limitations and further development would be required to create a feasible assay
Exploring the information seeking behaviour of Muslim migrants in Scotland, a Glasgow case of study
Get PDFIntroduction: Immigration is a global issue and the number of immigrants is rapidly increasing. Understanding the everyday information seeking behavior during the settlement period will facilitate the efforts to provide better relocation experience for, both, the newcomer and the host society. The purpose of this research is to understand the everyday information seeking behavior of Muslim migrants in Scotland, and the factors influencing their behaviours.;Design and methodology: This research has an interdisciplinary theoretical framework brings together Wilson's everyday information seeking behaviour model, Chatman's information poverty theory and social capital theory. Qualitative data is collected through in-depth semi-structure interviews with 19 Muslim individuals from both genders, who variously attended 10 Islamic community centres in the Greater Glasgow area. Participants were aged between 18 and 45 years old (avg. age 29) and had all moved to Glasgow from overseas within the last 5 years. The data is interpreted and analysed through the lens of the theoretical framework and utilizing thematic analysis and narrative analysis techniques.;Findings: the information needs of participants during their settlement periods in Scotland can be grouped into 13 needs categories across multiple topics placed into three groups, high occurrence needs (education, religion, and entertainment), medium occurrence needs (social norms, travel, health, and immigration), and low occurrence needs (shopping, employment, housing, financial support, driving licence, and technical support).;Participants variously discussed a number of information sources utilised, grouped into 8 categories, online and friends appear to be the most preferred information sources, followed by printed material, educational professionals and staff, health professionals and staff, family, and work colleagues. Preferences for information sources were mostly influenced by the tendency to seek experiential advice, to seek through authoritative sources, to seek second opinions, to seek through trusted sources.;This study provides evidence that the everyday information behaviours of the Muslim participants are largely influenced by the seekers' identity, their feelings of being stigmatised, and issues of trust. Mosques playing an important role as an information grounds and source of social capital.;Conclusion: this study provides insight into identity as a significant influencing factor in the information behaviours of Muslim migrants to Scotland, and the associated role of Mosques as important information grounds. Findings illustrate that identify has a positive trust related role when associated with experiential advice, and a negative role when associated with experiences and/or perceptions of stigma that can limit access to information. Recommendations are made for further investigation of issues of identity and stigma with further groups. Findings also have implications for the effective dissemination of important public information to Muslim migrants to Scotland (e.g. health, education, employment), and raise important questions regarding the role of Mosques. Again, recommendations are made for further research.Introduction: Immigration is a global issue and the number of immigrants is rapidly increasing. Understanding the everyday information seeking behavior during the settlement period will facilitate the efforts to provide better relocation experience for, both, the newcomer and the host society. The purpose of this research is to understand the everyday information seeking behavior of Muslim migrants in Scotland, and the factors influencing their behaviours.;Design and methodology: This research has an interdisciplinary theoretical framework brings together Wilson's everyday information seeking behaviour model, Chatman's information poverty theory and social capital theory. Qualitative data is collected through in-depth semi-structure interviews with 19 Muslim individuals from both genders, who variously attended 10 Islamic community centres in the Greater Glasgow area. Participants were aged between 18 and 45 years old (avg. age 29) and had all moved to Glasgow from overseas within the last 5 years. The data is interpreted and analysed through the lens of the theoretical framework and utilizing thematic analysis and narrative analysis techniques.;Findings: the information needs of participants during their settlement periods in Scotland can be grouped into 13 needs categories across multiple topics placed into three groups, high occurrence needs (education, religion, and entertainment), medium occurrence needs (social norms, travel, health, and immigration), and low occurrence needs (shopping, employment, housing, financial support, driving licence, and technical support).;Participants variously discussed a number of information sources utilised, grouped into 8 categories, online and friends appear to be the most preferred information sources, followed by printed material, educational professionals and staff, health professionals and staff, family, and work colleagues. Preferences for information sources were mostly influenced by the tendency to seek experiential advice, to seek through authoritative sources, to seek second opinions, to seek through trusted sources.;This study provides evidence that the everyday information behaviours of the Muslim participants are largely influenced by the seekers' identity, their feelings of being stigmatised, and issues of trust. Mosques playing an important role as an information grounds and source of social capital.;Conclusion: this study provides insight into identity as a significant influencing factor in the information behaviours of Muslim migrants to Scotland, and the associated role of Mosques as important information grounds. Findings illustrate that identify has a positive trust related role when associated with experiential advice, and a negative role when associated with experiences and/or perceptions of stigma that can limit access to information. Recommendations are made for further investigation of issues of identity and stigma with further groups. Findings also have implications for the effective dissemination of important public information to Muslim migrants to Scotland (e.g. health, education, employment), and raise important questions regarding the role of Mosques. Again, recommendations are made for further research
The design and development of a high-throughput ATR-FTIR serum diagnostics platform
Get PDFThis thesis was previously held under moratorium from 22nd April 2021 until 22nd April 2023Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy has demonstrable clinical ability and is well poised to address numerous clinical needs in virtue of operative ease, sample versatility, non-destructive testing, and good diagnostic prediction capabilities. Technical barriers stand in the way of clinical implementation, namely lack of high-throughput capabilities. Samples are individually deposited, prepared, analysed, then removed from a fixed Internal Reflection Element (IRE) amounting to a workflow bottleneck. IRE substrates are typically expensive and unamenable to manufacture and thus resigned to this workflow. We developed a low cost and disposable silicon (Si) IRE (SIRE) and universal infrared spectrometer accessory module enabling high-throughput analysis with high spectral quality and reproducibility. Spectral reproducibility was optimised through characterisation of intrinsic and extrinsic optical variance sources and subsequent mitigation. Si impurity variance had little impact on spectral reproducibility. Optimised batch sample preparation procedure and surface treatment diminished extrinsic variances. SIREs maintain comparable performance to a Diamond IRE in the detection and quantitation of archetypal carbohydrates, lipids, and proteins at clinically relevant concentrations demonstrating effectiveness across the biochemical ‘fingerprint’ region. A 300% increase in sample throughput over a conventional Diamond IRE was achieved. Sepsis, SIRS, and control patient samples were discriminated using spectra acquired from SIREs to demonstrate clinical suitability. A random forest classifier of sepsis (n=43), SIRS (n=59), and control (n=46) constructed from serum samples analysed on SIREs achieved high negative predictive value (93.55%), positive predictive value (76.08%), sensitivity (84.15%), specificity (90.43%), and accuracy (81.98%) for the detection of sepsis.Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy has demonstrable clinical ability and is well poised to address numerous clinical needs in virtue of operative ease, sample versatility, non-destructive testing, and good diagnostic prediction capabilities. Technical barriers stand in the way of clinical implementation, namely lack of high-throughput capabilities. Samples are individually deposited, prepared, analysed, then removed from a fixed Internal Reflection Element (IRE) amounting to a workflow bottleneck. IRE substrates are typically expensive and unamenable to manufacture and thus resigned to this workflow. We developed a low cost and disposable silicon (Si) IRE (SIRE) and universal infrared spectrometer accessory module enabling high-throughput analysis with high spectral quality and reproducibility. Spectral reproducibility was optimised through characterisation of intrinsic and extrinsic optical variance sources and subsequent mitigation. Si impurity variance had little impact on spectral reproducibility. Optimised batch sample preparation procedure and surface treatment diminished extrinsic variances. SIREs maintain comparable performance to a Diamond IRE in the detection and quantitation of archetypal carbohydrates, lipids, and proteins at clinically relevant concentrations demonstrating effectiveness across the biochemical ‘fingerprint’ region. A 300% increase in sample throughput over a conventional Diamond IRE was achieved. Sepsis, SIRS, and control patient samples were discriminated using spectra acquired from SIREs to demonstrate clinical suitability. A random forest classifier of sepsis (n=43), SIRS (n=59), and control (n=46) constructed from serum samples analysed on SIREs achieved high negative predictive value (93.55%), positive predictive value (76.08%), sensitivity (84.15%), specificity (90.43%), and accuracy (81.98%) for the detection of sepsis
Development of a novel multi-stage limb salvage technology for the optimisation of tissue viability in severely injured limbs
Get PDFBackground - In the recent wars, 77% of all British casualties received extremity injuries. The critical nature of these injuries resulted in amputations to preserve life, when the limb itself was potentially salvageable. In response, the present research has focussed on development of new technology to reduce amputations by preserving tissue viability.Materials and Methods - Novel technology was developed including; a dual-bladder pneumatic tourniquet; a cooling sock to reduce tissue temperature; and a perfusion support system to perfuse the limb independently of systemic circulation in hospital. Testing involved laboratory protocols, mimetic of the combat setting. The cooling sock and limb support system were tested using disarticulated porcine and ovine limbs. Techniques were employed to assess the impact of these technologies, including implanted thermistors, doppler flow, infrared scanning and neural stimulation. In ovine limbs histology and blood gas analysis was also studiedResults – Topical CO2 cooling was associated with deep cooling similar to ice packing, so was utilised while transporting disarticulated porcine limbs reducing deep tissue temperature by between 7.26-15.88oC. The limbs underwent neural stimulation to assess muscle contraction, showing twitch at procedure termination in 2 of the 3 intervention limbs but none of the control limbs. This work was repeated using disarticulated ovine limbs. There were 4 arms in this element; cooled – perfused, non-cooled – perfused, cooled – non-perfused and non-cooled – non-perfused. Deep tissue temperature reduction was very similar between the cooled and non-cooled tests (5.86±3.34oC and 5.23±0.28oC respectively). Baseline nerve stimulation showed that contraction was present in all limbs, however, at the end, contraction was detected only in perfused limbs.Discussion and Conclusions - Overall, these studies demonstrate that the benefit of cooling was less than expected, but, perfusing the limbs preserved tissue viability. The limb stabilisation technology has a clear tissue preserving effect and offers promise as a technology that can be of benefit to personnel injured in austere situations.Background - In the recent wars, 77% of all British casualties received extremity injuries. The critical nature of these injuries resulted in amputations to preserve life, when the limb itself was potentially salvageable. In response, the present research has focussed on development of new technology to reduce amputations by preserving tissue viability.Materials and Methods - Novel technology was developed including; a dual-bladder pneumatic tourniquet; a cooling sock to reduce tissue temperature; and a perfusion support system to perfuse the limb independently of systemic circulation in hospital. Testing involved laboratory protocols, mimetic of the combat setting. The cooling sock and limb support system were tested using disarticulated porcine and ovine limbs. Techniques were employed to assess the impact of these technologies, including implanted thermistors, doppler flow, infrared scanning and neural stimulation. In ovine limbs histology and blood gas analysis was also studiedResults – Topical CO2 cooling was associated with deep cooling similar to ice packing, so was utilised while transporting disarticulated porcine limbs reducing deep tissue temperature by between 7.26-15.88oC. The limbs underwent neural stimulation to assess muscle contraction, showing twitch at procedure termination in 2 of the 3 intervention limbs but none of the control limbs. This work was repeated using disarticulated ovine limbs. There were 4 arms in this element; cooled – perfused, non-cooled – perfused, cooled – non-perfused and non-cooled – non-perfused. Deep tissue temperature reduction was very similar between the cooled and non-cooled tests (5.86±3.34oC and 5.23±0.28oC respectively). Baseline nerve stimulation showed that contraction was present in all limbs, however, at the end, contraction was detected only in perfused limbs.Discussion and Conclusions - Overall, these studies demonstrate that the benefit of cooling was less than expected, but, perfusing the limbs preserved tissue viability. The limb stabilisation technology has a clear tissue preserving effect and offers promise as a technology that can be of benefit to personnel injured in austere situations
The role of a monomer/dimer equilibrium and the C-terminal tail in regulating translocation of sphingosine kinase 1 to the plasma membrane of breast cancer cells
Get PDFSphingosine kinase-1 (SK1) is able to translocate from the cytoplasm to the plasma membrane (PM) to catalyse the formation of sphingosine 1-phosphate (S1P) from sphingosine and adenosine triphosphate (ATP). It is known that both the expression and activity of SK1 is increased in many tumour types leading to a poorer prognostic outcome in terms of disease-specific survival (Heffernan-Stroud et al., 2013). In addition, the translocation/activation of SK1 to the plasma membrane induces oncogenesis. However, the mechanism of translocation requires further investigation in order to identify new targets for potential therapeutic intervention in the treatment of cancer. Therefore, the aim of the current study was to further examine the molecular mechanisms regulating the translocation of SK1 from the cytoplasm to the PM in MCF-7L breast cancer cells. Phorbol myristate acetate (PMA) induced the extracellular signal-regulated kinase (ERK)-dependent translocation of wild type (WT) mouse green fluorescent protein (GFP)-SK1 (mGFP-SK1) from the cytoplasm to lamellipodia in the PM of MCF-7L breast cancer cells. In addition, carbachol also induced translocation of WTmGFP-SK1 to lamellipodia, albeit in an ERK-independent manner.;In contrast, S1P induced the ERK-independent translocation of WTmGFP-SK1 to filopodia. Treatment of cells with either the phospholipase D (PLD) inhibitor, 5-Fluoro-2-Indolyl des-chlorohalopemide (FIPI), or the Gq inhibitor, YM254890 reduced translocation in response to phorbol myristate acetate (PMA), carbachol or S1P, suggesting that phosphatidic acid (PA) formation and Gq activation are required for phosphorylation-dependent and -independent translocation of SK1 to the PM of breast cancer cells. It has previously been proposed that SK1 might be able to exist as monomer and dimer in equilibrium. The dimeric structure would allow for a contiguous membrane engagement interface consisting of hydrophobic patches on the lipid binding loop (LBL)-1 loop and a cluster of positively charged residues at the dimeric interface. The possibility of a monomer/dimer equilibrium was investigated by generating a constitutively monomeric mGFP-SK1 mutant, mGFP-SK1-K49E by introducing charge opposition in dimer interface.;We also created a stabilized dimer mGFP-SK1 mutant, mGFP-SK1-I51C by engineering a disulphide bond in dimer interface. Carbachol and PMA promotedt he translocation of mGFP-SK1-K49E to lamellipodia, whereas in contrast to WTmGFPSK1, S1P also induced translocation of mGFP-SK1-K49E to lamellipodia. On the other hand, carbachol or PMA promoted the translocation of mGFP-SK1-I51C to filopodia in a manner similar to S1P. These novel findings suggest monomeric and dimeric SK1 translocate to different PM micro-domains and that the position of the monomer/dimer equilibrium is determined by the ligand. We additionally investigated the regulatory role of the C-terminal tail of SK1 by creating mutants of mGFP-SK1, termed T1-T5 in which 5 amino acids were sequentially truncated with the exception of T4 in which 19 amino acids in total were removed. We identified that mGFP-SK1 T1 in which 5 amino acids were removed exhibited markedly reduced translocation in response to carbachol and S1P.;However, further truncation of the C-terminus restored the ability of SK1 to translocate to the PM. These results are consistent with molecular modelling studies in which displacement of the C-terminus 'locking motif' (C-terminal amino acids 6-10) might be achieved by the binding of a putative adapter protein to the 'displacement motif' (C-terminal amino acids 1-5). It is proposed that this displacement of the C-terminal tail enables NTD:CTD twisting around a 'connecting rod' to produce alignment of membrane engagement determinants; namely the positive charge cluster and LBL-1 to promote translocation of SK1. Moreover, molecular modelling studies also suggest that the ERK-catalysed Ser225 phosphorylation might destabilize the auto-inhibitory C-terminal folding independently of the binding of the adapter protein. These findings represent a unified mechanism of SK1 translocation to the PM, involving either ERK-mediated phosphorylation of Ser225 or displacement of the C-terminal tail by a putative adaptor protein. These novel findings provide new information concerning the mechanism of SK1 translocation that might assist in the identification of novel therapeutics aimed at perturbing translocation of this enzyme in cancer and to therefore reduce its oncogenic potential.Sphingosine kinase-1 (SK1) is able to translocate from the cytoplasm to the plasma membrane (PM) to catalyse the formation of sphingosine 1-phosphate (S1P) from sphingosine and adenosine triphosphate (ATP). It is known that both the expression and activity of SK1 is increased in many tumour types leading to a poorer prognostic outcome in terms of disease-specific survival (Heffernan-Stroud et al., 2013). In addition, the translocation/activation of SK1 to the plasma membrane induces oncogenesis. However, the mechanism of translocation requires further investigation in order to identify new targets for potential therapeutic intervention in the treatment of cancer. Therefore, the aim of the current study was to further examine the molecular mechanisms regulating the translocation of SK1 from the cytoplasm to the PM in MCF-7L breast cancer cells. Phorbol myristate acetate (PMA) induced the extracellular signal-regulated kinase (ERK)-dependent translocation of wild type (WT) mouse green fluorescent protein (GFP)-SK1 (mGFP-SK1) from the cytoplasm to lamellipodia in the PM of MCF-7L breast cancer cells. In addition, carbachol also induced translocation of WTmGFP-SK1 to lamellipodia, albeit in an ERK-independent manner.;In contrast, S1P induced the ERK-independent translocation of WTmGFP-SK1 to filopodia. Treatment of cells with either the phospholipase D (PLD) inhibitor, 5-Fluoro-2-Indolyl des-chlorohalopemide (FIPI), or the Gq inhibitor, YM254890 reduced translocation in response to phorbol myristate acetate (PMA), carbachol or S1P, suggesting that phosphatidic acid (PA) formation and Gq activation are required for phosphorylation-dependent and -independent translocation of SK1 to the PM of breast cancer cells. It has previously been proposed that SK1 might be able to exist as monomer and dimer in equilibrium. The dimeric structure would allow for a contiguous membrane engagement interface consisting of hydrophobic patches on the lipid binding loop (LBL)-1 loop and a cluster of positively charged residues at the dimeric interface. The possibility of a monomer/dimer equilibrium was investigated by generating a constitutively monomeric mGFP-SK1 mutant, mGFP-SK1-K49E by introducing charge opposition in dimer interface.;We also created a stabilized dimer mGFP-SK1 mutant, mGFP-SK1-I51C by engineering a disulphide bond in dimer interface. Carbachol and PMA promotedt he translocation of mGFP-SK1-K49E to lamellipodia, whereas in contrast to WTmGFPSK1, S1P also induced translocation of mGFP-SK1-K49E to lamellipodia. On the other hand, carbachol or PMA promoted the translocation of mGFP-SK1-I51C to filopodia in a manner similar to S1P. These novel findings suggest monomeric and dimeric SK1 translocate to different PM micro-domains and that the position of the monomer/dimer equilibrium is determined by the ligand. We additionally investigated the regulatory role of the C-terminal tail of SK1 by creating mutants of mGFP-SK1, termed T1-T5 in which 5 amino acids were sequentially truncated with the exception of T4 in which 19 amino acids in total were removed. We identified that mGFP-SK1 T1 in which 5 amino acids were removed exhibited markedly reduced translocation in response to carbachol and S1P.;However, further truncation of the C-terminus restored the ability of SK1 to translocate to the PM. These results are consistent with molecular modelling studies in which displacement of the C-terminus 'locking motif' (C-terminal amino acids 6-10) might be achieved by the binding of a putative adapter protein to the 'displacement motif' (C-terminal amino acids 1-5). It is proposed that this displacement of the C-terminal tail enables NTD:CTD twisting around a 'connecting rod' to produce alignment of membrane engagement determinants; namely the positive charge cluster and LBL-1 to promote translocation of SK1. Moreover, molecular modelling studies also suggest that the ERK-catalysed Ser225 phosphorylation might destabilize the auto-inhibitory C-terminal folding independently of the binding of the adapter protein. These findings represent a unified mechanism of SK1 translocation to the PM, involving either ERK-mediated phosphorylation of Ser225 or displacement of the C-terminal tail by a putative adaptor protein. These novel findings provide new information concerning the mechanism of SK1 translocation that might assist in the identification of novel therapeutics aimed at perturbing translocation of this enzyme in cancer and to therefore reduce its oncogenic potential
Experimental and numerical analysis of the squat and resistance of ships advancing through the new Suez Canal
Get PDFWhen a ship is sailing in shallow and restricted waters such as harbours and canals, it is usually accompanied by obvious sinkage and trim, called squat. The ship squat has important influences on ship hydrodynamic performance in shallow and restricted water such as ship resistance. Squat is caused by the drop in pressure under the bottom of the ship, where the relative speed of the water is higher. Due to the squat effect, the hydrodynamic forces on the ship will increase largely, ship control will become difficult and risks of grounding may increase. A new division of the Suez Canal is called New Suez Canal, recently opened for international navigation. It is important to obtain accurate prediction data for ship squat to minimise the risk of grounding in this canal. Accurate prediction of the squat is of great significance to correctly evaluate ship hydrodynamic performance and to ensure navigation safety in the New Suez Canal. In this study, various methods for prediction of ship squat were conducted and introduced. A series of experiments were conducted with a model scale of the KRISO Container Ship (KCS) at 1:75 scale. The squat of the KCS was examined by measuring its sinkage, trim and resistance. The influences of ship speed, water depth, ship-bank distance on the squat and blockage effect were analysed. The results indicated that for Froude's number based on depth (Fnh) below 0.4, measured squat values do not change with either Fnh or depth to draft ratio (H/T). The squat increases with H/T values for the depth Froude numbers higher than 0.4. Moreover, a ship's speed can be increased to up to 9 knots inside the New Suez Canal with no adverse effects, thus significantly reducing the time for a ship to pass through the Canal. Next, the study of reduced the Canal width to 62.5% of its real-life cross sectional area, no significant effect was observed on ship squat. Moreover, a series of experimental tests were conducted at loading conditions under different trimming angles to examine the range of ship trim for safe and efficient sailing in canals. to detect the best trim angle for ships during sailing in restricted waters to reduce resistance and therefore fuel consumption.;The results show that for depth Froude's numbers higher than 0.4, the ship model sinkage is less for aft trim than for level trim or forward trim. Concurrently, it can be observed that there is less water resistance for aft trim than for forward trim, albeit level trim shows the least resistance. Furthermore, the present study combines numerical, analytical and empirical methods for a holistic approach in calm water. As a case-study, the KCS hullform is adopted, and analysed experimentally, via Computational Fluid Dynamics, using the slender body theory, and empirical formulae. The results reveal strong effect between the canal's cross section and all examined parameters. In addition, CFD calculations proved to be a reliable tool for predicting ship performance while navigating shallow and restricted waters. CFD simulations in multiphase and double body regime are performed to reveal the form factor and wave resistance of the KCS. This is performed in two different canals while varying the depth Froude number. The results suggest a dependency of the form factor on ship speed. Analytical and empirical methods were used for comparison, the slender body theory, provided good predictions in the low speed range, but did not agree well with the experimental data at high speeds. To model the sloping canal sides of the Suez Canal via the slender body theory, a rectangular canal with equivalent blockage was constructed, which may have influenced the accuracy of the theory.When a ship is sailing in shallow and restricted waters such as harbours and canals, it is usually accompanied by obvious sinkage and trim, called squat. The ship squat has important influences on ship hydrodynamic performance in shallow and restricted water such as ship resistance. Squat is caused by the drop in pressure under the bottom of the ship, where the relative speed of the water is higher. Due to the squat effect, the hydrodynamic forces on the ship will increase largely, ship control will become difficult and risks of grounding may increase. A new division of the Suez Canal is called New Suez Canal, recently opened for international navigation. It is important to obtain accurate prediction data for ship squat to minimise the risk of grounding in this canal. Accurate prediction of the squat is of great significance to correctly evaluate ship hydrodynamic performance and to ensure navigation safety in the New Suez Canal. In this study, various methods for prediction of ship squat were conducted and introduced. A series of experiments were conducted with a model scale of the KRISO Container Ship (KCS) at 1:75 scale. The squat of the KCS was examined by measuring its sinkage, trim and resistance. The influences of ship speed, water depth, ship-bank distance on the squat and blockage effect were analysed. The results indicated that for Froude's number based on depth (Fnh) below 0.4, measured squat values do not change with either Fnh or depth to draft ratio (H/T). The squat increases with H/T values for the depth Froude numbers higher than 0.4. Moreover, a ship's speed can be increased to up to 9 knots inside the New Suez Canal with no adverse effects, thus significantly reducing the time for a ship to pass through the Canal. Next, the study of reduced the Canal width to 62.5% of its real-life cross sectional area, no significant effect was observed on ship squat. Moreover, a series of experimental tests were conducted at loading conditions under different trimming angles to examine the range of ship trim for safe and efficient sailing in canals. to detect the best trim angle for ships during sailing in restricted waters to reduce resistance and therefore fuel consumption.;The results show that for depth Froude's numbers higher than 0.4, the ship model sinkage is less for aft trim than for level trim or forward trim. Concurrently, it can be observed that there is less water resistance for aft trim than for forward trim, albeit level trim shows the least resistance. Furthermore, the present study combines numerical, analytical and empirical methods for a holistic approach in calm water. As a case-study, the KCS hullform is adopted, and analysed experimentally, via Computational Fluid Dynamics, using the slender body theory, and empirical formulae. The results reveal strong effect between the canal's cross section and all examined parameters. In addition, CFD calculations proved to be a reliable tool for predicting ship performance while navigating shallow and restricted waters. CFD simulations in multiphase and double body regime are performed to reveal the form factor and wave resistance of the KCS. This is performed in two different canals while varying the depth Froude number. The results suggest a dependency of the form factor on ship speed. Analytical and empirical methods were used for comparison, the slender body theory, provided good predictions in the low speed range, but did not agree well with the experimental data at high speeds. To model the sloping canal sides of the Suez Canal via the slender body theory, a rectangular canal with equivalent blockage was constructed, which may have influenced the accuracy of the theory
Material, acoustic, and mechanical properties of mosquito and midge antennae
Get PDFThe aim of this PhD is to contribute to the understanding of antennal hearing in insects. To this end, Confocal Laser Scanning Microscopy (CLSM), Finite Element Modelling (FEM) and Laser Doppler Vibrometry (LDV) were employed. The combination of the first two allows, in absence of prior knowledge of the material properties of mosquito or midge antennae, to assess the material structure and to gauge which impact this distribution can have on the antenna's mechanical behaviour in response to sound. It was revealed that, rather than a simple beam of uniform cuticle, the antennae of the insects studied had patterns and distributions of hard and soft ring elements along the length of their antennae. These properties were simulated with FEM and showed that they can strongly influence the resonant frequency of the antennae. Further investigations were done on the vibrational behaviour of these insects with LDV. The males of T. brevipalpis, An. arabiensis and An. gambiae demonstrated strong self-oscillation with high Q-factors. Unlike the mosquitoes, vibrometry of C. riparius showed no relevant self-oscillation of the antenna. Female T. brevipalpis produced self-oscillation but weaker than the male. The three-dimensional pattern of self-oscillation in all investigated mosquito species follows a distorted elliptical path. When stimulated with sound, the self-oscillating antennae exhibited classic nonlinear behaviour such as entrainment and down-modulation. Taken together, this thesis highlights the complex mechanics of acoustic reception in mosquitoes and midges, both mechanically and structurally.The aim of this PhD is to contribute to the understanding of antennal hearing in insects. To this end, Confocal Laser Scanning Microscopy (CLSM), Finite Element Modelling (FEM) and Laser Doppler Vibrometry (LDV) were employed. The combination of the first two allows, in absence of prior knowledge of the material properties of mosquito or midge antennae, to assess the material structure and to gauge which impact this distribution can have on the antenna's mechanical behaviour in response to sound. It was revealed that, rather than a simple beam of uniform cuticle, the antennae of the insects studied had patterns and distributions of hard and soft ring elements along the length of their antennae. These properties were simulated with FEM and showed that they can strongly influence the resonant frequency of the antennae. Further investigations were done on the vibrational behaviour of these insects with LDV. The males of T. brevipalpis, An. arabiensis and An. gambiae demonstrated strong self-oscillation with high Q-factors. Unlike the mosquitoes, vibrometry of C. riparius showed no relevant self-oscillation of the antenna. Female T. brevipalpis produced self-oscillation but weaker than the male. The three-dimensional pattern of self-oscillation in all investigated mosquito species follows a distorted elliptical path. When stimulated with sound, the self-oscillating antennae exhibited classic nonlinear behaviour such as entrainment and down-modulation. Taken together, this thesis highlights the complex mechanics of acoustic reception in mosquitoes and midges, both mechanically and structurally
If it is Christian, can it be youth work? : an examination of the relationship between Christianity and youth work, from the mid 19th century to 2014
Get PDFPreviously held under moratorium from 21 May 2020 until 23 May 2022.The association between Christianity and youth work is evident to anyone who looks for it. Indeed, since the 1960s practitioners can be found arguing over whether it ought to have a place or not. Regardless of this, Christianity’s relationship with youth work has remained under researched and until now has lacked a comprehensive study. Similarly, no study into youth work has utilised the analytical method of Paul Ricoeur’s hermeneutical arc, along with the social philosophy of Charles Taylor and Alasdair MacIntyre’s work on language and translation to provide a deeper interpretation of the development of youth work.Through data gathered from texts and literature written by youth workers to inform youth work, from semi-structured interviews and from additional social and history studies, this thesis provides an événementille, a narrative of Christianity’s relationship with youth work as it developed over time and an account of its conjonctures, the often unseen evolution and changes within that relationship. Italso situates Christian faith-based practice within the current youth work environment.By providing an événementille of Christianity’s relationship with youth work, this thesis addresses a gap within its existing literature and reveals the extent of Christianity’s formative stimulus and continuing presence within youth work up until the 1960s.The conjonctures of this relationship are revealed through the use of Taylor’s concept of providential deism and MacIntyre’s ideas on language and translation.This exposed the way in which youth work expanded from being Christian endeavour into Judaism and providential deism, from Christian-as-faith to Christian-as-ethic, and finally being translated into a secular language. It also made visible the older, theistic language of youth work and suggests that the ideals of modern, post-1960s youth work – voluntary participation, democracy, equality – are present because of their Christian inheritance.Taylor’s interpretation of the post-1960s period as the Age of Authenticity enables this thesis to situate Christian faith-based practice within a wider interpretation of youth work. In doing so it encourages youth workers to ask new questions of generally accepted interpretations.The Ricoeurian-based methodology also provides a gateway for other research into the conjonctures of youth work: gender, class, models of practice, the masculine nature of youth work’s practice and literature, and the influence of changing economic and political environments.The association between Christianity and youth work is evident to anyone who looks for it. Indeed, since the 1960s practitioners can be found arguing over whether it ought to have a place or not. Regardless of this, Christianity’s relationship with youth work has remained under researched and until now has lacked a comprehensive study. Similarly, no study into youth work has utilised the analytical method of Paul Ricoeur’s hermeneutical arc, along with the social philosophy of Charles Taylor and Alasdair MacIntyre’s work on language and translation to provide a deeper interpretation of the development of youth work.Through data gathered from texts and literature written by youth workers to inform youth work, from semi-structured interviews and from additional social and history studies, this thesis provides an événementille, a narrative of Christianity’s relationship with youth work as it developed over time and an account of its conjonctures, the often unseen evolution and changes within that relationship. Italso situates Christian faith-based practice within the current youth work environment.By providing an événementille of Christianity’s relationship with youth work, this thesis addresses a gap within its existing literature and reveals the extent of Christianity’s formative stimulus and continuing presence within youth work up until the 1960s.The conjonctures of this relationship are revealed through the use of Taylor’s concept of providential deism and MacIntyre’s ideas on language and translation.This exposed the way in which youth work expanded from being Christian endeavour into Judaism and providential deism, from Christian-as-faith to Christian-as-ethic, and finally being translated into a secular language. It also made visible the older, theistic language of youth work and suggests that the ideals of modern, post-1960s youth work – voluntary participation, democracy, equality – are present because of their Christian inheritance.Taylor’s interpretation of the post-1960s period as the Age of Authenticity enables this thesis to situate Christian faith-based practice within a wider interpretation of youth work. In doing so it encourages youth workers to ask new questions of generally accepted interpretations.The Ricoeurian-based methodology also provides a gateway for other research into the conjonctures of youth work: gender, class, models of practice, the masculine nature of youth work’s practice and literature, and the influence of changing economic and political environments
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