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Peridynamics for damage prediction in ships and offshore structures
Get PDFShips and offshore structures can experience damages due to many reasons such as collisions, groundings, explosions, corrosion, fatigue, overloading, or extreme conditions, etc. To date, the prediction of progressive damages in these structures is a challenging research area. The classical continuum mechanics uses partial differential equations which become invalid in the presence of discontinuities. By contrast, the recently introduced nonlocal peridynamics (PD) theory uses integrodifferential equations that are valid in both continuous and discontinuous models. Therefore, the peridynamics theory is highly suitable for predicting crack initiation and crack growth. In this thesis, progressive damages in ship and offshore structures are predicted by using peridynamics. To do that, first, novel PD models for predicting linear elastic deformations of 3D beam structures and 3D shell structures are developed. The deformations of 3D beams and 3D shell structures predicted by using the developed PD beam and shell models agree very well with the FEA results with less than 3% relative errors. It is also found that the developed PD beam and shell models are suitable for predicting progressive brittle damages in ship and offshore structures. The PD shell model can also predict the ultimate bending moment of a ship with only 0.102% difference from the experimental result.;Second, novel nonlinear PD models for predicting damages in one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) structures, 3D beam structures, and plates subjected to large deformations are developed. The large deformations structures predicted by using the developed nonlinear PD models agree very well with the FEA results with maximum 5% relative errors. The developed nonlinear PD models show a capability to predict progressive damages for many complex problems. The damage patterns captured by the nonlinear PD models agree very well with the experimental results in the literature. Third, a novel energy-based PD model for fatigue cracking is also developed. Instead of using the cyclic bond strain range for PD fatigue equations available in the literature, the energy-based PD fatigue model proposes a definition of the cyclic bond energy release rate range and use this term for PD fatigue equations. The fatigue life of the structure predicted by the energy-based PD fatigue model is 4.108% different from the experimental results while the predicted fatigue crack growth, {cedil}{9D}{91}{9E} {acute}{88}{92} {cedil}{9D}{91}{81} curve agrees very well with experimental results. The energy-based PD fatigue model can be more suitable for beam and shell structures since in these structures, the bond energy release rate is unique although the bond strain consists of in-plane, shear, and bending components.;Finally, to reduce the computational cost for PD simulations, novel 1D and 2D peridynamic-based machine learning models for damage prediction are developed. The relations between displacements of a material point and the displacements of its family members as well as the externally applied forces are obtained by using linear regression. The machine learning models can easily be coupled with the PD models. Specifically, the PD model is used for the regions that are near crack surfaces or near boundary areas. Meanwhile, the ML model is used for the remaining regions to reduce the computational cost. Like the traditional PD model it is found that the coupled PD-ML model is also suitable for damage prediction. The crack patterns predicted by using the coupled PD-ML model agree very well with experimental results in many complex problems. Therefore, the hybrid approach of coupling ML with PD can be a potential approach for future research to reduce the computational cost for PD simulations while the capability of PD models in terms of damage prediction is maintained. After All, it is expected that the results of the studies carried out in this thesis can make a significant contribution to the development of peridynamic theory and expand its application to ship and offshore structures. More importantly, the PD models developed in this thesis without any special treatment can be used for practical structural analysis to predict potential brittle damages in ship and offshore structures in complex phenomena. Therefore, the potential of structural damages can be minimized and the safety of the structures can be improved.Ships and offshore structures can experience damages due to many reasons such as collisions, groundings, explosions, corrosion, fatigue, overloading, or extreme conditions, etc. To date, the prediction of progressive damages in these structures is a challenging research area. The classical continuum mechanics uses partial differential equations which become invalid in the presence of discontinuities. By contrast, the recently introduced nonlocal peridynamics (PD) theory uses integrodifferential equations that are valid in both continuous and discontinuous models. Therefore, the peridynamics theory is highly suitable for predicting crack initiation and crack growth. In this thesis, progressive damages in ship and offshore structures are predicted by using peridynamics. To do that, first, novel PD models for predicting linear elastic deformations of 3D beam structures and 3D shell structures are developed. The deformations of 3D beams and 3D shell structures predicted by using the developed PD beam and shell models agree very well with the FEA results with less than 3% relative errors. It is also found that the developed PD beam and shell models are suitable for predicting progressive brittle damages in ship and offshore structures. The PD shell model can also predict the ultimate bending moment of a ship with only 0.102% difference from the experimental result.;Second, novel nonlinear PD models for predicting damages in one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) structures, 3D beam structures, and plates subjected to large deformations are developed. The large deformations structures predicted by using the developed nonlinear PD models agree very well with the FEA results with maximum 5% relative errors. The developed nonlinear PD models show a capability to predict progressive damages for many complex problems. The damage patterns captured by the nonlinear PD models agree very well with the experimental results in the literature. Third, a novel energy-based PD model for fatigue cracking is also developed. Instead of using the cyclic bond strain range for PD fatigue equations available in the literature, the energy-based PD fatigue model proposes a definition of the cyclic bond energy release rate range and use this term for PD fatigue equations. The fatigue life of the structure predicted by the energy-based PD fatigue model is 4.108% different from the experimental results while the predicted fatigue crack growth, {cedil}{9D}{91}{9E} {acute}{88}{92} {cedil}{9D}{91}{81} curve agrees very well with experimental results. The energy-based PD fatigue model can be more suitable for beam and shell structures since in these structures, the bond energy release rate is unique although the bond strain consists of in-plane, shear, and bending components.;Finally, to reduce the computational cost for PD simulations, novel 1D and 2D peridynamic-based machine learning models for damage prediction are developed. The relations between displacements of a material point and the displacements of its family members as well as the externally applied forces are obtained by using linear regression. The machine learning models can easily be coupled with the PD models. Specifically, the PD model is used for the regions that are near crack surfaces or near boundary areas. Meanwhile, the ML model is used for the remaining regions to reduce the computational cost. Like the traditional PD model it is found that the coupled PD-ML model is also suitable for damage prediction. The crack patterns predicted by using the coupled PD-ML model agree very well with experimental results in many complex problems. Therefore, the hybrid approach of coupling ML with PD can be a potential approach for future research to reduce the computational cost for PD simulations while the capability of PD models in terms of damage prediction is maintained. After All, it is expected that the results of the studies carried out in this thesis can make a significant contribution to the development of peridynamic theory and expand its application to ship and offshore structures. More importantly, the PD models developed in this thesis without any special treatment can be used for practical structural analysis to predict potential brittle damages in ship and offshore structures in complex phenomena. Therefore, the potential of structural damages can be minimized and the safety of the structures can be improved
The development of alkali-metal zincate chemistry for application in synthesis and catalysis
Get PDFThe work reported within this thesis focuses on two main projects. With these projects involving the chemistry of the metal zinc. The first of these projects was to investigate the chemistry an unprecedented tetrazincated ferrocene complex (4) and the second project was to investigate the primarily interactions in the zincate [{K(HMDS)2ZnBn}∞]. The first project is a continuation of a previous study that resulted in the formation of a tetrazincated ferrocene complex (4), with the intention of using this as an intermediate for the synthesis of tetrasubstituted ferrocenes.;These functionalizations were attempted using three different electrophilic reagents, specifically I2, D2O and CO2. The results from this were often confusing and inconclusive. However, when using D2O for a quench of the tetrazincated ferrocene complex, this did in fact seem to produce the desired D4-ferrocene product. Furthermore, the reactivity of the tetrazincated ferrocene complex towards aromatic substrates was probed to provide understanding of how this species behaves as a base.;Previous studies had shown that when pyridine is added to compound 4, a polymeric γ-metallated pyridine species (6) is formed. However, this was only acquired in an isolated yield of 5%. Here, the reaction was optimized, improving the crystalline yield to 29%. This study has also revealed that this process is more complicated than originally thought, via electrophilic quenching reactions with I2, as it seems to also metallate at the β-position of pyridine and not exclusively the γ-position as previously thought.;During the course of this project, an alternative zinc reagent to tBu2Zn was desired in order to avoid safety issues. A synthesis of isomeric iBu2Zn has been successfully developed and was found to be reproducible to a yield of 78%. This compound was then tested in a series of reactions in order to form a comparison with tBu2Zn and its related bimetallic 'ate' bases.;The second of these two projects, focuses on a recent publication by Guan et al. which has shown that the polymeric potassium zincate [{K(HMDS)2ZnBn}∞] (8) can be used for the direct catalytic functionalization of the benzylic C-H bond of diarylmethanes. One of the main aims of this project was to achieve the isolation and characterisation of the proposed intermediate in the investigation performed by Guan et al., which was the metallated diphenylmethyl system [{KZn(HMDS)2(CHPh2)}∞]. Despite there being promising signs of achieving this, due to time constraints, this ultimately was not achieved.;The second main aim of this section was to investigate how the potassium atom in [{K(HMDS)2ZnBn}∞] primarily interacts with the zincate component by disrupting its polymeric nature. This was achieved through the use of the highly effective monomerizing agent Me6TREN which revealed that the monomeric unit should be considered as (HMDS)2ZnBnK rather than K(HMDS)2ZnBn as suggested by Guan. This can be rationalized due to the π-philicity of the heavier alkali metal which preferentially coordinates to the delocalised charge within the aryl ring rather than the localised charge of the amido nitrogen centres of the HMDS ligands when the hemisolvating Me6TREN ligand forces it to choose only one.The work reported within this thesis focuses on two main projects. With these projects involving the chemistry of the metal zinc. The first of these projects was to investigate the chemistry an unprecedented tetrazincated ferrocene complex (4) and the second project was to investigate the primarily interactions in the zincate [{K(HMDS)2ZnBn}∞]. The first project is a continuation of a previous study that resulted in the formation of a tetrazincated ferrocene complex (4), with the intention of using this as an intermediate for the synthesis of tetrasubstituted ferrocenes.;These functionalizations were attempted using three different electrophilic reagents, specifically I2, D2O and CO2. The results from this were often confusing and inconclusive. However, when using D2O for a quench of the tetrazincated ferrocene complex, this did in fact seem to produce the desired D4-ferrocene product. Furthermore, the reactivity of the tetrazincated ferrocene complex towards aromatic substrates was probed to provide understanding of how this species behaves as a base.;Previous studies had shown that when pyridine is added to compound 4, a polymeric γ-metallated pyridine species (6) is formed. However, this was only acquired in an isolated yield of 5%. Here, the reaction was optimized, improving the crystalline yield to 29%. This study has also revealed that this process is more complicated than originally thought, via electrophilic quenching reactions with I2, as it seems to also metallate at the β-position of pyridine and not exclusively the γ-position as previously thought.;During the course of this project, an alternative zinc reagent to tBu2Zn was desired in order to avoid safety issues. A synthesis of isomeric iBu2Zn has been successfully developed and was found to be reproducible to a yield of 78%. This compound was then tested in a series of reactions in order to form a comparison with tBu2Zn and its related bimetallic 'ate' bases.;The second of these two projects, focuses on a recent publication by Guan et al. which has shown that the polymeric potassium zincate [{K(HMDS)2ZnBn}∞] (8) can be used for the direct catalytic functionalization of the benzylic C-H bond of diarylmethanes. One of the main aims of this project was to achieve the isolation and characterisation of the proposed intermediate in the investigation performed by Guan et al., which was the metallated diphenylmethyl system [{KZn(HMDS)2(CHPh2)}∞]. Despite there being promising signs of achieving this, due to time constraints, this ultimately was not achieved.;The second main aim of this section was to investigate how the potassium atom in [{K(HMDS)2ZnBn}∞] primarily interacts with the zincate component by disrupting its polymeric nature. This was achieved through the use of the highly effective monomerizing agent Me6TREN which revealed that the monomeric unit should be considered as (HMDS)2ZnBnK rather than K(HMDS)2ZnBn as suggested by Guan. This can be rationalized due to the π-philicity of the heavier alkali metal which preferentially coordinates to the delocalised charge within the aryl ring rather than the localised charge of the amido nitrogen centres of the HMDS ligands when the hemisolvating Me6TREN ligand forces it to choose only one
Meaningful information extraction from IoT measurements using signal information processing
Get PDFThe advancements of modern technology have motivated researchers, business and governmental stakeholders to envision the idea of a unified network-based platform, known as the Internet of Things, that can interconnect devices and allow the bi-directional communication between relevant parties. The information exchanged through the Internet of Things can originate from a variety of fields, namely healthcare, environmental and infrastructure monitoring, transportation and logistics, smart grid and smart houses, which can produce a vast amount of diverse data in real time.;One of the most important challenges, emerging from the implementation of the Internet of things, is the acquisition of meaningful information using the data derived from the various smart devices and sensors. Therefore, it is essential to identify suitable data processing and analysis approaches, able to adapt depending on the application-specific requirements, and consequently transform the available data into useful information that can be utilised by any various stakeholders.;The main focus of this research thesis was in the field of Non-Intrusive Load Monitoring (NILM) in order to provide solutions suitable for low resolution smart metering data, similar to the specifications of the smart meters selected for deployment from most utilities and governmental stakeholders. Through an extensive and up-to-date review of the NILM field presented in this thesis, it has been identified that only recently, researchers have focused on disaggregating using only active power aggregate data for feature extraction at low sampling rates.;Therefore three unsupervised NILM methods were proposed as an outcome of this research, one using solely Dynamic Time Warping (DTW), a signal processing-based method, while the other two methods propose a combination of DTW and k-means, namely DTW+kM and kDTW, in order to address the computation complexity observed using the DTW-based method. The DTW+kM approach performs DTW for creating a library of appliance signatures and classification via clustering using k-means, and the kDTW is incorporating a DTW refinement post processing step in order to optimise the performance of the initial implementation.;The proposed methods were evaluated and benchmarked against various state-of-the-art NILM methods using the publicly available REDD [1] and REFIT [2, 3] datasets, and reported good performance.;Furthermore, the research presented in this thesis has investigated two other heterogeneous applications of the Internet of Things with respect to the emerging data challenge, and have proposed customised monitoring systems, and a variety of signal processing and machine learning approaches for analysing the corresponding data. More specifically, a prototype monitoring system was proposed for monitoring earthwork assets and preliminary findings reported in this thesis. In the context of visual content interaction using a video based eye tracking device, applicable in healthcare, computing,and even advertisement, the user's attention was evaluating using various statistical and signal processing methods, with the wavelet-based analysis being the best contestant for identifying features for extraction using pupil dilation and gaze fixation.The advancements of modern technology have motivated researchers, business and governmental stakeholders to envision the idea of a unified network-based platform, known as the Internet of Things, that can interconnect devices and allow the bi-directional communication between relevant parties. The information exchanged through the Internet of Things can originate from a variety of fields, namely healthcare, environmental and infrastructure monitoring, transportation and logistics, smart grid and smart houses, which can produce a vast amount of diverse data in real time.;One of the most important challenges, emerging from the implementation of the Internet of things, is the acquisition of meaningful information using the data derived from the various smart devices and sensors. Therefore, it is essential to identify suitable data processing and analysis approaches, able to adapt depending on the application-specific requirements, and consequently transform the available data into useful information that can be utilised by any various stakeholders.;The main focus of this research thesis was in the field of Non-Intrusive Load Monitoring (NILM) in order to provide solutions suitable for low resolution smart metering data, similar to the specifications of the smart meters selected for deployment from most utilities and governmental stakeholders. Through an extensive and up-to-date review of the NILM field presented in this thesis, it has been identified that only recently, researchers have focused on disaggregating using only active power aggregate data for feature extraction at low sampling rates.;Therefore three unsupervised NILM methods were proposed as an outcome of this research, one using solely Dynamic Time Warping (DTW), a signal processing-based method, while the other two methods propose a combination of DTW and k-means, namely DTW+kM and kDTW, in order to address the computation complexity observed using the DTW-based method. The DTW+kM approach performs DTW for creating a library of appliance signatures and classification via clustering using k-means, and the kDTW is incorporating a DTW refinement post processing step in order to optimise the performance of the initial implementation.;The proposed methods were evaluated and benchmarked against various state-of-the-art NILM methods using the publicly available REDD [1] and REFIT [2, 3] datasets, and reported good performance.;Furthermore, the research presented in this thesis has investigated two other heterogeneous applications of the Internet of Things with respect to the emerging data challenge, and have proposed customised monitoring systems, and a variety of signal processing and machine learning approaches for analysing the corresponding data. More specifically, a prototype monitoring system was proposed for monitoring earthwork assets and preliminary findings reported in this thesis. In the context of visual content interaction using a video based eye tracking device, applicable in healthcare, computing,and even advertisement, the user's attention was evaluating using various statistical and signal processing methods, with the wavelet-based analysis being the best contestant for identifying features for extraction using pupil dilation and gaze fixation
Experimental and numerical quantification of influences of drugs on zebrafish larvae swimming kinematics and energetics
Get PDFThe use of zebrafish larvae has aroused wide-interest in the medical field for its potential role in the development of new therapies. Compared to other species, the zebrafish larvae grow extremely quickly, and the embryos are nearly transparent, which allows easy examination of its internal structures using fluorescent imaging techniques. Its complete genome sequence has already been published and is quite similar to that of human beings. Together with other advantages such as 2-6mm tiny body size for large scale screening, zebrafish has been grown to be a valuable model to test drugs and human diseases. Different types of drugs might have different influences on zebrafish behaviors, these behavior changes are related to functional changes of motoneurons in the spinal cord in the central nervous system (CNS) and transformations of the zebrafish body such as muscle mechanical power and force variation, which cannot be measured directly by pure experimental observation.;Therefore, a knowledge of internal muscle mechanics can assist the understanding of the effects of drugs on swimming activity. In this study, a novel methodology has been developed to investigate the influences of drugs on zebrafish larvae kinematics and energetics including the internal muscle mechanics, which can supply additional information on zebrafish swimming behavior changes induced by drug applications.;The method includes both experimental measurement and numerical simulation. The experimental study is carried out with high-speed camera recordings on real zebrafish larvae swimming behaviors and post-processing with multi-function in-house MATLAB code to capture and extract the body motion data. The numerical simulation is based on coupling between open-source CFD toolbox OpenFOAM, and an open-source multibody dynamics software MBDyn to accurately quantify influences of drug applications on zebrafish larvae kinematic and energetic performances, and especially internal muscle mechanics. For the interactions between zebrafish larvae and surrounding fluid, OpenFOAM is used to solve fluid dynamics and deal with dynamic internal mesh motion; MBDyn is used for solid body analysis and provide kinematic data for OpenFOAM. The coupling of these two solvers is achieved by establishing an interface library to exchange data with the help of the TCP/IP protocol.;Test cases are studied to validate the feasibility and accuracy of the numerical methodology. The first step validation includes comparisons with past research of a 2-D jellyfish-like multi-body structure to prove that numerical coupling between OpenFOAM and MBDyn is feasible in simulating multi-body structure. The second step validation includes comparisons between 3-D zebrafish model and experimentally observed results with high-speed camera. To be specific, tail-beat angles and averaged forward velocity of zebrafish larvae are compared, and all the quantitative comparisons show acceptable similarities. Also, zebrafish body curvatures are compared between experiment and CFD during one period of time to supplement the validation for accuracy of numerical simulation.;Applications of our methodology include nociceptive and neuroactive drug influenceson zebrafish locomotion and additional information from our results such as internal muscle mechanisms, to assist the evaluation of Gypenosides protection from high concentration acetic acid. We firstly provide comparisons of zebrafish locomotion before and after treatments with 0.01% acetic acid, 500 {cedil}{9D}{9C}{87}{cedil}{9D}{91}{80} diphenylhydantoin (DPH),and 100mg/ml yohimbine to test whether our novel zebrafish model can simulate different types of drug effects (positive, negative and no effect) on zebrafish larvae ornot. The reason of choosing the three drugs is based on previous studies showing apparent physiology and behavioural changes under biological experiments. Based on our results, the three different drugs show positive, negative, and no impact on zebrafish swimming activities, respectively. These effects have been accurately quantified with parameters such as forward velocity, forces, and hydrodynamic and mechanical power distributions, etc.;Besides, we have evaluated the damage caused by 0.1% acetic acid to the muscle of 5 days post-fertilization (dpf) zebrafish larvae, and the effects of protection with saponin Gypenoside (GYP) extracted from Gynostemma pentaphyllum to demonstrate that our technique can support biological experiment. Quantitative real-time polymerase chain reaction (qRT-PCR) has been used to examine the effects of acetic acid and GYP onoxidative stress and inflammation, leading to the fact that co-treatment of GYP can mediate damage caused by acetic acid. At the same time, we have quantified the parameters related to muscle such as muscle power and the resultant hydrodynamic force, proving that GYP can alleviate the detrimental effect of acetic acid on zebrafish larvae, in the form of alleviation from swimming debility, and that the muscle status can be quantified to represent the degree of muscle damage due to the acetic acid and the recovery due to GYP. We have also linked the behavioral changes to alteration of antioxidant and inflammation gene expression.;These results provide novel insights into the reasons for pain-related behavioral changes in zebrafish larvae, especially from an internal muscle perspective which is hard to be provided with traditional biological experimental analysis. Using this approach, we might focus on evaluating potential analgesic drugs for pain relief and neuroactive drug effects on fish behaviors, which might help to understand the functions of the nervous system and explain drug effects on zebrafish larvae locomotion.The use of zebrafish larvae has aroused wide-interest in the medical field for its potential role in the development of new therapies. Compared to other species, the zebrafish larvae grow extremely quickly, and the embryos are nearly transparent, which allows easy examination of its internal structures using fluorescent imaging techniques. Its complete genome sequence has already been published and is quite similar to that of human beings. Together with other advantages such as 2-6mm tiny body size for large scale screening, zebrafish has been grown to be a valuable model to test drugs and human diseases. Different types of drugs might have different influences on zebrafish behaviors, these behavior changes are related to functional changes of motoneurons in the spinal cord in the central nervous system (CNS) and transformations of the zebrafish body such as muscle mechanical power and force variation, which cannot be measured directly by pure experimental observation.;Therefore, a knowledge of internal muscle mechanics can assist the understanding of the effects of drugs on swimming activity. In this study, a novel methodology has been developed to investigate the influences of drugs on zebrafish larvae kinematics and energetics including the internal muscle mechanics, which can supply additional information on zebrafish swimming behavior changes induced by drug applications.;The method includes both experimental measurement and numerical simulation. The experimental study is carried out with high-speed camera recordings on real zebrafish larvae swimming behaviors and post-processing with multi-function in-house MATLAB code to capture and extract the body motion data. The numerical simulation is based on coupling between open-source CFD toolbox OpenFOAM, and an open-source multibody dynamics software MBDyn to accurately quantify influences of drug applications on zebrafish larvae kinematic and energetic performances, and especially internal muscle mechanics. For the interactions between zebrafish larvae and surrounding fluid, OpenFOAM is used to solve fluid dynamics and deal with dynamic internal mesh motion; MBDyn is used for solid body analysis and provide kinematic data for OpenFOAM. The coupling of these two solvers is achieved by establishing an interface library to exchange data with the help of the TCP/IP protocol.;Test cases are studied to validate the feasibility and accuracy of the numerical methodology. The first step validation includes comparisons with past research of a 2-D jellyfish-like multi-body structure to prove that numerical coupling between OpenFOAM and MBDyn is feasible in simulating multi-body structure. The second step validation includes comparisons between 3-D zebrafish model and experimentally observed results with high-speed camera. To be specific, tail-beat angles and averaged forward velocity of zebrafish larvae are compared, and all the quantitative comparisons show acceptable similarities. Also, zebrafish body curvatures are compared between experiment and CFD during one period of time to supplement the validation for accuracy of numerical simulation.;Applications of our methodology include nociceptive and neuroactive drug influenceson zebrafish locomotion and additional information from our results such as internal muscle mechanisms, to assist the evaluation of Gypenosides protection from high concentration acetic acid. We firstly provide comparisons of zebrafish locomotion before and after treatments with 0.01% acetic acid, 500 {cedil}{9D}{9C}{87}{cedil}{9D}{91}{80} diphenylhydantoin (DPH),and 100mg/ml yohimbine to test whether our novel zebrafish model can simulate different types of drug effects (positive, negative and no effect) on zebrafish larvae ornot. The reason of choosing the three drugs is based on previous studies showing apparent physiology and behavioural changes under biological experiments. Based on our results, the three different drugs show positive, negative, and no impact on zebrafish swimming activities, respectively. These effects have been accurately quantified with parameters such as forward velocity, forces, and hydrodynamic and mechanical power distributions, etc.;Besides, we have evaluated the damage caused by 0.1% acetic acid to the muscle of 5 days post-fertilization (dpf) zebrafish larvae, and the effects of protection with saponin Gypenoside (GYP) extracted from Gynostemma pentaphyllum to demonstrate that our technique can support biological experiment. Quantitative real-time polymerase chain reaction (qRT-PCR) has been used to examine the effects of acetic acid and GYP onoxidative stress and inflammation, leading to the fact that co-treatment of GYP can mediate damage caused by acetic acid. At the same time, we have quantified the parameters related to muscle such as muscle power and the resultant hydrodynamic force, proving that GYP can alleviate the detrimental effect of acetic acid on zebrafish larvae, in the form of alleviation from swimming debility, and that the muscle status can be quantified to represent the degree of muscle damage due to the acetic acid and the recovery due to GYP. We have also linked the behavioral changes to alteration of antioxidant and inflammation gene expression.;These results provide novel insights into the reasons for pain-related behavioral changes in zebrafish larvae, especially from an internal muscle perspective which is hard to be provided with traditional biological experimental analysis. Using this approach, we might focus on evaluating potential analgesic drugs for pain relief and neuroactive drug effects on fish behaviors, which might help to understand the functions of the nervous system and explain drug effects on zebrafish larvae locomotion
Development and strategic application of metal-mediated methods in the synthesis towards Agariblazeispirol C
No full textWithin our research team, significant efforts towards the total synthesis of the natural product agariblazeispirol C (1) has been conducted. In our synthetic programme, and as aligned with the broader interests of our team, we proposed that the key core skeleton of the target could be constructed through a combination of two effective metal-mediated cyclisation processes. More specifically, intramolecular Heck and Pauson-Khandannulation techniques have been employed to construct the core structure of the desired natural product, leaving the installation of an oxygenated five carbon side-chain as the final requirement to complete the target. Througout this overall programme of work, each individual reaction sequence has been fully explored and strategic synthetic steps have been established, and optimised, to provide access to advanced intermediates. Disclosed in this thesis is an extensive exploration of the asymmetric intramolecular Heck cyclisation reaction to deliver an enantioenriched 6,6-bicyclic system (rings B and C).;This established the first quaternary stereocentre within the natural product, ultimately, dictating the overall diastereoselectivity in the downstream synthesis. Indeed, high enantioselectivityof the asymmetric Heck reaction was achieved via substantial optimisation processes, including a comprehensive chiral ligand screen - allowing the cobalt-mediated Pauson-Khand cyclisation to be studied next in our programme of work. This demanding cyclisation required the formation of the two cyclopentyl rings (rings D and E), constructing the overall polycyclic network containing a further quaternary centre within the congested system. In this regard, efficient cyclisation of two distinct Pauson-Khand precursors has delivered the overall core of the natural product as a single diastereomer, confirmed by X-ray crystallography. Exploration of the final synthetic manipulations to allow for the installation of the required oxygenated side-chain has been initiated, with promising methodology having emerged to allow the final target to be accessed. [See print copy for diagram]Within our research team, significant efforts towards the total synthesis of the natural product agariblazeispirol C (1) has been conducted. In our synthetic programme, and as aligned with the broader interests of our team, we proposed that the key core skeleton of the target could be constructed through a combination of two effective metal-mediated cyclisation processes. More specifically, intramolecular Heck and Pauson-Khandannulation techniques have been employed to construct the core structure of the desired natural product, leaving the installation of an oxygenated five carbon side-chain as the final requirement to complete the target. Througout this overall programme of work, each individual reaction sequence has been fully explored and strategic synthetic steps have been established, and optimised, to provide access to advanced intermediates. Disclosed in this thesis is an extensive exploration of the asymmetric intramolecular Heck cyclisation reaction to deliver an enantioenriched 6,6-bicyclic system (rings B and C).;This established the first quaternary stereocentre within the natural product, ultimately, dictating the overall diastereoselectivity in the downstream synthesis. Indeed, high enantioselectivityof the asymmetric Heck reaction was achieved via substantial optimisation processes, including a comprehensive chiral ligand screen - allowing the cobalt-mediated Pauson-Khand cyclisation to be studied next in our programme of work. This demanding cyclisation required the formation of the two cyclopentyl rings (rings D and E), constructing the overall polycyclic network containing a further quaternary centre within the congested system. In this regard, efficient cyclisation of two distinct Pauson-Khand precursors has delivered the overall core of the natural product as a single diastereomer, confirmed by X-ray crystallography. Exploration of the final synthetic manipulations to allow for the installation of the required oxygenated side-chain has been initiated, with promising methodology having emerged to allow the final target to be accessed. [See print copy for diagram
Metabolomic and metabolomic flux studies of the effects of sphingosine kinase inhibitors on prostate cancer cells using high-resolution mass spectrometry as an analytical technique
Get PDFThere is evidence of the involvement of sphingosine kinases (two isoforms termed SK1and SK2), which catalyse the formation of the bioactive lipid, sphingosine 1-phosphate(S1P), in various diseases including cancer. Over the last few years, metabolomics has become an increasingly critical part in many fields of research. Therefore, metabolomic and lipidomic analysis was performed to investigate the effect of different sphingosine kinase inhibitors in prostate cancer cells in order to establish the role of SK1 and SK2 in this cancer. Previous studies have shown that the SK1/2 inhibitor, SKi (2-(phydroxyanilino)- 4-(pchlorophenyl)thiazole) inhibits aerobic glycolysis (Warburg effect) and this might contribute to the anti-cancer activity of this compound. This was further investigated in the current study, where 13C6- glucose was employed to determine the flux through different metabolic and lipid pathways, including the glycolysis in androgenin dependent LNCaP-AI prostate cancer cells.;The LNCaP-AI cell line was treated with SKi in the presence of 13C6-glucose for 24 hours before extraction and global metabolite analysis of cell lysate by LC-MS. The levels of glycolytic metabolites, pentose phosphate pathway, glutathione disulfide (GSSG) and sn-G3P were increased in response to the SKi. On the other hand, NADPH, some metabolites in TCA, nucleotides were found to be lower in the SKi-treated cells. These findings suggest that SKi reprograms cellular metabolism of LNCaP-AI cells, which results in reduced flux through glycolytic and TCA cycles andre-diversion of glucose to produce, sn-G3P, which is capable of increasing ROS production, and which might programme senescent death in these cells. The flux in the13C experiment suggests that much of glucose is metabolized through the pentose glucuronate interconversion pathway in LNCaP-AI cells. In order to recapitulate a more aggressive phenotype in prostate cancer cells, SK1b was stably expressed in androgen-sensitive LNCaP cells.;These LNCaP-SK1b cells were then treated with SKi and compared with LNCaP cells. The treatment of LNCaP-SK1b cells with SKi increased the levels of sphingomyelins, ceramides, lysoPC and PC and these changes were more substantial than in LNCaP cells. It is proposed that the over-expression of SK1b increases flux through sphingolipid and phospholipid pathways such that inhibition of SK1b with SKi results in a more profound increase in lipid metabolites compared with LNCaP cells. Part of this effect is in blockade of the sphingolipid rheostat and inhibition of phospholipid turnover that is limited by the availability of S1P. The use of the SK2 inhibitor, ROMe in LNCaP-SK1b cells suggests that both SK1 and SK2 regulate the sphingolipid rheostat, but inhibition of these enzymes with SKi results indifferential effects on ceramide and phospholipid metabolism.;Indeed, the effect of ROMe tends to be more robust in LNCAP cells compared with LNCaP-SK1b cells, with linkage of SK2 with sphinganine and sphinganine-1-phosphate metabolism. Several highly potent selective SK1 and SK2 inhibitors (PLR24, ST55 and ST81) were also used in LNCaP-AIcells and LNCaP-SK1b cells, and shown to disrupt the sphingolipid rheostat and modulate phospholipid turnover. The major conclusion of this thesis is that SK1 and SK2 regulate the metabolome (Warburg effect) and the lipidome to protect prostate cancer cells from apoptosis/senescence and this might contribute to certain hallmarks of cancer including replicative immortality and increased cell survival.There is evidence of the involvement of sphingosine kinases (two isoforms termed SK1and SK2), which catalyse the formation of the bioactive lipid, sphingosine 1-phosphate(S1P), in various diseases including cancer. Over the last few years, metabolomics has become an increasingly critical part in many fields of research. Therefore, metabolomic and lipidomic analysis was performed to investigate the effect of different sphingosine kinase inhibitors in prostate cancer cells in order to establish the role of SK1 and SK2 in this cancer. Previous studies have shown that the SK1/2 inhibitor, SKi (2-(phydroxyanilino)- 4-(pchlorophenyl)thiazole) inhibits aerobic glycolysis (Warburg effect) and this might contribute to the anti-cancer activity of this compound. This was further investigated in the current study, where 13C6- glucose was employed to determine the flux through different metabolic and lipid pathways, including the glycolysis in androgenin dependent LNCaP-AI prostate cancer cells.;The LNCaP-AI cell line was treated with SKi in the presence of 13C6-glucose for 24 hours before extraction and global metabolite analysis of cell lysate by LC-MS. The levels of glycolytic metabolites, pentose phosphate pathway, glutathione disulfide (GSSG) and sn-G3P were increased in response to the SKi. On the other hand, NADPH, some metabolites in TCA, nucleotides were found to be lower in the SKi-treated cells. These findings suggest that SKi reprograms cellular metabolism of LNCaP-AI cells, which results in reduced flux through glycolytic and TCA cycles andre-diversion of glucose to produce, sn-G3P, which is capable of increasing ROS production, and which might programme senescent death in these cells. The flux in the13C experiment suggests that much of glucose is metabolized through the pentose glucuronate interconversion pathway in LNCaP-AI cells. In order to recapitulate a more aggressive phenotype in prostate cancer cells, SK1b was stably expressed in androgen-sensitive LNCaP cells.;These LNCaP-SK1b cells were then treated with SKi and compared with LNCaP cells. The treatment of LNCaP-SK1b cells with SKi increased the levels of sphingomyelins, ceramides, lysoPC and PC and these changes were more substantial than in LNCaP cells. It is proposed that the over-expression of SK1b increases flux through sphingolipid and phospholipid pathways such that inhibition of SK1b with SKi results in a more profound increase in lipid metabolites compared with LNCaP cells. Part of this effect is in blockade of the sphingolipid rheostat and inhibition of phospholipid turnover that is limited by the availability of S1P. The use of the SK2 inhibitor, ROMe in LNCaP-SK1b cells suggests that both SK1 and SK2 regulate the sphingolipid rheostat, but inhibition of these enzymes with SKi results indifferential effects on ceramide and phospholipid metabolism.;Indeed, the effect of ROMe tends to be more robust in LNCAP cells compared with LNCaP-SK1b cells, with linkage of SK2 with sphinganine and sphinganine-1-phosphate metabolism. Several highly potent selective SK1 and SK2 inhibitors (PLR24, ST55 and ST81) were also used in LNCaP-AIcells and LNCaP-SK1b cells, and shown to disrupt the sphingolipid rheostat and modulate phospholipid turnover. The major conclusion of this thesis is that SK1 and SK2 regulate the metabolome (Warburg effect) and the lipidome to protect prostate cancer cells from apoptosis/senescence and this might contribute to certain hallmarks of cancer including replicative immortality and increased cell survival
Patterns in an elastic bar
Get PDFWe consider Yip's formulation of the Ericksen model for an elastic bar on an elastic foundation [63] which leads to the Euler-Lagrange equation for the functional ε(u) = ∫ between 0 and 1 (γu²xx +W(ux) + ɑu²)dx, where x is an element of the set (0, 1). with double Dirichlet boundary conditions. Here the potential W(p) = ((|p| - 1)²), is not differentiable at p = 0.;We define and prove existence and uniqueness of periodic solutions with any number n ≥ 0 of internal zeroes for all ɑ, γ > 0 and discuss the existence of non-periodic solutions.;The Euler-Lagrange equation contains conditions that make it diffcult to track, and then dropping one of them we obtain a weak formulation for this reduced problem,which we then prove it has a unique solution. Next, we use a combination of two numerical methods, namely the Finite Elements Method (FEM) to approximate the model and the Derivative Free Optimization (DFO) to find the location of the jump.We consider Yip's formulation of the Ericksen model for an elastic bar on an elastic foundation [63] which leads to the Euler-Lagrange equation for the functional ε(u) = ∫ between 0 and 1 (γu²xx +W(ux) + ɑu²)dx, where x is an element of the set (0, 1). with double Dirichlet boundary conditions. Here the potential W(p) = ((|p| - 1)²), is not differentiable at p = 0.;We define and prove existence and uniqueness of periodic solutions with any number n ≥ 0 of internal zeroes for all ɑ, γ > 0 and discuss the existence of non-periodic solutions.;The Euler-Lagrange equation contains conditions that make it diffcult to track, and then dropping one of them we obtain a weak formulation for this reduced problem,which we then prove it has a unique solution. Next, we use a combination of two numerical methods, namely the Finite Elements Method (FEM) to approximate the model and the Derivative Free Optimization (DFO) to find the location of the jump
Nanoparticle design for drug delivery to atherosclerotic plaques
Get PDFCardiovascular disease remains the main cause of death worldwide, and at the core of most cardiac problems is atherosclerosis. This progressive condition is characterised by the hardening and narrowing of the arteries. Often a cholesterol-lowering drug known as a statin is prescribed. Studies have shown these drugs to have many advantageous properties including an anti-inflammatory effect, the ability to improve endothelial function and the power to stabilise plaques. It was hypothesised that delivering the statin to the plaque could enhance these therapeutic effects since the disease is triggered from a local, rather than systemic, event.;Research focussed around the drug carrier design, with initial effort to investigate potential particles for the core. Nobel metal nanoparticles, such as gold and silver, are widely studied for use in medicine, owing to their plasmon resonance and facile surface chemistry. It is their interaction with light that makes the nanoparticles trackable via surface enhanced Raman spectroscopy (SERS) and capable of exchanging light to heat. In the literature, studies have shown that the heat generated during plasmonic interrogation can trigger drug release and hence could facilitate localised statin delivery. All these properties make metallic nanoparticles an appealing candidate for the core of the drug delivery design.;Iron oxide nanoparticles were synthesised and characterised as an initial vector for a drug carrier design. It was anticipated that a thin gold coating would facilitate the ability to functionalise and track the particles in vivo. As an alternative approach, hollow gold nanoparticles were investigated as the core nanoparticle, with their vacant centre allowing for higher drug payloads. Their synthesis, photothermal properties and enhancement of Raman scattering was investigated. An interesting relationship between the Raman signal and the plasmonic heating of the nanoparticles was observed. This phenomenon is not currently published in the literature, and this research theorises that an increase in 'adatom' density causes the signal enhancement.;This project validated a nanoparticle vehicle for the localised delivery of statins to atherosclerotic plaques. The combination of metallic nanoparticles with SERS was studied to better understand the possibility of such a treatment.Cardiovascular disease remains the main cause of death worldwide, and at the core of most cardiac problems is atherosclerosis. This progressive condition is characterised by the hardening and narrowing of the arteries. Often a cholesterol-lowering drug known as a statin is prescribed. Studies have shown these drugs to have many advantageous properties including an anti-inflammatory effect, the ability to improve endothelial function and the power to stabilise plaques. It was hypothesised that delivering the statin to the plaque could enhance these therapeutic effects since the disease is triggered from a local, rather than systemic, event.;Research focussed around the drug carrier design, with initial effort to investigate potential particles for the core. Nobel metal nanoparticles, such as gold and silver, are widely studied for use in medicine, owing to their plasmon resonance and facile surface chemistry. It is their interaction with light that makes the nanoparticles trackable via surface enhanced Raman spectroscopy (SERS) and capable of exchanging light to heat. In the literature, studies have shown that the heat generated during plasmonic interrogation can trigger drug release and hence could facilitate localised statin delivery. All these properties make metallic nanoparticles an appealing candidate for the core of the drug delivery design.;Iron oxide nanoparticles were synthesised and characterised as an initial vector for a drug carrier design. It was anticipated that a thin gold coating would facilitate the ability to functionalise and track the particles in vivo. As an alternative approach, hollow gold nanoparticles were investigated as the core nanoparticle, with their vacant centre allowing for higher drug payloads. Their synthesis, photothermal properties and enhancement of Raman scattering was investigated. An interesting relationship between the Raman signal and the plasmonic heating of the nanoparticles was observed. This phenomenon is not currently published in the literature, and this research theorises that an increase in 'adatom' density causes the signal enhancement.;This project validated a nanoparticle vehicle for the localised delivery of statins to atherosclerotic plaques. The combination of metallic nanoparticles with SERS was studied to better understand the possibility of such a treatment
Gait stability and balance strategies of both acquired and congenital lower limb prosthetic users in response to perturbations
Get PDFFalls are a health care problem for lower limb prosthetic users. The study of gait stability in lower limb prosthetic users facilitates improved insight and knowledge in different adaptation strategies of the human body in order to walk as functionally as possible with a prosthesis. The aim of this thesis was to determine how prosthetic users cope with unbalanced situations during walking and how these coping strategies may differ from able-bodied individuals. Improved understanding of such mechanisms may help reduce fall incidence. A number of prosthetic factors were considered including the use of a prosthetic foot incorporating an ankle joint, compared to a conventional prosthetic foot. Additionally, the effect of different alignments and the aetiology of the amputation or absence (congenital vs acquired amputation) was also considered.The study was conducted using an advanced dual-belt instrumented treadmill (CAREN). The protocol of perturbations in the study was adopted from a previous work by a group of researchers in University of Strathclyde (Roeles et al., 2018). Interventions used were anteroposterior (AP) perturbations by means of sudden changes in the walking speed to mimic a slip that can be faced in real-life situations. Main Outcome Measurements measured were AP and ML margins of stability (MoS) Hof et al. (2005). Step length, width and time were also measured to investigate the coping strategy following perturbation.Prosthetic users were less stable than able-bodied individuals. The involvement of the prosthetic side to recover stability was limited therefore, during rehabilitation stability training tasks for the intact side may help the prosthetic users enhance their overall stability and may reduce the fall incidence rate. Energy storing and return prosthetic feet may provide a sufficient level of stability compared to the feet which incorporate a moving ankle mechanism. The Ossur Pro-Flex foot demonstrated enhanced stability in the AP direction. Alignment changes from the optimal alignment may impose extra challenge to the stability. A short prosthesis was found to be the most challenging alignment change in response to perturbation. The prosthetic user with congenital related limb anomaly was found to be more stable than the prosthetic users with other lower limb loss.The outcomes of this study are novel and have potential to improve the understanding of how prosthetic users (acquired and congenital) react in when stability is compromised and the variables which may affect this further (foot design and alignment). It is envisaged that greater understanding of different adaptation strategies of the human body may help influence future prosthetic treatment, prescription, alignment and potentially component design.Falls are a health care problem for lower limb prosthetic users. The study of gait stability in lower limb prosthetic users facilitates improved insight and knowledge in different adaptation strategies of the human body in order to walk as functionally as possible with a prosthesis. The aim of this thesis was to determine how prosthetic users cope with unbalanced situations during walking and how these coping strategies may differ from able-bodied individuals. Improved understanding of such mechanisms may help reduce fall incidence. A number of prosthetic factors were considered including the use of a prosthetic foot incorporating an ankle joint, compared to a conventional prosthetic foot. Additionally, the effect of different alignments and the aetiology of the amputation or absence (congenital vs acquired amputation) was also considered.The study was conducted using an advanced dual-belt instrumented treadmill (CAREN). The protocol of perturbations in the study was adopted from a previous work by a group of researchers in University of Strathclyde (Roeles et al., 2018). Interventions used were anteroposterior (AP) perturbations by means of sudden changes in the walking speed to mimic a slip that can be faced in real-life situations. Main Outcome Measurements measured were AP and ML margins of stability (MoS) Hof et al. (2005). Step length, width and time were also measured to investigate the coping strategy following perturbation.Prosthetic users were less stable than able-bodied individuals. The involvement of the prosthetic side to recover stability was limited therefore, during rehabilitation stability training tasks for the intact side may help the prosthetic users enhance their overall stability and may reduce the fall incidence rate. Energy storing and return prosthetic feet may provide a sufficient level of stability compared to the feet which incorporate a moving ankle mechanism. The Ossur Pro-Flex foot demonstrated enhanced stability in the AP direction. Alignment changes from the optimal alignment may impose extra challenge to the stability. A short prosthesis was found to be the most challenging alignment change in response to perturbation. The prosthetic user with congenital related limb anomaly was found to be more stable than the prosthetic users with other lower limb loss.The outcomes of this study are novel and have potential to improve the understanding of how prosthetic users (acquired and congenital) react in when stability is compromised and the variables which may affect this further (foot design and alignment). It is envisaged that greater understanding of different adaptation strategies of the human body may help influence future prosthetic treatment, prescription, alignment and potentially component design
Towards continuous crystallization-based separation, chiral resolution and deracemization of chiral compounds
Get PDFA large number of modern active pharmaceutical ingredients (API) are chiral molecules. In most cases only one enantiomer has the desired effect in the human body, while the other enantiomer can have no effect or be harmful. Therefore the pharmaceutical industry aims for the direct production of the only the target enantiomer through asymmetric catalyzed chiral synthesis. However the asymmetric syntheses route is not always available and the racemate is produced instead, therefore chiral separation techniques are needed. Crystallization based chiral separation techniques have shown to be a selective and efficient tool for the separation, resolution and deracemization of chiral racemates. As there is a drive in the pharmaceutical industry towards continuous processes, the aim of this thesis is to demonstrate a number of new resolution and deracemization process configurations easily adaptable to continuous operation. In chapter 3, a batch and continuous antisolvent deracemization process is introduced, to investigate if and to which extend control over secondary nucleation can be preserved during an antisolvent crystallization. As antisolvent crystallization causes a fast drop in solubility and causes high local supersaturations, often thought to trigger chrially unselective primary nucleation, it is usually not selected for chiral separation. In this chapter the objective is to extend the scope of existing deracemization processes with antisolvent crystallization. Preferential crystallization has been used to successfully separate chiral conglomerate forming systems. However conglomerate systems are rather rare with racemic compound forming systems being the majority. While direct separation through preferential crystallization is not possible at racemic composition for compound forming systems, at the eutectic the pure enantiomer and racemic compound can be separated. This can be used in a hybrid process, where a primary method is used to enrich a racemic solution to eutectic composition, followed by a preferential crystallization. The objective of chapter 4 is to investigate and compare a semi-batch parallel and serial process configuration for the separation of racemic compound and pure enantiomer at eutectic solution composition, with regards to feasibility and process operating conditions. While crystallization based chiral separation processes provide a selective and efficient method for separation, there are a large number of process configurations for different compound types. The objective of chapter 5 is to develop and validate a general process design configuration which allows for the crystallization based separation, resolution and deracemization for racemic compound, as well as conglomerate forming systems with and without racemization.The findings in this thesis, together with work found in literature are used in chapter 6 to construct industrially relevant guidelines and criteria, based on process specifications such as productivity, yield and enantiomeric excess, to choose continuous crystallization-based chiral separation processes.A large number of modern active pharmaceutical ingredients (API) are chiral molecules. In most cases only one enantiomer has the desired effect in the human body, while the other enantiomer can have no effect or be harmful. Therefore the pharmaceutical industry aims for the direct production of the only the target enantiomer through asymmetric catalyzed chiral synthesis. However the asymmetric syntheses route is not always available and the racemate is produced instead, therefore chiral separation techniques are needed. Crystallization based chiral separation techniques have shown to be a selective and efficient tool for the separation, resolution and deracemization of chiral racemates. As there is a drive in the pharmaceutical industry towards continuous processes, the aim of this thesis is to demonstrate a number of new resolution and deracemization process configurations easily adaptable to continuous operation. In chapter 3, a batch and continuous antisolvent deracemization process is introduced, to investigate if and to which extend control over secondary nucleation can be preserved during an antisolvent crystallization. As antisolvent crystallization causes a fast drop in solubility and causes high local supersaturations, often thought to trigger chrially unselective primary nucleation, it is usually not selected for chiral separation. In this chapter the objective is to extend the scope of existing deracemization processes with antisolvent crystallization. Preferential crystallization has been used to successfully separate chiral conglomerate forming systems. However conglomerate systems are rather rare with racemic compound forming systems being the majority. While direct separation through preferential crystallization is not possible at racemic composition for compound forming systems, at the eutectic the pure enantiomer and racemic compound can be separated. This can be used in a hybrid process, where a primary method is used to enrich a racemic solution to eutectic composition, followed by a preferential crystallization. The objective of chapter 4 is to investigate and compare a semi-batch parallel and serial process configuration for the separation of racemic compound and pure enantiomer at eutectic solution composition, with regards to feasibility and process operating conditions. While crystallization based chiral separation processes provide a selective and efficient method for separation, there are a large number of process configurations for different compound types. The objective of chapter 5 is to develop and validate a general process design configuration which allows for the crystallization based separation, resolution and deracemization for racemic compound, as well as conglomerate forming systems with and without racemization.The findings in this thesis, together with work found in literature are used in chapter 6 to construct industrially relevant guidelines and criteria, based on process specifications such as productivity, yield and enantiomeric excess, to choose continuous crystallization-based chiral separation processes
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