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Towards understanding fouling mechanisms in continuous crystallisation processes
Get PDFFouling involves the unwanted deposition and build-up of solid material on surfaces within a process. This problem is widely encountered in multiphase and solid phase processing in many industries including oil and gas, pharmaceutical and fine chemical manufacturing sectors.;Although it is acknowledged to impact both batch and continuous processing methods it poses a particular challenge to the controlled operation of continuous crystallisation processes where extended operation under non-equilibrium conditions is required. Whilst the factors impacting on fouling have been proposed, there have been only a relatively limited number of studies into fouling mechanisms to date.;With increased interest in deploying continuous crystallisation processes for pharmaceutical manufacturing, the motivation for this work was to develop an improved understanding of the influence of material properties and process conditions on fouling processes.;In this work, a number of studies were conducted in which key materials and process parameters were investigated. These have included different materials of construction (MOCs), process conditions (flow, supersaturation, temperature gradients (ΔT)) and crystallising solutions (solute and solvent). Primary fouling studies were conducted using a small scale batch crystallisation setup to explore the influence on MOCs, supersaturation and agitation rate upon both bulk crystal nucleation and surface fouling of paracetamol.;The prominent fouling mechanism was found to be particle deposition which was influenced by supersaturation, agitation rate, different MOCs and exposure time.;Fouling is known to occur on heat exchange interfaces due to the localised supersaturation that can be generated e.g. in a plug flow continuous cooling crystalliser. A novel surface induced continuous crystallisation fouling assessment platform (C-FAP) was developed in conjunction with Cambridge Reactor Design (CRD). The C-FAP was evaluated as an assessment tool by exploring different MOCs and process conditions upon fouling and fouling mechanisms via in situ imaging and temperature measurement.;The platform was characterised and used to explore surface induction mechanisms in which initiation and growth was strongly influenced by different MOCs, with stainless steel showing a greater tendency than PTFE, in addition to the degree of supersaturation. The temperature difference across the MOC interface (ΔTMOC) was demonstrated to influence nucleation and growth to varying extents.;An ideal scenario would be to be able to predict or rule out unfavourable combinations of solute, solvent and MOC properties early in process design to avoid late stage problems. A screen was carried out to assess the potential to develop a multivariate predictive model for fouling propensity and fouling behaviour. The models provide insight into the most influential parameters comprising MOC, solute, solvent and process descriptors to steer subsequent experiments.;The importance of MOC properties and process conditions was highlighted for all models. A variety of assessment tools were demonstrated within this work in which recommendations for fouling evaluation were provided in addition to methods to further develop fouling understanding.Fouling involves the unwanted deposition and build-up of solid material on surfaces within a process. This problem is widely encountered in multiphase and solid phase processing in many industries including oil and gas, pharmaceutical and fine chemical manufacturing sectors.;Although it is acknowledged to impact both batch and continuous processing methods it poses a particular challenge to the controlled operation of continuous crystallisation processes where extended operation under non-equilibrium conditions is required. Whilst the factors impacting on fouling have been proposed, there have been only a relatively limited number of studies into fouling mechanisms to date.;With increased interest in deploying continuous crystallisation processes for pharmaceutical manufacturing, the motivation for this work was to develop an improved understanding of the influence of material properties and process conditions on fouling processes.;In this work, a number of studies were conducted in which key materials and process parameters were investigated. These have included different materials of construction (MOCs), process conditions (flow, supersaturation, temperature gradients (ΔT)) and crystallising solutions (solute and solvent). Primary fouling studies were conducted using a small scale batch crystallisation setup to explore the influence on MOCs, supersaturation and agitation rate upon both bulk crystal nucleation and surface fouling of paracetamol.;The prominent fouling mechanism was found to be particle deposition which was influenced by supersaturation, agitation rate, different MOCs and exposure time.;Fouling is known to occur on heat exchange interfaces due to the localised supersaturation that can be generated e.g. in a plug flow continuous cooling crystalliser. A novel surface induced continuous crystallisation fouling assessment platform (C-FAP) was developed in conjunction with Cambridge Reactor Design (CRD). The C-FAP was evaluated as an assessment tool by exploring different MOCs and process conditions upon fouling and fouling mechanisms via in situ imaging and temperature measurement.;The platform was characterised and used to explore surface induction mechanisms in which initiation and growth was strongly influenced by different MOCs, with stainless steel showing a greater tendency than PTFE, in addition to the degree of supersaturation. The temperature difference across the MOC interface (ΔTMOC) was demonstrated to influence nucleation and growth to varying extents.;An ideal scenario would be to be able to predict or rule out unfavourable combinations of solute, solvent and MOC properties early in process design to avoid late stage problems. A screen was carried out to assess the potential to develop a multivariate predictive model for fouling propensity and fouling behaviour. The models provide insight into the most influential parameters comprising MOC, solute, solvent and process descriptors to steer subsequent experiments.;The importance of MOC properties and process conditions was highlighted for all models. A variety of assessment tools were demonstrated within this work in which recommendations for fouling evaluation were provided in addition to methods to further develop fouling understanding
Real-time control of a robot using brain activity
No full textBackground: Motor neuron disease (MND) describes a range of pathologies in which a person's voluntary muscle control becomes progressively impaired. Whether MND is on-set alone, or - as it commonly would be - paired with muscular atrophy, sufferers of the disease can face difficulty in establishing and maintaining their movement. These impediments, however, do not necessarily impinge on an individual's cognitive skills. MND, as well as other neurological diseases, such as atrophies and spinal cord injuries, affect neural pathways which may impair ones movement but spares the brain which may remain capable of performing cognitive tasks. Aim: This project aims to develop a proof-of-concept system: a small robot that can be controlled by brain activity through a brain-computer interface. The user will be able to have directional control over the robot. This platform would serve as a test bed for a device to be used by a neurologically impaired, cognitively intact person to communicate or control their environment. Method: The system interface will rely on a pseudo real-time input that is streaming from pre-recorded artefact-free electroencephalogram (EEG) signals. The system consists of mainly of two computing units: a transmitter (Tx) and a receiver (Rx). Tx will process the EEG signal and send a classification signal to the Rx unit. The receiver processes the signal so that the signal is classified into one of four distinct groups. Once classified, the receiver will transmit a control command to the receiver where it will be produce a respective output, thereby controlling the robot. Result: System operation transpires successfully with a latency of less than 160 ms; EEG processing in 40 ms and 118.5 ms from Bluetooth latency. Programmatic EEG classifications occur successfully to various extents and can be easily improves [sic] in future revisions.Background: Motor neuron disease (MND) describes a range of pathologies in which a person's voluntary muscle control becomes progressively impaired. Whether MND is on-set alone, or - as it commonly would be - paired with muscular atrophy, sufferers of the disease can face difficulty in establishing and maintaining their movement. These impediments, however, do not necessarily impinge on an individual's cognitive skills. MND, as well as other neurological diseases, such as atrophies and spinal cord injuries, affect neural pathways which may impair ones movement but spares the brain which may remain capable of performing cognitive tasks. Aim: This project aims to develop a proof-of-concept system: a small robot that can be controlled by brain activity through a brain-computer interface. The user will be able to have directional control over the robot. This platform would serve as a test bed for a device to be used by a neurologically impaired, cognitively intact person to communicate or control their environment. Method: The system interface will rely on a pseudo real-time input that is streaming from pre-recorded artefact-free electroencephalogram (EEG) signals. The system consists of mainly of two computing units: a transmitter (Tx) and a receiver (Rx). Tx will process the EEG signal and send a classification signal to the Rx unit. The receiver processes the signal so that the signal is classified into one of four distinct groups. Once classified, the receiver will transmit a control command to the receiver where it will be produce a respective output, thereby controlling the robot. Result: System operation transpires successfully with a latency of less than 160 ms; EEG processing in 40 ms and 118.5 ms from Bluetooth latency. Programmatic EEG classifications occur successfully to various extents and can be easily improves [sic] in future revisions
Developing working memory and numeracy skills in primary-aged school pupils by computerised training programmes : the effectiveness of adaptive multi-domain working memory training
Get PDFSystematic reviews indicate that while working memory training programmes may yield 'near-transfer' effects with improved scores on measures of working memory, there is less convincing evidence for 'far-transfer' effects generalising to academic skills. This thesis aims to further investigate training-transfer effects by evaluation of two computerised training programmes to develop working memory and numeracy in primary school-aged pupils.;Three studies are reported. The first is a quasi-experimental design comparing effects upon 7-8 year old pupils of a 7-week computerised working memory training programme Memory Quest Flex (Junior) (Truedsson & Strohmayer, 2010) (n=25) with a 7-week computerised numeracy training programme Study Ladder (Study Ladder Holdings Ltd., 2013) (n=27), both relative to a non-active control condition receiving their regular curriculum (n=24).;The computerised numeracy training programme served as both treatment and active control conditions, to control for the Hawthorne Effect. Training-transfer effects are measured using performance scores on dependent variables of working memory, fluid reasoning and numeracy, and independent variables of treatment condition, time-point and gender. Children's scores on the Pupil's Perceptions of Numeracy Questionnaire (PPNQ), a short scale developed for this study, were considered to illuminate findings of the main study.;Findings from the main study change score analysis revealed the adaptive computerised working memory training programme yielded significant near-transfer effects to a complex working memory task, [F(2,73) = 13.9, p .251).;In the second study, Principal Components Analysis confirmed the PPNQ had a unidimensional structure and good internal consistency reliability (Cronbach's a = .806). Findings revealed a positive shift in PPNQ scores following intervention in understanding numeracy instruction. Findings for the control condition support conclusions that the PPNQ was sufficiently sensitive to detect increasingly negative perceptions of numeracy. This study suggests how the PPNQ might be used to identify children's perceptions of numeracy and access to the numeracy curriculum.;The third study used qualitative methods to investigate issues of implementation fidelity important for acceptability and feasibility of computerised training programmes in the primary schools.;This thesis identifies dual benefits of adaptive, multi-domain computerised working memory training not fully explained by the Hawthorne Effect. Recommendations are discussed towards the development of a computerised working memory training paradigm in schools.Systematic reviews indicate that while working memory training programmes may yield 'near-transfer' effects with improved scores on measures of working memory, there is less convincing evidence for 'far-transfer' effects generalising to academic skills. This thesis aims to further investigate training-transfer effects by evaluation of two computerised training programmes to develop working memory and numeracy in primary school-aged pupils.;Three studies are reported. The first is a quasi-experimental design comparing effects upon 7-8 year old pupils of a 7-week computerised working memory training programme Memory Quest Flex (Junior) (Truedsson & Strohmayer, 2010) (n=25) with a 7-week computerised numeracy training programme Study Ladder (Study Ladder Holdings Ltd., 2013) (n=27), both relative to a non-active control condition receiving their regular curriculum (n=24).;The computerised numeracy training programme served as both treatment and active control conditions, to control for the Hawthorne Effect. Training-transfer effects are measured using performance scores on dependent variables of working memory, fluid reasoning and numeracy, and independent variables of treatment condition, time-point and gender. Children's scores on the Pupil's Perceptions of Numeracy Questionnaire (PPNQ), a short scale developed for this study, were considered to illuminate findings of the main study.;Findings from the main study change score analysis revealed the adaptive computerised working memory training programme yielded significant near-transfer effects to a complex working memory task, [F(2,73) = 13.9, p .251).;In the second study, Principal Components Analysis confirmed the PPNQ had a unidimensional structure and good internal consistency reliability (Cronbach's a = .806). Findings revealed a positive shift in PPNQ scores following intervention in understanding numeracy instruction. Findings for the control condition support conclusions that the PPNQ was sufficiently sensitive to detect increasingly negative perceptions of numeracy. This study suggests how the PPNQ might be used to identify children's perceptions of numeracy and access to the numeracy curriculum.;The third study used qualitative methods to investigate issues of implementation fidelity important for acceptability and feasibility of computerised training programmes in the primary schools.;This thesis identifies dual benefits of adaptive, multi-domain computerised working memory training not fully explained by the Hawthorne Effect. Recommendations are discussed towards the development of a computerised working memory training paradigm in schools
Primary and secondary crystal nucleation of pharmaceutics
Get PDFControl of the crystallisation process is essential in the consistent and reliable production of many particulate materials in the pharmaceutical and chemical industries. Crystal Nucleation defines the crystal size distribution of the obtained crystal population affecting downstream operations. The literature agrees on crystal nucleation division as primary and secondary nucleation depending on the conditions of the used supersaturated solution. Primary nucleation occurs in a clear supersaturated solution, while secondary nucleation is induced by at least one parent crystal present in the solution. Despite the large amount of research conducted on this field, several challenges for primary and secondary nucleation fundamental understanding are still identifiable. The aim of this thesis is to develop meticulous and accurate methods to measure primary and secondary nucleation in order to systematically study nucleation mechanisms relevant to industrial scales. This thesis is constituted of two main parts: one part studies primary nucleation and develops a method for control and measure primary nucleation rate within the metastable zone width (Chapter 2) using different volumes and hydrodynamics (Chapter 3). The second part concerns studies of secondary nucleation under well-controlled conditions providing a systematic method to measure secondary nucleation rates (Chapter 4), which can be integrated in industrial workflows (Chapter 5) and applied to study the chiral outcomes (Chapter 6). The developed methods decouple primary and secondary nucleation events improving crystallisation processes understanding. The reliability and reproducibility of the novel proposed methods offer an appropriate process control strategy to address existing challenges on crystal nucleation.Control of the crystallisation process is essential in the consistent and reliable production of many particulate materials in the pharmaceutical and chemical industries. Crystal Nucleation defines the crystal size distribution of the obtained crystal population affecting downstream operations. The literature agrees on crystal nucleation division as primary and secondary nucleation depending on the conditions of the used supersaturated solution. Primary nucleation occurs in a clear supersaturated solution, while secondary nucleation is induced by at least one parent crystal present in the solution. Despite the large amount of research conducted on this field, several challenges for primary and secondary nucleation fundamental understanding are still identifiable. The aim of this thesis is to develop meticulous and accurate methods to measure primary and secondary nucleation in order to systematically study nucleation mechanisms relevant to industrial scales. This thesis is constituted of two main parts: one part studies primary nucleation and develops a method for control and measure primary nucleation rate within the metastable zone width (Chapter 2) using different volumes and hydrodynamics (Chapter 3). The second part concerns studies of secondary nucleation under well-controlled conditions providing a systematic method to measure secondary nucleation rates (Chapter 4), which can be integrated in industrial workflows (Chapter 5) and applied to study the chiral outcomes (Chapter 6). The developed methods decouple primary and secondary nucleation events improving crystallisation processes understanding. The reliability and reproducibility of the novel proposed methods offer an appropriate process control strategy to address existing challenges on crystal nucleation
Many-body decoherence with cold atoms in optical lattices
Get PDFUltracold atoms in optical lattices have proven to be an ideal testbed for simulating strongly correlated condensed matter physics. The microscopic understanding of the underlying Hamiltonian and precise control over the Hamiltonian parameters via external fields allow faithful realisation of interesting many-body systems that are otherwise hard to study theoretically or experimentally. This thesis addresses the issue of many-body decoherence, using analytical and numerical techniques, in these optical lattice experiments that arises due to coupling to the environment. We specifically study fermionic systems to investigate the effects of incoherent light scattering on the dynamics. Starting from the atomic structure of fermionic species that are experimentally relevant we provide a framework to derive a microscopic master equation and look at the regimes of strong interactions. The interplay between the atomic physics and many-body physics is found to give rise to interesting observations like suppression of the decoherence effect for magnetically ordered insulators that occur for strong repulsive interactions and an enhancement of the decoherence effect for the case of superfluid pairs that occur for strong attractive interactions. The master equation framework is then applied to a recent experiment looking at the effect of controlled decoherence on a many-body localised system of ultracold fermions in an optical lattice. We determine the dissipative processes in the system looking at the atomic structure of the fermionic species. Lastly we study a system of two species bosons to investigate the effect of interspecies interaction in terms of bipartite entanglement between the species, and how this impacts upon the visibility of the momentum distribution. This study proposes a solution to a recent experimental observation of effects on the momentum distribution of impurity atoms in a Bose-Einstein condensate that would not be explained by polaronic behaviour alone.Ultracold atoms in optical lattices have proven to be an ideal testbed for simulating strongly correlated condensed matter physics. The microscopic understanding of the underlying Hamiltonian and precise control over the Hamiltonian parameters via external fields allow faithful realisation of interesting many-body systems that are otherwise hard to study theoretically or experimentally. This thesis addresses the issue of many-body decoherence, using analytical and numerical techniques, in these optical lattice experiments that arises due to coupling to the environment. We specifically study fermionic systems to investigate the effects of incoherent light scattering on the dynamics. Starting from the atomic structure of fermionic species that are experimentally relevant we provide a framework to derive a microscopic master equation and look at the regimes of strong interactions. The interplay between the atomic physics and many-body physics is found to give rise to interesting observations like suppression of the decoherence effect for magnetically ordered insulators that occur for strong repulsive interactions and an enhancement of the decoherence effect for the case of superfluid pairs that occur for strong attractive interactions. The master equation framework is then applied to a recent experiment looking at the effect of controlled decoherence on a many-body localised system of ultracold fermions in an optical lattice. We determine the dissipative processes in the system looking at the atomic structure of the fermionic species. Lastly we study a system of two species bosons to investigate the effect of interspecies interaction in terms of bipartite entanglement between the species, and how this impacts upon the visibility of the momentum distribution. This study proposes a solution to a recent experimental observation of effects on the momentum distribution of impurity atoms in a Bose-Einstein condensate that would not be explained by polaronic behaviour alone
Exploring the dynamic landscape of small molecule-DNA binding
Get PDFDeoxyribonucleic acid (DNA) is a fundamental component in all living organisms found in Nature. Although both the double-helix structure of this biomolecule and the fact that it stores all the genetic information required by the organism to survive are well understood there are still aspects related to this molecule which are not as clear. Particularly the interactions underpinning the formation of complexes between other molecules, such as proteins, and DNA remain unclear. One of these is the process underlying the formation of small molecule-DNA complexes. Such complexes are known to form via interactions between these small molecules and the DNA minor groove, it has proven to be complicated to develop a set of rational rules for the synthesis of binders to target particular DNA sequences. Such rules are complicated by the complex molecular environment found within the DNA minor groove as well as the role of the spine of hydration found within this groove. Another aspect of the behaviour of DNA which has attracted a lot of attention is related to the mechanism underlying the melting of short DNA sequence. It is important to gain a better understanding of these mechanisms as this process is thought to be important in DNA transcription, replication and repair as well as being important for the application and development of DNA scaffolds. Additionally, it is thought that understanding the impact of binding on this transition could be used to gain further insights into the interactions underpinning these complexes.;Here, FT-IR, ultrafast IR pump-probe and two-dimensional infrared (2D-IR) spectroscopy have been applied to investigate the interactions underpinning the formation of small molecule-DNA. Utilising a specifically designed minor groove binding ligand, incorporating an azide moiety as a non-natural IR probe, the questions outlined above were addressed. The spectroscopy of the of azides and the DNA bases were initially studied separately, in order to gain the understanding of the spectroscopy of these vibrational modes necessary to maximise the information extracted from the DNA complexes. From the initial investigation of the asymmetric azide stretch of benzyl azide, a model compound, it was found that this mode could be used to determine the electrostatic potential and hydrogen bonding strength of the local environment. In the case of the DNA base modes, it was found that both changes in the structure of the duplex, due to alterations in the sequence and the binding of an archetypical minor groove binder, Hoechst 33258, could be reliably extracted. For the binding of Hoechst 33258, these modes reveal details about the interactions underpinning the formation of complexes with both its target and a sub-optimal DNA sequences. The insights gained were then brought together to study the complexes formed between DNA and the specially-designed ligand. This allowed both the interactions underlying these complexes and the nature of the water in the minor groove to be explored. Finally, these new spectroscopic methods were then utilised to begin to reveal details of the melting transition of these DNA duplexes and the impact on melting of ligand binding.Deoxyribonucleic acid (DNA) is a fundamental component in all living organisms found in Nature. Although both the double-helix structure of this biomolecule and the fact that it stores all the genetic information required by the organism to survive are well understood there are still aspects related to this molecule which are not as clear. Particularly the interactions underpinning the formation of complexes between other molecules, such as proteins, and DNA remain unclear. One of these is the process underlying the formation of small molecule-DNA complexes. Such complexes are known to form via interactions between these small molecules and the DNA minor groove, it has proven to be complicated to develop a set of rational rules for the synthesis of binders to target particular DNA sequences. Such rules are complicated by the complex molecular environment found within the DNA minor groove as well as the role of the spine of hydration found within this groove. Another aspect of the behaviour of DNA which has attracted a lot of attention is related to the mechanism underlying the melting of short DNA sequence. It is important to gain a better understanding of these mechanisms as this process is thought to be important in DNA transcription, replication and repair as well as being important for the application and development of DNA scaffolds. Additionally, it is thought that understanding the impact of binding on this transition could be used to gain further insights into the interactions underpinning these complexes.;Here, FT-IR, ultrafast IR pump-probe and two-dimensional infrared (2D-IR) spectroscopy have been applied to investigate the interactions underpinning the formation of small molecule-DNA. Utilising a specifically designed minor groove binding ligand, incorporating an azide moiety as a non-natural IR probe, the questions outlined above were addressed. The spectroscopy of the of azides and the DNA bases were initially studied separately, in order to gain the understanding of the spectroscopy of these vibrational modes necessary to maximise the information extracted from the DNA complexes. From the initial investigation of the asymmetric azide stretch of benzyl azide, a model compound, it was found that this mode could be used to determine the electrostatic potential and hydrogen bonding strength of the local environment. In the case of the DNA base modes, it was found that both changes in the structure of the duplex, due to alterations in the sequence and the binding of an archetypical minor groove binder, Hoechst 33258, could be reliably extracted. For the binding of Hoechst 33258, these modes reveal details about the interactions underpinning the formation of complexes with both its target and a sub-optimal DNA sequences. The insights gained were then brought together to study the complexes formed between DNA and the specially-designed ligand. This allowed both the interactions underlying these complexes and the nature of the water in the minor groove to be explored. Finally, these new spectroscopic methods were then utilised to begin to reveal details of the melting transition of these DNA duplexes and the impact on melting of ligand binding
Is the European Union competition law regime suitable for the Republic of Turkey : does one size fit all?
Get PDFNo abstract available.No abstract available
Metabolomic profiling of the effects of melittin and cisplatin on ovarian cancer cells using high resolution mass spectrometry
Get PDFOver the last few years, metabolomics has come to play an increasingly important part in many fields of research, notably medical studies. However, there is a dearth of research on metabolomics in the area of ovarian cancer and the increase in anti-cancer (platinum) drug resistance. Thus further studies on the modes of anticancer action and the mechanisms of resistance of ovarian cancer cells at the metabolome level are needed. The aim of this study was to characterise the metabolic profiles of two human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant), in response to their exposure to melittin, cisplatin and melittin-cisplatin combination therapy. It has been suggested that melittin may have potential as an anti-cancer therapy; combining cisplatin and melittin may increase response and tolerability in cancer treatment, as well as reducing drug resistance.The A2780 and A2780CR cell lines were treated with sub-lethal doses of melittin, cisplatin and melittin-cisplatin combination therapy for 24 hours before extraction and global metabolite analysis of cell lysates by LC-MS using a HPLC system. Phenotype MicroArray™ experiments were also applied in order to test carbon substrate utilisation or sensitivity in both cell lines after exposure to melittin and cisplatin. Data extraction was carried out with MZmine 2.10 with metabolite searching against an in-house database. The data were analysed using univariate and multivariate methods.The changes induced by melittin in the cisplatin-sensitive cells mainly resulted in reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, ATP and NAD+. It was necessary to evaluate the effect of a melittin on lipid activities of ovarian cancer cell lines. In order to do so, an LC coupled to an Orbitrap Exactive mass spectrometer using an ACE silica gel column was employed. The two cell lines had distinct lipid compositions, with the A2780CR cells having lower levels of several ether lipids than the A2780 cells. The changes induced by melittin in both cell lines mainly led to a decrease the level of PC and PE. Lipids were significantly altered in both A2780 and A2780CR cells. The observed effect was much more marked in the cisplatin-sensitive cells, suggesting that the sensitive cells undergo much more extensive membrane re-modelling in responsexviito melittin in comparison with the resistant cells. Regarding the metabolic effects of cisplatin on A2780 cells, these mainly resulted decreased levels of acetylcarnitine, phosphocreatine, arginine, proline and glutathione disulfide, as well as to increased levels of tryptophan and methionine. A number of metabolites were differently affected between the A2780 and A2780CR cells following cisplatin treatment, with A2780CR cells presenting increased levels of lysine, and decreased levels of N-acetyl-glutamate, oxoglutarate and 2-oxobutanoate compared to sensitive cells. However, when the combination treatment was applied, there were significant changes in both cell lines, mainly resulting in a reduction of levels of citrate cycle, oxidative phosphorylation, purine, pyrimidine and arginine/proline pathways. The combination of melittin with cisplatin has a synergistic effect when targeting these pathways. The melittin-cisplatin combination had stronger effect on A2780 cell lines than it had on those of A2780CR.Overall, this study suggests that melittin may have some potential as an adjuvant therapy in cancer treatment. A global metabolomics approach can be a useful tool for evaluating the pharmacological effects of anti-cancer compounds or synergetic sensitisers using mass spectrometry.Over the last few years, metabolomics has come to play an increasingly important part in many fields of research, notably medical studies. However, there is a dearth of research on metabolomics in the area of ovarian cancer and the increase in anti-cancer (platinum) drug resistance. Thus further studies on the modes of anticancer action and the mechanisms of resistance of ovarian cancer cells at the metabolome level are needed. The aim of this study was to characterise the metabolic profiles of two human ovarian cancer cell lines, A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant), in response to their exposure to melittin, cisplatin and melittin-cisplatin combination therapy. It has been suggested that melittin may have potential as an anti-cancer therapy; combining cisplatin and melittin may increase response and tolerability in cancer treatment, as well as reducing drug resistance.The A2780 and A2780CR cell lines were treated with sub-lethal doses of melittin, cisplatin and melittin-cisplatin combination therapy for 24 hours before extraction and global metabolite analysis of cell lysates by LC-MS using a HPLC system. Phenotype MicroArray™ experiments were also applied in order to test carbon substrate utilisation or sensitivity in both cell lines after exposure to melittin and cisplatin. Data extraction was carried out with MZmine 2.10 with metabolite searching against an in-house database. The data were analysed using univariate and multivariate methods.The changes induced by melittin in the cisplatin-sensitive cells mainly resulted in reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, ATP and NAD+. It was necessary to evaluate the effect of a melittin on lipid activities of ovarian cancer cell lines. In order to do so, an LC coupled to an Orbitrap Exactive mass spectrometer using an ACE silica gel column was employed. The two cell lines had distinct lipid compositions, with the A2780CR cells having lower levels of several ether lipids than the A2780 cells. The changes induced by melittin in both cell lines mainly led to a decrease the level of PC and PE. Lipids were significantly altered in both A2780 and A2780CR cells. The observed effect was much more marked in the cisplatin-sensitive cells, suggesting that the sensitive cells undergo much more extensive membrane re-modelling in responsexviito melittin in comparison with the resistant cells. Regarding the metabolic effects of cisplatin on A2780 cells, these mainly resulted decreased levels of acetylcarnitine, phosphocreatine, arginine, proline and glutathione disulfide, as well as to increased levels of tryptophan and methionine. A number of metabolites were differently affected between the A2780 and A2780CR cells following cisplatin treatment, with A2780CR cells presenting increased levels of lysine, and decreased levels of N-acetyl-glutamate, oxoglutarate and 2-oxobutanoate compared to sensitive cells. However, when the combination treatment was applied, there were significant changes in both cell lines, mainly resulting in a reduction of levels of citrate cycle, oxidative phosphorylation, purine, pyrimidine and arginine/proline pathways. The combination of melittin with cisplatin has a synergistic effect when targeting these pathways. The melittin-cisplatin combination had stronger effect on A2780 cell lines than it had on those of A2780CR.Overall, this study suggests that melittin may have some potential as an adjuvant therapy in cancer treatment. A global metabolomics approach can be a useful tool for evaluating the pharmacological effects of anti-cancer compounds or synergetic sensitisers using mass spectrometry
Protection, fault location & control in high voltage multi terminal direct current (HV-MTDC) grids
Get PDFWith an increased penetration of renewable energy sources, balancing the supply and demand is likely to be one of the major challenges in future power systems. Consequently, there is a growing need for meshed interconnections between countries in order to effectively share the available power capacity and thereby increase operational exibility and security of supply. This has been raised as a major issue in Europe but also in Asia and United States of America.;The concept of supergrid has been identifed as a possible solution towards a newback bone transmission system, permitting massive integration of renewable energy sources. High voltage direct current (HVDC) links, utilising voltage-source converters (VSCs),are expected to become the preferred technology for the realisation of such a supergrid. This is due to the fact that such systems offer improvements in terms of system stability, lower cost and operational losses.;A natural extension of the existing point-to-point HVDC transmission technology is a multi-terminal direct-current (MTDC) system which utilises more than two VSC stations, effectively forming a DC grid. Such a configuration can provide further technological and economical advantages and hence accelerate the realisation of a supergrid. However, technical limitations still exist, and it is not yet a straightforward task to construct and operate an MTDC grid, as several outstanding issues need to be solved.;Consequently, it is essential to study, analyse and address potential challenges imposed by MTDC systems in order to enable widespread adoption.;Even though numerous challenges are introduced for the practical implementation of MTDC networks, this thesis deals with the challenges related to the DC-side faults, which is the main issue when considering HVDC technology. DC-side faults in HVDC systems are characterised by large inrush currents caused by the discharge of trapped energy in the system capacitances, escalating over a very short period of time. These include lumped capacitors installed on the DC side of converters, transmission line capacitances, and also the sub-module capacitors contained within modular multi-level converters.;When faults occur in multi-terminal HVDC grids, the DC protection system is expected to minimise the detrimental effects by disconnecting only the faulted section while permitting the remaining healthy part of the grid to continue normal operation. Such requirements introduce the need for transient DC fault characterisation and subsequent development of a discriminative, fast, sensitive and reliable DC protection method.;Therefore, one of the main objectives of this thesis is to provide demonstrable solutions to the key challenges involved in protecting MTDC grids, and hence enabling the realisation of HVDC-based supergrids. Two alternative, novel protection schemes are proposed, designed and assessed with the aid of transient simulation. The key advantages of the proposed schemes consist in enhanced reliability, fast fault detection, superior stability, and high level of selectivity. To further validate the practical feasibility of the schemes, small-scale laboratory prototypes have been developed to test the performance of the schemes under real-time fault conditions.;It should be also highlighted that when a permanent fault occurs in an HVDC transmission system, accurate estimation of its location is of major importance in order to accelerate restoration, reduce the system down-time, minimise repair cost, and hence, increase the overall availability and reliability of HVDC grids. As such, another contribution of this thesis is related to the challenges involved in accurate fault location in HVDC networks, including non-homogeneous transmission media (i.e. the lines which include multiple segments of both underground cables and overhead lines).;Two novel fault location methods have been developed and systematically assessed. It is demonstrated that the schemes can reliably identify the faulted segment of the line while consistently maintaining high accuracy of fault location across a wide range of fault scenarios. Further sensitivity analysis demonstrates that the proposed schemes are robust against noisy inputs.;In its concluding section, the thesis also outlines a few possible avenues of further research in this area.With an increased penetration of renewable energy sources, balancing the supply and demand is likely to be one of the major challenges in future power systems. Consequently, there is a growing need for meshed interconnections between countries in order to effectively share the available power capacity and thereby increase operational exibility and security of supply. This has been raised as a major issue in Europe but also in Asia and United States of America.;The concept of supergrid has been identifed as a possible solution towards a newback bone transmission system, permitting massive integration of renewable energy sources. High voltage direct current (HVDC) links, utilising voltage-source converters (VSCs),are expected to become the preferred technology for the realisation of such a supergrid. This is due to the fact that such systems offer improvements in terms of system stability, lower cost and operational losses.;A natural extension of the existing point-to-point HVDC transmission technology is a multi-terminal direct-current (MTDC) system which utilises more than two VSC stations, effectively forming a DC grid. Such a configuration can provide further technological and economical advantages and hence accelerate the realisation of a supergrid. However, technical limitations still exist, and it is not yet a straightforward task to construct and operate an MTDC grid, as several outstanding issues need to be solved.;Consequently, it is essential to study, analyse and address potential challenges imposed by MTDC systems in order to enable widespread adoption.;Even though numerous challenges are introduced for the practical implementation of MTDC networks, this thesis deals with the challenges related to the DC-side faults, which is the main issue when considering HVDC technology. DC-side faults in HVDC systems are characterised by large inrush currents caused by the discharge of trapped energy in the system capacitances, escalating over a very short period of time. These include lumped capacitors installed on the DC side of converters, transmission line capacitances, and also the sub-module capacitors contained within modular multi-level converters.;When faults occur in multi-terminal HVDC grids, the DC protection system is expected to minimise the detrimental effects by disconnecting only the faulted section while permitting the remaining healthy part of the grid to continue normal operation. Such requirements introduce the need for transient DC fault characterisation and subsequent development of a discriminative, fast, sensitive and reliable DC protection method.;Therefore, one of the main objectives of this thesis is to provide demonstrable solutions to the key challenges involved in protecting MTDC grids, and hence enabling the realisation of HVDC-based supergrids. Two alternative, novel protection schemes are proposed, designed and assessed with the aid of transient simulation. The key advantages of the proposed schemes consist in enhanced reliability, fast fault detection, superior stability, and high level of selectivity. To further validate the practical feasibility of the schemes, small-scale laboratory prototypes have been developed to test the performance of the schemes under real-time fault conditions.;It should be also highlighted that when a permanent fault occurs in an HVDC transmission system, accurate estimation of its location is of major importance in order to accelerate restoration, reduce the system down-time, minimise repair cost, and hence, increase the overall availability and reliability of HVDC grids. As such, another contribution of this thesis is related to the challenges involved in accurate fault location in HVDC networks, including non-homogeneous transmission media (i.e. the lines which include multiple segments of both underground cables and overhead lines).;Two novel fault location methods have been developed and systematically assessed. It is demonstrated that the schemes can reliably identify the faulted segment of the line while consistently maintaining high accuracy of fault location across a wide range of fault scenarios. Further sensitivity analysis demonstrates that the proposed schemes are robust against noisy inputs.;In its concluding section, the thesis also outlines a few possible avenues of further research in this area
Impacts of high penetration of DFIG wind turbines on rotor angle stability of power systems
Get PDFThis thesis investigates the effects of increased penetration levels of DFIG based wind turbines on rotor angle stability of power systems and how these impacts could be mitigated. The main outcome of this research is the comprehensive assessment of the stability improvements that can be achieved through a novel cost-effective control approach using existing DFIG equipments. A control strategy for both the rotor-side converter (RSC) and grid-side converter (GSC) of the DFIG is proposed to mitigate DFIGs impacts on the system stability. DFIG-GSC is utilised as a static synchronous compensator (STATCOM) to provide reactive power support during the active crowbar time when controlling of both reactive and active power is lost and a large amount of reactive power is absorbed. In addition, a supplementary power system stabiliser (PSS) is designed taking into account the influence of the crowbar system. To overcome the effects of PSS active power modulation, the PSS is designed to be implemented in the reactive power control loop of DFIG-RSC.The proposed approaches are examined on IEEE 9-bus and IEEE 39-bus systems under both small and large disturbances. The simulation results show the effectiveness and robustness of both approaches to enhance rotor angle stability. As the levels of wind penetration are increased, the benefit of such a control scheme is that the DFIG-based wind farms are able to take over the synchronous generators responsibility to support power system stability.As wind power is stochastic and fluctuates with the variation of wind speed, the proposed DFIG PSS should have the capability to damp power system oscillations effectively under non-uniform variable wind speeds across the wind farm. Therefore, the feasibility of the proposed fixed parameters PSS is evaluated using the IEEE 39-bus test system taking into account the non-uniform and variable wind speed profiles. The results confirm the robustness and stabilising effect against various operating modes and under various wind speeds.This thesis investigates the effects of increased penetration levels of DFIG based wind turbines on rotor angle stability of power systems and how these impacts could be mitigated. The main outcome of this research is the comprehensive assessment of the stability improvements that can be achieved through a novel cost-effective control approach using existing DFIG equipments. A control strategy for both the rotor-side converter (RSC) and grid-side converter (GSC) of the DFIG is proposed to mitigate DFIGs impacts on the system stability. DFIG-GSC is utilised as a static synchronous compensator (STATCOM) to provide reactive power support during the active crowbar time when controlling of both reactive and active power is lost and a large amount of reactive power is absorbed. In addition, a supplementary power system stabiliser (PSS) is designed taking into account the influence of the crowbar system. To overcome the effects of PSS active power modulation, the PSS is designed to be implemented in the reactive power control loop of DFIG-RSC.The proposed approaches are examined on IEEE 9-bus and IEEE 39-bus systems under both small and large disturbances. The simulation results show the effectiveness and robustness of both approaches to enhance rotor angle stability. As the levels of wind penetration are increased, the benefit of such a control scheme is that the DFIG-based wind farms are able to take over the synchronous generators responsibility to support power system stability.As wind power is stochastic and fluctuates with the variation of wind speed, the proposed DFIG PSS should have the capability to damp power system oscillations effectively under non-uniform variable wind speeds across the wind farm. Therefore, the feasibility of the proposed fixed parameters PSS is evaluated using the IEEE 39-bus test system taking into account the non-uniform and variable wind speed profiles. The results confirm the robustness and stabilising effect against various operating modes and under various wind speeds
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