'La Violence et la mauvaise foi': Context and rhetoric in Pierre Bayle's Ce que c'est que la France toute Catholique

My thesis presents an examination of Ce que c'est que la France toute Catholique (1686) by Pierre Bayle, a prominent figure in the Republic of Letters and the Huguenot Refuge in the seventeenth century. This pamphlet was the first occasional text that Bayle published following the Revocation of the Edict of Nantes in which the religious toleration afforded to the Huguenot minority in France was repealed, a pivotal moment in the history of early modern France. In my thesis, I analyse the specific context within which Bayle wrote this pamphlet as a means of addressing a number of issues, including the legitimacy of forced conversions, the impact of the religious controversy upon exchanges in the Republic of Letters, the nature of religious zeal and finally the alliance of Church and state discourses in the early modern period. An examination of this context provides a basis from which to re-interpret the rhetorical strategies at work within the pamphlet, and also to come to an increased understanding of how, why and to what end he wrote it. In turn this allowed me to examine the relationship between this often overlooked pamphlet and the more extensively studied Commentaire Philosophique, in which Bayle argued in favour of religious toleration. Ultimately, understanding the relationship between these two texts proves essential in order to characterise his response to the Revocation of the Edict of Nantes and to understand the place of the pamphlet within his oeuvre. Furthermore, an analysis of the pamphlet and the Commentaire Philosophique provide a lens through which to elucidate both Bayle's intellectual development at this early stage in his career, and also the wider context of the rise of toleration theory and the evolution of modes of civility within the Republic of Letters on the eve of the Enlightenment.

Feasibility of combined wind-wave energy platforms

The European Union has set out an ambitious 20% target for renewable energy use by 2020. It is expected that this will be met mainly by wind energy. Looking towards 2050, reductions in greenhouse gas emissions of 80-95% are to be sought. Given the issues securing this target in the transport and agriculture sectors, it may only be possible to achieve this target if the power sector is carbon neutral well in advance of 2050. This has permitted the vast expansion of offshore renewables, wind, wave and tidal energy. Offshore wind has undergone rapid development in recent years however faces significant challenges up to 2020 to ensure commercial viability without the need for government subsidies. Wave energy is still in the very early stages of development so as yet there has been no commercial roll out. As both of these technologies are to face similar challenges in ensuring they are a viable alternative power generation method to fossil fuels, capitalising on the synergies is potentially a significant cost saving initiative. The advent of hybrid solutions in a variety of configurations is the subject of this thesis. A singular wind-wave energy platform embodies all the attributes of a hybrid system, including sharing space, transmission infrastructure, O&M activities and a platform/foundation. This configuration is the subject of this thesis, and it is found that an OWC Array platform with multi-MegaWatt wind turbines is a technically feasible, and potentially an economically feasible solution in the long term. Methods of design and analysis adopted in this thesis include numerical and physical modelling of power performance, structural analysis, fabrication cost modelling, simplified project economic modelling and time domain reliability modelling of a 210MW hybrid farm. The application of these design and analysis methods has resulted in a hybrid solution capable of producing energy at a cost between €0.22/kWh and €0.31/kWh depending on the source of funding for the project. Further optimisation through detailed design is expected to lower this further. This thesis develops new and existing methods of design and analysis of wind and wave energy devices. This streamlines the process of early stage development, while adhering to the widely adopted Concept Development Protocol, to develop a technically and economically feasible, combined wind-wave energy hybrid solution.

Electromagnetic tracking and steering for catheter navigation

This thesis explores the use of electromagnetics for both steering and tracking of medical instruments in minimally invasive surgeries. The end application is virtual navigation of the lung for biopsy of early stage cancer nodules. Navigation to the peripheral regions of the lung is difficult due to physical dimensions of the bronchi and current methods have low successes rates for accurate diagnosis. Firstly, the potential use of DC magnetic fields for the actuation of catheter devices with permanently magnetised distal attachments is investigated. Catheter models formed from various materials and magnetic tip formations are used to examine the usefulness of relatively low power and compact electromagnets. The force and torque that can be exerted on a small permanent magnet is shown to be extremely limited. Hence, after this initial investigation we turn our attention to electromagnetic tracking, in the development of a novel, low-cost implementation of a GPS-like system for navigating within a patient. A planar magnetic transmitter, formed on a printed circuit board for a low-profile and low cost manufacture, is used to generate a low frequency magnetic field distribution which is detected by a small induction coil sensor. The field transmitter is controlled by a novel closed-loop system that ensures a highly stable magnetic field with reduced interference from one transmitter coil to another. Efficient demodulation schemes are presented which utilise synchronous detection of each magnetic field component experienced by the sensor. The overall tracking accuracy of the system is shown to be less than 2 mm with an orientation error less than 1°. A novel demodulation implementation using a unique undersampling approach allows the use of reduced sample rates to sample the signals of interest without loss of tracking accuracy. This is advantageous for embedded microcontroller implementations of EM tracking systems. The EM tracking system is demonstrated in the pre-clinical environment of a breathing lung phantom. The airways of the phantom are successfully navigated using the system in combination with a 3D computer model rendered from CT data. Registration is achieved using both a landmark rigid registration method and a hybrid fiducial-free approach. The design of a planar magnetic shield structure for blocking the effects of metallic distortion from below the transmitter is presented which successfully blocks the impact of large ferromagnetic objects such as operating tables. A variety of shielding material are analysed with MuMetal and ferrite both providing excellent shieling performance and an increased signal to noise ratio. Finally, the effect of conductive materials and human tissue on magnetic field measurements is presented. Error due to induced eddy currents and capacitive coupling is shown to severely affect EM tracking accuracy at higher frequencies.

Improved kinematic sensing for motion control applications

New compensation methods are presented that can greatly reduce the slit errors (i.e. transition location errors) and interval errors induced due to non-idealities in optical incremental encoders (square-wave). An M/T-type, constant sample-time digital tachometer (CSDT) is selected for measuring the velocity of the sensor drives. Using this data, three encoder compensation techniques (two pseudoinverse based methods and an iterative method) are presented that improve velocity measurement accuracy. The methods do not require precise knowledge of shaft velocity. During the initial learning stage of the compensation algorithm (possibly performed in-situ), slit errors/interval errors are calculated through pseudoinversebased solutions of simple approximate linear equations, which can provide fast solutions, or an iterative method that requires very little memory storage. Subsequent operation of the motion system utilizes adjusted slit positions for more accurate velocity calculation. In the theoretical analysis of the compensation of encoder errors, encoder error sources such as random electrical noise and error in estimated reference velocity are considered. Initially, the proposed learning compensation techniques are validated by implementing the algorithms in MATLAB software, showing a 95% to 99% improvement in velocity measurement. However, it is also observed that the efficiency of the algorithm decreases with the higher presence of non-repetitive random noise and/or with the errors in reference velocity calculations. The performance improvement in velocity measurement is also demonstrated experimentally using motor-drive systems, each of which includes a field-programmable gate array (FPGA) for CSDT counting/timing purposes, and a digital-signal-processor (DSP). Results from open-loop velocity measurement and closed-loop servocontrol applications, on three optical incremental square-wave encoders and two motor drives, are compiled. While implementing these algorithms experimentally on different drives (with and without a flywheel) and on encoders of different resolutions, slit error reductions of 60% to 86% are obtained (typically approximately 80%).

Operational expenditure costs for wave energy projects and impacts on financial returns

This paper examines 'availability' and the input metrics of operational expenditure (OPEX) for wave energy projects and reports on a case study which assesses the impact of these inputs on project profit returns. Case study simulations modelled a 75 MW wave energy project at two locations; the west coast of Ireland and the north coast of Portugal. Access and availability with respect to weather windows at both locations are discussed and their impact on energy output and wave farm operations is quantified. The input metrics used to calculate OPEX of wave energy projects are defined as well as the impact of OPEX on project net present value (NPV) and internal rate of return (IRR). Results indicate that access and resultant availability factors have a significant impact on case study results by reducing energy output and correspondingly financial returns. Furthermore, the technology maturity level designated for a project also impacts on availability factors and consequently energy output and NPV. Case study profits proved to be very sensitive to annual OPEX, especially if overhaul and replacement costs were accounted for. As a result of the impact of 'availability' on project profit returns. Feed-in tariffs will need to be tailored to the location in question as well as the device technology maturity level, with case study simulations indicating that high FIT will be required to support early stage WEC projects. (C) 2012 Elsevier Ltd. All rights reserved.

Design, fabrication and characterization of resonant waveguide grating based optical biosensors

The absence of rapid, low cost and highly sensitive biodetection platform has hindered the implementation of next generation cheap and early stage clinical or home based point-of-care diagnostics. Label-free optical biosensing with high sensitivity, throughput, compactness, and low cost, plays an important role to resolve these diagnostic challenges and pushes the detection limit down to single molecule. Optical nanostructures, specifically the resonant waveguide grating (RWG) and nano-ribbon cavity based biodetection are promising in this context. The main element of this dissertation is design, fabrication and characterization of RWG sensors for different spectral regions (e.g. visible, near infrared) for use in label-free optical biosensing and also to explore different RWG parameters to maximize sensitivity and increase detection accuracy. Design and fabrication of the waveguide embedded resonant nano-cavity are also studied. Multi-parametric analyses were done using customized optical simulator to understand the operational principle of these sensors and more important the relationship between the physical design parameters and sensor sensitivities. Silicon nitride (SixNy) is a useful waveguide material because of its wide transparency across the whole infrared, visible and part of UV spectrum, and comparatively higher refractive index than glass substrate. SixNy based RWGs on glass substrate are designed and fabricated applying both electron beam lithography and low cost nano-imprint lithography techniques. A Chromium hard mask aided nano-fabrication technique is developed for making very high aspect ratio optical nano-structure on glass substrate. An aspect ratio of 10 for very narrow (~60 nm wide) grating lines is achieved which is the highest presented so far. The fabricated RWG sensors are characterized for both bulk (183.3 nm/RIU) and surface sensitivity (0.21nm/nm-layer), and then used for successful detection of Immunoglobulin-G (IgG) antibodies and antigen (~1μg/ml) both in buffer and serum. Widely used optical biosensors like surface plasmon resonance and optical microcavities are limited in the separation of bulk response from the surface binding events which is crucial for ultralow biosensing application with thermal or other perturbations. A RWG based dual resonance approach is proposed and verified by controlled experiments for separating the response of bulk and surface sensitivity. The dual resonance approach gives sensitivity ratio of 9.4 whereas the competitive polarization based approach can offer only 2.5. The improved performance of the dual resonance approach would help reducing probability of false reading in precise bio-assay experiments where thermal variations are probable like portable diagnostics.

Open-source virtual bronchoscopy for image guided navigation

This thesis describes the development of an open-source system for virtual bronchoscopy used in combination with electromagnetic instrument tracking. The end application is virtual navigation of the lung for biopsy of early stage cancer nodules. The open-source platform 3D Slicer was used for creating freely available algorithms for virtual bronchscopy. Firstly, the development of an open-source semi-automatic algorithm for prediction of solitary pulmonary nodule malignancy is presented. This approach may help the physician decide whether to proceed with biopsy of the nodule. The user-selected nodule is segmented in order to extract radiological characteristics (i.e., size, location, edge smoothness, calcification presence, cavity wall thickness) which are combined with patient information to calculate likelihood of malignancy. The overall accuracy of the algorithm is shown to be high compared to independent experts' assessment of malignancy. The algorithm is also compared with two different predictors, and our approach is shown to provide the best overall prediction accuracy. The development of an airway segmentation algorithm which extracts the airway tree from surrounding structures on chest Computed Tomography (CT) images is then described. This represents the first fundamental step toward the creation of a virtual bronchoscopy system. Clinical and ex-vivo images are used to evaluate performance of the algorithm. Different CT scan parameters are investigated and parameters for successful airway segmentation are optimized. Slice thickness is the most affecting parameter, while variation of reconstruction kernel and radiation dose is shown to be less critical. Airway segmentation is used to create a 3D rendered model of the airway tree for virtual navigation. Finally, the first open-source virtual bronchoscopy system was combined with electromagnetic tracking of the bronchoscope for the development of a GPS-like system for navigating within the lungs. Tools for pre-procedural planning and for helping with navigation are provided. Registration between the lungs of the patient and the virtually reconstructed airway tree is achieved using a landmark-based approach. In an attempt to reduce difficulties with registration errors, we also implemented a landmark-free registration method based on a balanced airway survey. In-vitro and in-vivo testing showed good accuracy for this registration approach. The centreline of the 3D airway model is extracted and used to compensate for possible registration errors. Tools are provided to select a target for biopsy on the patient CT image, and pathways from the trachea towards the selected targets are automatically created. The pathways guide the physician during navigation, while distance to target information is updated in real-time and presented to the user. During navigation, video from the bronchoscope is streamed and presented to the physician next to the 3D rendered image. The electromagnetic tracking is implemented with 5 DOF sensing that does not provide roll rotation information. An intensity-based image registration approach is implemented to rotate the virtual image according to the bronchoscope's rotations. The virtual bronchoscopy system is shown to be easy to use and accurate in replicating the clinical setting, as demonstrated in the pre-clinical environment of a breathing lung method. Animal studies were performed to evaluate the overall system performance.

Gene delivery for the treatment of prostate cancer

Prostate cancer is one of the most common cancers diagnosed in men. Whilst treatments for early-stage disease are largely effective, current therapies for metastatic prostate cancer, particularly for bone metastasis, offer only a few months increased lifespan at best. Hence new treatments are urgently required. Small interfering RNA (siRNA) has been investigated for the treatment of prostate cancer where it can ‘silence’ specific cancer-related genes. However the clinical application of siRNA-based gene therapy is limited due to the absence of an optimised gene delivery vector. The optimisation of such gene delivery vectors is routinely undertaken in vitro using 2D cell culture on plastic dishes which does not accurately simulate the in vivo bone cancer metastasis microenvironment. The goal of this thesis was to assess the potential of two different targeted delivery vectors (gold or modified β-cyclodextrin derivatives) to facilitate siRNA receptor-mediated uptake into prostate cancer cells. Furthermore, this project aimed to develop a more physiologically relevant 3D in vitro cell culture model, to mimic prostate cancer bone metastasis, which is suitable for evaluating the delivery of nanoparticulate gene therapeutics. In the first instance, cationic derivatives of gold and β-cyclodextrin were synthesized to complex anionic siRNA. The delivery vectors were targeted to prostate cancer cells using the anisamide ligand which has high affinity for the sigma receptor that is overexpressed by prostate cancer cells. The gold nanoparticle demonstrated high levels of uptake into prostate cancer PC3 cells and efficient gene silencing when transfection was performed in serum-free media. However, due to the absence of a poly(ethylene glycol) (PEG) stabilising group, the formulation was unsuitable for use in serum-containing conditions. Conversely, the modified β-cyclodextrin formulation demonstrated enhanced stability in the presence of serum due to the inclusion of a PEG chain onto which the anisamide ligand was conjugated. However, the maximum level of gene silencing efficacy from three different prostate cancer cell lines (DU145, VCaP and PC3 cells) was 30 %, suggesting that further optimisation of the formulation would be required prior to application in vivo. In order to develop a more physiologically-relevant in vitro model of prostate cancer bone metastasis, prostate cancer cells (PC3 and LNCaP cells) were cultured in 3D on collagenbased scaffolds engineered to mimic the bone microenvironment. While the model was suitable for assessing nanoparticle-mediated gene knockdown, prostate cancer cells demonstrated a phenotype with lower invasive potential when grown on the scaffolds relative to standard 2D cell culture. Hence, prostate cancer cells (PC3 and LNCaP cells) were subsequently co-cultured with bone osteoblast cells (hFOB 1.19 cells) to enhance the physiological relevance of the model. Co-cultures secreted elevated levels of the MMP9 enzyme, a marker of prostate cancer metastasis, relative to prostate cancer cell monocultures (2D and 3D) indicating enhanced physiological relevance of the model. Furthermore, the coculture model proved suitable for investigating nanoparticle-mediated gene silencing. In conclusion, the work outlined in this thesis identified two different sigma receptor-targeted gene delivery vectors with potential for the treatment of prostate cancer. In addition, a more physiologically relevant model of prostate cancer bone metastasis was developed with the capacity to help optimise gene delivery vectors for the treatment of prostate cancer.

Dynamic classifiers for neonatal brain monitoring

Brain injury due to lack of oxygen or impaired blood flow around the time of birth, may cause long term neurological dysfunction or death in severe cases. The treatments need to be initiated as soon as possible and tailored according to the nature of the injury to achieve best outcomes. The Electroencephalogram (EEG) currently provides the best insight into neurological activities. However, its interpretation presents formidable challenge for the neurophsiologists. Moreover, such expertise is not widely available particularly around the clock in a typical busy Neonatal Intensive Care Unit (NICU). Therefore, an automated computerized system for detecting and grading the severity of brain injuries could be of great help for medical staff to diagnose and then initiate on-time treatments. In this study, automated systems for detection of neonatal seizures and grading the severity of Hypoxic-Ischemic Encephalopathy (HIE) using EEG and Heart Rate (HR) signals are presented. It is well known that there is a lot of contextual and temporal information present in the EEG and HR signals if examined at longer time scale. The systems developed in the past, exploited this information either at very early stage of the system without any intelligent block or at very later stage where presence of such information is much reduced. This work has particularly focused on the development of a system that can incorporate the contextual information at the middle (classifier) level. This is achieved by using dynamic classifiers that are able to process the sequences of feature vectors rather than only one feature vector at a time.

Hepatitis C virus modulation of lipid and autophagy pathways

Hepatitis C virus [HCV] infects 170 million people worldwide. We investigated interactions between HCV proteins and cellular proteins involved in autophagy and lipid metabolism. We sought to develop an infection model using patient derived human serum containing HCV and human hepatocytes, Huh7 cells. Using the model, we have shown intracellular expression of incoming HCV RNA (5′ UTR region and region spanning the E1/E2 glycoproteins), expression of the HCV proteins, core and NS5B, and a cellular response to HCV infection. These data suggests this model can be used to analyse the early stage of HCV infection. HCV utilises the autophagy pathway to both establish infection and to complete its life cycle. We investigated HCV interaction with the early stage autophagy protein ATG5. We found that although ATG5 mRNA is unchanged in HCV infected cells, protein expression of ATG5 is significantly upregulated. These data indicated HCV controls the post-transcriptional regulation of ATG5. We used the upstream open reading frame (uORF) and the 5′ UTR region of ATG5 to examine the post-transcriptional regulation. Our data suggest HCV RNA replication either directly or indirectly causes post-transcriptional regulation of the early autophagy protein, ATG5 in a 5′ UTR and uORF independent manner. HCV infection leads to an increase in SREBP controlled genes e.g. HMG-CoA Reductase, cholesterol, LDL and fatty acid synthesis. We hypothesised that HCV infection causes the activation of SREBP pathway by interacting directly or indirectly with proteins involved in the initiation of the pathway. We sought to determine if HCV interacts with SCAP or INSIG. We confirmed a change in LD distribution and HMG-CoA reductase activity as a result of HCV RNA replication. Significantly, we show SCAP protein expression was also altered during HCV RNA replication and HCV core protein possibly interacts with SCAP.