Cell-Taught Gene Therapy for the Preservation and Regeneration of Cardiac Tissue Following Chronic Heart Failure

Heart failure is the primary cause of mortality and morbidity in the Western world. Although cell therapy has demonstrated improvement in cardiac function, these benefits are being attributed to the activation of paracrine factors, rather than the differentiation and integration of the transplanted cells into the host tissue. Based on this knowledge the focus of this thesis work was to deliver paracrine factors, and evaluate its effect on cardiac function. Gene therapy has evolved as a promising option to deliver pro-angiogenic proteins to infarct zones, thus providing cardiac benefit. This study has identified a gene design without the use of viral vectors, to deliver transient, yet therapeutic levels of an angiogenic chemokine, Stromal-Derived-Cell-Factor-1 (SDF-1) in rodents with chronic heart failure, and has reported significant improvement in cardiac function. The use of Kozak sequences and translational enhancers helped boost gene expressions which could be accurately measured using bio-fluorescence imaging techniques. This improvement in gene expression was directly proportional to the improvement in cardiac function in rodents with chronic heart failure. However effective plasmid delivery, via the systemic route, requires the encapsulation and targeting of the plasmid to infarct zones. An infarct-specific peptide was identified with the help of phage panning techniques and nanoparticles, formulated with poly lactide-co-glycolide (PLGA), were employed to encapsulate a fluorescent dye, 6-Coumarin (6C). Targeted and efficient delivery was achieved by tagging the surface of the nanoparticles with the targeting peptide. Another aspect of this study was to identify novel paracrine factors responsible for reverse ventricular remodeling, following the treatment of chronic heart failure with mesenchymal stem cell (MSC) therapy, using microarray analysis. Overall, this study has identified the design and delivery technique for a therapeutic, cardiac-benefiting gene to the infarct zone, in rodents with heart fail

Cell-Taught Gene Therapy for the Preservation and Regeneration of Cardiac Tissue Following Chronic Heart Failure

Heart failure is the primary cause of mortality and morbidity in the Western world. Although cell therapy has demonstrated improvement in cardiac function, these benefits are being attributed to the activation of paracrine factors, rather than the differentiation and integration of the transplanted cells into the host tissue. Based on this knowledge the focus of this thesis work was to deliver paracrine factors, and evaluate its effect on cardiac function. Gene therapy has evolved as a promising option to deliver pro-angiogenic proteins to infarct zones, thus providing cardiac benefit. This study has identified a gene design without the use of viral vectors, to deliver transient, yet therapeutic levels of an angiogenic chemokine, Stromal-Derived-Cell-Factor-1 (SDF-1) in rodents with chronic heart failure, and has reported significant improvement in cardiac function. The use of Kozak sequences and translational enhancers helped boost gene expressions which could be accurately measured using bio-fluorescence imaging techniques. This improvement in gene expression was directly proportional to the improvement in cardiac function in rodents with chronic heart failure. However effective plasmid delivery, via the systemic route, requires the encapsulation and targeting of the plasmid to infarct zones. An infarct-specific peptide was identified with the help of phage panning techniques and nanoparticles, formulated with poly lactide-co-glycolide (PLGA), were employed to encapsulate a fluorescent dye, 6-Coumarin (6C). Targeted and efficient delivery was achieved by tagging the surface of the nanoparticles with the targeting peptide. Another aspect of this study was to identify novel paracrine factors responsible for reverse ventricular remodeling, following the treatment of chronic heart failure with mesenchymal stem cell (MSC) therapy, using microarray analysis. Overall, this study has identified the design and delivery technique for a therapeutic, cardiac-benefiting gene to the infarct zone, in rodents with heart fail

Advances in Reinforcement Learning

Reinforcement Learning (RL) is a very dynamic area in terms of theory and application. This book brings together many different aspects of the current research on several fields associated to RL which has been growing rapidly, producing a wide variety of learning algorithms for different applications. Based on 24 Chapters, it covers a very broad variety of topics in RL and their application in autonomous systems. A set of chapters in this book provide a general overview of RL while other chapters focus mostly on the applications of RL paradigms: Game Theory, Multi-Agent Theory, Robotic, Networking Technologies, Vehicular Navigation, Medicine and Industrial Logistic

Assisted Viewpoint Interaction for 3D Visualization

Many three-dimensional visualizations are characterized by the use of a mobile viewpoint that offers multiple perspectives on a set of visual information. To effectively control the viewpoint, the viewer must simultaneously manage the cognitive tasks of understanding the layout of the environment, and knowing where to look to find relevant information, along with mastering the physical interaction required to position the viewpoint in meaningful locations. Numerous systems attempt to address these problems by catering to two extremes: simplified controls or direct presentation. This research attempts to promote hybrid interfaces that offer a supportive, yet unscripted exploration of a virtual environment.Attentive navigation is a specific technique designed to actively redirect viewers' attention while accommodating their independence. User-evaluation shows that this technique effectively facilitates several visualization tasks including landmark recognition, survey knowledge acquisition, and search sensitivity. Unfortunately, it also proves to be excessively intrusive, leading viewers to occasionally struggle for control of the viewpoint. Additional design iterations suggest that formalized coordination protocols between the viewer and the automation can mute the shortcomings and enhance the effectiveness of the initial attentive navigation design.The implications of this research generalize to inform the broader requirements for Human-Automation interaction through the visual channel. Potential applications span a number of fields, including visual representations of abstract information, 3D modeling, virtual environments, and teleoperation experiences

Software engineering: Testing real-time embedded systems using timed automata based approaches

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Real-time Embedded Systems (RTESs) have an increasing role in controlling society infrastructures that we use on a day-to-day basis. RTES behaviour is not based solely on the interactions it might have with its surrounding environment, but also on the timing requirements it induces. As a result, ensuring that an RTES behaves correctly is non-trivial, especially after adding time as a new dimension to the complexity of the testing process. This research addresses the problem of testing RTESs from Timed Automata (TA) specification by the following. First, a new Priority-based Approach (PA) for testing RTES modelled formally as UPPAAL timed automata (TA variant) is introduced. Test cases generated according to a proposed timed adequacy criterion (clock region coverage) are divided into three sets of priorities, namely boundary, out-boundary and in-boundary. The selection of which set is most appropriate for a System Under Test (SUT) can be decided by the tester according to the system type, time specified for the testing process and its budget. Second, PA is validated in comparison with four well-known timed testing approaches based on TA using Specification Mutation Analysis (SMA). To enable the validation, a set of timed and functional mutation operators based on TA is introduced. Three case studies are used to run SMA. The effectiveness of timed testing approaches are determined and contrasted according to the mutation score which shows that our PA achieves high mutation adequacy score compared with others. Third, to enhance the applicability of PA, a new testing tool (GeTeX) that deploys PA is introduced. In its current version, GeTeX supports Control Area Network (CAN) applications. GeTeX is validated by developing a prototype for that purpose. Using GeTeX, PA is also empirically validated in comparison with some TA testing approaches using a complete industrial-strength test bed. The assessment is based on fault coverage, structural coverage, the length of generated test cases and a proposed assessment factor. The assessment is based on fault coverage, structural coverage, the length of generated test cases and a proposed assessment factor. The assessment results confirmed the superiority of PA over the other test approaches. The overall assessment factor showed that structural and fault coverage scores of PA with respect to the length of its tests were better than the others proving the applicability of PA. Finally, an Analytical Hierarchy Process (AHP) decision-making framework for our PA is developed. The framework can provide testers with a systematic approach by which they can prioritise the available PA test sets that best fulfils their testing requirements. The AHP framework developed is based on the data collected heuristically from the test bed and data collected by interviewing testing experts. The framework is then validated using two testing scenarios. The decision outcomes of the AHP framework were significantly correlated to those of testing experts which demonstrated the soundness and validity of the framework.This study is funded by Damascus University, Syri

Automated analysis of security protocol implementations

Security protocols, or cryptographic protocols, are crucial to the functioning of today’s technology-dependant society. They are a fundamental innovation, without which much of our online activity, mobile communication and even transport signalling would not be possible. The reason for their importance is simple, communication over shared or publicly accessible networks is vulnerable to interception, manipulation, and impersonation. It is the role of security protocols to prevent this, allowing for safe and secure communication. Our reliance on these protocols for such critical tasks, means it is essential to engineer them with great care, just like we do with bridges or a safety-critical aircraft engine control system, for example. As with all types of engineering, there are two key elements to this process – design and implementation. In this thesis we produce techniques to analyse the latter. In particular, we develop automated tooling which helps to identify incorrect or vulnerable behaviour in the implementations of security protocols. The techniques we present follow a theme of trying to infer as much as we can about the protocol logic implemented in a system, with as little access to it’s inner workings as possible. In general, we do this through observations of protocol messages on the network, executing the system, but treating it as a black-box. Within this particular framework, we design two new techniques – one which identifies a specific vulnerability in TLS/SSL, and another, more general approach, which systematically extracts a protocol behaviour model from protocols like the WiFi security handshakes. We then argue that it his framework limits the potential of model extraction, and proceed to develop a solution to this problem by utilising grey-box insights. Our proposed approach, which we test on a variety of security protocols, represents a paradigm shift in the well established model learning field. Throughout this thesis, as well as presenting general results from testing the efficacy of our tools, we also present a number of vulnerabilities we discover in the process. This ranges from major banking apps vulnerable to Man-In-The-Middle attacks, to CVE assigned ciphersuite downgrades in popular WiFi routers

Tools and Algorithms for the Construction and Analysis of Systems

This open access book constitutes the proceedings of the 28th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2022, which was held during April 2-7, 2022, in Munich, Germany, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2022. The 46 full papers and 4 short papers presented in this volume were carefully reviewed and selected from 159 submissions. The proceedings also contain 16 tool papers of the affiliated competition SV-Comp and 1 paper consisting of the competition report. TACAS is a forum for researchers, developers, and users interested in rigorously based tools and algorithms for the construction and analysis of systems. The conference aims to bridge the gaps between different communities with this common interest and to support them in their quest to improve the utility, reliability, exibility, and efficiency of tools and algorithms for building computer-controlled systems