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Targeting DNA has the advantage over proteins for cancer remediation because of the fewer copies of the ligands required for the desired therapeutic effect. Traditionally, covalent DNA binders like alkylating agents have been used to induce genetic instability through the formation of DNA lesions and strand breaks, leading to cellular apoptosis. The primary drawback of this treatment is the non-specific binding that affects both cancerous and non-cancerous cells. G-quadruplexes are the DNA secondary structures that are present in abundance near the promoter regions of the oncogenes and are involved in the regulation of their activities. A ligand-mediated stabilization of G-quadruplexes in the promoter regions and down-regulation of the associated oncogenes have been validated. In contrast to alkylating agents, G-quadruplex ligands induce genetic stabilization through non-covalent interactions. They can be designed to interact specifically with G-quadruplex DNA over duplex DNA, which reduce side effects arising from the off-targeting. G-quadruplex ligands invariably have the large planar aromatic moiety to interact with G-quadruplexes through π- π stacking interactions. For determining the size effect of the aromatic moiety on stabilization of G-quadruplexes, a series of ligands were synthesized by conjugating nucleobases or 1,10-phenanthroline with an aminoglycoside, neomycin. The resulting conjugates increased the binding affinity synergistically and enabled us to study the effect of the stacking moiety required for G-quadruplex stabilization. Nucleobase-neomycin conjugates did not show stabilization stabilize of human telomeric G-quadruplex. 1,10-Phenanthroline-neomycin conjugate (7b) on the other hand binds to human telomeric G-quadruplex with a Ka of (8.92.4)×108 M-1 and inhibits telomerase activity at 1.56 µM probably through G-quadruplex stabilization. Moving forward, we further enlarged the aromatic moiety by tethering two 1,10-phenantholine molecules together through a five-atom linker. The resulting molecule (2-Clip-phen) was conjugated with various amino-containing side chains. 2-Clip-phen derivatives showed at least 30 times weaker binding to duplex DNA over G-quadruplex DNA. In addition, compounds showed a preference for the antiparallel G-quadruplex conformation over parallel and hybrid G-quadruplex conformations, as shown in the CD spectroscopy studies. Ligands 11 and 13 induced the formation of an antiparallel G-quadruplex from random coils and stabilize it to 60 oC (Tm) in a salt-free condition. Mass spectrometry study showed the formation of a two-tetrad G-quadruplex with the 2-Clip-phen ligand. Docking study showed that the ligand interacts most favorably with antiparallel G-quadruplex conformation, which is supported further by the larger thermal stabilization effect on antiparallel G-quadruplex compared with other G-quadruplex conformations. Our study suggests that 2-Clip-phen can be used as a scaffold for designing G-quadruplex binding ligands that preferentially bind to antiparallel G-quadruplexes, which has never been reported before.

Proteins are molecular machines of life in the truest sense. Being the expressors of genotype, proteins have been a focus in structural biology. Since the first characterization and structure determination of protein molecule more than half a century ago1, our understanding of protein structure is improving only incrementally. While computational analysis and experimental techniques have helped scientist view the structural features of proteins, our concepts about protein folding remain at the level of simple hydrophobic interactions packing side-chain at the core of the protein. Furthermore, because the rate of genome sequencing is far more rapid than protein structure characterization, much more needs to be achieved in the field of structural biology. As a step in this direction, my dissertation research uses computational analysis and experimental techniques to elucidate the fine structural features of the tertiary packing in proteins. With these set of studies, the knowledge of the field of structural biology extends to the fine details of higher order protein structure.

Eine belangvolle Transformation ist das zwölfte Buch (Lambda) der „Metaphysik“ des Aristoteles durch verschiedene Interpretationen im Laufe der Jahrhunderte widerfahren, sodass es als eine theologische Schrift bis heute überliefert ist (1. Kapitel). Dabei waren sowohl der ursprüngliche Sinn des Autors als auch die Struktur des Textes kaum erkennbar geworden. Die vorliegende Arbeit ist eine historische Rekonstruktion der verschiedenen Interpretationen des Textes seit den ersten peripatetischen Denkern bis zur Gegenwart, insbesondere die von Michael Frede (2. Kapitel), Lindsay Judson (3. Kapitel) und Stephen Menn (4. Kapitel). Frede behauptet, das Buch Lambda sei eine Untersuchung der Substanz (Ousiologie); Judson denkt, dass es die erste Philosophie vorlegt; Menn argumentiert, es sei eher eine Forschung der ersten Prinzipien (Archäologie). Hier wird eine weitere Meinung vertreten, nämlich, dass Lambda die Untersuchung der Prinzipien der Substanz ist und somit verkörpert es Aristoteles’ Verständnis der Sophia (5. Kapitel). Überdies löst diese neuartige Lesart des Textes das Problem der Stelle des zwölften Buches innerhalb der „Metaphysik“ dank der Abfassung einer Karte, die seine Struktur verdeutlicht (Anhänge). / The twelfth book (Lambda) of the “Metaphysics” of Aristotle has undergone a crucial transformation through the diverse interpretations over the centuries. Thus it has been transmitted up to today as a theological writing (chapter 1). But this made hardly recognizable both the original intention of the author and the structure of the text. The present work is a historical reconstruction of the various interpretations of the text since the first Peripatetic thinkers until today, especially those by Michael Frede (chapter 2), Lindsay Judson (chapter 3) and Stephen Menn (chapter 4). Frede states that the book Lambda is an inquiry into the substance (ousiology); Judson thinks that it presents the first philosophy; Menn argues that it is rather an investigation about the first principles (archaeology). A different opinion is set forth here, namely, that the book Lambda explores the principles of the substance, and in doing so it embodies Aristotle’s understanding of the sophia (chapter 5). Moreover, this new reading of the text solves the problem of the position of the twelfth book in the “Metaphysics” thanks to the composition of a map, which clarifies its structure (appendix).

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No / Recent studies have revealed extensive cortical demyelination in patients with progressive multiple sclerosis (MS). Demyelination in gray matter lesions is associated with activation of microglia. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we examined the extent of microglial activation in the cerebral cortex and the relationship of microglial activation and MPO activity to cortical demyelination. Twenty-one cases of neuropathologically confirmed multiple sclerosis, with 34 cortical lesions, were used to assess microglial activation. HLA-DR immunolabeling of activated microglia was significantly higher in demyelinated MS cortex than control cortex and, within the MS cohort, was significantly greater within cortical lesions than in matched non-demyelinated areas of cortex. In homogenates of MS cortex, cortical demyelination was associated with significantly elevated MPO activity. Immunohistochemistry revealed MPO in CD68-positive microglia within cortical plaques, particularly toward the edge of the plaques, but not in microglia in adjacent non-demyelinated cortex. Cortical demyelination in MS is associated with increased activity of MPO, which is expressed by a CD68-positive subset of activated microglia, suggesting that microglial production of reactive oxygen species is likely to be involved in cortical demyelination.

<p dir="ltr">The research focuses on integrating automation, specifically security and Infrastructure as Code (IaC), into the Software Development Life Cycle (SDLC). This integration aims to enhance the efficiency, quality, and security of software development processes. The study explores the benefits and challenges associated with implementing DevSecOps practices, which combine development, security, and operations into a unified process.</p><h3>Background and Motivation</h3><p dir="ltr">The rise of new technologies and increasing demand for high-quality software have made software development a crucial aspect of business operations. The SDLC is essential for ensuring that software meets user requirements and maintains high standards of quality and security. Security, in particular, has become a critical focus due to the growing threat of cyber-attacks and data breaches. By integrating security measures early in the development process, companies can better protect their software and data.</p><h3>Objectives</h3><p dir="ltr">The primary objectives of this research are:</p><ol><li><b>Examine the Benefits and Challenges</b>: To investigate the advantages and difficulties of integrating DevSecOps and IaC within the SDLC.</li><li><b>Analyze Impact on Security and Quality</b>: To assess how automation affects the security and quality of software developed through the SDLC.</li><li><b>Develop a Framework</b>: To create a comprehensive framework for integrating DevSecOps and IaC into the SDLC, thereby improving security and reducing time to market.</li></ol><h3>Methodology</h3><p dir="ltr">The research employs a mixed-methods approach, combining qualitative and quantitative methods:</p><ul><li><b>Qualitative</b>: A literature review of existing research on DevSecOps, IaC, and SDLC, providing a theoretical foundation and context.</li><li><b>Quantitative</b>: Building a CI/CD (Continuous Integration/Continuous Deployment) pipeline from scratch to collect empirical data. This pipeline serves as a case study to gather insights into how automation impacts software security and quality.</li></ul><h3>Tools and Technologies</h3><p dir="ltr">The study utilizes various tools, including:</p><ul><li><b>GitHub</b>: For version control and code repository management.</li><li><b>Jenkins</b>: To automate the CI/CD pipeline, including building, testing, and deploying applications.</li><li><b>SonarQube</b>: For static code analysis, detecting code quality issues, and security vulnerabilities.</li><li><b>Amazon Q</b>: An AI-driven tool used for code generation and security scanning.</li><li><b>OWASP Dependency-Check</b>: To identify vulnerabilities in project dependencies.</li><li><b>Prometheus and Grafana</b>: For monitoring and collecting metrics.</li><li><b>Terraform</b>: For defining and deploying infrastructure components as code.</li></ul><h3>Key Findings</h3><ul><li><b>Reduction in Defect Density</b>: Automation significantly reduced defect density, indicating fewer bugs and higher code quality.</li><li><b>Increase in Code Coverage</b>: More comprehensive testing, leading to improved software reliability.</li><li><b>Reduction in MTTR, MTTD, and MTTF</b>: Enhanced system reliability and efficiency, with faster detection and resolution of issues.</li><li><b>Improved System Performance</b>: Better performance metrics, such as reduced response time and increased throughput.</li></ul><h3>Conclusion</h3><p dir="ltr">The study concludes that integrating security and IaC automation into the SDLC is crucial for improving software quality, security, and development efficiency. However, despite the clear benefits, many companies are hesitant to adopt these practices due to perceived challenges, such as the upfront investment, complexity of implementation, and concerns about ROI (Return on Investment). The research underscores the need for continued innovation and adaptation in software development practices to meet the evolving demands of the technological landscape.</p><h3>Areas for Further Research</h3><p dir="ltr">Future studies could explore the broader impact of automation on developer productivity, job satisfaction, and long-term security practices. There is also potential for developing advanced security analysis techniques using machine learning and artificial intelligence, as well as investigating the integration of security and compliance practices within automated SDLC frameworks.</p>

This study of contemporary jazz discourse and gender applies the techniques of critical discourse analysis, inspired by M.A.K. Halliday's systemic functional linguistics and Norman Fairclough's qualitative critical discourse analysis, to explicate the unequal distribution of power in society as represented by the institutions of jazz and mass media, in discourse about jazz vocal artists. Specifically, the study focuses on the way the genres of jazz CD review, jazz performance review, and interviews with jazz artists – disseminated via the institutions JazzTimes and Live New Orleans – represent the artists' identities, roles, achievements and skills. Following Norman Fairclough and the feminist scholar Mary Talbot, the study assumes that institutions of mass media not only discursively construct the gender of jazz vocal artists, but also represent the performers' achievement and skills from a hegemonic standpoint, reflecting the commonsense assumptions about women and men and their roles in patriarchal society.

Ce manuscrit présente l'étude de l'effet photorefractif dans le proche infrarouge et, plus particulièrement, l'étude des matériaux sensibles dans cette gamme de longueurs d'onde. la première partie du travail a consiste a étudier les matériaux existants, provenant de la microélectronique, le GaAs et l'InP. Les études réalisées, tant expérimentales que théoriques, ont permis de comprendre leurs propriétés et de mettre en évidence leurs limitations, notamment pour les applications dans la gamme de longueurs d'onde autour de 1,3 m. au vu de ces résultats, nous avons propose une technique d'optimisation des performances de gaas utilisant l'irradiation électronique. L'irradiation induit une légère variation du niveau de fermi, qui doit favoriser l'effet photorefractif a 1,3 m. Les résultats obtenus ont montre que l'effet attendu était fortement contrebalance par la création au milieu de la bande interdite, d'un défaut d'irradiation. L'influence directe de ce défaut a été établie grâce au développement d'un modèle théorique de l'effet photorefractif prenant en compte deux niveaux de pièges profonds. En parallèle a cette étude de l'effet d'irradiation, nous avons travaille sur les composes ii-vi, comme le CdTe. Les premiers cristaux étudiés présentent des gains photorefractifs intéressants avec des faisceaux de faible puissance. Ces résultats confirment les promesses de ces cristaux pour une extension de l'effet photorefractif vers 1,5 m. Pour finir, nous présentons une technique d'amplification du gain photorefractif qui utilise l'application d'un champ alternatif carre. une augmentation du gain d'un ordre de grandeur est obtenue.

Research has shown that literacy acquisition and the ultimate realisation of literacy, comprehension of the written text requires more than the ability to decode individual words. This study brings together a synthesis of current research on early language acquisition, language structure, vocabulary development and its intrinsic underpinning of comprehension in monolinguals thereby providing a theoretical framework for a comparative study of limited English proficient learners (LEP’s)/English language learners (ELLs) acquiring first time literacy with the attendant vocabulary deficits and age appropriate decoding skills. A quantitative and qualitative study examines the statistical differences between reading, vocabulary, rapid automatic naming (RAN/decoding) and comprehension when a learner born of foreign parents acquires first time literacy in a language other than the language spoken at home. The study isolates and specifies an at risk educational minority through the identification of a hidden comprehension deficit (HCD). In summarising the main findings from the literature review and the empirical investigation, an “at risk educational minority” was identified and isolated through the identification of the HCD. The envisioned outcome was achieved and the hypothesis accepted. / Educational Studies / M. Ed. (Inclusive Education)