Opium, the dried resin obtained from the unripe seedpods of the poppy flower, has been used for medicinal and euphoric purposes since ancient times. Morphine, the main active ingredient of opium, and other clinically useful opioid analgesics all mediate their effects through activating the mu opioid receptor. Studies involving the mu opioid receptor knockout mice showed that the interaction with the mu opioid receptor is also responsible for many notorious side effects associated with these drugs including dependence and addiction. Therefore, selective antagonists for the mu opioid receptor are needed to study its function in drug abuse and addiction. Previously, based on molecular modeling studies and the “message-address” concept, a series of 14-O-substituted naltrexone derivatives were designed and synthesized. These compounds carried an ester-linked heteroaromatic substitution at the 14-position of naltrexone which was designed to interact with the putative “address” site, that was identified in the mu opioid receptor through molecular modeling studies. The lead compound of this series was determined to have a high affinity and selectivity for the mu opioid receptor. Because the 14-O-substituted naltrexone derivatives were not very stable, the ester linkage in these compounds was replaced by an amide one and a series of 14-N-substituted naltrexone derivatives were synthesized. The affinity and selectivity of these novel naltrexone derivatives were determined in a competitive radioligand binding assay. Interestingly, the 14-N-substituted naltrexone derivatives did not maintain the high selectivity of the 14-O-substituted series. It was hypothesized that the conformational constraint introduced by the amide linker was detrimental to the mu opioid receptor selectivity. Therefore, three 14-N-substituted naltrexone derivatives which carried more flexible linkages were synthesized and evaluated. The mu opioid receptor selectivity was not recovered by introducing rotational freedom into the linker. Some of these 14-N-substitued naltrexone derivatives were determined to be mu-kappa opioid receptor dual selective antagonists. Since the mu opioid receptor antagonists are effective at treating drug addiction, while growing evidence suggests that the kappa opioid receptor antagonists may be beneficial in lowering drug cravings, these novel mu-kappa opioid receptor dual selective antagonists may find unique clinical utility in the treatment of opioid dependence.

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The socio-musical practice of sampling is closely associated with the re-use of pre-existing sound recordings and the technological processes of looping. These practices, based on appropriation and repetition, have been particularly common within the genres of hip-hop and Electronic Dance Music (EDM). Yet early digital sampling instruments such as the Fairlight Computer Musical Instrument (CMI) were not designed for these purposes. The technologists at Fairlight Instruments in Australia were primarily interested in the use of digital synthesis to imitate the sounds of acoustic instruments; sampling was a secondary concern. In the first half of the thesis, I follow digital sampling instruments like the Fairlight CMI and the E-mu Emulator by drawing on interviews with their designers and users to trace how they were used to sample the sounds of everyday life, loop sequenced patterns of sampled sounds, and sample extracts from pre-existing sound recordings. The second half of the thesis consists of case studies that follow the users of digital sampling technologies across a range of socio-musical worlds to examine the diversity of contemporary sampling practices. Using concepts from the field of Science and Technology Studies (STS), this thesis focuses on the ‘user-technology nexus’ and continues a shift in the writing of histories of technologies from a focus on the designers of technologies towards the contexts of use and ‘the co-construction’ or ‘mutual shaping’ of technologies and their users. As an example of the ‘interpretative flexibility’ of music technologies, digital sampling technologies were used in ways unimagined by their designers and sampling became synonymous with re-appropriation. My argument is that a history of digital sampling technologies needs to be a history of both the designers and the users of digital sampling technologies.

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement could lead to development of compounds with different pharmacologic properties. Additionally, exploring other ring systems would diversify and enrich our library of compounds and aid in establishing a comprehensive structure-activity relationship. Therefore, newly synthesized compounds included thiophene derivatives of 6α/β-naltrexamine with potential to be used in the treatment of opioid abuse/addiction. Preliminary in vivo screening revealed that compounds 8 and 11 could be acting as antagonists. To aid in the design and synthesis of newer generation of MOR selective analogs, a 3-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Comparative Molecular Field Analysis (CoMFA) on 6β-N-heterocyclic substituted naltrexamine derivatives was conducted. After rigorous optimizations, the best CoMFA model possessed low predictive power. Results obtained suggested that small structural changes could lead to significant change in binding modes of these ligands. To further validate this observation, molecular docking studies were performed which revealed that these ligands indeed possessed multiple distinct binding modes thereby offering rationale for the CoMFA results. Thus, overall this study furnished useful information about the complexity of protein-ligand interactions which will aid in designing more potent and selective MOR ligands.

Le $\lambda \mu^{\wedge \vee}$-calcul est une extension du $\lambda$-calcul associée à la déduction naturelle classique où sont considérés tous les connecteurs.<br>Les principaux résultats de cette thèse sont :<br>- La standardisation, la confluence et une extension de la machin de J.-L. Krivine en $\lambda \mu^{\wedge \vee}$-calcul.<br>- Une preuve sémantique de la forte normalisation du théorème d'élimination des coupures.<br>- Une sémantique de réalisabilité pour le $\lambda \mu^{\wedge \vee}$-calcul qui permet de caractériser le comportement calculatoire de certains termes typés et clos.<br>- Un théorème de complétude pour le $\lambda \mu$-calcul simplement typé.<br>- Une introduction à un $\lambda \mu^{\wedge \vee}$-calcul par valeur confluent.

La vérification formelle est indispensable pour assurer la fiabilité des applications critiques comme les protocoles de communication et les systèmes répartis. La technique de vérification basée sur les modèles (model-checking) consiste à traduire l'application vers un système de transitions étiquetées (STE), sur lequel les propriétés attendues, exprimées en logique temporelle, sont vérifiées à l'aide d'outils appelés évaluateurs (model-checkers). Cependant, les logiques temporelles "classiques", définies sur un vocabulaire d'actions atomiques, ne sont pas adaptées aux langages de description comme LOTOS, dont les actions contiennent des valeurs typées. Cette thèse définit un formalisme appelé XTL (eXecutable Temporal Language) qui permet d'exprimer des propriétés temporelles portant sur les données du programme à vérifier. XTL est basé sur une extension du mu-calcul modal avec des variables typées. Les valeurs contenues dans le STE, extraites à l'aide d'opérateurs modaux étendus, peuvent être passées en paramètre aux opérateurs de point fixe ou manipulées à l'aide de constructions d'inspiration fonctionnelle comme "let", "if-then-else", "case", etc. Les propriétés portant sur des séquences d'actions du programme sont décrites succinctement au moyen d'expressions régulières. Des méta-opérateurs spéciaux permettent l'évaluation des formules sur un STE et l'expression de propriétés temporelles non-standard par exploration de la relation de transition. La sémantique de XTL est formellement définie et des algorithmes efficaces sont proposés pour évaluer des formules temporelles XTL sur des modèles STEs. Un évaluateur XTL est développé et utilisé avec succès pour la validation d'applications industrielles comme le protocole BRP développé par Philips et la couche liaison du bus série IEEE-1394 ("FireWire").

Nous abordons les automates cellulaires (AC) en cherchant à dégager des informations quantitatives et en particulier à préciser les comportements répandus. Nous étudions en guise de prélude des AC présentant une forte symétrie de la règle locale (AC dits multi-ensemblistes). Les règles locales qui les définissent ont la propriété de pouvoir être utilisées facilement pour différente tailles de voisinage, et nous exhibons des règles, pour chaque dimension, qui sont universelles pour une infinité de tailles. Nous formalisons ensuite la notion de densité d'une propriété parmi l'ensemble des AC. En remarquant que les propriétés répandues sont liées aux propriétés des objets aléatoires au sens de Kolmogorov, et en utilisant divers outils combinatoires nous montrons la négligeabilité (au sens quantitatif) de propriétés non seulement syntaxiques (injectivité, surjectivité, présence d'états persistants ou envahissants), mais aussi dynamiques (nilpotence, certaines contraintes sur l'ensemble limite...). Et nous montrons à l'opposé que l'universalité intrinsèque , propriété qui semble à priori exigeante, est pour de nombreuses sous-familles une propriété très répandue. En ce qui concerne le comportement typique à long terme d'un AC fixé, la mu-nipotence, que nous introduisons à partir de la notion d'ensembles mu-limites, permet de caractériser les AC convergeant presque toujours vers une configuration unique. Nous montrons que celle-ci n'est ni récursivement énumérable ni co-récursivement énumérable. Ceci montre que la difficulté calculatoire de la prédiction du comportement à long terme des AC n'est pas due à des ensembles de configurations négligeables. Nous exhibons aussi des ensembles mu-limites aux langages non récursifs. Enfin nous montrons des résultats d'existence et de non-existence d'AC universels pour la relation de simulation dite surjective parmi certaines sous-familles.

The sustainable development concept has entered the urban planning agenda of Turkey mainly after Habitat II Conference held in Istanbul in 1996. Turkey is trying to adopt the experiences of developed countries to improve the planning system including the sustainable development criteria. In this study, planning experience of Mugla is selected as a case study to criticize and evaluate on the changing planning process of cities in Turkey in terms of sustainable development criteria, which requires new approaches that are integrative and participative between local and global context. In the case of Mugla, the urban form has shaped according to the development areas declared in the plans as additional districts to the traditional city since 1930s / that is, the result was not sustainable in the long run because of some environmental, socio-economic and political values. In the thesis, the problems of the case related to planning experience through sustainable development objectives are stated and solutions are proposed for a sustainable city.

Erdogmus-Yenigediz graben is one of the major structural elements of Aksehir-Simav Fault System (ASFS), which is a major extensional structure in the southwestern Anatolian extensional neotectonic province (SWAEP). It is about 6-10-km-wide, 15-km-long and approximately ENE-trending and is actively growing structure as indicated by the 1970.03.28 (Mw= 7.2) Gediz earthquake. The graben is characterized by two distinct units, separated by an angular unconformity: (i) Miocene-middle Pliocene Arica formation and (ii) Plio Quaternary Erdogmus formation. The former unit commences with a basal conglomerate above the basement rocks and is composed mainly of coal-bearing continental and lacustrine sediments with lava flows and pyroclastics, particularly common in the middle parts of the sequence. The volcanics are dated at 18.4 &plusmn / 0.1 Ma (Ar-Ar mica ages). They record evidence for two deformation phases as suggested by twosets of overprinting slickenlines, intense folding, thrust and strike-slip faulting. The Erdogmus formation commences with terrace conglomerates and is composed mainly of travertines, older and younger alluvial deposits, fan-apron sediments and the recent axial graben floor sediments. Kinematic analysis of the graben-bounding normal faults, growth faults within the graben-infill and those deforming the sediments are consistent with three distinct phases of deformation: (i) Miocene middle Pliocene extensional phase, (ii) interveining NE SW contractional phase and (iii) Plio-Quaternary extensional phase. The data also suggests a distributed stress field and a multi-directional recent extension in predominantly NNE&ndash / SSW, E&ndash / W and NE&ndash / SW directions. This is also consistent with available focal mechanism solutions for the region. The graben therefore has an episodic evolutionary history with two extensional phases and an intervening short-term contraction, as described in many different parts of the SWAEP. The latter phase of extension is considered as the part of Neotectonic regime, which therefore commenced by the Late Pliocene.

Proper autonomic regulation of mammalian cardiac function is dependent upon very complex and precise communication among the intracardiac ganglia and individual neurons within the ganglia. An array of neuromodulators is found within the ganglia that direct neuronal activity by modulating the movement of calcium. The current study determines that opioidergic agonists, which have been found to contribute to severe cardiac disease states and intracellular calcium mobilization, are also responsible for changes in the function of the intracardiac neuron via their effects on store-operated calcium channels (SOCs). Previous studies suggest that phosphorylation plays a role in SOC regulation. Using Fura-2 calcium fluorometry, we determined that protein kinase A (PKA), protein kinase C (PKC), and cyclic adenosine monophosphate (cAMP) had no effect on store-operated calcium entry in the presence of antagonists, phorbol 12, 13 dibutyrate (PDBu), forskolin, and 8-Br cAMP, respectively. We also found pharmacologically that using both electrophysiology and calcium imaging that μ-opioid agonists, met-enkephalin (ME) and endomorphin (EM) depress SOC activity in intracardiac neurons. Arachidonic acid (AA), which has been found to depress SOC function in rat liver cells and μ-opioid receptor activation (MOR), blocked both store-operated calcium entry (SOCE) and the calcium release-activated current (ICRAC) significantly. Contrastingly, AA metabolites, prostaglandin E2)(PGE2) and prostaglandin D2 (PGD2), do not significantly influence SOCE which suggests that the effects of AA may be direct. The block elicited by EM was partially reversed by pertussis toxin (PTX), indicative of activation of a PTX-sensitive G-protein following MOR activation. Similarly, PLA2 inhibitors, OBAA and AACOCF3, decreased the percent block of SOCE due to opioid agonist-induced inhibition. Using the perforated-patch method of I-clamp electrophysiology, we demonstrated that gadolinium, at low micromolar concentrations, reversibly reduced action potential firing. Importantly, these results suggest that SOCs may influence action potential firing in mammalian intracardiac neurons. Similarly, AA and EM depressed action potential firing. Taken together, these experiments suggest that a pathway involving EM and AA influences repetitive firing through SOC inhibition. The importance of SOCs in the maintenance of action potential firing and more specifically, the expression and biophysical functionality of the individual pore-forming subunits (Orai1, 2, and 3) in any neuronal cell type has previously not been explored. Quantitative RT-PCR along with I-clamp electrophysiology revealed that Orai3 was exclusive to repetitively firing neurons. As a result, we hypothesize that robust Ca2+-dependent fast inactivation, also associated Orai3, is a factor in the maintenance of repetitive action potential firing. Using Fura-2 calcium fluorometry and patch-clamp electrophysiology, we determined pharmacologically that μ-opioid receptor activation precedes an intracellular cascade that is dependent on a PTX-sensitive G-protein and AA but independent of prostaglandin and protein kinase activity. Finally, we used RT-PCR to determine the Orai subunits expressed in the intracardiac neurons and their influence on neuronal firing patterns. This study is the first to determine the role expressed subunits has in the maintenance of the electrical activity of the neuron.