The purpose of this thesis project was to examine the effects of chronic alcohol on the excitability and molecular adaptation of GABA neurons of the ventral tegmental area (VTA). GABA neurons are of interest with regards to ethanol intoxication, reinforcement, and dependence due to their widespread distribution and connectivity to mesocorticolimbic dopamine (DA) neurons implicated in alcohol reward and addiction. Since we have previously shown adaptation of VTA GABA neuron firing rate to chronic ethanol (Gallegos, Criado et al. 1999) and suppression of gap-junction (GJ) mediated coupling between these neurons by acute ethanol (Stobbs, Ohran et al. 2004), we wanted to further characterize the effects of chronic ethanol on VTA GABA neuron excitability, electrical coupling and molecular adaptation. In particular, we analyzed the GJ mediated coupling and protein regulation of VTA GABA neurons following a three week period of continuous ethanol exposure via liquid diet. Although some animals showed tolerance, there was no significant tolerance to ethanol inhibition of GJ-mediated electrical coupling. In addition, we were able to characterize differences in mRNA expression levels for the DA synthesizing enzyme tyrosine hydroxylase (TH), the DA D2 receptor and the NMDAR2B receptor subunit in DA versus GABA neurons, all three of which were expressed at higher levels in DA neurons. We also determined the effects of chronic ethanol on mRNA levels of these same proteins as well as μ-opioid receptors (μORs) and connexin-36 (Cx36) GJs. Most significantly, we found a down-regulation of the DA D2 receptor, confirming that molecular modification occurs in these VTA GABA neurons with chronic alcohol. While we reject our hypothesis that acute ethanol inhibition of VTA GABA neuron electrical coupling would undergo tolerance to chronic ethanol in these non-dependent rats, which was the focus of this thesis, it remains to be determined if tolerance to chronic ethanol might be obtained in ethanol-dependent rats.

Multi-User Multi-Input Multi-Output (MU-MIMO) systems are considered to be the sustainable technologies of the current and future of the upcoming wireless and mobile networks generations. The perspectives of these technologies under several scenarios is the focus of the present thesis. The initial system model covers the MU-MIMO, especially in the massive form that is considered to be the promising ideas and pillars of the 5G network. It is observed that the optimal number of users should be served in the time-frequency resource even though the maximum limitation of the MU-MIMO is governed by the total receiving antennas (K) is less than or equal to the base station antennas (M). The system capacity of the massive MIMO (mMIMO) under perfect channel state information (CSI) of uncorrelated channel is investigated and studied. Two types of precoders were applied, one is directly based on channel inversion, and the other uses the Eigen decomposition that is derived subject to the signal to a leakage maximization problem. The two precoders show a degree of equivalency under certain assumptions for the number of antennas at the user end. The convex optimization of multi-antenna networks to achieve the design model of optimum beamformer (BF) based on the uniform linear array (ULA) is studied. The ULA is selected for its simplicity to analyse many scenarios and its importance to match the future network applied millimetre wave (mmWave) spectrum. The maximum beams generated by the ULA are explored in terms of several physical system parameters. The duality between the MU-MIMO and ULA and how they are related based on beamformer operation are detailed and discussed. Finally, two approaches for overloaded systems are presented when the availability of massive array that is not guaranteed due to physical restrictions since the existence of a large number of devices will result in breaking the dimension rule (i.e., K ≤ M). As a solution, a low complexity users selection algorithm is proposed. The channel considered is uncorrelated with full and perfect knowledge at the BS. In particular, these two channel conditions may not be available in all scenarios. The CSI may be imperfect, and even the instantaneous form does not exist. A hybrid precoder between the mixed CSI (includes imperfect and statistical) and rate splitting approach is proposed to deal with an overloaded system under a low number of BS antennas. / Ministry of Higher Education and Scientific Research of Iraq

No description available.

Opioid analgesics have been a major contribution to pain therapy with opioids being used as an effective treatment for various recalcitrant pain conditions. The drug class has come under increased scrutiny due to the raising concerns about the public health crisis of opioid misuse and addiction, thereby increasing the need for alternative and safer analgesics. The exploration of alternative pharmacotherapy for pain management has led to an increasing paradigm shift towards the development of a single-drug-multiple-target approach that takes inspiration from numerous naturally occurring drugs. The mu-opioid receptor has been the primary target for the management of pain; however, the voltage-gated sodium channel Nav1.7 is gaining attention as a putative antinociceptive target based on human genetic evidence. The proposed research aims to develop multi-target directed ligands (MTDL) that modulates two key targets for pain perception, the MOR, and Nav1.7 to generate analgesics with reduced side effects and enhanced analgesia. This will be achieved by exploiting polypharmacology to develop hybrid analgesia in two ways: (i) performing structure-activity relationship (SAR) studies to design a single drug with two pharmacophores that specifically interacts with both the targets (ii) exploiting in silico techniques by performing structure-based virtual ligand screening (VLS) of a chemical library. In our work, we report that through SAR studies and molecular docking studies that the designed compounds having in combination the pharmacophore of PZM21 and aryl sulfonamide demonstrate significant interactions between the active compounds and both the MOR and Nav1.7 proteins. This study also reports the first ever bifunctional virtual ligand screening where a library consisting of over a million compounds was screened for bifunctional activity at the MOR and the Nav1.7 ion channel. We also report the development of a novel mechanism-specific membrane potential assay to that can be used to screen for subtype selective Nav1.7 inhibitors. The research performed in this thesis will serve as a platform to explore the possibility of MTDL as potential therapeutic solutions to diseases of complex etiologies such as chronic pain. It will also serve as a starting point to exploring bifunctional VLS as a way to screen large chemical libraries for MTDLs.

Les dérivés de l’opium (opioïdes) et du cannabis (cannabinoïdes) présentent de nombreuses propriétés intéressantes. Suite à l’identification de leurs récepteurs respectifs, diverses stratégies pharmacologiques ont tenté d’exploiter leurs propriétés analgésiques. Le clonage des récepteurs cannabinoïdes CB1 et CB2 a favorisé la découverte de composés endogènes pour ces récepteurs, les endocannabinoïdes, dont les deux plus étudiés sont l’anandamide et le 2-arachidonyl glycérol (2-AG). Cette découverte a également mené à l’identification d’enzymes qui catalysent l’inactivation de ces cannabinoïdes endogènes : une amidohydrolase des acides gras ou FAAH ainsi qu’une monoacylglycérol lipase ou MAGL. Le système cannabinoïde endogène est régulé à la hausse dans une variété de processus pathologiques, tels que les douleurs inflammatoire et neuropathique. Cette augmentation est habituellement interprétée comme une réaction physiologique visant à rétablir l’homéostasie et elle a notamment été observée en périphérie. Les endocannabinoïdes semblent donc agir de façon spécifique à des moments clés dans certains tissus ciblés afin de minimiser les conséquences reliées au déclenchement de ces douleurs. Cette observation est très intéressante d’un point de vue thérapeutique puisqu’elle suggère la possibilité de cibler les enzymes de dégradation des endocannabinoïdes dans le but d’augmenter leurs concentrations locales et d’ainsi prolonger leur action neuromodulatrice. En périphérie, l’activation des récepteurs cannabinoïdes induit des effets antinociceptifs bénéfiques tout en minimisant les effets indésirables souvent associés à leur activation centrale. Nous avons orienté nos travaux vers la modulation périphérique de ce système endogène à l’aide d’inhibiteurs des enzymes de dégradation des endocannabinoïdes afin d’évaluer leur potentiel thérapeutique et d’élucider les mécanismes d’action qui sous-tendent leurs effets dans des modèles animaux de douleurs inflammatoire et neuropathique. Nous avons démontré que cette approche permet de soulager les symptômes associés à ces deux types de douleurs, et ce via les récepteurs CB1 et CB2. Les systèmes cannabinoïde et opioïde présentent des similitudes, dont des localisations similaires le long des voies de la douleur, des mécanismes d’action relayés par des récepteurs couplés aux protéines G et des propriétés pharmacologiques communes telles que l’analgésie. Le système opioïde est impliqué dans les effets antinociceptifs induits par les cannabinoïdes. À l’inverse, le rôle joué par le système cannabinoïde dans ceux induits par la morphine demeure incertain. Nous avons démontré que les effets antinociceptifs périphériques et spinaux produits par la morphine sont diminués chez les souris génétiquement modifiées chez lesquelles l’expression des récepteurs CB1 ou CB2 a été éliminée, laissant supposer un rôle pour ces récepteurs dans les effets de la morphine. Nous avons de plus démontré que la diminution de l'analgésie produite par la morphine dans ces souris n'est pas causée par un dysfonctionnement des récepteurs opioïdes mu (MOP) ni par une régulation à la baisse de ces récepteurs. Nos résultats confirment l'existence d'interactions fonctionnelles entre les systèmes cannabinoïde et opioïde au niveau périphérique et spinal. Ces observations sont prometteuses d’un point de vue thérapeutique puisqu’une modulation périphérique ciblée des niveaux d’endocannabinoïdes et d’opioïdes endogènes permettrait de produire des effets analgésiques bénéfiques potentiellement synergiques tout en minimisant les effets indésirables associés à l’activation centrale de ces systèmes. / Opium (opioids) and cannabis (cannabinoids) derivatives present many interesting properties. Following the identification of their respective receptors, various pharmacological strategies have tried to exploit their analgesic properties. The cloning of cannabinoid CB1 and CB2 receptors has promoted the discovery of endogenous agonists of these receptors named endocannabinoids. The two mostly studied endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG). This has also led to the identification of enzymes that catalyze the inactivation of these endogenous cannabinoids: a fatty acid amide hydrolase or FAAH and a monoacylglycerol lipase or MAGL. It is known that the endogenous cannabinoid system is upregulated in a variety of pathological processes, such as inflammatory and neuropathic pain. This increase is usually interpreted as a physiological response to restore homeostasis and it was particularly observed in the periphery. Endocannabinoids seem to act specifically at key moments in targeted tissues to minimize the consequences related to the onset of pain. This observation is very interesting from a therapeutic perspective because it suggests the possibility of targeting the endocannabinoid degrading enzymes in order to increase their local concentrations and thus prolong their neuromodulatory action. At the peripheral level, the activation of cannabinoid receptors induces beneficial antinociceptive effects while minimizing side effects often associated with their central activation. We focused our work on the peripheral modulation of this endogenous system using inhibitors of endocannabinoid degrading enzymes to assess their therapeutic potential and to elucidate the mechanisms of action underlying their effects in animal models of inflammatory and neuropathic pain. We have demonstrated that this approach can relieve the symptoms associated with these two types of pain, through the activation of CB1 and CB2 receptors. The opioid and cannabinoid systems have similarities, including comparable locations along the pain pathways, mechanisms of action relayed by G protein-coupled receptors and common pharmacological properties such as analgesia. The opioid system is involved in the antinociceptive effects induced by cannabinoids. In contrast, the participation of the cannabinoid system in those induced by morphine remains uncertain. We have demonstrated that peripheral and spinal antinociceptive effects induced by morphine are reduced in genetically modified mice in which the expression of CB1 and CB2 receptors was eliminated, suggesting a role for these receptors in the effects of morphine. We have further demonstrated that the decrease in morphine-induced analgesia in these mice is not caused by a malfunction of the mu opioid receptors (MOP) or by a down-regulation of these receptors. Our results confirm the existence of functional interactions between cannabinoid and opioid systems at the peripheral and spinal levels. These findings are promising from a therapeutic perspective since a targeted modulation of the levels of endocannabinoids and endogenous opioids would induce potentially synergistic beneficial analgesic effects while minimizing side effects associated with the central activation of these systems.

Les classificateurs ga (cl. 16), ku (cl. 17) et mu (cl. 18) marquent respectivement les valeurs de « contact », de « distance » et d’« intériorité » : a) lorsqu’ils sont préfixés à la base ‑úma /endroit/ ; b) lorsqu’ils apparaissent dans le verbe conjugué ou préfixés aux thèmes des déterminants ; c) lorsqu’ils sont suivis d’un nom en isolation ; d) ou lorsqu’ils ils sont suivis d’un verbe.Bu (cl. 14) marque en outre une valeur « abstraite » lorsqu’il se combine avec des bases lexicales ; il exprime le temps, la comparaison et la cause, lorsqu’il est préfixé aux thèmes des déterminants ; il sert en troisième lieu à marquer l’hypothèse lorsqu’il est employé sous la forme d’un morphème libre. / Classifiers ga (cl. 16), ku (cl. 17) and mu (cl. 18) express respectively “contact”, “distance” and “interiority”: a) when they are prefixed by ‑úma /place/; b) when they appear in conjugated verbs or are prefixed by themes of determinants; c) when they are followed by a name in the form of a free morpheme; d) or when they are followed by a verb. Bu (cl. 14) expresses, in addition, “abstract” value when it is combined to lexical bases; when it is prefixed to the themes of determinants, it carries temporal, comparative and causal values; it serves thirdly to mark the hypothesis in the form of a free morpheme.

The research reported in this thesis is concerned with robust precoder and transceiver optimization in multiuser multi-antenna wireless communication systems in the presence of imperfect channel state information(CSI). Precoding at the transmit side, which utilizes the CSI, can improve the system performance and simplify the receiver design. Transmit precoding is essential for inter-user interference cancellation in multiuser downlink where users do not cooperate. Linear and non-linear precoding have been widely investigated as low-complexity alternatives to dirty paper coding-based transmission scheme for multiuser multiple-input multiple-output(MU-MIMO)downlink. Similarly, in relay-assisted networks, precoding at the relay nodes have been shown to improve performance. The precoder and joint precoder/receive filter (transceiver) designs usually assume perfect knowledge of the CSI. In practical systems, however, the CSI will be imperfect due to estimation errors, feedback errors and feedback delays. Such imperfections in CSI will lead to deterioration of performance of the precoders/transceivers designed assuming perfect CSI. In such situations, designs which are robust to CSI errors are crucial to realize the potential of multiuser multi-antenna systems in practice. This thesis focuses on the robust designs of precoders and transceivers for MU-MIMO downlink, and for non-regenerative relay networks in the presence of errors in the CSI. We consider a norm-bounded error(NBE) model, and a stochastic error(SE) model for the CSI errors. These models are suitable for commonly encountered errors, and they allow mathematically and computationally tractable formulations for the robust designs. We adopt a statistically robust design in the case of stochastic error, and a minimax or worst-case robust design in the case of norm-bounded error. We have considered the robust precoder and transceiver designs under different performance criteria based on transmit power and quality-of-service(QoS) constraints. The work reported in this thesis can be grouped into three parts, namely,i ) robust linear pre-coder and transceiver designs for multiuser downlink, ii)robust non-linear precoder and transceiver designs for multiuser downlink, and iii)robust precoder designs for non-regenerative relay networks. Linear precoding: In this part, first, a robust precoder for multiuser multiple-input single-output(MU-MISO)downlink that minimizes the total base station(BS)transmit power with constraints on signal-to-interference-plus-noise ratio(SINR) at the user terminals is considered. We show that this problem can be reformulated as a second order cone program(SOCP) with the same order of computational complexity as that of the non-robust precoder design. Next, a robust design of linear transceiver for MU-MIMO downlink is developed. This design is based on the minimization of sum mean square error(SMSE) with a constraint on the total BS transmit power, and assumes that the error in the CSI at the transmitter(CSIT) follows the stochastic error model. For this design, an iterative algorithm based on the associated Karush-Kuhn-Tucker(KKT) conditions is proposed. Our numerical results demonstrate the robust performance of the propose designs. Non-linear precoding: In this part, we consider robust designs of Tomlinson-Harashima precoders(THP) for MU-MISO and MU-MIMO downlinks with different performance criteria and CSI error models. For MU-MISO systems with imperfect CSIT, we investigate the problem of designing robust THPs under MSE and total BS transmit power constraints. The first design is based on the minimization of total BS transmit power under constraints on the MSE at the individual user receivers. We present an iterative procedure to solve this problem, where each iteration involves the solution of a pair of convex optimization problems. The second design is based on the minimization of a stochastic function of the SMSE under a constraint on the total BS transmit power. We solve this problem efficiently by the method of alternating optimization. For MU-MIMO downlink, we propose robust THP transceiver designs that jointly optimize the TH precoder and receiver filters. We consider these transceiver designs under stochastic and norm-bounded error models for CSIT. For the SE model, we propose a minimum SMSE transceiver design. For the NBE model, we propose three robust designs, namely, minimum SMSE design, MSE-constrained design, and MSE-balancing design. Our proposed solutions to these robust design problems are based on iteratively solving a pair of sub-problems, one of which can be solved analytically, and the other can be formulated as a convex optimization problem that can be solved efficiently. Robust precoder designs for non-regenerative relay networks: In this part, we consider robust designs for two scenarios in the case of relay-assisted networks. First, we consider a non-regenerative relay network with a source-destination node pair assisted by multiple relay nodes, where each node is equipped with a single antenna. The set of the cooperating relay nodes can be considered as a distributed antenna array. For this scenario, we present a robust distributed beam former design that minimizes the total relay transmit power with a constraint on the SNR at the destination node. We show that this robust design problem can be reformulated as a semi-definite program (SDP)that can be solved efficiently. Next, we consider a non-regenerative relay network, where a set of source-destination node pairs are assisted by a MIMO-relay node, which is equipped with multiple transmit and multiple receive antennas. For this case, we consider robust designs in the presence of stochastic and norm-bounded CSI errors. We show that these problems can be reformulated as convex optimization problems. In the case of norm-bounded error, we use an approximate expression for the MSE in order to obtain a tractable solution.

L’étude ici présentée porte sur l’histoire de la traduction et de la réception de Stendhal en Chine depuis les années 1920. Il s’agit de mettre en relief, par une approche comparatiste, les images nuancées du romancier et les caractéristiques de la réception de ses œuvres dans les différentes époques. En effet, les études sur Stendhal en Chine sont étroitement liées au contexte social et politique de la société chinoise. Le Rouge et le Noir, roman étranger qui connaît le plus de traductions chinoises, est considéré tantôt comme un chef-D’œuvre de la littérature réaliste, tantôt comme une « herbe vénéneuse » contre le Parti communiste. La réception de Stendhal en Chine reflète, dans une certaine mesure, celle de toute la littérature occidentale. Nous avons essayé de mettre en évidence les facteurs essentiels à la réception de Stendhal en Chine et les transformations des œuvres du romancier face à l’épreuve d’une culture et d’une société étrangères. / The study hereby presented tackles the history of the translation and reception of Stendhal in China since the 1920s. The aim is to point out, by the comparative approach, different images of the novelist and features of reception of Stendhal’s works in China during different periods. The study of Stendhal in China is closely associated with social and political contexts of China’s society. The Red and the Black, the most translated foreign novel in China, is sometimes considered as a masterpiece of realist literature, sometimes as a poisonous weed against the Communist Party. The reception of Stendhal in China reflects the whole history of reception of western literature to some degree. We have tried to reveal the essential factors for the reception of Stendhal in China and the transformation of his literary works during this experience in the foreign culture and society.

Chapter One contains a lengthy discussion of tafsír, outlining its meaning, its need to the present study and the different forms in which it exists, whilst at the same time clarifying its obscurities and commending it as an indispensable science. Chapter Two offers a concise overview of five Qur'ánic commentators selected for this particular study. This assessment is based on the eras from which they emerged which has a definite bearing on their commentaries. Chapter Three is a résumé of my subject's biography adopted primarily from Qur'ánic sources. As a frequently mentioned prophet in the Qur'án the story of Músá [p.b.u.h] is drawn from various chapters highlighting substantial aspects of his life. Chapter Four concentrates on two frequently mentioned events in the life of prophet Músá [ p.b.u.h], namely, his call to prophethood and the proclamation to the pharaoh and his people. Chapter Five concludes this work by presenting an overview of the perspectives of the different commentators. / Religious Studies and Arabic / M.A.

L'addiction ou dépendance aux substances psychoactives est une affection chronique, fréquente et grave, émaillée de rechutes et de périodes d'abstinence. Les études épidémiologiques montrent que l'abstinence aux opiacés est fortement associée à une prévalence accrue de la dépression. Nous résumons ici les principaux aspects cliniques de la dépendance aux opiacés et de la dépression, en détaillant leurs mécanismes physiopathologiques. Puis, nous présentons notre modèle d'abstinence aux opiacés chez la souris. Suite à un traitement morphinique chronique et au cours de l'abstinence apparaissent progressivement des comportements apparentés à la dépression. Ce traitement morphinique modifie profondément le fonctionnement du système sérotoninergique, notamment dans le noyau du raphé dorsal. De plus, les déficits comportementaux observés peuvent être prévenus par un traitement chronique par la fluoxétine, un antidépresseur ciblant ce système. Nous avons généralisé ce modèle à l'héroïne, un autre opiacé illicite. Nous avons révélé par des approches génétiques de délétion constitutive et conditionnelle les rôles distincts des 3 récepteurs opioïdes (mu, delta et kappa) lors de l'abstinence à l'héroïne. Enfin, nous avons initié une étude de caractérisation, à l'échelle de l'ensemble du génome, des adaptations transcriptomiques (ARN messagers et micro-ARN) dans le noyau du raphé dorsal au cours de l'abstinence à l'héroïne et du traitement antidépresseur. Ce travail devrait permettre d'améliorer notre compréhension des mécanismes neurobiologiques à l'œuvre dans la comorbidité entre dépendance aux opiacés et dépression et pourrait suggérer de nouvelles pistes thérapeutiques.