Heterogeneous electrocatalysis is the usage of solid materials to decrease the amount of energy needed to produce chemicals using electricity. It is of core importance for modern life, as it enables production of chemicals, such as chlorine gas and sodium chlorate, needed for e.g. materials and pharmaceuticals production. Furthermore, as the need to make a transition to usage of renewable energy sources is growing, the importance for electrocatalysis used for electrolytic production of clean fuels, such as hydrogen, is rising. In this thesis, work aimed at understanding and improving electrocatalysts used for these purposes is presented. A main part of the work has been focused on the selectivity between chlorine gas, or sodium chlorate formation, and parasitic oxygen evolution. An activation of anode surface Ti cations by nearby Ru cations is suggested as a reason for the high chlorine selectivity of the “dimensionally stable anode” (DSA), the standard anode used in industrial chlorine and sodium chlorate production. Furthermore, theoretical methods have been used to screen for dopants that can be used to improve the activity and selectivity of DSA, and several promising candidates have been found. Moreover, the connection between the rate of chlorate formation and the rate of parasitic oxygen evolution, as well as the possible catalytic effects of electrolyte contaminants on parasitic oxygen evolution in the chlorate process, have been studied experimentally. Additionally, the properties of a Co-doped DSA have been studied, and it is found that the doping makes the electrode more active for hydrogen evolution. Finally, the hydrogen evolution reaction on both RuO2 and the noble-metal-free electrocatalyst material MoS2 has been studied using a combination of experimental and theoretically calculated X-ray photoelectron chemical shifts. In this way, insight into structural changes accompanying hydrogen evolution on these materials is obtained. / Heterogen elektrokatalys innebär användningen av fasta material för att minska energimängden som krävs för produktion av kemikalier med hjälp av elektricitet. Heterogen elektrokatalys har en central roll i det moderna samhället, eftersom det möjliggör produktionen av kemikalier såsom klorgas och natriumklorat, som i sin tur används för produktion av t ex konstruktionsmaterial och läkemedel. Vikten av användning av elektrokatalys för produktion av förnybara bränslen, såsom vätgas, växer dessutom i takt med att en övergång till användning av förnybar energi blir allt nödvändigare. I denna avhandling presenteras arbete som utförts för att förstå och förbättra sådana elektrokatalysatorer. En stor del av arbetet har varit fokuserat på selektiviteten mellan klorgas och biprodukten syrgas i klor-alkali och kloratprocesserna. Inom ramen för detta arbete har teoretisk modellering av det dominerande anodmaterialet i dessa industriella processer, den så kallade “dimensionsstabila anoden” (DSA), använts för att föreslå en fundamental anledning till att detta material är speciellt klorselektivt. Vi föreslår att klorselektiviteten kan förklaras av en laddningsöverföring från ruteniumkatjoner i materialet till titankatjonerna i anodytan, vilket aktiverar titankatjonerna. Baserat på en bred studie av ett stort antal andra dopämnen föreslår vi dessutom vilka dopämnen som är bäst lämpade för produktion av aktiva och klorselektiva anoder. Med hjälp av experimentella studier föreslår vi dessutom en koppling mellan kloratbildning och oönskad syrgasbildning i kloratprocessen, och vidare har en bred studie av tänkbara elektrolytföroreningar utförts för att öka förståelsen för syrgasbildningen i denna process. Två studier relaterade till elektrokemisk vätgasproduktion har också gjorts. En experimentell studie av Co-dopad DSA har utförts, och detta elektrodmaterial visade sig vara mer aktivt för vätgasutveckling än en standard-DSA. Vidare har en kombination av experimentell och teoretisk röntgenfotoelektronspektroskopi använts för att öka förståelsen för strukturella förändringar som sker i RuO2 och i det ädelmetallfria elektrodmaterialet MoS2 under vätgasutveckling. / <p>QC 20151119</p>

Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The degeneration of the neurons of the substantia nigra in the midbrain leads to the loss of dopamine from the striatum, which is responsible for the motor symptoms of PD. In the brain, the enzyme, monoamine oxidase B (MAOB), An analysis of the Lineweaver-Burk plots indicated that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone inhibits MAO-B with a Ki value of 2.7 nM. An analysis of the structure-activity relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro- 2(1H)-quinolinone moiety leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and phenylpropoxy substitution on this position. In spite of this, C6-substituted 3,4-dihydro-2(1H)-quinolinone with potent MAO-B inhibitory activities were also identified. An analyses of selected properties of the 3,4-dihydro-2(1H)- quinolinones showed that the compounds are highly lipophilic with logP values in the range of 3.03- 4.55. LogP values between 1 and 3 are, however, in the ideal range for bioavailability. The compounds synthesised have logP values higher than 3, which may lead to lower bioavailability. Laboratory data further showed that none of the 3,4-dihydro-2(1H)-quinolinones are highly toxic to cultured cells at the concentrations, 1 μM and 10 μM, tested. For example, the most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, reduced cell viability to 88.11% and 86.10% at concentrations of 1 μM and 10 μM, respectively. These concentrations are well above its IC50 value for the inhibition of MAO-B. At concentrations required for MAO-B inhibition, the more potent 3,4-dihydro-2(1H)-quinolinones are thus unlikely to be cytotoxic. It may thus be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising highly potent and selective MAO-B inhibitors, and thus leads for the therapy of Parkinson’s disease. represents a major catabolic pathway of dopamine. Inhibitors of MAO-B conserve the depleted supply of dopamine and are thus used in the therapy of PD. In the present study, a series of 3,4- dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. These quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives, which has been reported to act as MAO-B inhibitors. C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized by reacting 6- or 7- hydroxy-3,4-dihydro-2(1H)-quinolinone with an appropriately substituted alkyl bromide in the presence of base. To evaluate the MAO inhibitory properties (IC50 values) of the quinolinone derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition of a representative 3,4-dihydro-2(1H)-quinolinone derivative was examined by measuring the recovery of enzyme activity after the dilution of the enzyme-inhibitor complexes, while the mode of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine the lipophilicity of the 3,4-dihydro-2(1H)-quinolinone derivatives, the logP values were measured. The toxicity of the 3,4-dihydro-2(1H)-quinolinone derivatives towards cultured cells (cytotoxicity) was also measured. The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. As a MAO-B inhibitor, this compound is approximately equipotent to the most potent coumarin derivative (IC50 = 1.14 nM) reported in literature. Since MAO-B activity could be recovered after dilution of enzyme-inhibitor mixtures, it may be concluded that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)- quinolinone is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the inhibition of MAO-B by 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone were linear and intersected on the y-axis. These data indicated that this compound also is a competitive MAO-B inhibitor. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Résumé : La signalisation biaisée représente la capacité des récepteurs couplés aux protéines G (RCPG) d'engager des voies de signalisation distinctes avec des efficacités variables selon le ligand utilisé ou la mutation dans le récepteur. Un meilleur contrôle des voies activées ou inhibées par des médicaments pourrait permettre de réduire leurs effets indésirables. Malheureusement, les mécanismes structuraux impliqués dans la transmission du signal à travers la membrane plasmique par l'entremise des RCPG sont peu connus, ce qui limite le développement rationnel de nouvelles molécules ciblant des voies de signalisation particulières. Le récepteur de type 1 à l'angiotensine II (AT[indice inférieur 1]), un RCPG de classe A prototypique, peut activer différents effecteurs suite à sa stimulation par le ligand endogène angiotensine II (AngII), incluant la protéine G[indice inférieur q/11] et les β-arrestines. Il est suggéré que l'activation de ces deux voies de signalisation peut être associée à des conformations différentes du récepteur AT[indice inférieur 1]. Pour vérifier cette hypothèse, nous avons utilisé des simulations de dynamique moléculaire afin d'explorer les interactions et les mouvements qui définissent le paysage conformationnel du récepteur AT[indice inférieur 1]. De plus, nous avons vérifié comment était modifié le paysage conformationnel par des mutations (N111G, N111W et D74N) et des ligands (AngII et [Sar[indice supérieur 1], Ile[indice supérieur 8]]AngII) ayant des profils signalétiques différents pour la voie de la protéine G[indice inférieur q/11] et la voie des β-arrestines. Les résultats obtenus nous éclairent sur le rôle d'un réseau de ponts hydrogène entre des résidus polaires conservés au coeur du récepteur dont font partie les résidus N111[indice supérieur 3.35] et D74[indice supérieur 2.50]. Les résultats révèlent la présence d'un groupe de résidus hydrophobes juste au-dessus du réseau de ponts hydrogène et adjacent à la pochette de liaison du récepteur qui semble important pour la stabilisation de l'état inactif du récepteur ainsi que pour son activation par un ligand. Dans l'ensemble, les résultats suggèrent que l'activation de la voie de la protéine G[indice inférieur q/11] est associée avec une transition conformationnelle spécifique stabilisée par l'agoniste alors que l'activation de la voie des β-arrestines est associée à une stabilisation de l'état de repos du récepteur. / Abstract: Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. Having better control over the signaling pathways activated or inhibited by drugs could lead to fewer undesirable effects. Unfortunately, the structural mechanisms involved in the transmission of signal across the cell membrane through the receptors are poorly understood, which limits the rational development of new molecules targetting specific signaling pathways. The angiotensin-II type 1 (AT[subscript 1]) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the G[subscript q/11] protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT[subscript 1] receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore interactions and movements that define the conformational landscape of the AT[subscript 1] receptor. We have also verified how this conformational landscape is modified by mutations (N111G, N111W, D74N) and ligands (AngII, [Sar[superscript 1]Ile[superscript 8]]AngII) that have different signaling properties on the G[subscript q/11] pathway and the β-arrestin pathway. The results provide a better understanding of the role of a hydrogen bond network formed of conserved polar residues in the receptor core which include residues N111[superscript 3.35] and D74[superscript 2.50]. The results also reveal the existence of a cluster of hydrophobic residues located right above the hydrogen bonds network and adjacent to the binding pocket that appears important for the stabilization of the ground state of the receptor as well as its ligand-induced activation. As a whole, the results suggest that activation of the G[supbscript q/11] pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor.

Approved for public release; distribution is unlimited. / This thesis investigates the effect of marital and family status on the performance and job productivity of male U.S. Marine Corps officers. The analysis includes evaluation of fitness reports, retention, and promotion to O-4 and O-5 ranks as performance measures. The primary goal is to examine the existence of any marriage premium on officers' performance and productivity and to investigate potential causal hypotheses. The personnel database used for the analysis includes more than 27,000 male Marine officers who entered the Marine Corps between FY 1980 and 1999. After controlling for selection, estimating fixed effects and using panel data in order to capture timely-varying effects, this study finds that there is a marriage premium for all performance measures. The thesis rejects the explanation that such premiums are due to supervisor favoritism. Moreover, married male officers obtain higher fitness report scores, higher promotion probabilities, and higher retention probabilities than single officers. Each additional year spent in marriage increases fitness report scores and retention probabilities. Having additional non-spousal dependents increase fitness report scores and retention probabilities. On the other hand, being a currently single but "to-be-married" officer yields higher premium, as married officers, for all productivity and performance indicators. This supports selectivity into marriage as a partial explanation of the source of the marriage premium. / Lieutenant Junior Grade, Turkish Navy / First Lieutenant, Turkish Army

In this thesis, gas sensors based on on-chip hydrothermally grown 1-D zinc oxide (ZnO) nanostructures are presented, to improve the sensitivity, selectivity, and stability of the gas sensors. Metal-oxide-semiconductor (MOS) gas sensors are well-established tools for the monitoring of air quality indoors and outdoors. In recent years, the use of 1-D metal oxide nanostructures for sensing toxic gases, such as nitrogen dioxide, ammonia, and hydrogen, has gained significant attention. However, low-dimensional nanorod (NR) gas sensors can be enhanced further. Most works synthesize the NRs first and then transfer them onto electrodes to produce gas sensors, thereby resulting in large batch-to-batch difference. Therefore, in this thesis six studies on 1-D ZnO NR gas sensors were carried out. First, ultrathin secondary ZnO nanowires (NWs) were successfully grown on a silicon substrate. Second, an on-chip hydrothermally grown ZnO NR gas sensor was developed on a glass substrate. Its performance with regard to sensing nitrogen dioxide and three reductive gases, namely, ethanol, hydrogen, and ammonia, was tested. Third, three 1-D ZnO nanostructures, namely, ZnO NRs, dense ZnO NWs, and sparse ZnO NWs, were synthesized and tested toward nitrogen dioxide. Fourth, hydrothermally grown ZnO NRs, chemical vapor deposited ZnO NWs, and thermal deposited ZnO nanoparticles (NPs) were tested toward ethanol. Fifth, the effect of annealing on the sensitivity and stability of ZnO NR gas sensors was examined. Sixth, ZnO NRs were decorated with palladium oxide NPs and tested toward hydrogen at high temperature. The following conclusions can be drawn from the work in this thesis: 1) ZnO NWs can be obtained by using a precursor at low concentration, temperature of 90 °C, and long reaction time. 2) ZnO NR gas sensors have better selectivity to nitrogen dioxide compared with ethanol, ammonia, and hydrogen. 3) Sparse ZnO NWs are highly sensitive to nitrogen dioxide compared with dense ZnO NWs and ZnO NRs. 4) ZnO NPs have the highest sensitivity to ethanol compared with dense ZnO NWs and ZnO NRs. The sensitivity of the NPs is due to their small grain sizes and large surface areas. 5) ZnO NRs annealed at 600 °C have lower sensitivity toward nitrogen dioxide but higher long-term stability compared with those annealed at 400 °C. 6) When decorated with palladium oxide, both materials form alloy at a temperature higher than 350 °C and decrease the amount of ZnO, which is the sensing material toward hydrogen. Thus, controlling the amount of palladium oxide on ZnO NRs is necessary.

Until now, most metabolomics protocols have been optimized towards high sample throughput and high metabolite coverage, parameters considered to be highly important for identifying influenced biological pathways and to generate as many potential biomarkers as possible. From an analytical point of view this can be troubling, as neither sample throughput nor the number of signals relates to actual quality of the detected signals/metabolites. However, a method’s selectivity for a specific signal/metabolite is often closely associated to the quality of that signal, yet this is a parameter often neglected in metabolomics. This thesis demonstrates the importance of considering selectivity when developing NMR and LC-MS metabolomics methods, and introduces a novel approach for measuring chromatographic and signal selectivity in LC-MS metabolomics. Selectivity for various sample preparations and HILIC stationary phases was compared. The choice of sample preparation affected the selectivity in both NMR and LC-MS. For the stationary phases, selectivity differences related primarily to retention differences of unwanted matrix components, e.g. inorganic salts or glycerophospholipids. Metabolites co-eluting with these matrix components often showed an incorrect quantitative signal, due to an influenced ionization efficiency and/or adduct formation. A novel approach for measuring selectivity in LC-MS metabolomics has been introduced. By dividing the intensity of each feature (a unique mass at a specific retention time) with the total intensity of the co-eluting features, a ratio representing the combined chromatographic (amount of co-elution) and signal (e.g. in-source fragmentation) selectivity is acquired. The calculated co-feature ratios have successfully been used to compare the selectivity of sample preparations and HILIC stationary phases. In conclusion, standard approaches in metabolomics research might be unwise, as each metabolomics investigation is often unique.  The methods used should be adapted for the research question at hand, primarily based on any key metabolites, as well as the type of sample to be analyzed. Increased selectivity, through proper choice of analytical methods, may reduce the risks of matrix-associated effects and thereby reduce the false positive and false negative discovery rate of any metabolomics investigation.

Many different chemicals are used in the everyday life, like detergents and pharmaceuticals. However, their production has a big impact on health and environment as much of the raw materials are not renewable and the standard ways of production in many cases includes toxic and environmentally hazardous components. As the population and as the life standard increases all over the planet, the demand for different important chemicals, like pharmaceuticals, will increase. A way to handle this is to apply the concept of Green chemistry, where biocatalysis, in the form of enzymes, is a very good alternative. Enzymes do not normally function in industrial processes and needs modifications through protein engineering to cope in such conditions. To be able to efficiently improve an enzyme, there is a need to understand the mechanism and characteristics of that enzyme. Acyloins (α-hydroxy ketones) are important building blocks in the synthesis of pharmaceuticals. In this thesis, the enzyme alcohol dehydrogenase A (ADH-A) from Rhodococcus ruber has been in focus, as it has been shown to display a wide substrate scope, also accepting aryl-substituted alcohols. The aim has been to study the usefulness of ADH-A as a biocatalyst towards production of acyloins and its activity with aryl-substituted vicinal diols and to study substrate-, regio-, and enantioselectivity of this enzyme. This thesis is based on four different papers where the focus of the first has been to biochemically characterize ADH-A and determine its mechanism, kinetics and its substrate-, regio-, and enantioselectivity. The second and third paper aims towards deeper understanding of some aspects of selectivity of ADH-A. Non-productive binding and its importance for enantioselectivity is studied in the second paper by evolving ADH-A towards increased activity with the least favored enantiomer through protein engineering. In the third paper, regioselectivity is in focus, where an evolved variant displaying reversed regioselectivity is studied. In the fourth and last paper ADH-A is studied towards the possibility to increase its activity towards aryl-substituted vicinal diols, with R-1-phenyl ethane-1,2-diol as the model substrate, and the possibility to link ADH-A with an epoxide hydrolase to produce acyloins from racemic epoxides.

Les récepteurs couplés aux protéines G forment des complexes multimériques comprenant protéines G et effecteurs. Nous cherchons à caractériser de tels complexes comprenant les récepteurs opioïdes delta (DOR) et les canaux Kir3, qui nous sont d’intérêt vu leur implication dans l’analgésie des opioïdes. Des expériences d’immunopurification, de BRET et de liaison GTPgS ont été réalisées à l’intérieur de cellules HEK293 transfectées. Les canaux Kir3 ont été co-immunopurifiés avec les DOR, suggérant une interaction spontanée entre récepteur et effecteur. Des essais BRET ont corroboré que l’interaction était présente dans des cellules vivantes et nous ont permis d’identifier une interaction spontanée et spécifique entre DOR/Gg et Gg/Kir3, indiquant leur coexistence en un même complexe. Puisque l’activation du récepteur implique la présence de changements conformationnels à l’intérieur de celui-ci, nous étions intéressés à vérifier si l’information conformationnelle circule à partir du récepteur lié au ligand jusqu’à l’effecteur en aval. Ainsi, nous avons déterminé l’effet de différents ligands sur le signal BRET généré par les paires suivantes : DOR/Gbg, DOR/Kir3 et Kir3/Gbg. Nous avons constaté une modulation de l’interaction DOR/Gbg et Gbg/Kir3 suivant l’ordre d’efficacité des ligands à stimuler la protéine G, ce que nous n’avons pas observé entre DOR et Kir3. Donc, nous concluons que l’information conformationnelle circule du récepteur au canal Kir3 via la protéine Gbg. Ces résultats nous ont permis de développer un biosenseur BRET (EYFP-Gg2/Kir3.1-Rluc) qui pourrait être utilisé dans le criblage à haut débit afin de détecter de nouvelles molécules ayant une grande efficacité à activer les canaux Kir3. / G protein-coupled receptors form multimeric complexes comprising G protein and effectors. We want to characterize such complexes comprising delta opioid receptors (DOR) and Kir3 channels, which interest us due to their involvement in opioid analgesia. Immunopurification, BRET and GTPgS binding experiments were done in transfected HEK293 cells. Kir3 channels were co-immunopurified with DOR, implying a spontaneous interaction between the receptor and effector. BRET assays corroborated the presence of this interaction in living cells and allowed us to identify a spontaneous and specific interaction between DOR/Gg and Gg/Kir3, indicating their co-existence within the same complex. Since the activation of the receptor implies it undergoes conformational changes, we were interested in evaluating if the conformational information flows from the ligand-bound receptor until the downstream effector. Hence, we determined the effect of different ligands on the BRET signal that was generated by the following pairs: DOR/Gbg, DOR/Kir3 and Kir3/Gbg. We noticed a modulation of the DOR/Gbg and Gbg/Kir3 interactions that followed the order of efficacy of the ligands to activate the G protein, which we did not observe between DOR and Kir3. Therefore, we concluded that the conformational information flows from the receptor to the Kir3 channel via the Gbg protein. These results allowed us to develop a BRET biosensor (EYFP-Gg2/Kir3.1-Rluc), which could be used in high throughput screening to detect new molecules that activate Kir3 channels with high efficacy.

Les opiacés figurent parmi les analgésiques les plus puissants pour le traitement des douleurs sévères. Les agonistes du DOR (récepteur delta opiacé) induisent moins d'effets secondaires que ceux du mu, ce qui les rend une cible d'intérêt pour le traitement des douleurs chroniques. Cependant, ils induisent la tolérance à l'analgésie. Des hypothèses récentes proposent que le potentiel des drogues à induire la tolérance soit la conséquence de la stabilisation de différentes conformations du récepteur induites par la liaison avec différents ligands, chacune ayant différentes propriétés de trafic. Dans ce contexte, nous avons déterminé si différents ligands du DOR différaient dans leur capacité à induire la signalisation et le trafic du récepteur. Nos résultats indiquent que DPDPE et SNC-80 sont les drogues les plus efficaces à inhiber la production d’AMPc, suivis par UFP-512, morphine et TIPP. DPDPE et SNC-80 induisent à eux seuls l’internalisation du DOR dans les cellules HEK-293 de façon dépendante de la β-arrestine mais pas de la GRK2 ni PKC. Ces deux drogues induisent également l’internalisation du DOR dans les neurones corticaux et c’est seulement le DPDPE qui permet au DOR de regagner la membrane des cellules HEK-293 et des neurones après récupération. Cette capacité de recyclage était suggérée comme un mécanisme protégeant contre la survenue de la tolérance. Ces observations indiquent que le DOR peut subir différentes régulations en fonction du ligand lui étant associé. Cette propriété de sélectivité fonctionnelle des ligands pourrait être utile pour le développement de nouveaux opiacés ayant une activité analgésique plus durable. / Opiates are among the most powerful painkillers to treat severe pain. Delta opioid receptor (DOR) agonists induce fewer side effects than mu opioid receptor agonists, which makes them a target of interest for the treatment of chronic pain. However, they induce tolerance to analgesia. Recent hypotheses suggest that drugs tolerance is the result of stabilization of ligand-specific conformations of the receptor, with distinct traffic properties such as internalization and/or recycling. In this context, we determined whether different DOR ligands differed with respect to their ability to induce signaling and receptor trafficking. Our results indicate that DPDPE and SNC-80 are the most effective drugs to inhibit the production of cAMP, followed by UFP-512, morphine and TIPP. Only DPDPE and SNC-80 manage to induce DOR internalization in HEK-293 cells. This effect is dependent on β-arrestin but not on GRK2 or PKC. Of these two internalizing agonists, only DPDPE allows the DOR to recycle back to the membrane of HEK-293 cells after recovery. DPDPE and SNC-80 also trigger similar DOR internalization in cortical neurons, and as observed in HEK293 cells only DPDPE allowed the receptor to recycle back to the membrane. This recycling capacity was suggested as a mechanism to protect against the onset of tolerance. These observations indicate that the DOR can undergo different regulations depending on the ligand bound to it. This property of functional selectivity of DOR ligands could be useful for the development of new opiates with longer lasting analgesic properties.

Plusieurs applications modernes nécessitent un traitement de flux massifs de données XML, cela crée de défis techniques. Parmi ces derniers, il y a la conception et la mise en ouvre d'outils pour optimiser le traitement des requêtes XPath et fournir une estimation précise des coûts de ces requêtes traitées sur un flux massif de données XML. Dans cette thèse, nous proposons un nouveau modèle de prédiction de performance qui estime a priori le coût (en termes d'espace utilisé et de temps écoulé) pour les requêtes structurelles de Forward XPath. Ce faisant, nous réalisons une étude expérimentale pour confirmer la relation linéaire entre le traitement de flux, et les ressources d'accès aux données. Par conséquent, nous présentons un modèle mathématique (fonctions de régression linéaire) pour prévoir le coût d'une requête XPath donnée. En outre, nous présentons une technique nouvelle d'estimation de sélectivité. Elle se compose de deux éléments. Le premier est le résumé path tree: une présentation concise et précise de la structure d'un document XML. Le second est l'algorithme d'estimation de sélectivité: un algorithme efficace de flux pour traverser le synopsis path tree pour estimer les valeurs des paramètres de coût. Ces paramètres sont utilisés par le modèle mathématique pour déterminer le coût d'une requête XPath donnée. Nous comparons les performances de notre modèle avec les approches existantes. De plus, nous présentons un cas d'utilisation d'un système en ligne appelé "online stream-querying system". Le système utilise notre modèle de prédiction de performance pour estimer le coût (en termes de temps / mémoire) d'une requête XPath donnée. En outre, il fournit une réponse précise à l'auteur de la requête. Ce cas d'utilisation illustre les avantages pratiques de gestion de performance avec nos techniques / Many modern applications require processing of massive streams of XML data, creating difficult technical challenges. Among these, there is the design and implementation of applications to optimize the processing of XPath queries and to provide an accurate cost estimation for these queries processed on a massive steam of XML data. In this thesis, we propose a novel performance prediction model which a priori estimates the cost (in terms of space used and time spent) for any structural query belonging to Forward XPath. In doing so, we perform an experimental study to confirm the linear relationship between stream-processing and data-access resources. Therefore, we introduce a mathematical model (linear regression functions) to predict the cost for a given XPath query. Moreover, we introduce a new selectivity estimation technique. It consists of two elements. The first one is the path tree structure synopsis: a concise, accurate, and convenient summary of the structure of an XML document. The second one is the selectivity estimation algorithm: an efficient stream-querying algorithm to traverse the path tree synopsis for estimating the values of cost-parameters. Those parameters are used by the mathematical model to determine the cost of a given XPath query. We compare the performance of our model with existing approaches. Furthermore, we present a use case for an online stream-querying system. The system uses our performance predicate model to estimate the cost for a given XPath query in terms of time/memory. Moreover, it provides an accurate answer for the query's sender. This use case illustrates the practical advantages of performance management with our techniques