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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
81

Activation of Satellite Cells Following Eccentrically-Biased Exercise in Humans

O'Reilly, Ciara E. 12 1900 (has links)
<p> We aimed to examine the satellite cell response and the potential of HGF signaling in mediating satellite cell activation and proliferation. To achieve this, we determined the time course of satellite cell activation and expression of HGF, HGFA, HAI-l, HAI-2 and the MRFs in skeletal muscle, as well as HGF protein in the blood, before and over five days following an acute bout of eccentrically-biased exercise. Eight recreationally active participants (20.6 ± 2.1 y; 180.5 ± 5.2 cm; 81.4 ± 9.8 kg) were recruited for the study. Subjects were required to perform 300 eccentric contractions involving the quadriceps femoris muscles at 180 °/s, over a 60° range of motion with a randomly selected leg. A baseline biopsy (PRE) was taken from the opposite leg. Muscle and blood samples were taken before the exercise (PRE) and at 4 h (T4), 24 h (T24), 72 h (T72) and 120 h (T120) following the exercise. The exercise protocol resulted in an increase in the number of satellite cells (N-CAM labeled cells), expressed both relative to myofiber number and relative to total myonuclei, between PRE and T4 which was sustained over the time course (p<0.001). Further increases in N-CAM labeled cells, expressed relative to myofibre cross-section, were observed between T4 and T24 (p=0.01) and between T4 and T72 (p=0.002). Myf5 mRNA expression increased significantly from both PRE and T4 by T24 (p=0.04). MyoD mRNA increased significantly from PRE by T4 (p=0.02). Myogenin mRNA increased significantly at T24 versus PRE (p=0.02). No significant change was observed over time for MRF4. HGF protein increased significantly in serum from baseline (PRE) to T4 (p=0.04). Active HGF protein was detected in skeletal muscle at rest (14.4±1.3 avg IDV/actin avg IDV) and tended to increase from PRE to T24 (p=0.12). HGFA protein increased significantly from PRE to T24 (p=0.04). HAI-2 increased significantly from PRE at T72 (p=0.03) and T120 (p=0.04). HAI-1 protein increased significantly from PRE to T24 (p=0.02). HAI-2 (32 kDa) increased significantly from baseline (PRE) by T24 (p=0.03), and also by T72 and T120 (p=0.02). HAI-2 (28 kDa) protein showed no significant change over time HGF, HGFA, HAI-1, and HAI-2 transcripts were undetected over the time course. We conclude that a single bout of high-intensity exercise is sufficient to activate satellite cells, which may involve both a local and systemic response to exercise-induced injury. Furthermore, we propose that HGF signaling plays an important role in the regulation of satellite cells in the post exercise period.</p> / Thesis / Master of Science (MSc)
82

Three Essays on Dynamic Contests

Cai, Yichuan 23 June 2022 (has links)
This dissertation consists of three essays studying the theory of dynamic contest. This analysis mainly focuses on how the outcome and the optimal design in a dynamic contest varies on contest technology, heterogeneous players, contest architecture, and bias instruments. The first chapter outlines the dissertation by briefly discussing the motivations, methods, and main findings in the following chapters. Chapter 2 considers a situation in which two groups compete in a series of battles with complete information. Each group has multiple heterogeneous players. The group who first wins a predetermined number of battles wins a prize which is a public good for the winning group. A discriminatory state-dependent contest success function will be employed in each battle. We found that in the subgame perfect Nash equilibrium (equilibria), the lower valuation players can only exert effort in earlier battles, while the higher valuation players may exert effort throughout the entire series of battles. The typical discouragement effect in a multi-battle contest is mitigated when players compete as a group. We also provide two types of optimal contest designs that can fully resolve the free-rider problem in group contests. Chapter 3 investigates optimal contest design with multiple heterogeneous players. We allow the contest designer to have one or multiple/mixed objectives, which includes the following parts: the total effort; the winner's effort; the maximal effort; and the winning probability of the strongest player. We provide a one-size-fits-all contest design that is optimal given any objective function. In the optimal contest, the designer will have one of the weaker players exhaust the strongest in the contest with infinite battles. We obtain the required conditions on different contest frameworks (e.g., all-pay auctions and lottery contests) and bias instruments (e.g., head starts and multiplicative bias). This means the contest designer has multiple alternatives to design the optimal contest. The last chapter investigates a situation where two players compete in a series of sequential battles to win a prize. A player can obtain certain points by winning a single battle, and the available points may vary across the battles. The player who first obtains predetermined points wins the prize. We fully characterize the subgame perfect Nash equilibrium by describing the indifference continuation value interval. We found that when two players are symmetric, they only compete in the separating battle. In the general case, we found that winning a battle may not create any momentum when the weight of the battle is small. A small enough adjustment of a battle's weight will not change both players' incentive to win the battle. Increasing (or decreasing) a battle's weight weakly increases (or weakly decreases) both players' incentive to win. / Doctor of Philosophy / A contest in economics is defined as a situation in which players exert positive effort to win a prize. The effort can be money, time, energy, or any resource that is used in a competition. The prize can be monetary or other perks from winning a competition. In this dissertation, we explore dynamic multi-battle contests where the winner is not decided by one single competition but by a series of sequential competitions. For example, the US presidential primary begins sometime in January or February and ends about mid-June and candidates will compete in different states during the time. In NBA finals, the winner is decided by a best-of-seven contest. The team that first wins four games becomes the champion. In the second chapter, we explore multi-battle group contest in which each group has multiple heterogeneous players. The group who first wins a certain number of battles wins a prize. The prize is a public good within the winning group so players in the winning group can enjoy the prize regardless their effort. We found that players with high prize valuation will be discouraged in earlier battles due to high expected effort in later battles. This may make high-value players only exert effort in later and more decisive battles. The low-value players will exert effort in earlier battles and will free rider on high-value players in later battles. We also provide the optimal contest design that can fully resolve the free-rider problem. In the optimal contest design, the designer should completely balance two groups in every battle. In the third chapter, we explore the optimal contest design in the multi-battle contests with multiple heterogeneous players. The contest designer can have one or multiple/mixed objectives. We found a "one size fits all" multi-battle contest design that is optimal for various objective functions. In the optimal contest design, the designer should give different advantages to the strongest player and one of the weaker players. More specifically, the weaker player is easier to win each battle, while the strongest player needs to win fewer battles. This overturns the conventional wisdom that the advantage should be only given to the weaker players. In the fourth quarter, we explore the multi-battle contest that in which each battle has a different weight, that is, some battles may more or less important than others. We found that when a battle's weight is small, players may feel indifference between winning or losing the battle. Therefore, winning such battles will not create any momentum, and players tend to give up those battles by exerting no effort. We also found that when we increase or decrease a battle's weight, if the adjustment is small, it will not change players' incentive to win a battle. However, if the adjustment is large enough, it will increase or decrease players' incentive to win in the same direction.
83

Characterization of the expression patterns of the retrogene-parental gene pairs in the African malaria vector Anopheles coluzzii

Miller, Duncan Joseph 09 July 2020 (has links)
Retrogenes are a group of functional genes produced by gene retroduplication events during evolution. It has been observed that many retrogenes have formed since the evolutionary divergence of Anopheles mosquitoes from the Aedes lineage as a result of developing heteromorphic sex chromosomes. It has been further observed that these retroduplications predominately occur from parent genes on the heteromorphic X chromosome to autosomes and have a predisposition to have enriched expression in testis. In order to investigate the nature of this male-biased expression in testis, we utilized bioinformatic techniques to identify retrotransposition events and assign them relative ages based on evolutionary branches of divergence. This list of parent genes and retrogenes were then analyzed and a total of twenty-five gene pairs were selected for further examination. Available gene expression data in the form of RNA-seq and DNA microarray were used in tandem with gene annotation data to computationally investigate gene pairs in An. coluzzii. These pairs were further investigated experimentally by means of RT-PCR conducted on dissected head, thorax, abdomen, and reproductive organs in both male and female Anopheles coluzzii Mopti strain. Testis and male accessory glands (MAGs) were also investigated by this method in An. coluzzii. Available expression data support previously observed testis enriched expression of retrogenes and provides evidence for the predominate expression of retrogenes occurring in postmeiotic cells suggesting retrogene involvement in sperm development. Experimental evidence revealed a small group of five retrogenes which exhibit the expected male-biased expression in male testis with little to no expression in female ovaries, although a shared expression in the heads of both sexes was observed. Of the five retrogenes, four carry out energy related functions involving mitochondria, suggesting contribution to energy requirements of developing sperm. Testis and MAG experiments in An. coluzzii revealed a predisposition for retrogenes to be expressed in testis while parent genes tended to have higher expression in MAGs, and this phenomenon is partially supported by DNA microarray expression data. Overall, these results suggest further investigation of retrogenes in An. coluzzii may reveal unique functions in male mosquito fertility that are exploitable in genetic approaches to mosquito control. / Master of Science in Life Sciences / Malaria is a potentially deadly disease which effects thousands of people every year. Malaria around the world is spread by multiple species of mosquitoes in a genus called Anopheles. Controlling the populations of these disease spreading mosquitoes is essential to preventing the spread of malaria. Current insecticide-based approaches used to stop mosquitoes are becoming less effective overtime as mosquitoes become resistant. A potential way to develop new techniques for mosquito control is through research involving mosquito reproductive genetics. Understanding the genes involved in how mosquitoes reproduce could improve future techniques designed to reduce or prevent mosquitos from reproducing. This research focuses on a group of genes called retrogenes which have formed over the evolution of these mosquitoes via the duplication from a separate parent gene. In mosquitoes these retrogenes are understood to be involved in male reproduction. The retrogenes involved in male mosquito reproduction could have important functions in male sexual reproduction and sterility. These important genes could be manipulated to interrupt whatever important functions these genes have in reproduction. In this research we first computationally identified retrogenes and their parent genes and categorized them by age. We then utilized available annotation and expression data to analyze the potential significance of retrogenes to male fertility and found that multiple retrogenes tended to be expressed during sperm development. Lastly, we conducted gene expression experiments using dissected head, thorax, abdomen, and reproductive organs in both male and female Anopheles mosquitoes. Results revealed unique patterns of expression that suggest male specific roles of five retrogenes in testes and head expression in both males and females suggesting a possible role in mating behavior. These results provide evidence that retrogenes do have functional roles in male fertility specifically related to the maturation and development of sperm.
84

Manufacturing of Poly(vinylidene fluoride) and Evaluation of its Mechanical Properties

Esterly, Daniel Mason 23 August 2002 (has links)
Poly(vinylidene fluoride) (PVDF) receives an increasing amount of attention because it exhibits the strongest piezoelectric response of any commercially available polymer. These piezoelectric properties have proved useful as actuators and sensors. Current manufacturing processes limit PVDF to thin films and restricting their uses largely to sensors. Further applications utilizing the changes in mechanical properties of piezoelectric polymers are being realized. Evaluating to what extent the mechanical properties will change with applied electric field and finding new ways to manufacture PVDF will lead to new applications of piezoelectric polymers. In-situ mechanical testing of biased piezoelectric PVDF films successfully measured changes in loss and storage modulus. In-situ creep testing measured an increase in stiffness while in-situ dynamic mechanical analysis (DMA) measured and overall decrease in loss and storage modulus. Differences in results between the two experiments are attributed to orientation of the polymer and piezoelectric forces acting on the equipment. DMA results are accepted as being the most accurate and measured changes of over 20% in elastic modulus. Results were believed to be greatly influence by attached electrodes and actuation forces. Cryogenic mechanical milling successfully converted a phase PVDF powder to b phase as measured with wide-angle x-ray diffraction. This is the first recorded instance of b phase powders forming from the a phase through ball milling. These b phase powders maintained their crystal structure during compression molding at 70&#176;C. / Master of Science
85

Computergestützte Simulation und Analyse zufälliger dichter Kugelpackungen

Elsner, Antje 19 November 2009 (has links)
In dieser interdisziplinär geprägten Arbeit wird zunächst eine Übersicht über kugelbasierte Modelle und die algorithmischen Ansätze zur Generierung zufälliger Kugelpackungen gegeben. Ein Algorithmus aus der Gruppe der Kollektiven-Umordnungs-Algorithmen -- der Force-Biased-Algorithmus -- wird ausführlich erläutert und untersucht. Dabei werden die für den Force-Biased-Algorithmus als essenziell geltenden Verschiebungsfunktionen bezüglich ihres Einflusses auf den erreichbaren Volumenanteil der Packungen untersucht. Nicht nur aus der Literatur bekannte, sondern auch neu entwickelte Verschiebungsfunktionen werden hierbei betrachtet. Daran anschließend werden Empfehlungen zur Auswahl geeigneter Verschiebungsfunktionen gegeben. Einige mit dem Force-Biased-Algorithmus generierte Kugelpackungen, zum Beispiel hochdichte monodisperse Packungen, lassen den Schluss zu, dass insbesondere strukturelle Umbildungsvorgänge an solchen Packungen sehr gut zu untersuchen sind. Aus diesem Grund besitzt das Modell der mit dem Force-Biased-Algorithmus dicht gepackten harten Kugeln große Bedeutung in der Materialwissenschaft, insbesondere in der Strukturforschung. In einem weiteren Kapitel werden wichtige Kenngrößen kugelbasierter Modelle erläutert, wie z. B. spezifische Oberfläche, Volumenanteil und die Kontaktverteilungsfunktionen. Für einige besonders anwendungsrelevante Kenngrößen (z. B. die spezifische Oberfläche) werden Näherungsformeln entwickelt, an Modellsystemen untersucht und mit bekannten Näherungen aus der Literatur verglichen. Zur Generierung und Analyse der Kugelpackungen wurde im Rahmen dieser Arbeit die Simulationssoftware „SpherePack“ entwickelt, deren Aufbau unter dem Aspekt des Softwareengineerings betrachtet wird. Die Anforderungen an dieses Simulationssystem sowie dessen Architektur werden hier beschrieben, einschließlich der Erläuterung einzelner Berechnungsmodule. An ausgewählten praxisnahen Beispielen aus der Materialwissenschaft kann die Vielfalt der Einsatzmöglichkeiten eines Simulationssystems zur Generierung und Analyse von zufälligen dicht gepackten Kugelsystemen gezeigt werden. Vor allem die hohe Aussagekraft der Untersuchungen in Bezug auf Materialeigenschaften unterstreicht die Bedeutung des Modells zufällig dicht gepackter harter Kugeln in der Materialforschung und verwandten Forschungsgebieten.
86

An exploratoration into job satisfaction and motivation among senior and middle managers in Egyptian textile industry : explore the similarities and differences in managerial perceptions regarding motivation and job satisfaction among senior and middle managers in Egyptian textile industry and address the effect of their different personal characteristics

Matar, Sameh Fikry January 2010 (has links)
This study is an attempt to improve job satisfaction and work motivation of the Egyptian textile managers and to fill the gap in the managerial literature regarding the Egyptian textile working context. The main objective of this study is to explore the motivation and job satisfaction of the Egyptian senior and middle managers. A research model was developed in order to explain and to understand the satisfaction and motivation process of senior and middle managers and was empirically tested in the actual textile context. Egyptian textile managers' motivation and job satisfaction were explored by using a total of 247 survey questionnaires and 33 interviews. The major findings indicated that the personal, organisational, and cultural factors were found to influence managers' job satisfaction and motivation. Managers were satisfied with their working conditions, job security, and their personal relationships. However, managers were dissatisfied with their pay, promotion, company policies, training, and their appraisal system. Moreover, managers have placed more concern for job content factors rather than for job context factors. The Egyptian culture was positively related with managers' concern for good personal relationships, achievement, responsibility, and for seeking to more knowledge. However, it negatively affected women managers' status as it led to a gender-biased discrimination towards them. The findings suggest a need to consider the personal differences between managers, improve the promotion system, review salary structure, adopt a results-focused appraisal system, pay more attention to the content job factors, improve training system, increase coordination and delegation of authority, give women equal rights, and increase managers' involvement in decision-making process.
87

Busca virtual de agonistas enviesados não peptídicos do receptor de angiotensina II do tipo 1 / Angiotensin II type 1 receptor non-peptidic biased agonists\' virtual screening

Magalhães, Juliana Gallottini de 30 January 2015 (has links)
Os inibidores do receptor de angiotensina II do tipo 1 (AT1R), fármacos da classe das sartanas, são muito utilizados na terapêutica da insuficiência cardíaca. Apesar de serem eficientes por baixarem a pressão arterial, esses inibidores diminuem a contratilidade do músculo cardíaco, acentuando a patologia. Nesse sentido, os agonistas enviesados para &#946;-arrestina do AT1R surgem como uma solução para esse problema. Estudos com o mais promissor peptídeo com ação agonista enviesada (TRV120027) mostram que ele é capaz de diminuir a pressão arterial sem causar o efeito inotrópico negativo no coração. Tendo em vista esse novo e promissor mecanismo de ação e a característica peptídica do novo agonista enviesado que restringe sua utilização, o presente trabalho visou à busca de ligantes não peptídicos com potencial ação enviesada. Foram realizados estudos de ancoramento seguidos de dinâmica molecular, no AT1R, de sete peptídeos agonistas e agonistas enviesados descritos na literatura, empregando-se os programas Surflex-Dock 2.0 e o GROMACS 4.5, além de análises de campos de interação molecular no programa GRID. Os dados das interações intermoleculares retirados da dinâmica e dos campos de interação guiaram a construção de um farmacóforo que foi utilizado posteriormente em uma busca virtual na base de dados ZINC, com o módulo UNITY 3D do pacote Sybyl-X Suite 2.0. Após ancoramento e análise visual das moléculas selecionadas na busca, foram identificadas 15 moléculas promissoras, sendo cinco delas consideradas de maior interesse. As moléculas selecionadas na busca poderão ser futuramente testadas quanto ao perfil de ação enviesada em receptores AT1R. Os resultados obtidos nesse estudo podem levar à descoberta de um novo protótipo mais eficiente e seguro para o tratamento de doenças cardiovasculares, como a insuficiência cardíaca. / Angiotensin II type 1 receptor (AT1R) inhibitors, the sartans, are widely used in the treatment of heart failure. Although they are effective for lowering blood pressure, these inhibitors decrease the contractility of the heart muscle, accentuating the pathology. Accordingly, &#946;-arrestin biased agonists for AT1R emerge as a solution to this problem. Studies with the most promising biased agonist peptide (TRV120027) show that it is able to lower blood pressure without causing negative inotropic effect on the heart. Given this promising new mechanism of action and the peptide feature of the new agonist that restricts its use, this work aims the search for non-peptide ligands with a potential biased action. Docking studies, followed by molecular dynamics simultions, were performed for seven full and biased agonists in the AT1R, using the Surflex-Dock 2.0 and 4.5 GROMACS programs, besides molecular interaction fields analysis with GRID software. The data of intermolecular interactions from the molecular dynamic\'s analysis and the molecular interaction fields guided to the construction of a pharmacophore model which was subsequently used in a virtual screening from ZINC database, employing the 3D UNITY module from Sybyl-X Suite 2.0 package. After a docking study and visual analysis of the primary selected molecules, 15 promising molecules have been identified, five of them considered of most interest. The molecules selected in the search can be further tested for biased action on AT1R. The results of this study may lead to the discovery of a more efficient and secure lead for the treatment of cardiovascular diseases, such as heart failure.
88

Busca virtual de agonistas enviesados não peptídicos do receptor de angiotensina II do tipo 1 / Angiotensin II type 1 receptor non-peptidic biased agonists\' virtual screening

Juliana Gallottini de Magalhães 30 January 2015 (has links)
Os inibidores do receptor de angiotensina II do tipo 1 (AT1R), fármacos da classe das sartanas, são muito utilizados na terapêutica da insuficiência cardíaca. Apesar de serem eficientes por baixarem a pressão arterial, esses inibidores diminuem a contratilidade do músculo cardíaco, acentuando a patologia. Nesse sentido, os agonistas enviesados para &#946;-arrestina do AT1R surgem como uma solução para esse problema. Estudos com o mais promissor peptídeo com ação agonista enviesada (TRV120027) mostram que ele é capaz de diminuir a pressão arterial sem causar o efeito inotrópico negativo no coração. Tendo em vista esse novo e promissor mecanismo de ação e a característica peptídica do novo agonista enviesado que restringe sua utilização, o presente trabalho visou à busca de ligantes não peptídicos com potencial ação enviesada. Foram realizados estudos de ancoramento seguidos de dinâmica molecular, no AT1R, de sete peptídeos agonistas e agonistas enviesados descritos na literatura, empregando-se os programas Surflex-Dock 2.0 e o GROMACS 4.5, além de análises de campos de interação molecular no programa GRID. Os dados das interações intermoleculares retirados da dinâmica e dos campos de interação guiaram a construção de um farmacóforo que foi utilizado posteriormente em uma busca virtual na base de dados ZINC, com o módulo UNITY 3D do pacote Sybyl-X Suite 2.0. Após ancoramento e análise visual das moléculas selecionadas na busca, foram identificadas 15 moléculas promissoras, sendo cinco delas consideradas de maior interesse. As moléculas selecionadas na busca poderão ser futuramente testadas quanto ao perfil de ação enviesada em receptores AT1R. Os resultados obtidos nesse estudo podem levar à descoberta de um novo protótipo mais eficiente e seguro para o tratamento de doenças cardiovasculares, como a insuficiência cardíaca. / Angiotensin II type 1 receptor (AT1R) inhibitors, the sartans, are widely used in the treatment of heart failure. Although they are effective for lowering blood pressure, these inhibitors decrease the contractility of the heart muscle, accentuating the pathology. Accordingly, &#946;-arrestin biased agonists for AT1R emerge as a solution to this problem. Studies with the most promising biased agonist peptide (TRV120027) show that it is able to lower blood pressure without causing negative inotropic effect on the heart. Given this promising new mechanism of action and the peptide feature of the new agonist that restricts its use, this work aims the search for non-peptide ligands with a potential biased action. Docking studies, followed by molecular dynamics simultions, were performed for seven full and biased agonists in the AT1R, using the Surflex-Dock 2.0 and 4.5 GROMACS programs, besides molecular interaction fields analysis with GRID software. The data of intermolecular interactions from the molecular dynamic\'s analysis and the molecular interaction fields guided to the construction of a pharmacophore model which was subsequently used in a virtual screening from ZINC database, employing the 3D UNITY module from Sybyl-X Suite 2.0 package. After a docking study and visual analysis of the primary selected molecules, 15 promising molecules have been identified, five of them considered of most interest. The molecules selected in the search can be further tested for biased action on AT1R. The results of this study may lead to the discovery of a more efficient and secure lead for the treatment of cardiovascular diseases, such as heart failure.
89

Conception et synthèse de ligands peptidomimétiques du récepteur de la ghréline / Design and synthesis of peptidomimetic ligands of ghrelin receptor

Maingot, Mathieu 18 November 2015 (has links)
La ghréline est une hormone de 28 acides aminés, synthétisée principalement par l'estomac. D'abord identifiée comme un sécretagogue de l'hormone de croissance, elle joue également un rôle central dans la prise alimentaire, la glycémie ainsi que dans certains processus liés à l'addiction. Ces effets sont médiés par un récepteur couplé aux protéines G : le GHS-R1a (Growth Hormone Secretagogue Receptor). Ce récepteur possède une activité constitutive élevée et un réseau de signalisation intra-cellulaire relativement complexe via l'activation de β-arrestines et de différentes isoformes de protéines G (Gq, Gi/o, G12/13). Compte tenu de ces multiples effets, les ligands du GHS-R1a présentent un intérêt thérapeutique certain.Cette thèse est consacrée au développement d'antagonistes et d'agonistes inverses du hGHS-R1a, dont la structure est basée sur le motif 1,2,4-triazole 3,4,5-trisubstitué. Grâce à une étude successive des différents substituants de cette plateforme peptido-mimétique nous avons identifié des antagonistes d'affinités nanomolaires ainsi que des agonistes inverses possédant une efficacité significative. Ces composés paraissent donc être des candidats intéressants pour des études in vivo sur des modèles de prise alimentaire ou d'addiction. D'autre part, une étude pharmacologique sophistiquée, menée sur nos composés, a démontré qu'il est possible d'obtenir des ligands biaisés sur la base du motif triazole. Ces résultats fournissent de nouvelles informations sur la sélectivité fonctionnelle du GHS-R1a. Ainsi, associés à des études in vivo complémentaires, ces données pourraient être précieuses pour la conception de nouveaux médicaments possédant des effets secondaires limités. / Ghrelin is a hormone of 28 amino acids, mostly synthesized in the stomach. Firstly identified as a growth hormone secretagogue, this peptide is also involved in food intake, blood glucose and in some processes related to addiction. Ghrelin effects are mediated by a G protein-coupled receptor: GHS-R1a (Growth Hormone Secretagogue Receptor). This receptor has a high constitutive activity and a complex intra-cellular signaling network via the activation of β-arrestin and different isoforms of G protein (Gq, Gi / o, G12 / 13). Given these multiple effects, ligands of GHS-R1a have a therapeutic interest.This thesis is devoted to the development of antagonists and inverse agonists of hGHS-R1a whose structure is based on the 3,4,5-trisubstituted 1,2,4-triazole scaffold. Thanks to a successive study of the various substituents of the peptidomimetic platform we identified antagonists with nanomolar affinity and inverse agonists with a significant efficiency. These compounds appear to be attractive candidates for in vivo studies on food intake or addiction models. On the other hand, a sophisticated pharmacological study, conducted on our compounds, has demonstrated that it is possible to obtain biased ligands based on the triazole motif. These results provide new informations about the functional selectivity of GHS-R1a. Thus, these data, combined with additional in vivo studies, could be useful for the design of new drugs with limited side effects.
90

Postglacial Population History of the Common Shrew (<i>Sorex araneus</i>) in Fennoscandia : Molekylära studier av återkolonisation, könsbundet genflöde och kromosomrasbildning. / Den vanliga näbbmusens (<i>Sorex araneus</i>) postglaciala populationshistoria i Fennoskandien : Molekylära studier av återkolonisation, könsbundet genflöde och kromosomrasbildning.

Andersson, Anna-Carin January 2004 (has links)
<p>The common shrew, <i>Sorex araneus</i>, has one of the most variable karyotypes among mammals, displaying numerous chromosomes races throughout its distribution, which can be categorized into different karyotypic groups. The objective of this thesis was to examine the postglacial population history of Fennoscandian common shrews using autosomal microsatellites, mitochondrial DNA (mtDNA) and a Y chromosome specific microsatellite (L8Y).</p><p>Autosomal microsatellites and mtDNA revealed weak genetic structure over a hybrid zone between the karyotypically divergent Northern and Western karyotypic groups. However, the genetic structure displayed by the Y chromosome microsatellite was orders of magnitude higher. Hence, considerable chromosomal differences between the groups do not prevent female gene flow, while male gene flow is reduced (cf. Haldane's rule). Further, the results suggest that the Haldane effect may be caused by the chromosomal differences between the karyotypic groups.</p><p>No mtDNA differentiation was observed either between chromosome races or between the Northern and Western karyotypic groups in Fennoscandia. The combined pattern of karyotypic and mtDNA variation of Fennoscandian common shrews, suggest bi-directional postglacial recolonisation from a single refugium in Europe. The variation of the Y-linked microsatellite supported this conclusion. In contrast, significant mtDNA structure, discordant with the karyotypic variation, revealed that common shrews in southern Finland belong to a different lineage than remaining Fennoscandian regions, implying postglacial recolonisation from a different source.</p><p>MtDNA variation of the chromosome races in Sweden supports the hypothesis that three races of the Western karyotypic group have been formed through whole arm reciprocal translocations (WARTs), as suggested by their mutual karyotypic variation. The variation of the molecular markers supports the theory of rapid karyotypic evolution in the common shrew.</p>

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