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Mažeika, Robertas. "Logistikos centras „logista“ aerouosto g. 5." Bachelor's thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130619_091300-40980.
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Bakalaurinio baigiamajame darbe projektuojamas vieno aukšto ypatingas statinys – logistikos centras „Logista“. Pastatas projektuojamas Šiaulių miesto pramoniniame rajone, Aerouosto gatvėje. Bendras sklypo plotas 6831,68 m2, užstatymo plotas 1539,49 m2.<br>In this final work is designed one-story special building – logistic centre „Logista“. Building is designed in industrail district of Šiauliai, Aerouosto street. Overall area is 6831,68 m2, built-up area 1539,49 m2.
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Kvachnina, Elena. "Characterization of the 5-HT₇(a) receptor specific receptor-G-protein interactions /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972602003.
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Joubert, Lara. "Le récepteur 5-HT4 : états conformationnels et protéines d'intéraction." Montpellier 2, 2004. http://www.theses.fr/2004MON20021.
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Sallander, Eva Jessica. "The mechanism of G protein coupled receptor activation: the serotonin receptors." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/77901.
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Una de las principales cuestiones en farmacología molecular de los GPCR es entender los mecanismos estructurales de las siete hélices transmembrana (TM) que se producen para estabilizar ya sea Rg o los diferentes estados R*. Para entender el mecanismo que cambia el equilibrio del conjunto a un estado activo R* se construyeron tres de los receptores de la serotonina (5-HT4, 5-HT6, y 5 HT7) sobre la base de su información más reciente de cristalografía de rayos X. Dando lugar a dos modelos de cada receptor: una inactiva y otra activa. Los modelos, mejorados y evaluados con la ayuda de datos farmacológicos y químicos se utilizaron principalmente para comprender la interacción entre un ligando y su receptor y su mecanismo de acción. Estos hallazgos estructurales pueden a su vez resultar útiles para el diseño de nuevos fármacos más eficaces y selectivos.<br>One of the main questions in G protein coupled receptors (GPCRs) molecular pharmacology is to understand the structural arrangements of the seven transmembrane (TM) helices that occur to stabilize either the ground state (Rg) or different active states (R*) of the receptors. In order to understand the mechanism that shift the equilibrium of the ensemble to an active R* state models of the inactive and the active state of three serotonin receptors (5-HT4, 5-HT6, and 5-HT7) were built based on the latest information from X-ray crystallography. The resulting models were mainly used to understand the interaction between a ligand and its receptor and the mechanism of action. With the help of pharmacological and chemical data these models and complexes were improved and evaluated. These findings may prove valuable for structural based drug discovery efforts and facilitate the design of more effective and selective pharmaceuticals.
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Howlett, Alyson Cerny. "Role of molecular chaperones in G protein "beta"5-regulator of G protein signaling dimer assembly and G protein "beta""gamma" specificity /." Diss., CLICK HERE for online access, 2009. http://contentdm.lib.byu.edu/ETD/image/etd2874.pdf.
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Babich, Aleksei. "Biochemische und funktionelle Charakterisierung der G-Protein-Isoform [beta]5 [beta5]." [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2005/107/index.html.
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Iordanoglou, Dimitrios. "Literary loves : interpretations of Dioscorides 1-5 and 7 G-P /." Uppsala : Dept. of Classical Philology [Institutionen för klassiska språk], Univ. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3594.
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Kumari, Sunita. "Role of RNA G-quadruplexes within 5' UTRs in translation regulation." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612262.
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Kerr, Jason Stuart. "Heterotrimeric G-protein interactions and activation in chemokine receptor 5 signalling." Thesis, University of East Anglia, 2010. https://ueaeprints.uea.ac.uk/10571/.
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Activation of the G-protein coupled receptor (GPCR) chemokine receptor 5 (CCR5) has been shown to result in activation of the Gαi family of heterotrimeric G-proteins. However, little is currently known about the temporal characteristics of G-protein heterotrimer activation by CCR5. Furthermore, this simplistic model does not account for the range of changes CCR5 activation brings about. Recent evidence suggests that GPCRs may be able to signal through numerous permutations of heterotrimer. In order to assess G-protein activation and interaction with CCR5 functional stably transfected cell lines were created expressing Gαi2 fused to ECFP and Gβ1 fused to EYFP. The interaction of these constructs was confirmed by measuring fluorescent resonance energy transfer (FRET). Stably transfected cells exhibited a FRET ratio of 2.63% (±0.345%, n=3) over that of control cells. Following CCR5 stimulation with CCL3, Gαi2β1γ activation could be monitored in real time, in whole cell populations, on a fluorescent plate reader by monitoring FRET emissions. This assay system represents a novel approach to measuring G-protein activation which can be used as a foundation to build more powerful FRET based assays. Measurement of G-protein interactions was further invested by BRET based studies. Transfection of dominant negative and constitutively active G-proteins alongside siRNA knockdown of G-proteins revealed that CCR5 is capable of signalling through other members of the Gαi family, with strikingly similar efficacy and potency to CCL3 stimulation. Dual knockdown of Gαi subunits and Gαq resulted in much attenuated calcium release following CCL3 stimulation, providing evidence that CCR5 may functionally couple to several types of G-proteins. Findings also support the theory that GPCRs can participate in domain swapping in order to rescue function. Treatment with gallein resulted in higher resting cytosolic cAMP but did not prevent CCR5 mediated inhibition of cAMP production. Gallein treatment also resulted in significant increases in calcium release following CCR5 activation, highlighting Gβγ as a potential target for modulating CCR5 signalling events. Data herein emphasize the complexity of GPCR signalling, and also provide a foundation for exploring GPCR signalling using fluorescence resonance energy transfer methods in the future.
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Rached, Marici Rached. "Papel do HLA-G na endometriose." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-06092017-121750/.
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A endometriose é uma doença inflamatória crônica, estrógeno-dependente e de etiologia multifatorial, caracterizada pela implantação e crescimento de tecido endometrial fora da cavidade uterina e associada à dor pélvica e infertilidade. A doença é classificada de acordo com os estádios e sítios de acometimento nos órgãos pélvicos. Variantes genéticas, endócrinas e ambientais podem contribuir para a geração de uma deficiência na resposta imune local permitindo a implantação das células ectópicas na cavidade pélvica. Alterações constatadas no padrão de citocinas presentes no microambiente pélvico poderiam promover um ambiente imunossupressor, justificando a diminuição da resposta imune efetora verificada na endometriose. Dentre os possíveis fatores imunomoduladores, está o antígeno leucocitário humano-G (HLA-G), cuja expressão se dá intensamente nas células trofoblásticas, sendo reconhecido por induzir a tolerância materno-fetal. A proteína HLA-G pode ser expressa na membrana celular ou ser secretada na forma solúvel. HLA-G encontra receptores inibitórios nas células do sistema imune inato e adaptativo e tem sua expressão induzida sob condições não fisiológicas, como em transplantes alogênicos, doenças inflamatórias ou neoplasias malignas. Assim, a hipótese deste estudo é a de que a proteína HLA-G seria produzida em níveis superiores nas mulheres com endometriose, o que poderia contribuir para a imunossupressão no microambiente da doença. Para testar esta hipótese, a proteína solúvel foi mensurada no soro e no fluido peritoneal de mulheres com e sem endometriose, por ensaio de imunoabsorção enzimática (ELISA). Além disto, a expressão gênica de HLA-G foi avaliada nos tecidos de endométrio, por qRT-PCR, bem como a expressão da proteína, avaliada por imunohistoquímica, nos tecidos de endométrio e de lesão de endometriose, em mulheres com e sem a doença. Como resultados, verificaram-se maiores níveis da proteína solúvel no soro de mulheres que apresentavam endometriose em estádios avançados, especialmente naquelas com endometriose ovariana. Entretanto, na comparação entre os fluidos peritoneais, não houve diferença significativa entre os grupos com e sem endometriose. A expressão do transcrito gênico (mRNA) se mostrou maior no endométrio de mulheres sem a doença, mas a presença da proteína foi semelhante entre os endométrios de mulheres com e sem endometriose. Por outro lado, a expressão da proteína HLA-G nos tecidos de lesão de endometriose avançada se mostrou superior à do endométrio de mulheres sem a doença, indicando que a expressão de HLA-G seria induzida ectopicamente, no microambiente pélvico da doença. Portanto, os resultados apontam para um aumento da expressão de HLA-G em endometriose avançada<br>Endometriosis is a chronic inflammatory, estrogen-dependent disease of multifactorial etiology characterized by implantation and growth of endometrial tissue outside the uterine cavity, and associated with pelvic pain and infertility. Endometriosis is classified according to the stages and sites of the disease. Genetic, endocrine and environmental factors may contribute to the deficit on local immune response, allowing ectopic implantation of endometrial cells into the pelvic cavity. Changes in cytokines pattern in the pelvic microenvironment might promote an immune suppressor environment and explain the decreased immune effector cells response verified in endometriosis. Among possible immunomodulatory factors is the human leucocytary antigen-G (HLA-G) which is intensively expressed in trophoblasts and recognized by inducing maternal-fetal tolerance. HLA-G protein is expressed in both membrane-bound and soluble forms. HLA-G binds inhibitory receptors on innate and adaptive immune cells surface and its expression is induced in non-physiological conditions, such as allogeneic transplants, inflammatory diseases or neoplastic malignancies. Thus, this study hypothesizes that the HLA-G protein would be overexpressed in women with endometriosis, and could contribute to the immunosuppression in the disease microenvironment. To test this hypothesis soluble HLA-G protein was measured in serum and peritoneal fluid of women with and without endometriosis. Moreover, HLA-G gene expression were evaluated on endometrial tissue using RT-qPCR, and HLA-G protein expression were evaluated in matched ectopic and eutopic endometrium of women with and without endometriosis. As results, higher levels of soluble HLA-G were found in serum of women with advanced endometriosis, especially in those with ovarian endometriosis. However, soluble HLA-G levels in peritoneal fluid did not show significant differences between women with and without endometriosis. HLA-G mRNA expression were higher in eutopic endometrium of women without endometriosis, but the HLA-G protein expression were similar in eutopic endometrium of women with and without endometriosis. On the other hand, HLA-G protein expression in ectopic endometrium of women with advanced endometriosis was higher than in eutopic endometrium of women without endometriosis, suggesting that HLA-G expression was induced ectopically, in the pelvic microenvironment of the disease. In conclusion, the results point to an upregulation of HLA-G expression in advanced endometriosis
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Barclay, Elaine. "Characterisation of palmitoylation in alpha₂_A adrenoceptor and 5-HT₁_A serotonin receptor-G₀₁α G protein fusion proteins". Thesis, University of Glasgow, 2004. http://theses.gla.ac.uk/4998/.
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Palmitoylation variant GPCR-G protein fusion proteins were created between the porcine u2A-adrenoceptor or the human 5-HT1A-serotonin receptor and the pertussis toxin resistant, Cys35lIle, form of the rat Go1u protein. These palmitoylation-variant fusions were transiently expressed in HEK293T cells prior to analysis of the regulation of palmitoylation and the functional consequences of palmitoylation for both the GPCR and G protein parts of the fusions. When the regulation of palmitoylation was studied for u2A-adrenoceptor-GoluCys35IIle fusion proteins, dynamic palmitoylation and depalmitoylation of both the Cys442residue of the u2A-adrenoceptor and the Cys ' residue of the GoluCys351Ile protein were found to occur. However, only the GOluCys351Ileprotein part of the fusion was found to undergo adrenaline-stimulated regulation of palmitoylation and the effect of adrenaline required G protein activation. Adrenaline regulation proceeded in a concentration-dependent manner correlating with agonist occupancy of the u2A-adrenoceptor. Such agonist effects were found to be, at least in part, due to agonist-stimulation of GOluCys351Ile protein depalmitoylation. The requirements for palmitoylation of the u2A-adrenoceptor and GoluCys351Ile protein elements of the u2A-adrenoceptor-GoluCys35IUe fusion proteins were subsequently assessed for various functional properties. Palmitoylation of neither the U2Aadrenoceptor nor the GoluCys351Ile protein parts of the fusion determined fusion protein expression levels, affinity for the agonist adrenaline, affinity for the antagonist RS- 79948-197, ability to bind or to hydrolyse GTP or their ability to influence the efficiency of RGS 16 protein to accelerate the GTPase reaction. In regulation of palmitoylation studies for 5-HTIA-receptor-GoluCys35IIle fusion proteins, dynamic palmitoylation of the Cys' residue of the GoluCys351Ue protein and the Cys417 residue of the 5-HTIA-receptor was observed as well as a lack of incorporation of palmitate into Cys420 of the 5-HT1A-receptor. Dynamic depalmitoylation was only observed for the Cys' residue of the GoluCys351Ile protein, not for the 5-HT1A-receptor. In the latter case, palmitate once incorporated appeared to remain stably attached. Both the 5-HT1A-receptor and the GoluCys351Ile protein parts of the fusion were found to undergo 8-0H-DPAT-stimulated regulation ofpalmitoylation. 8-0H-DPAT was able to regulate palmitoylation levels of both proteins in a concentration-dependent manner. For the regulation of GoluCys351Ile protein palmitoylation such agonist effects were found likely to be, at least in part, due to an agonist-stimulated rate of depalmitoylation. For the regulation of 5-HT1A-receptor palmitoylation such agonist-stimulated increases in observed palmitoylation levels were only attributable to the addition of palmitate, given that no depalmitoylation of the 5- HT1A-receptor could be detected. The requirements for palmitoylation of the 5-HT1A-receptor and GoluCys351Ile protein elements of the 5-HT1A-receptor-GoluCys351Ile fusion proteins were also assessed for a selection of functional properties. Similar to the results obtained with Go1uCys351Ile protein constrained to the uZA-adrenoceptor, the palmitoylation of the GoluCys351Ile protein did not determine fusion protein expression levels, their affinity for the antagonist WAYI00635, or their ability to bind GTP. Palmitoylation of 5-HT1Areceptor did not alter fusion protein expression levels or their affinity for the antagonist WAYI00635. However, in contrast, it did cause enhanced levels of GTP binding to the 5-HT1A-receptor-GoluCys351Ile fusion proteins. The results of this investigation suggest that there are different requirements for regulation of GPCR and G protein palmitoylation dependent on the GPCR-G protein fusion in question. These requirements may be responsible for the specific functional properties displayed by such fusions. The current study also demonstrates that GPCR-G protein fusion proteins can be successfully used as tools to study both the regulation of palmitoylation and the functional consequences of this modification.
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Kvachnina, Elena. "Characterization of the 5-HT7(a) receptor specific receptor G protein interactions /." Doctoral thesis, [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972602003.
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Jyssum, Kari. "Particle Mobility in Mucus : Role of Surface Interactions and Use of G-blocks." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for bioteknologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-16806.
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The mucus layers on the internal surfaces of the human body serve as an important barrier against foreign material, but it also create restrictions regarding drug delivery. Discovering methods to overcome this barrier would lead us closer to an efficient delivery of larger drugs and nanoparticles. Recent studies have shown that alginate G-block polymers can modify the physical properties of mucus, and that the G-blocks make the mucin network more open and increase particle transport through mucus. This shows that G-blocks are an interesting candidate, for use in drug delivery across mucosal barriers, but further work to understand the mechanisms by which the G-blocks interact with mucus is still desirable. Studies have shown that neutral particles diffuse more easily through mucus than charged particles. In this thesis the interactions between nanoparticles with different surface structures and mucus components were compared by dynamic light scattering and the effect of G-block on these interactions was established. The diffusions of all particle types were compared in pig gastric mucin (PGM) from Sigma, by the use of confocal microscopy and multiple particle tracking (MPT). Then alginate G-blocks were added and the diffusion of the particle types was compared. The results showed that G-blocks can reduce the amount of mucin components accumulating on to positively charged surfaces but not to negatively charged particles. The MPT showed that the surface charge of the nanoparticles is the primary determining factor when it comes to diffusion through Sigma mucin, and that the effect on the diffusions caused by G-blocks is relatively small, most probably due to the matrix of Sigma mucin, lacking the large networking polymers on which G-blocks previously have shown their effect. It was found that G-blocks make the distribution of trajectories more homogenous, but that this did not affect the mean displacements.
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Panetta, Rosemarie. "Human somatostatin receptor 5(hSSTR5) : a novel pituitary selective G protein-coupled receptor." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40419.
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Using a combination of polymerase chain reaction (PCR) and genomic library screening, a human (h) gene for a subtype of the somatostatin (SST) receptor (SSTR), termed hSSTR5, was cloned. Human SSTR5 consists of a 363-residue polypeptide exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. The receptor displays 45% to 52% sequence identity to the other four cloned hSSTR subtype genes (SSTRl-SSTR4). Pharmacological analysis of hSSTR5 revealed that this receptor bound SST-28 with a 12.6-fold greater affinity compared with SST-14, indicating that hSSTR5, unlike the other four SSTR subtypes, is SST-28 selective. hSSTR5 was negatively coupled to adenylyl cyclase via a pertussis toxin-sensitive G protein. Northern blot analysis of SSTR5 mRNA revealed a 2.4kb transcript in normal rat pituitary and GH$ sb3$ rat pituitary tumour cells and a 4.0 kb transcript in normal human pituitary. Reverse transcriptase PCR revealed expression of the hSSTR5 gene in fetal human pituitary and hypothalamus but not in human adult cerebral cortex. Expression of SSTR5 mRNA was compared with that of SSTR 1-4 mRNA in normal rat and human pituitary, purified rat somatotrophs, rodent pituitary cell lines (GH$ sb3$, GH$ sb4$C$ sb1$, AtT-20), and human secretory and nonsecretory pituitary tumours. All of these tissues expressed several SSTR gene subtypes, SSTR2 being the predominant form. Since tumour cells are monoclonal in origin, and somatotrophs are an individual subpopulation of pituitary cell, these studies have additionally demonstrated that multiple SSTR genes are expressed in individual cells. SST-28 pre-treatment of CHO-K1 cells stably expressing hSSTR5 markedly attenuated the potency of SST-28 to inhibit cAMP formation, indicating receptor desensitization. Human SSTR5 was also internalized in a time- and temperature-dependent manner upon agonist exposure. The possible role of putative residues and structural domains in the carboxyl-terminal ta
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Maaz, Bilal. "Allocation des ressources radio dans les réseaux sans fil de la 5 G." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLV010/document.
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La communication mobile est considérée comme l'un des piliers des villes intelligentes, où les citoyens devraient pouvoir bénéficier des services de télécommunications partout et quand ils les souhaitent, d'une manière sûre et peu coûteuse. Cela est possible grâce à un déploiement dense des réseaux mobiles à large bande de dernière génération. Ce déploiement dense entraînera une consommation énergétique plus élevée et donc plus d'émissions de gaz et de pollution. Par conséquent, il est crucial d'un point de vue environnemental de réduire la consommation d'énergie. Dans le cadre de cette thèse, nous introduisons des méthodes dynamiques de gestion de ressources permettant d'augmenter le débit et l'efficacité énergétique, et réduisant ainsi la pollution. Ainsi, nous ciblons les réseaux multicellulaires verts où l'augmentation de l'efficacité énergétique doit tenir en compte de l'accroissement de la demande de débit par les utilisateurs mobiles. Cette augmentation, exponentielle en terme de débit, a poussé les opérateurs à utiliser la totalité du spectre fréquentiel dans toutes les cellules des réseaux mobiles de dernière génération. Par conséquence, l'interférence intercellulaire (ICI : Inter-Cell Interference) devient prépondérante et dégrade la performance des utilisateurs, en particulier ceux ayant de mauvaises conditions radios. Dans cette thèse, nous nous focalisons sur la technique du contrôle de puissance considérée comme une des méthodes clé de la coordination d'interférence Intercellulaire (ICIC : Inter-Cell Interference Coordination), tout en mettant l'accent sur des méthodes efficaces énergétiquement. Nous formulons ce problème d'allocation de la puissance, sur le lien descendant en mettant en œuvre des méthodes centralisées et décentralisées: les méthodes centralisées ayant recours à l'optimisation convexe alors que les méthodes décentralisées se basant sur la théorie des jeux non-coopératifs. Par ailleurs nous proposons ensuite une heuristique de contrôle de puissance qui a l'avantage d'être stable et basée sur des messages de signalisation déjà existant dans le système. Cette heuristique permet d'éviter le gaspillage de la bande passante par des signalisations intercellulaires et de réduire le ICI. De plus, le problème de contrôle de puissance a un impact important sur l'allocation des ressources radios et sur l'association des utilisateurs mobiles à une station de base. Ainsi, dans la deuxième partie de la thèse, nous avons formulé un problème globale englobant le contrôle de puissance, le contrôle d'allocation de ressources radios, et le contrôle de l'association des utilisateurs à une station de base, cela afin d'obtenir une solution globalement efficace. Ces trois sous problèmes sont traités itérativement jusqu'à convergence de la solution globale. En particulier nous proposons pour la problématique d'association des utilisateurs trois algorithmes: un algorithme centralisé, un algorithme semi-distribué et finalement un algorithme complètement distribué se basant sur l'apprentissage par renforcement. Par ailleurs, pour l'allocation de puissance, nous implémentons des solutions centralisées et des solutions distribuées. Les preuves de convergence des algorithmes ont été établies et les simulations approfondies ont permis d'évaluer et de comparer quantitativement les performances, l'efficacité énergétique et le temps de convergence des algorithmes proposés<br>Mobile communication is considered as one of the building blocks of smart cities, where citizens should be able to benefit from telecommunications services, wherever they are, whenever they want, and in a secure and non-costly way. This can be done by dense deployment of the latest generation of mobile broadband networks. However, this dense deployment will lead to higher energy consumption, and thus more gas emission and pollution. Therefore, it is crucial from environmental point of view to propose solution reducing energy consumption. In this thesis, we introduce dynamic resource management methods that increase throughput and energy efficiency, and thus reduce pollution. In this framework, we are targeting green multi-cell networks where increased energy efficiency must take into account the increased demand of data by mobile users. This increase, which is exponential in terms of throughput, pushed operators to use the entire frequency spectrum in all cells of the latest generation of mobile networks. As a result, Inter-Cellular Interference (ICI) became preponderant and degraded the performance of users, particularly those with poor radio conditions. In this thesis, we focus on the techniques of power control on the downlink direction, which is considered as one of the key methods of Inter-Cell Interference Coordination (ICIC) while focusing on energy efficient methods. We propose centralized and decentralized methods for this problem of power allocation: centralized methods through convex optimization, and decentralized methods based on non-cooperative game theory. Furthermore, we propose a power control heuristic which has the advantage of being stable and based on signaling messages already existing in the system. The power control problem has a relevant impact on the allocation of radio resources and on the association of mobile users with their servicing Base Station. Therefore, in the second part of the thesis, we formulated a global problem encompassing power control, radio resources allocation, and control of users’ association to a base station. These three sub-problems are treated iteratively until the convergence to the overall solution. In particular, we propose three algorithms for the user association problem: a centralized algorithm, a semi-distributed algorithm and finally a fully distributed algorithm based on reinforcement learning. In addition, for power allocation we implement centralized solutions and distributed solutions. The proof of convergence for the various algorithms is established and the in-depth simulations allow us to evaluate and compare quantitatively the performance, the energy efficiency, and the convergence time of the proposed algorithms
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McLoughlin, David J. "Analysis of the ligand binding site of the human 5-HTâ†1â†A serotonin receptor." Thesis, University of Kent, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285980.
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Krapp, Stephan. "Röntgenstrukturanalyse von humanen IgG1-Fc-Glykosylierungsvarianten und Röntgenstrukturanalyse des katalytischen Teils der murinen CMP-5-N-Acetylneuraminsäure-Synthetase." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969349378.
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Howlett, Alyson Cerny. "Role of molecular chaperones in G protein B5-Regulator of G protein signaling dimer assembly and G protein By dimer specificity." BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/2065.
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In order for G protein signaling to occur, the G protein heterotrimer must be assembled from its nascent polypeptides. The most difficult step in this process is the formation of the Gβγ dimer from the free subunits since both are unstable in the absence of the other. Recent studies have shown that phosducin-like protein (PhLP1) works as a co-chaperone with the cytosolic chaperonin complex (CCT) to fold Gβ and mediate its interaction with Gγ. However, these studies did not address questions concerning the scope of PhLP1 and CCT-mediated Gβγ assembly, which are important questions given that there are four Gβs that form various dimers with 12 Gγs and a 5th Gβ that dimerizes with the four regulator of G protein signaling (RGS) proteins of the R7 family. The data presented in Chapter 2 shows that PhLP1 plays a vital role in the assembly of Gγ2 with all four Gβ1-4 subunits and in the assembly of Gβ2 with all twelve Gγ subunits, without affecting the specificity of the Gβγ interactions. The results of Chapter 3 show that Gβ5-RGS7 assembly is dependent on CCT and PhLP1, but the apparent mechanism is different from that of Gβγ. PhLP1 seems to stabilize the interaction of Gβ5 with CCT until Gβ5 is folded, after which it is released to allow Gβ5 to interact with RGS7. These findings point to a general role for PhLP1 in the assembly of all Gβγ combinations, and suggest a CCT-dependent mechanism for Gβ5-RGS7 assembly that utilizes the co-chaperone activity of PhLP1 in a unique way. Chapter 4 discusses PhLP2, a recently discovered essential protein, and member of the Pdc family that does not play a role in G protein signaling. Several studies have indicated that PhLP2 acts as a co-chaperone with CCT in the folding of actin, tubulin, and several cell cycle and pro-apoptotic proteins. In a proteomics screen for PhLP2A interacting partners, α-tubulin, 14-3-3, elongation factor 1α, and ribosomal protein L3 were found. Further proteomics studies indicated that PhLP2A is a phosphoprotein that is phosphorylated by CK2 at threonines 47 and 52.
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Mikulic, Nikolina. "Assoziation spezifischer kognitiver Fähigkeiten mit dem -1438A/G Polymorphismus des Serotoninrezeptorgens 5-HT-2A." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-117089.
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Lester, K. N. "Identification of a role for G protein-coupled receptor kinase 5 in regulating apoptosis." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1418752/.
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The G protein-coupled receptor kinases (GRKs) are best known for their role in phosphorylating G protein-coupled receptors (GPCRs). In addition to their canonical role, the GRKs have a number of non-receptor substrates and binding partners. GRK5 contains functional nuclear localisation and export sequences and many newly discovered binding partners of the kinase are, indeed, nuclear. My thesis outlines the discovery of novel nuclear GRK5 binding partners, class I histone deacetylases (HDACs), HDACs 1, 3 and 8, as well as the repressor protein, Swi-independent 3 (Sin3) A, and reports a role for GRK5 in regulating B cell lymphoma protein 2 (Bcl-2) gene transcription in conjunction with this repressor complex. Attempts to map the HDAC1 and Sin3A binding sites on GRK5 were carried out using GRK5 peptide arrays. Suspected GRK5 residues involved in binding were identified and mutated, but no viable binding deficient mutants were identified. Using HDAC and Sin3A inhibitors, I show GRK5 to negatively regulate Bcl-2 transcription in a class I HDAC and, most likely, a Sin3A dependent manner. Bcl-2, an anti-apoptotic protein, is upregulated in the early stages of many colorectal cancers (CRCs) and is, at least in part, responsible for the apoptotic resistance of metastatic CRCs. Notably, GRK5 expression levels are low in the colon cancer cell line, HT-29, in comparison to other tumour-derived cancer cell lines and overexpressing the kinase in HT-29 cells by cDNA transfection increases the susceptibility of these cells to chemotherapeutically induced apoptosis. Furthermore, overexpression of an inhibitor of miR-135a, a micro RNA (miRNA) that is upregulated in CRC, increases endogenous GRK5 expression as well as apoptosis in HT-29 cells, highlighting the potential use of a miR-135a inhibitor as a novel therapeutic strategy to treat CRC patients.
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Kelliher, Diarmaid. "Solidarity, class and labour agency : mapping networks of support between London and the coalfields during the 1984-5 miners' strike." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8030/.
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From March 1984 to March 1985, over 150,000 British coal miners walked out on strike in protest at plans for widespread closures in the industry. Alongside the strike developed a large and diverse support movement, both within Britain and internationally. This thesis focuses on the solidarity campaign in London, a city far from the heartlands of the coal industry. The support movement outside of the coalfield areas has been relatively understudied in the years since the dispute, and this thesis is a contribution to recuperating this important history. The four central empirical chapters are organised thematically. The first explores relationships developed between London and the coalfields from the late 1960s, arguing that the support of 1984-5 must be rooted in ongoing mutual relationships of solidarity. The second describes the diverse spaces and sites in which the support movement was enacted, and how distinct tactics such as twinning and forms of politicised mobility reduced the distance between London and mining areas, enabling the development of personal relationships across space. The third focuses on the weaknesses of the support movement, working-class opposition to the strike, and the relationship between this absence of solidarity and the anti-union rhetoric of elites. In the fourth empirical chapter, I emphasise how the intersecting politics of class, race, gender and sexuality were raised through the miners’ strike solidarity movement, and the forging of new relationships across spatial and social boundaries. Through a study of the miners’ support movement, this thesis makes a number of central theoretical contributions. It is concerned firstly with developing an account of translocal solidarity as a generative relationship that can construct connections across social and geographical boundaries, and develop new political theories and practices. Secondly, I argue for an intersectional approach to class as a way of rejecting simplistic divisions between the politics of class, gender, sexuality and race. In particular, I highlight intersectionality as a historical process whereby relationships of solidarity across space inform a politics that is simultaneously able to recognise differences and develop commonalities. Thirdly, I emphasise how translocal networks of solidarity contribute to relational constructions of place, but that such an understanding is not inimical to a deep, historically rooted local development of class. Fourthly, I argue that a spatially and temporally dynamic understanding of the construction of cultures of mutual solidarity can contribute significantly to how we think about labour agency.
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Cabrejos, Diego Antonio Leonardo. "Especificidade na montagem de filamentos de Septinas: o caso da interface G entre SEPT5 e SEPT8." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-27102016-102703/.
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Septinas abrangem uma família conservada de proteínas que ligam e hidrolisam GTP e formam heterofilamentos, anéis e redes para realizar as suas funções. Apresentam três domínios estruturais: o domínio N-terminal contendo uma sequência polibásica (para ligar membranas), o domínio de ligação ao nucleotídeo (G) e o domínio C-terminal que inclui uma sequência predita de formar um coiled-coil. Em humanos, as 13 septinas são classificadas em quatro grupos (I, II, III e IV) baseadas nas sequências de aminoácidos. O único filamento caracterizado estruturalmente, até hoje, é o formado por SEPT2-SEPT6-SEPT7, mostrando que as subunidades interagem através de duas interfaces (chamadas G e NC). Os determinantes estruturais da montagem correta do filamento são pouco conhecidos, sendo o estudo limitado pela complexidade em purificar e cristalizar complexos triméricos ou tetraméricos. Uma abordagem alternativa é estudar interfaces individuais de um filamento (G e/ou NC) por separado. Assim, o presente projeto objetivou estudar, utilizando uma abordagem biofísica e estrutural, a interface G formada por SEPT5 e SEPT8 para elucidar os fatores importantes em determinar a sua especificidade. Os domínios GTPase de SEPT5 e SEPT8 foram clonadas em vetor de expressão bicistrônico pET-Duet, co-expressas e co-purificadas. Estudos de análise do estado oligomérico e homogeneidade foram conduzidos utilizando cromatografia de exclusão molecular, espalhamento dinâmico de luz e ultracentrifugação analítica, revelando um complexo dimérico e monodisperso. O complexo apresenta uma mistura aproximadamente equimolar de nucleotídeos (GTP e GDP) ligados enquanto SEPT8(G) sozinha é incapaz de ligar qualquer um dos dois. Além disto o complexo apresenta uma termoestabilidade maior que SEPT8(G), verificado por um aumento em Tm de 5°C. Com o intuito de observar os determinantes estruturais da especificidade, ensaios de cristalização foram conduzidos e assim, cristais do complexo SEPT5-SEPT8(G) que difrataram apenas a muito baixa resolução foram obtidos. Na ausência de uma estrutura cristalográfica, modelagem por homologia foi realizada para analisar as interfaces G entre diferentes combinações de septinas. Identificamos uma interação entre aminoácidos característicos (aminoácidos únicos para cada grupo de septinas) para o complexo formado entre membros do grupo III, (incluindo SEPT5) e membros do grupo II, (incluindo SEPT8). Esta interação entre Phe131 (grupo III) e Thr19 (grupo II) pode explicar a especificidade na formação de uma interface G entre septinas destes grupos durante a formação do filamento e além disso, a importância da presença do GTP ligado ao septina do grupo II. Com isto, propomos pela primeira vez uma explicação plausível da relevância da perda de atividade catalítica das septinas deste grupo, um fato inexplicado até o momento. Mutação dos resíduos identificados levou a uma mudança no seu perfil de eluição do complexo durante purificação por exclusão molecular indicando alterações na formação do complexo mutante.<br>Septins are a conserved family of proteins that bind and hydrolyze GTP and form heterofilaments, rings and networks in order to carry out their functions. They have three structural domains: an N-terminal domain containing a polybasic sequence (for membrane binding), a nucleotide-binding (G) domain and a C-terminal domain including a sequence predicted to form a coiled-coil. In humans, 13 septins have been classified into four groups (I, II, III and IV) based on their amino acid sequences. The only structurally characterized filament described to date is formed by SEPT2-SEPT6-SEPT7, which reveals that the subunits interact through two different interfaces (G and NC). The structural determinants of correct filament assembly are poorly known, and this is limited by the complexity of purifying and crystallizing trimeric or tetrameric complexes. An alternative approach is to study a single filament interface (G or NC) on its own. Here, we aimed to study, using biophysical and structural approaches, the G interface formed between SEPT5 and SEPT8 to elucidate the factors relevant to determining its specificity. The GTPase domain of SEPT5 and SEPT8, were cloned into the bicistronic expression vector pET-Duet, co-expressed and co-purified. Studies to determine the oligomeric state and homogeneity of the complex were conducted using size exclusion chromatography, dynamic light scattering and analytical ultracentrifugation, revealing a monodisperse dimer for SEPT5-SEPT8(G). The complex elutes with an approximately equimolar mixture of bound nucleotides (GTP and GDP) whereas SEPT8(G) alone is shown to be unable to bind either. Furthermore, the complex has a greater thermostability than SEPT8(G), demonstrated by an increase of 5°C in Tm. In order to determine the structural determinants of specificity, crystallization trials were conducted and crystals of the SEPT5-SEPT8(G) complex were obtained, but these diffracted to only very low resolution. In the absence of a crystal structure, homology modeling was performed to analyze the potential G interfaces between different septin combinations. An interaction between characteristic amino acids (those which are unique to given septin group) was identified for the complex formed between group III septins (including SEPT5) and group II septins (including SEPT8). This interaction, between Phe131 (group II) and Thr19 (group III) may explain the specificity in the formation of a G interface between septins of these groups during filament formation and furthermore the importance of GTP bound to the group II septin. These observations allow us to propose for the first time a plausible explanation for relevance of the loss of catalytic activity by this septin group, an unexplained fact up until now. Mutation of the identified residues resulted in a change in the elution profile of the complex from the size exclusion column suggesting structural alterations in the mutants.
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Perez, Rodrigo Oliva. "Determinação da expressão da Ciclina G no câncer do reto." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5154/tde-19032007-130511/.
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Introdução: A identificação de mecanismos genéticos envolvidos no processo de carcinogênese do câncer colorretal levou ao surgimento de novas estratégias terapêuticas como a terapia gênica. Através do bloqueio ou estímulo de determinados alvos genéticos ou moleculares seria possível interromper o ciclo celular de células transformadas. Uma das estratégias sugeridas foi a utilização de seqüências anti-sense do gene da ciclina G que revelou resultados iniciais clínicos e experimentais promissores em diversas neoplasias, inclusive na colorretal. Assim seria esperado que a expressão da ciclina G estivesse freqüentemente alterada de maneira seletiva nas células do câncer colorretal quando comparado às células normais. Por estas razões, decidiu-se estudar a expressão da ciclina G em pacientes com câncer do reto. Métodos: Dados clínicos, epidemiológicos, anátomo-patológicos e de sobrevivência de 36 pacientes com câncer do reto foram obtidos e correlacionados com os resultados de expressão imunohistoquímica da ciclina G. O tecido neoplásico e normal distante da lesão primária foram submetidos a reação imunohistoquímica com anticorpo monoclonal anti-ciclina G e quantificados através de três métodos: (1) quantitativo, obtido a partir da contagem de células determinando a razão entre o número de células positivas e o número total de células contadas em 10 campos; (2) semi-quantitativo (cruzes), obtido a partir da pontuação em sistema de cruzes conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante; (3) semi-quantitativo (escore), obtido a partir da pontuação em sistema de escore (alto ou baixo) conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante. O estudo estatístico incluiu teste T de student, Qui-quadrado, exato de Fisher, teste t pareado, Wilcoxon, log-rank e curva ROC sendo considerados significativos quando o valor de p<0,05. Resultados: A expressão da ciclina G foi positiva em 76,5±30% da células contadas, com média de 3,2±1,1 cruzes e escore alto em 32 pacientes no tecido tumoral. No tecido normal dos pacientes a positividade foi de 42,2±27,4%, com média de 1,9±1,1 cruzes e escore alto em 16 casos. Quando comparados os tecidos tumoral e normal de cada paciente, o resultado tumor>normal foi obtido em 28 (77,8%) pacientes (quantitativa), 27 (75%) pacientes (semi-quantitativa/cruzes) e 18 (50%) pacientes (semi-quantitativa/escore). A diferença de expressão entre tecido tumoral e tecido normal maior que 10% apresentou correlação com ausência de metástases sistêmicas enquanto que a diferença maior que 38% apresentou correlação com a ausência de metástases linfonodais (área da curva 0,69 nos dois casos). Houve correlação entre o resultado tumor>normal e a ausência de metástases linfonodais quando o método de quantificação foi semi-quantitativo (cruzes e escore;p=0,02 e 0,04). Não houve correlação entre o resultado tumor>normal e as demais características. Não houve influência do resultado tumor>normal nas curvas de sobrevivência (3 anos). Conclusões: A expressão da ciclina G é maior no tecido neoplásico do câncer colorretal quando comparada ao tecido normal. Apesar disso, a expressão da ciclina G é raramente nula no tecido normal. A expressão de ciclina G tumor>normal esteve associada a ausência de metástases linfonodais quando mensurada através de métodos semi-quantitativos. Apesar disso, a expressão alterada da ciclina G não tem influência sobre sobrevivência precoce em pacientes com câncer do reto.<br>Introduction: Identification of genetic mechanisms involved in colorectal cancer carcinogenesis led to the development of new treatment strategies such as gene therapy. The aim of this strategy is to interrupt cell-cycle of transformed malignant cells by blocking or stimulating specific gene expression. Utilization of cyclin G antisense constructs has been suggested with clinical and experimental promising results in various neoplasias, including colorectal cancer. In this setting, one would expect that cyclin G would be selectively overexpressed in colorectal cancer cells as opposed to normal tissue. For this reason, we decided to study cyclin G expression in patients with rectal cancer. Methods: Clinical, epidemiological, pathological and survival data from 36 patients with rectal cancer was collected and correlated with Cyclin G immunohistochemical expression. Neoplastic and non-adjacent normal tissue were stained with monoclonal anti-Cyclin G antibody and quantified according to 3 different methods: (1) quantitative, obtained from cell count and determined by the ratio between positive counted cells and total number of counted cells observed in 10 microscopic fields; (2) semi-quantitative (crosses), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas; (3) semi-quantitative (score), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas. Statistical analysis included ROC curves, student\'s T, Chi-square, Fisher\'s exact, log rank, Wilcoxon, and paired t test. Significant differences were considered for p<0.05. Results: In tumor-tissue, positive Cyclin G expression was observed in 76.5±30% of counted cells, with a mean number of 3.2±1.1 crosses and high expression score in 32 patients (89%). In normal tissue, positive cyclin G expression was observed in 42.2±27.4% of counted cells, with a mean of 1.9±1.1 crossed and high expression score in 16 patients. When comparing tumor and normal tissue within each patient, a result of tumor>normal cyclin G expression was observed in 28 (77.8%) patients (quantitative method), 27 (75%) patients (semi-quantitative crosses) and 18(50%) patients (semi-quantitative score). A difference of cyclin G expression between tumor and normal tissue greater than 10% was associated with the absence of metastatic disease. A difference of cyclin G expression between tumor and normal tissue greater than 38% was associated with the absence of lymph node metastases (ROC curve area of 0.69 in both cases). There was significant association between cyclin G expression tumor>normal result and the absence of lymph node metastases when using semi-quantitative quantification methods (p=0.02 for crosses; p=0.04 for score). There was no association between cyclin G expression and other patient\'s characteristics or survival. Conclusion: Cyclin G expression is greater in tumor tissue when compared to normal tissue in patients with rectal cancer. However, cyclin G expression in normal tissue is rarely absent. Tumor>normal cyclin G expression is significantly associated with absence of lymph node metastases when quantified using semiquantitative methods. However, cyclin G expression had no influence in short-term survival.
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Memetzidis, Georgios. "Pharmacochimie de la tétrahydro-5, 6, 13, 13a 8H-dibenzo [a, g] quinolizine ou berbine." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37616245j.
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Kamel, Rehab. "Anticorps anti-récepteur 5-HT4 : importance physiopathologique et caractérisation pharmacologique." Strasbourg 1, 2005. http://www.theses.fr/2005STR13040.
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Les récepteurs couplés aux protéines G (RCPG) sont impliqués dans divers processus physiologiques. Le récepteur (R) 5-HT4 fait parti de la famille des RCPGS. L'implication des autoanticorps (autoAc) anti-R5-HT4 dans les symptômes du lupus néonatal (LN) spécialement le bloc auriculo-ventriculaire congénital (BAVc) fut démontrée par Eftekhari et coll. Ceci fut controversé par Buyon et coll. Nous avons démontré que cette divergence était due à des différences techniques. 16% des sérums de mères ayant des enfants atteints de BAVc ont montré une réactivité avec la seconde boucle extracellulaire (SBE) du R5-HT4 (peptide G21V). Malgré leur présence dans une minorité de mères ayant des enfants atteints de BAVc, les autoAc anti-R5-HT4 représentent un facteur de risque contribuant à la pathogenèse du BAVc. Pour comprendre le rôle du R5-HT4 dans le LN, nous avons produit des Ac polyclonaux de lapin dirigés contre 2 isoformes du récepteur afin d'étudier leur expression par immunofluorescence durant le développement embryonnaire de souris. Le récepteur ainsi que ses ARNm sont identifiés durant les étapes de développement précoces. Des femelles BALB/c ont été immunisées avec le G21V et accouplées. Des anomalies ont été observées chez les embryons dès le 12ème jour de gestation. Ceci suggère l'implication du R5-HT4 dans le LN quand la présence d'Ac anti-R coïncide avec l'expression du récepteur. Afin de pouvoir étudier la structure du paratope pathogène, nous avons isolé un Ac monoclonal dirigé contre le G21V. La reconnaissance du R5-HT4 par l'Ac a été démontrée par immunoempreinte et immunofluorescence. Les expériences de résonance plasmonique de surface ont démontré que l'Ac a une affinité de l'ordre du pM pour le G21V. L'Ac inhibe de façon compétitive la liaison du [3H]-GR113808 au R5-HT4. Il diminue le niveau basal de l'AMPc dans les cellules CHO exprimant le R5-HT4 et inhibe l'effet de la 5-HT. L'Ac représente un modulateur de forte affinité dirigé contre le R5-HT4<br>G protein-coupled receptors (GPCR) are involved in different physiologic processes. The 5-HT4 receptor (R) is a member of Gs PCR family. The role of anti-5-HT4 R autoantibodies (autoAb) in neonatal lupus (NL) symptoms especially the congenital heart block (CHB) has been demonstrated by Eftekhari et al. These results have been contradicted by Buyon et al. We have clarified that this discrepancy was due to technical differences in ELISA test. 16 % of mother's sera whose children have CHB showed reactivity against the second extracellular loop (SEL) of the 5-HT4 R (G21V peptide). Though 5-HT4 R autoAb are present in a minor subset of mothers whose children have CHB, they represent an additional risk factor which may contribute to the pathogenesis of disease. In order to understand the role of 5-HT4 R in NL, we have raised rabbit polyconal Ab against 2 isoforms of the receptor to study their expression during mouse embryonic development by immunofluorescence. The receptor as well as its mRNA has been identified during early development stages. BALB/c females have been immunised with G21V peptide and mated. Abnormalities have been observed among embryos starting from the 12th gestation day. These results suggest the involvement of 5-HT4 R in NL when the presence of anti-R Ab coincides with receptor expression. To study pathogenic paratope structure, we have isolated a monoclonal Ab directed against G21V peptide. The Ab recognised 5-HT4 R by immunoblotting and immunocytofluorescence. Surface plasmon resonance experiments showed that the Ab has pM affinity to G21V peptide. The Ab competitively inhibited [3H]GR113808 binding to 5-HT4 R. It showed an inverse agonist effect on the basal activity of CHO cells expressing 5-HT4 R and inhibited 5-HT effect. The Ab represents a high affinity modulator of 5-HT4 R
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Fischoeder, Arnim G. [Verfasser]. "Ablagerungsbildung durch Heizöl EL und 5% Heizöl EL-FAME-Blends bei der Verdampfung / Arnim G Fischoeder." Aachen : Shaker, 2007. http://d-nb.info/1170527132/34.
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Welsby, Philip J. "Pharmacological characterisation of the human 5-HTâ†1â†A receptor and its inhibitory G protein fusions." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366338.
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Park, Jung Hee. "Crystal structure of ligand-free G-protein-coupled receptor opsin." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16049.
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Rhodopsin ist als Sehpigment der Photorezeptorzellen einer der am aktivsten untersuchten GPCRs. Es besteht aus dem Apoprotein Opsin und dem inversen Agonisten 11-cis-Retinal. Der inaktivierende Ligand ist in der sieben Transmembran- Helix (TM)-Struktur des Rezeptors kovalent gebunden und muss durch Licht cis/trans-isomerisiert werden, um den Rezeptor zu aktivieren. Der aktivierte Rezep-tor katalysiert den Nukleotidaustausch im G-Protein und zerfällt innerhalb von Minuten in Opsin und all-trans-Retinal. Das visuelle Pigment wird dann durch erneute Beladung des Opsins mit 11-cis-Retinal wieder hergestellt. In der vorliegenden Arbeit wird die erfolgreiche Kristallisation des nativen Opsins aus der Stäbchenzelle der Rinderretina und die Bestimmung der Proteinstruktur bei 2.9 Å Auf-lösung dargestellt. Im Vergleich zur bekannten Struktur des inaktiven Rhodopsins zeigt Opsin deutliche Strukturänderungen in den konservierten E(D)RY und NPxxY(x)5,6F Regionen und in TM5-TM7. Auf der intrazellulären Seite ist TM6 ca. 6-7 Å nach außen gekippt, während die TM5 Helix verlängert und näher zu TM6 verschoben ist. Durch die strukturellen Änderungen, von denen einige einem aktiven GPCR Zustand zugeschrieben werden können, wird die leere Retinalbindungstasche reorganisiert, um zwei Öffnungen für Aus- und Eintritt von Retinal bereitzustellen. Die Struktur von Opsin liefert neue Erkenntnisse zur Bindung von hydrophoben Liganden an GPCRs, zur GPCR-Aktivierung und zur Signalübertragung auf das G-Protein.<br>Rhodopsin as the visual pigment in photoreceptor cells is one of the most actively studied GPCRs. It consists of the apoprotein opsin and the inverse agonist, 11-cis-retinal. The inactivating ligand is bound in the seven-transmembrane helix (TM) bundle and cis/trans-isomerized by light to activate the receptor. The active receptor state is capable of catalyzing nucleotide exchange in the G protein and decays within minutes into opsin and all-trans-retinal. The visual pigment is then restored by reloading opsin with new 11-cis-retinal. In the present work, the successful crystallization of native opsin from bovine retinal rod cells and determination of the protein structure to 2.9 Å resolution is presented. Compared with the known structure of inactive rhodopsin, opsin displays prominent structural changes in the conserved E(D)RY and NPxxY(x)5,6F regions and TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 Å, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, of which some are attributed to an active GPCR state, reorganize the empty retinal binding pocket to disclose two openings for exit and entry of retinal. The opsin structure thus sheds new light on binding of hydrophobic ligands to GPCRs, GPCR activation and signal transfer to the G protein.
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Prado, Fernanda Manso. "Hidroperóxido de timina como fonte biológica de oxigênio molecular singlete [O2 (1Δg)]." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-20072010-162617/.
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A oxidação do DNA por espécies reativas de oxigênio, como o oxigênio molecular singlete [O2 (1Δg)] , pode estar relacionada ao aparecimento de mutações e ao desenvolvimento de doenças. O O2 (1Δg) pode ser gerado biologicamente por reação de fotossensibilização, pela reação de H2O2 e HOCl e pela decomposição de peróxidos orgânicos contendo hidrogênio alfa (α-ROOH), na presença de metais de transição (Fe2+, Cu2+) ou HOCl. A decomposição de α-ROOH, como hidroperóxidos de lipídeos ou proteínas na presença de metais de transição, pode gerar O2 (1Δg) via mecanismo de Russell. Neste mecanismo, a oxidação de α -ROOH gera radicais peroxila, que podem reagir entre si, formando um intermediário tetraóxido linear. Este intermediário tetraóxido linear pode decompor através de um mecanismo cíclico e produzir O2 (1Δg), um álcool e um composto carbonílico. Como a decomposição de α-ROOH pelo mecanismo de Russell pode ser uma importante fonte biológica de O2 (1Δg) decidimos investigar se o α-hidroperóxido de timina, 5-(hidroperoximetil)uracil (5-HMPU), poderia gerar esta espécie reativa na presença de metais (Ce4+, Fe2+, Cu2+) e HOCl. Outro objetivo foi avaliar os efeitos oxidativos, em DNA plasmidial (pBR322), da decomposição de 5-HPMU na presença de Cu2+. A geração de O2 (1Δg) na reação de 5-HPMU e Ce4+ ou HOCl foi demonstrada por meio do monitoramento da emissão de luz monomolecular de O2 (1Δg) na região do infravermelho próximo (IR-próximo, λ = 1270 nm) e bimolecular na região do visível (λ = 634 e 703 nm). A aquisição do espectro de emissão de O2 (1Δg) forneceu evidências inequívocas da geração desta espécie reativa na reação de 5-HPMU e Ce4+ ou HOCl. Além disto, a formação de O2 (1Δg) na reação de 5-HPMU e Fe2+, Cu2+ ou HOCl foi demonstrada através da captação química de O2 (1Δg) utilizando 9,10- divinilsulfonatoantraceno (AVS) e detecção por HPLC/MS/MS do endoperóxido (AVSO2) formado. A detecção por HPLC/MS/MS dos produtos de decomposição de 5-HPMU, 5- (hidroximetil)uracila (5-HMU) e 5-formiluracila (5-FoU), reforçaram a hipótese de geração de O2 (1Δg) pelo mecanismo de Russell. A análise dos resultados da incubação de pBR322, 5-HPMU e crescente concentração de Cu2+ mostraram o aumento da forma circular aberta (OC), indicando a formação de quebra de fita simples do DNA, provavelmente proveniente da presença dos radicais peroxila e alcoxila de 5-HPMU. Já a utilização das enzimas de reparo FPG e NTH na incubação de pBR322, 5-HPMU e Cu2+ forneceu evidências da formação preferencial de purinas oxidadas, especialmente de 2’-desoxiguanosina (dGuo). O aumento significativo da forma OC na presença de FPG indicou a formação de 8-oxo-2’-desoxiguanosina, resultante da oxidação da dGuo por O2 (1Δg) e/ou pelos radicais derivados de 5-HPMU. Podemos concluir que 5-HPMU pode ser uma importante fonte biológica de O2 (1Δg) . Além disto, a presença de 5-HPMU pode levar a propagação dos danos oxidativos no DNA, pois sua decomposição pode gerar radicais peroxila e alcoxila<br>Oxidation of DNA by singlet molecular oxygen O2 (1Δg) can be involved in the development of mutations and diseases. In vivo, O2 (1Δg) can be generated by photosensitization reaction, H2O2 and HOCl reaction and decomposition of organic hydroperoxides with α-hydrogen (α-ROOH) in the presence of metal ions (Fe2+, Cu2+) or HOCl. The α-ROOH decomposition, such as lipid or protein hydroperoxides in the presence of metal ions or HOCl can generate O2 (1Δg) by Russell mechanism. In this mechanism, the self-reaction of peroxyl radicals generates a linear tetraoxide intermediate that decomposes to O2 (1Δg) , an alcohol and an aldehyde. Therefore, the purpose of this work is to investigate if O2 (1Δg) can be generated by α-thymine hydroperoxide, 5- (hydroperoxymethyl)uracil (5-HPMU) in the presence of Ce4+, Fe2+, Cu2+ or HOCl. Another purpose is to study base modification and strand breaks formation in plasmid DNA (pBR322) by 5-HPMU decomposition in the presence of Cu2+. The generation of O2 (1Δg) in the reaction of 5- HPMU and Ce4+ or HOCl was monitored by monomol light emission in the near-infrared region (NIR, λ = 1270 nm) and dimol light emission in the visible region (λ = 634 e 703 nm). The generation of O2 (1Δg) during the reaction of 5-HPMU and Ce4+ or HOCl was confirmed by acquisition of the light emission spectrum in the NIR. Furthermore, the generation of O2 (1Δg) produced by 5-HPMU and Fe2+, Cu2+ or HOCl was also confirmed by chemical trapping using anthracene-9,10-divinylsulfonate (AVS) and HPLC/MS/MS detection of the corresponding endoperoxide (AVSO2). The detection by HPLC/MS/MS of 5-(hydroxymethyl)uracil (5-HMU) and 5-formyluracil (5-FoU), two 5-HPMU decomposition products, support the Russell mechanism. Plasmid results from pBR322, 5-HPMU and Cu2+ reaction showed formation of DNA open circular form (OC), probably produced by 5-HPMU peroxyl and alkoxyl radicals. Additionally, the reaction of pBR322, 5-HPMU and Cu2+ following by Fpg and NTH enzyme treatment demonstrated evidences of purine modification, especially 2’-deoxyguanosine (dGuo). The use of FPG enzyme indicated the formation of 8-oxo-7,8-dihydro-2’-deoxyguanosine, a dGuo oxidation product formed by O2 (1Δg) and/or 5-HPMU peroxyl and alkoxyl radicals. We can conclude that 5-HPMU can be a biological source of O2 (1Δg)] and 5-HPMU decomposition can lead to an enhancing of DNA oxidative damage by 5-HPMU peroxyl and alkoxyl radicals formation
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Gatehouse, Michelle. "Desensitisation of the pituitary vasopressin receptor : development of a model system to assess involvement of G protein-coupled receptor kinase 5." Thesis, University of Canterbury. School of Biological Sciences, 2008. http://hdl.handle.net/10092/2627.
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The hypothalamic peptide arginine vasopressin (AVP) is an important regulator of adrenocorticotropin (ACTH) release from the anterior pituitary. AVP stimulates ACTH secretion from corticotroph cells by activating the pituitary vasopressin receptor (V1b-R), a member of the G protein-coupled receptor (GPCR) family. In vitro, repeated stimulus of anterior pituitary cells with AVP results in rapid desensitisation. The aim of this research was to develop methods needed to use RNA interference (RNAi) to investigate the role of G protein-coupled receptor kinase 5 (GRK5) in this desensitisation process. This required the development of a model system using human embryonic kidney (HEK) 293 cells transfected with the pituitary vasopressin receptor, V1b-R. AVP binding to the V1bR activates the phosphoinositide signalling pathway, leading to production of inositol phosphates (IPs), which can be measured following radiolabelling of cells with myo-[³H]inositol. Stimulation of V1b-R-transfected cells for 15 min with AVP (100nM) increased IP production to 235.5 ± 23.4 % (n=3, p<0.02) of that seen in un-stimulated control cells. Following a 5 minute pre-treatment with 5nM VP, the IP response to stimulation with 100nM VP for 15 min was reduced to 62.8 ± 9.1 % (n=4, p<0.02) of that seen in control cells that were not pre-treated. These data indicate that AVP-desensitisation can be induced and measured in V1bR-transfected HEK293 cells following a brief pre-treatment with a physiological concentration of AVP. This model system will enable RNAi to be used to investigate the role of GRK5 in AVP-desensitisation. When using RNAi, it is essential to establish that the effects observed are the result of small interfering RNA (siRNA) specific degradation of the target mRNA. Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of GRK5 at the mRNA level in HEK293 cells. Human GRK5 mRNA was amplified using qRT-PCR with GRK5 specific primers, providing confirmation that GRK5 is expressed endogenously in HEK293 cells. GRK5 expression studies were carried out to evaluate whether the qRT-PCR methods developed would be suitable to measure knockdown of GRK5 mRNA using RNAi. These experiments were also designed to assess the impact of HEK293 cell culture methods on expression of GRK5. Expression of GRK5 did not vary with passage number (2-26 passages). The GRK5 expression in HEK293 cells that were maintained in culture for 5 days (grown to a confluence of approximately 100%) was 7.4 ± 0.9 fold greater (n=2, p<0.05) than for cells cultured for 3 days (grown to a confluence of approximately 65%). These data indicate that GRK5 expression is affected by HEK293 culture conditions. Furthermore, the results demonstrated that a significant difference in GRK5 expression could be measured in HEK293 cells using qRT-PCR. Therefore the results reported in this thesis provide the basis for future studies utilising RNAi to investigate mechanisms underlying V1b-R desensitisation.
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Aguiar, André Andrade de. "Avaliação da microbiota bucal em pacientes sob uso crônico de penicilina G benzatina." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-24092009-171538/.
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A Febre Reumática, complicação tardia de uma infecção de orofaringe causada pelo Streptococcus pyogenes (estreptococo -hemolítico do grupo A de Lancefield), tem como conseqüência a Cardiopatia Reumática, explicada pelo mimetismo molecular entre proteínas cardíacas humanas e a associação de proteínas e carboidratos da membrana do S. pyogenes. A profilaxia secundária com a PGB 1.200.000 UI IM propõe-se a evitar novos surtos, sendo administrada em intervalos de vinte e um dias nos países com alto índice de estreptococcia. A lesão valvar predispõe à Endocardite Infecciosa, que resulta de bacteriemias causadas por focos infecciosos de origem bucal em cerca de 40% dos casos. Os Streptococcus Viridans constituem o grupo mais comumente encontrado nas Endocardites Infecciosas, em especial os Streptococcus sanguinis e Streptococcus oralis. O efeito do uso crônico da PGB não foi estudado com especificidade para essa microbiota. Assim, foi avaliada, qualitativa e quantitativamente, a microbiota bucal de 100 pacientes, aos 7 e 21 dias, após profilaxia secundária para a Febre Reumática com a PGB 1.200.000 UI IM e comparada com a de 100 pacientes portadores de doença arterial coronariana sem antecedentes de Febre Reumática. As espécies avaliadas foram divididas em S. sanguinis, S. oralis e outras espécies de Streptococcus Viridans Foram coletadas amostras de saliva pela mastigação de goma de parafina e transportadas em meio VMGA II S. As culturas foram semeadas em ágar Columbia CNA com 5% de sangue desfibrinado puro de carneiro com acréscimo de penicilina G. e incubadas a 35ºC em estufa de CO2 por 72 horas. As colônias sugestivas de Streptococcus foram submetidas a testes bioquímicos para confirmação de gênero e espécie. A concentração inibitória mínima foi determinada pelo método Etest e interpretada segundo os padrões do Clinical and Laboratory Standards Institute. Não houve diferença quanto à presença do S. sanguinis nos grupos estudados (P=0,40). O S. oralis prevaleceu aos 7 dias de PGB em relação ao grupo controle (P=0,01). Quanto à identificação de outras espécies, houve maior número de cepas nos pacientes do grupo controle quando comparados aos do grupo de estudo aos 7 e 21 dias de PGB (P<0,001). Os números de UFC/ml de S. sanguinis, S. oralis e de outras espécies foram comparados entre os grupos e não houve diferença entre eles (P=0,96; P=0,60 e P=0,77; respectivamente). Quanto às CIM do S. sanguinis e do S. oralis, não houve diferença entre os grupos (P=0,79 e P=0,13; respectivamente). Todos os testes estatísticos foram realizados em um nível de significância de 5%. Concluiu-se que o S. oralis prevaleceu aos 7 dias de PGB 1.200.000 UI IM; os Streptococcus Viridans de outras espécies prevaleceram no grupo controle; o número de UFC/mL de saliva não diferiu nos grupos estudados, a susceptibilidade dos S. sanguinis e S. oralis à penicilina G não foi alterada pela ação da PGB 1.200.000 UI IM a cada 21 dias e, por fim, a PGB não provocou reações de hipersensibilidade em nenhum paciente do estudo<br>Rheumatic fever is the result of a Streptococcus pyogenes (group A -hemolytic Streptococcus) infection of the upper respiratory tract. Rheumatic heart disease is a rheumatic fever consequence and is elucidated by the molecular mimicry between human cardiac proteins and group A streptococcal proteins and carbohydrates association. The secondary prophylaxis with 1,200,000 U BPG every three weeks is used for prevention of recurrent rheumatic fever in developing countries. Valvar defects are a risk for infective endocarditis which is resulted of bacteriemia caused for oral infectious focuses in 40% of cases. Viridans streptococci are the predominant group recovered in infective endocarditis, specially Streptococcus sanguinis and Streptococcus oralis. The effect of chronic BPG wasnt studied with specificity to these pathogens yet. Therefore, the oral microbiota was evaluated, qualitatively and quantitatively, at 7 and 21 days after secondary prophylaxis with BPG to rheumatic fever (study group), in a hundred patients and in comparison to another hundred patients with coronary heart disease who never acquired rheumatic fever (control group). The species evaluated were divided in S. sanguinis, S. oralis and another Streptococcus species. It was collected samples of chewing-stimulated saliva (1ml) and transported in VMGA II S medium. The samples were cultured in pure and with penicillin G 5% sheep blood Columbia ágar (CNA), incubated for 72 hours in an atmosphere containing 5% CO2 at 35ºC. The strains that were suggestive to Streptococcus were identified by biochemical tests to confirm bacteria species and genus. Minimal inhibitory concentration was determined by Etest method and interpreted in accordance to Clinical and Laboratory Standards Institute. The results showed that there was no difference in S. sanguinis presence in all groups (P=0.40). S. oralis prevailed in 7 days BPG group in comparison to control group (P=0.01). The control group showed the highest number of others species in comparison to 7 and 21 days BPG (P<0.001). CFU/ml numbers of S. sanguinis, S. oralis and other species strains were compared in 7 and 21 days BPG to control group and there was no difference among themselves (P=0.96, P=0.60 and P=0.77; respectively). There was no difference in S. sanguinis and S. oralis MICs among the study and control groups (P=0.79 and P=0.13). All statistic tests were done at 5% significance level. It was concluded that S. oralis prevailed in 7 days BPG group in comparison to control group; other species of Viridans streptococci prevailed in control group. The number of CFU/mL did not differ in both studied groups; the penicillin susceptibility of S. sanguinis and S. oralis did not change by BPG every three weeks and, by the end, it was not observed hypersensitivity reactions to penicillin in neither of the patients of this study
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Schwanzer, Petra. "Untersuchung des C(-1019)G 5-HT1A-Promotorpolymorphismus an einer Patientengruppe mit Persönlichkeitsstörungen nach DSM-IV-TR." kostenfrei, 2008. http://nbn-resolving.de/urn/resolver.pl?urn=nbn:de:bvb:20-opus-27373.
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Dassah, MaryAnn. "Identifying and characterizing suppressors of intronic +1 G mutations and cryptic 5' splice sites in Caenorhabditis elegans /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2008. http://uclibs.org/PID/11984.
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Barthet, Gaël. "Régulation des voies de signalisation dépendante et indépendante des protéines G activées par le récepteur 5-HT4." Montpellier 1, 2007. http://www.theses.fr/2007MON1T014.
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Les récepteurs à 7 domaines transmembranaires (R-7TM) ont longtemps été caractérisés par leur aptitude à activer les protéines G et à générer la production de seconds messagers. Ce type de signalisation est régulé au cours du processus de désensibilisation qui implique les GRK (G protein-coupled receptors kinases) et les β-arrestines. Récemment, ces dernières ont été mises en évidence dans l'activation indépendante des protéines G des ERK1/2 (extracellular-related kinases 1/2) par certains R-7TM. En utilisant le récepteur 5-HT4 (R-5-HT4) comme modèle de R-7TM, nous avons pu observer une régulation de sa signalisation Gs/AMPc par la GRK2 qui ne fait pas intervenir son activité kinase. Cette désensibilisation est également distincte de l'endocytose consécutive au recrutement des β-arrestines par le récepteur. Nous avons également mis en évidence une activation des ERK1/2 par le R-5-HT4 via la tyrosine kinase Src, à la fois indépendante des protéines G et des β-arrestines. Cette signalisation est régulée de façon autonome par une autre GRK, la GRK5, et la β-arrestine1 sous sa forme phosphorylée. Cette régulation est également indépendante de l'endocytose du R-5-HT4 puisqu'au contraire, l'internalisation du R-5-HT4 est bloquée au cours de ce processus. Des protéines communément impliquées dans la régulation de la signalisation dépendante des protéines G sont donc également capables de réguler des signalisations indépendantes des protéines G, bien que les événements moléculaires soient distincts.
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Quinn, Jeffrey Alan. "Requirement of integrin [alpha]5[beta]1 and tyrosine phosphorylation of SHC for prohb-EGF release by GPR30, a seven transmembrane receptor for estrogen /." View online ; access limited to URI, 2006. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3225328.
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Eberley, William Arthur. "Hydrogen-bonding residues at the asymmetric dimer site of tRNAHis guanylyltransferase and their contributions to oligomeric state and activity." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306943230.
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Sheffler, Douglas James. "The Regulation of G Protein-Coupled Receptor (GPCR) Signal Transduction by p90 Ribosomal S6 Kinase 2 (RSK2)." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1130777469.
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Li, Xiao Yu 1973. "Beta-adrenoreceptor mediated atria specific up-regulation of regulator of G-protein signaling (RGS) 5 in rodent atrium." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80318.
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Due to a 195 fold cardiac overexpression of beta2-Adrenoreceptor (beta2AR), the hearts of transgenic TG4 mice are chronically overstimulated and, indeed, show little stimulatory response to further betaAR agonists. Previous investigations had suggested that signaling from the overexpressed beta 2ARs was dampened in the atria of TG4 mice. Regulators of G-protein Signaling (RGSs) are a family of negative regulators of G-Protein Coupled Receptor (GPCR) signaling that are frequently induced by GPCR stimulation. Using an RT-PCR based strategy, we have identified RGS5 as being a candidate RGS that is up-regulated in the atria of TG4 mice. Northern blot analysis demonstrated that RGS5 levels are 2--3 fold higher in the atria of TG4 mice when compared to their non-transgenic littermates. To further characterize RGS5 expression, we generated an RGS5 specific anti-serum. Results indicate that RGS5 is a housekeeping RGS in the heart and in skeletal muscle but its betaAR mediated induction in the atria suggests that it also has a highly specialized function.
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Jean-Baptiste, Gaël. "Analysis of regulators of G protein signaling (RGS) 5 regulation and lysophosphatidic acid (LPA) signaling in muscle cells." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98734.
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G protein-coupled Receptor (GPCR) signalling pathways are essential for all aspects of cell and organ physiology and the involved proteins work together to transmit signals across the plasma membrane. This process is highly regulated by a number of proteins including RGS (Regulators of G protein Signalling) proteins, which serve as GTPase-activating proteins for the Galpha subunit of heterotrimeric G proteins. Previous work in our lab has identified RGS5 as being expressed in the heart as well as being up regulated in the atria but not the ventricules of transgenic (TG4) mice that have a 195-fold cardiac increase in beta2AR levels. To further characterize RGS5 expression, an RGS5 specific antiserum was generated. Western Blot analysis of a panel of rat tissues demonstrated that basal expression of RGS5 protein was confined to the heart and skeletal muscle tissues, as well as the respective cell lines HL-1 and C2C12. Although GPCRs and RGSs are actively being studied in the heart, little is known regarding the role of GPCRs and RGSs in skeletal muscle. Moreover, several conditions such as atrophy, which is characterized by apoptosis of the muscle fibers, are associated with GPCRs in the skeletal muscle. As a prelude to investigating the role of RGS5 in the regulation of GPCR signaling, we identified a number of GPCRs that are able to signal via ERK1/2 in C2C12 skeletal muscle cells. The signalling and responses induced by one GPCR agonist, Lysophosphatidic Acid (LPA), a potent inducer of survival and apoptosis, were analyzed in C2C12 skeletal muscle cells.
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Anderson, Carisa Claudia. "Ultraviolet light mutagenesis of the tyrA gene in Escherichia coli produces T - G transversions at 5'-CT sites /." Available to subscribers only, 2005. http://proquest.umi.com/pqdweb?did=1083540061&sid=7&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Thesis (M.S.)--Southern Illinois University Carbondale, 2005.<br>"Department of Molecular Biology, Microbiology and Biochemisty." Includes bibliographical references (leaves 65-72). Also available online.
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Moorhouse, Adam Donald. "Applications of Click Chemistry Towards Anti-Cancer Drug Discovery : G-quadruplex ligands, Azide Synthesis and LDH-5 Inhibitors." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517786.
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Vanik, Hans G. [Verfasser]. "Thermomechanische Behandlung von endabmessungsnah gegossenen und direkt gewalzten Stahlbändern bei Gießdicken von 5-20 mm / Hans G Vanik." Aachen : Shaker, 2003. http://d-nb.info/1179032578/34.
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Lee, Sang C., Jack Zhang, Josh Strom, et al. "G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress." AMER SOC MICROBIOLOGY, 2017. http://hdl.handle.net/10150/622753.
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Inhibition of protein synthesis serves as a general measure of cellular consequences of chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of the NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in the 5' untranslated region (UTR) of NRF2 mRNA, as measured by circular dichroism, nuclear magnetic resonance, and dimethylsulfate footprinting analyses. Such a structure is important for 5'-UTR activity, since its removal by sequence mutation eliminated H2O2-induced activation of the NRF2 5' UTR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics revealed elongation factor 1 alpha (EF1a) as a protein binding to the G-quadruplex sequence. Cells responded to H2O2 treatment by increasing the EF1a protein association with NRF2 mRNA, as measured by RNA-protein interaction assays. The EF1a interaction with small and large subunits of ribosomes did not appear to change due to H2O2 treatment, nor did post translational modifications, as measured by two-dimensional (2-D) Western blot analysis. Since NRF2 encodes a transcription factor essential for protection against tissue injury, our data have revealed a novel mechanism of cellular defense involving de novo NRF2 protein translation governed by the EF1a interaction with the G-quadruplex in the NRF2 5' UTR during oxidative stress.
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Castillo, Miguel Angel Zuñiga. "Expressão do antígeno leucocitário humano G, interleucina 10 e macrófagos M2 no melanoma lentiginoso acral." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-31072017-125708/.
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INTRODUÇÃO: O melanoma lentiginoso acral (MLA) é um subtipo pouco frequente do melanoma cutâneo que geralmente apresenta evolução desfavorável e agressiva. Os mecanismos patogenéticos relacionados a essa evolução clínica não são totalmente conhecidos. Atualmente, estudos da literatura enfocam os mecanismos de evasão imunológica relacionados ao microambiente do melanoma, uma vez que os mesmos podem inibir a resposta imune antitumoral permitindo a progressão da doença. A expressão do Antígeno Leucocitário Humano G (HLA-G) e da Interleucina 10 (IL-10) e os macrófagos M2 (MM2) do microambiente tumoral são estratégias de evasão imune desenvolvidas por algumas neoplasias. Esses fatores, entretanto, não têm sido estudados especificamente no MLA. OBJETIVOS: Com o propósito de verificar se a expressão tumoral do HLA-G, IL-10 e a população de MM2 no microambiente tumoral estão relacionados com as características histopatológicas preditivas de pior comportamento biológico do melanoma e o evento de metástase, fez-se a comparação desses marcadores e de MM2 entre grupos de MLA e de melanoma extensivo superficial (MES). MÉTODOS: A casuística estudada compreendeu 67 espécimes de MLAs e 67 de MESs. Os tumores foram classificados de acordo com sua espessura, ulceração, presença de mitoses e associação com metástases. Fez-se a demonstração da expressão do HLA-G, IL-10 e de MM2 (CD163+ e CD206+) por técnica de imuno-histoquímica. A expressão (fração de área tumoral imunomarcada) do HLA-G e IL-10, assim como o número de MM2 por unidade de área do microambiente intra e peritumoral foram comparados entre os grupos de tumores classificados como acima mencionado, utilizando-se os testes de Kruskal-Wallis e Wilcoxon. Verificou-se a correlação entre os marcadores HLA-G e IL-10 e entre CD163 e CD206 pelo teste de correlação de Pearson. Fez-se um modelo de regressão logística binária no qual foram incluídas incialmente todas as variáveis do estudo e sua interação com o evento presença de metástase. RESULTADOS: A expressão do HLA-G e IL-10 tumoral, assim como o número de MM2 da região intra e peritumoral dos espécimes de MLA foi maior que nos de MES (p < 0,05). Houve correlação positiva entre a expressão do HLA-G e IL-10, assim como entre o número de MM2 marcados por CD163 e CD206. No modelo de regressão logística binária, a variável número de macrófagos imunomarcados pelo anticorpo CD206 da região intratumoral mostrou-se significativa e relacionada com o evento metástase. CONCLUSÕES: As moléculas imunorreguladoras HLA-G e IL-10 expressas pelas células neoplásicas, assim como o número elevado de MM2 do microambiente tumoral devem ser considerados fatores envolvidos no comportamento biológico mais agressivo do MLA<br>BACKGROUND: Acral lentiginous melanoma (ALM) is an uncommon cutaneous tumor that usually has an aggressive behavior and results in an unfavorable prognosis. The pathogenic mechanism related to the clinical evolution remains unknown. Currently, evasion mechanisms related to the melanoma microenvironment, which can inhibit the anti-tumor immune response allowing disease progression, are the focus of numerous studies. The expression of human leukocyte antigen-G (HLA-G), Interleukin- 10 (IL-10) and M2-Macrophages (MM2) at the tumor site represents one of these immunosuppressive strategies developed for some neoplasms. However, those factors have not been studied specifically in ALM. OBJECTIVES: In order to verify if HLAG and IL-10 tumoral expression as well as MM2 population in the melanoma microenvironment are related to the histopathological features predictive of unfavorable prognosis in melanoma and metastasis, we compared those markers and cells between ALM and superficial spreading melanoma (SSM) groups. METHODS: We analyzed 67 ALM and 67 SSM cases. The tumors were classified in groups according thickness, ulceration, mitosis and metastasis. HLA-G, IL-10 and MM2 (CD163+ and CD206+) expression were evaluated using immunohistochemistry. The expression (tumoral positive area fraction) of HLA-G and IL-10, as well as the number of MM2 in the intratumoral and peritumoral area was compared between the groups of melanomas using Kruskal-Wallis and Wilcoxon\'s tests. The Pearson\'s test was used to establish the correlation between HLA-G and IL-10, as well as between CD163 and CD206. Also, a binary logistic regression model was used to analyze all variables in relation to metastasis. RESULTS: HLA-G and IL-10 tumoral expression as well as the number of MM2 in the intratumoral and peritumoral area was increased in ALM compared with SSM (p < 0.05). There was positive correlation between HLA-G and IL-10 tumoral expression, as well as between the number of MM2 marked by CD163 and CD206. In the binary logistic regression model, the MM2 CD206+ of the intratumoral area was significantly associated with metastasis. CONCLUSIONS: The HLA-G and IL-10 melanoma expression likewise the high number of MM2 in the tumoral microenvironment must be considered as features associated with the increased aggressiveness of the ALM
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Troppmann, Britta, Sabine Balfanz, Arnd Baumann, and Wolfgang Blenau. "Inverse agonist and neutral antagonist actions of synthetic compounds at an insect 5-HT1 receptor." Universität Potsdam, 2010. http://opus.kobv.de/ubp/texte_eingeschraenkt_verlag/2010/4434/.
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Background and purpose:
5-Hydroxytryptamine (5-HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5-HT1 receptor of an insect model for neurobiology, physiology and pharmacology.
Experimental approach:
A cDNA encoding for the Periplaneta americana 5-HT1 receptor was amplified from brain cDNA. The receptor was stably expressed in HEK 293 cells, and the functional and pharmacological properties were determined in cAMP assays. Receptor distribution was investigated by RT-PCR and by immunocytochemistry using an affinity-purified polyclonal antiserum.
Key results:
The P. americana 5-HT1 receptor (Pea5-HT1) shares pronounced sequence and functional similarity with mammalian 5-HT1 receptors. Activation with 5-HT reduced adenylyl cyclase activity in a dose-dependent manner. Pea5-HT1 was expressed as a constitutively active receptor with methiothepin acting as a neutral antagonist, and WAY 100635 as an inverse agonist. Receptor mRNA was present in various tissues including brain, salivary glands and midgut. Receptor-specific antibodies showed that the native protein was expressed in a glycosylated form in membrane samples of brain and salivary glands.
Conclusions and implications:
This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5-HT1 receptor. The results presented here should facilitate further analyses of 5-HT1 receptors in mediating central and peripheral effects of 5-HT in insects.
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Rossi, Dania V. "Regional differences in the regulation of 5-HT₁A receptor function at the level of 5-HT₁A receptor-G protein interaction following chronic antidepressant treatment : a dissertation /." San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1428839281&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Werner, Franziska [Verfasser], G. [Akademischer Betreuer] Fischer, J. [Akademischer Betreuer] Neumann, and F. U. [Akademischer Betreuer] Müller. "Substrate und Bedeutung der Protein-Phosphatase 5 im Säugetierherzen / Franziska Werner. Betreuer: G. Fischer ; J. Neumann ; F. U. Müller." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2010. http://d-nb.info/1025011066/34.
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Blumrath, Kira. "Der Stammzellmarker LGR5 (Leucine-Rich Repeat G-protein Coupled Receptor 5) übernimmt keine tumortreibende Funktion in der kolorektalen Karzinogenese." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-177265.
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Maragno, Luciana. "Caracterização da resposta autoimune humoral e do perfil imuno-histopatológico das lesões cutâneas do couro cabeludo dos doentes de pênfigos foliáceo e vulgar." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-06122016-154414/.
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INTRODUÇÃO: Pênfigo é um grupo de doenças bolhosas, autoimunes, intraepidérmicas, mediadas por autoanticorpos, sobretudo da classe IgG, direcionados a desmogleínas (Dsg) 1 e 3, caracterizadas pela acantólise, ou seja, perda de adesão entre os queratinócitos, sendo o pênfigo foliáceo (PF) e vulgar (PV) as principais formas. O acometimento do couro cabeludo nestes doentes é frequente e geralmente relacionado à evolução crônica e recalcitrante, apesar do tratamento instituído. OBJETIVOS: Caracterizar as subclasses de IgG circulantes e in situ em doentes com diagnóstico de pênfigo, foliáceo e vulgar, com acometimento de couro cabeludo e correlacionar esta forma de apresentação clínica com manifestações não usuais destas dermatoses. MÉTODOS: Trinta e oito doentes com diagnóstico de pênfigo foliáceo (n=20) e vulgar (n=18), com lesões no couro cabeludo foram incluídos neste estudo. Todos foram acompanhados no ambulatório de doenças bolhosas autoimunes do Hospital das Clínicas FMUSP, e submetidos a avaliação laboratorial: exame anátomo-patológico de lesão no couro cabeludo, imunofluorescência direta (IFD) de área perilesional, com IgG total e subclasses de IgG (IgG1, IgG2, IgG3 e IgG4), imunofluorescência indireta (IFI), com IgG total e ELISA para Dsg 1 e 3. RESULTADOS: Grupo PF: Entre os doentes com PF (=20), dois apresentavam a forma clínica localizada e 18, a forma generalizada. Acantólise com clivagem subcórnea foi observada em 16 de 20 amostras. Na IFD, depósitos de IgG e C3, intercelulares, intraepidérmicos foram encontrados em 19 deles; entretanto, apenas sete entre os 20 apresentaram fluorescência nos folículos pilosos (FP) nas amostras estudadas. Considerando as subclasses de IgG, observou-se IgG4 isolada em 16 espécimes e, associada a IgG1, em sete. Fluorescência específica, às custas de IgG1 e IgG4 no FP foi detectada em 16 das 20 amostras. A IFI foi positiva para IgG total em 19 pacientes do grupo estudado, sendo a média dos títulos de 1:640. O ELISA foi positivo para Dsg-1 em 18 indivíduos, e um paciente apresentou reatividade contra Dsg-1 e -3. Grupo PV: Neste grupo, 16 doentes apresentavam acometimento mucocutâneo e apenas 2, lesões cutâneas exclusivas. Na histopatologia, acantólise com clivagem suprabasal foi observada em 17 das amostras estudadas. Todos os participantes deste grupo apresentaram depósitos de IgG e C3, intercelulares e intraepidérmicos na IFD com IgG total, sendo que em 11 esta fluorescência esteve também presente nos FP. No estudo das subclasses de IgG na IFD, 13 entre 18 doentes apresentaram deposição de IgG4 isolada e 5, do mesmo grupo, apresentaram IgG1 e IgG4, todos com fluorescência nos FP. A IFI foi positiva em todos os participantes do grupo PV, com titulação média de 1:160. Através do ELISA, observou-se reatividade para Dsg-1 e -3 em 12 doentes com PV, dois apresentaram anticorpos apenas contra Dsg-3 e quatro pacientes mostraram reatividade apenas contra Dsg-1. Por fim, o fenômeno de epitope spreading (ES) foi observado em quatro doentes acompanhados neste período: três evoluíram de PV para PF e apenas um se converteu de PF para PV. CONCLUSÕES: O acometimento do couro cabeludo no pênfigo esteve relacionado com evoluções longas da doença (média de 7 anos e 2 meses) e pode estar associado a achados clínicos não usuais, tais como paroníquia e lesões umbilicais. Depósitos de IgG1 e IgG4 intercelulares, intraepidérmicos em lesões de couro cabeludo foram os principais achados do estudo, e não apresentaram relação com a atividade da doença. A presença de anticorpos circulantes contra Dsg-1 e Dsg-3 também predominou neste grupo de pacientes; entretanto, novos antígenos poderão ser identificados<br>INTRODUCTION: Pemphigus is an intraepidermal blistering disease with IgG autoantibodies (mostly IgG4) against desmogleins (Dsg) 1 and 3, resulting in acantholysis. Pemphigus foliaceus (PF) and vulgaris (PV) are the main forms of this group of disease. Scalp involvement may occur and is recalcitrant to treatment. OBJECTIVES: 1) To characterize the circulating and in situ IgG profile of scalp lesions in patients with pemphigus foliaceus and vulgaris; 2) To correlate the scalp involvement with unusual clinical manifestations. METHODS: Thirty-eight adults diagnosed as pemphigus (PF=20, PV=18), with scalp involvement were assessed. Laboratory evaluation included histopathology (HP) of scalp lesions, direct immunofluorescence (DIF) IgG and subclasses, indirect immunofluorescence (IIF) with total IgG, and ELISA (Enzyme linked immunosorbent assay, Dsg-1 and Dsg-3). RESULTS: PF patients (n=20) were characterized as localized (2/20) and generalized (18/20). Laboratory findings showed: HP: subcorneal cleavage with acantholysis (16/20); DIF: IgG and C3 deposits, intraepidermal (19/20) and in hair follicle (7/20); DIF with subclasses: intraepidermal IgG4 (16/ 20), IgG1 and IgG4 (7/20), and IgG1 and/or IgG4 in hair follicle (16/20); IIF: IgG (19/20), median titre 1:640; ELISA: reactivity to Dsg-1 (18/20) and to Dsg-1 and Dsg-3 (1/20). PV patients (n=18) were characterized as mucocutaneous (16/18) and cutaneous (2/18). Laboratory findings detected: HP: suprabasilar cleavage with acantholysis (17/18); DIF: intraepidermal IgG and C3 deposits (18/18) and in hair follicle (11/18); DIF with subclasses: intraepidermal IgG4 (13/18), IgG1 and IgG4 (5/18), all with HF deposits; IIF: IgG (18/18), median titre 1:160; ELISA: reactivity to Dsg-1 (4/18), Dsg-3 (2/18) and to Dsg-1 and Dsg-3 (12/18). Epitope spreading (ES) was seen in 4 of 18 patients (PV to PF= 3 and PF to PV =1). CONCLUSIONS: Hair follicle involvement in pemphigus was related to long lasting disease (average of 7 years and 2 months) and may be associated with unusual clinical findings such as paronychia and umbilical lesions. In situ intercellular, intraepidermal IgG1 and IgG4 deposits were the predominant IgG isotypes in scalp lesions, and had no association with disease activity. Serological profile of pemphigus with scalp involvement detected anti-Dsg-1 and -3 antibodies, but potential novel target antigens remain to be identified
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Paschoal, Patricia Olaya. "Reatividade a múltiplas proteínas da dieta em crianças com alergia ao leite de vaca mediada pela imunoglobulina E." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-11012012-092018/.
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Objetivos: Determinar a reatividade dos soros e determinação dos isotipos IgG e IgE a proteínas de sementes da dieta de crianças com alergia ao leite de vaca IgE mediada. Métodos: Foram avaliados soros de três grupos de crianças: alérgicas ao leite de vaca IgE mediada, crianças tolerantes ao leite e um grupo controle com crianças não atópicas. Foram usados extratos protéicos de diferentes tipos de sementes utilizando o teste de ELISA para análise da reatividade dos isotipos IgG e IgE. Resultados: Comparando as concentrações séricas de IgG dos diferentes grupos, observou-se concentrações mais elevadas e estatisticamente significante no grupo alérgico em relação aos grupos tolerante e controle, exceto para as sementes de soja e feijão roxinho. Em relação ao isotipo IgE observou-se os mesmos padrões de reatividade mostradas nas analises para IgG, com diferença significante do grupo alérgico em relação ao controle, exceto para milho. Observou-se que para a soja houve grande dispersão das concentrações séricas tanto no grupo alérgico quanto no tolerante, em valores superiores ao do grupo controle. Conclusão: A comparação entre os diversos grupos avaliados mostra que pacientes alérgicos ao leite e os tolerantes apresentam concentrações mais elevadas de IgG e IgE a outros alimentos que as crianças do grupo controle, o que pode sugerir possível alteração de permeabilidade da mucosa intestinal nestes grupos, mesmo na ausência de sintomatologia gastrintestinal<br>Objective: To determine the reactivity of serum and determination of IgG and IgE isotypes to seed proteins included in the diet of children with cow\'s milk allergy IgE mediated. Methods: We evaluated sera from three groups of children: cow\'s milk allergic patients, tolerant children and a control group with non-atopic children. It was used protein extracts from different types of seeds using an ELISA assay to analyze the reactivity of IgG and IgE isotypes. Results: Comparing the IgG serum from different groups, it was observed higher concentrations and statistically significant in the allergic group compared to the tolerant and control groups, except for soybeans and kidney beans. To the IgE isotype it was observed the same patterns of reactivity shown in the analysis for IgG, with significant difference in the allergic group compared to control, except for corn. It was observed that for soybeans there were values of serum, both in the allergic and tolerant group higher than in the control group. Conclusion: Our study showed that the allergic and tolerant groups of CMA patients presented higher IgG and IgE concentrations to many seeds than the control group. These findings may suggest possible changes in permeability intestinal mucosa in these groups