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1
Burgess, R. Alan. "Elucidating Molecular Interactions of Shigella Type Three Secretion System Components Critical for Pathogenesis." DigitalCommons@USU, 2018. https://digitalcommons.usu.edu/etd/6968.
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Shigella spp. are Gram-negative, non-motile bacterial pathogens that are the causative agent of bacillary dysentery in humans. During infection, Shigella utilize a complex type three secretion system (T3SS) to inject effector proteins and take over host cell functions. With the rise of multi-antibiotic resistant Shigella strains, the T3SS is a promising alternative therapeutic target. While the needle and syringe-like apparatus of the T3SS has been extensively studied in Shigella, several components and mechanisms of this system remain unclear. The research presented here addresses two major knowledge gaps in the current understanding of the T3SS ATPase, Spa47, and the initial host-pathogen interaction at the tip of the apparatus. In this work, high resolution crystal structures of Spa47 guided the creation of an oligomer model which suggested ATP hydrolysis may be supported by specific side chain contributions from adjacent protomers within the complex. Mutagenesis experiments targeting predicted active site residues and the oligomerization domain revealed that active site residues alone are not responsible for Spa47 oligomerization while protein oligomerization is crucial for ATPase activity. Together with in vivo experiments, we show that ATP hydrolysis and proper Spa47 oligomer formation is critical for T3SS apparatus formation, effector secretion, and overall Shigella virulence. Additionally, we have combined the Langmuir Blodgett technique with fluorescent microscopy to visualize the interaction between key T3SS tip proteins with defined artificial phospholipid membranes. These membranes were generated using Langmuir Blodgett which provided control over lipid phase and composition. Lipid phase and protein localization were monitored using lipophilic dyes and selective fluorescent protein labeling. These experiments suggest a differential interaction between the tip protein IpaB with the membrane components cholesterol and sphingomyelin based on IpaB oligomerization. IpaC, another T3SS tip protein, was found to destabilize membranes when alone, but was stabilized in the presence of IpaB. These experiments suggest that IpaB confers IpaC stability within membranes and that tip protein localization is dependent on lipid phase and composition. Overall, these new insights into the T3SS ATPase and tip proteins provide a more complete understanding of Shigella virulence that will aid in future endeavors to identify alternative therapeutic targets for treatment.
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David, Marion. "Rôle de l’axe Autotaxine (ATX)- Acide Lysophosphatidique (LPA) et récepteur LPA1 dans la dissémination métastatique des cancers du sein." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10314/document.
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Les métastases sont des conséquences dramatiques lors de la progression des cancers. Malgré les traitements actuels la médiane de survie de patients atteints de métastases osseuses n’est que de 24 mois. Donc l’identification de nouvelles cibles thérapeutiques dans le traitement ou la prévention des métastases revêt un caractère crucial. L’objectif de ce travail de thèse est d’étudier le rôle de l’acide lysophosphatidique (LPA) et de l’autotaxine (ATX) dans la dissémination métastatique des cancers du sein. Notre laboratoire a montré que le LPA contrôle la croissance tumorale et la progression des métastases osseuses dans le contexte des cancers du sein. On sait depuis peu qu’en raison de son activité lysophospholipase D, ATX produit du LPA à partir de la lysophosphatidylcholine et contrôle les niveaux de LPA dans la circulation sanguine. ATX est une protéine sécrétée présentant des propriétés métastatiques. Les travaux présentés dans cette thèse montrent que l'expression d'ATX par les cellules tumorales contrôle les événements précoces de la dissémination métastatique des cancers du sein ainsi que le processus plus tardif de formation et de progression des métastases osseuses en agissant sur la fonction ostéoclastique. Il existe un grand nombre de récepteurs capables de transmettre l’activation cellulaire par le LPA (LPA1-6). Ce travail de thèse montre également que le niveau d’expression du récepteur LPA1 au niveau de la tumeur primaire est un facteur prédictif de la rechute métastatique chez les patientes ayant un cancer du sein. D’autre part dans un modèle animal préclinique, nous avons observé que le ciblage thérapeutique précoce de LPA1 par le DEBIO-0719 bloque efficacement la dissémination métastatique des cellules de cancer du sein. En conclusion, nos résultats montrent que le ciblage de l’axe ATX/LPA/LPA1 présente un haut potentiel thérapeutique chez des patientes atteintes d’un cancer du sein à fort risque métastatiqueMetastases consist of poor disease progression for patients with cancers. Bone metastases are frequently found in multiple cancers. Despite the improvement of current therapies, the survival of bone metastasis patients is only 24 months. The aim of this work consisted in understanding the role of lysophosphatidic acid (LPA), autotaxin (ATX) and the LPA receptor LPA1 in the metastatic dissemination of breast cancers. Our laboratory showed previously that LPA produced tumor growth and the progression of osteolytic bone metastases of breast cancer cells. Due to its lysophospholipase D activity, ATX generates LPA from lysophosphatidylcholine and controls LPA levels in the blood. ATX is a secreted protein with metastatic properties. In the present thesis, we first demonstrated that ATX expressed by tumors cells controls early events of metastatic dissemination of breast cancer cells and latter bone metastases formation and progression by acting on osteoclastic function. There is a large number of receptors mediating the cellular activation of LPA (LPA1-6). This work showed additionally that the LPA1 expression level at the primary tumor site is predictive for the metastatic relapse of breast cancers. On the other hand, in a preclinical animal model, we observed that targeting LPA1 at early stage of tumor development with the DEBIO-0719 decreased efficiently the metastatic dissemination of breast cancer cells. Altogether, these results indicate that targeting the ATX/LPA/LPA1 track has a high therapeutic potential against metastasis formation for patients with breast cancer
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Boucharaba, Ahmed. "Rôle de l'acide lysophosphatidique (LPA) et du récepteur LPA1 dans la formation des métastases osseuses." Paris 7, 2006. http://www.theses.fr/2006PA077219.
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Les cancers du sein induisent fréquemment la formation de métastases osseuses. Les cellules tumorales présentes aux sites osseux produisent de nombreux facteurs (cytokines, PTHrP) qui stimulent l'activité de résorption des ostéoclastes entraînant la dégradation de l'os et libérant les facteurs de croissance piégés dans la matrice osseuse. Les traitements actuels permettent seulement de ralentir la progression de la destruction osseuse. Il est donc important de mieux comprendre les mécanismes moléculaires impliqués dans le développement des métastases osseuses. Parmi les facteurs présentant un fort potentiel dans la régulation du développement tumoral, l'acide lysophosphatidique (LPA) est un lipide biologique libéré massivement par les plaquettes sanguines au moment de leur activation. Mes travaux, ont pour but de comprendre le rôle de l'acide lysophosphatidique (LPA) in vitro et in vivo dans les processus du développement tumoral au tissu osseux et d'évaluer si le LPA et/ou ses récepteurs sont des cibles thérapeutiques potentielles dans le traitement des patients atteints de métastases osseuses. Mes résultats montrent que le LPA est produit au site même des métastases osseuses et qu'il y joue un rôle stimulateur de leur progression en agissant sur la croissance tumorale et sur la sécrétion des interleukines stimulatrices de la résorption osseuse (IL-6 et IL-8), que l'interaction entre les plaquettes sanguines et les cellules tumorales est à l'origine de la production de LPA par le: plaquettes activées, et enfin de montrer que le récepteur LPA1 est une cible thérapeutique prometteuse dans le traitement des métastases osseusesBreast cancers frequently metastasize to bone. Bonemetastases are associated with hypercalcemia due to bone destruction, intractable bone pain, and pathological fractures. In bone metastasis, there is a vicious cycle wherein bone-residing tumor cells stimulate osteoclast-mediated bone résorption and bone-derived growth factors released from resorbed bone promote tumor growth. However, current treatments aimed to inhibit bone resorption (bisphosphonates) only delay the progression of osteolytic lesions in metastatic patients. Therefore, in addition to bone-derived growth factors, other endogenous sources of growth factors are probably involved in promoting skeletal tumor growth. In this respect, human blood platelets activation is an important source of LPA, and platelet aggregation plays a primordial role in the metastatic spreading of melanoma and Lewis lung carcinoma cells in bone and lungs, respectively. Here we provide experimental evidence for a direct role of LPA in the progression of bone metastasis in breast cancer. We identify platelet-derived LPA as an endogenous source that, in the bone microenvironment, stimulates both tumor growth and bone destruction. Although a role for LPA in cancer was emerging, there was a paucity of experimental evidence to support it. This study is to the best of our knowledge, the first to demonstrate a role for LPA and its receptor LPA1 in thé growth of breast cancer bone metastasis
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Alioli, Adebayo Candide. "Etude du rôle du récepteur LPA1 dans l'ostéogénèse au cours de la croissance du squelette : implication dans l'acquisition de masse osseuse." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30254.
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L'os est un organe dynamique qui se renouvelle constamment grâce à une activité coordonnée des ostéoblastes et des ostéocytes qui forment la matrice osseuse nouvelle, et des ostéoclastes qui la dégradent. De la naissance à la fin de l'adolescence, le squelette subit une croissance rapide, médiée par une activité de formation osseuse intense, encore appelée modelage osseux. Cette acquisition de masse osseuse est finement régulée grâce à l'action de nombreux facteurs systémiques et locaux. L'acide lysophosphatidique (LPA) est un médiateur lipidique naturel dont les fonctions biologiques affectent de nombreux organes et de nombreux types cellulaires, y compris les cellules osseuses, ostéoblastes, ostéocytes ostéoclastes. L'action du LPA sur le tissu osseux a été mise en évidence pour la première fois dans notre laboratoire, dans un modèle murin dans lequel l'expression de son récepteur LPA1 a été désactivée de façon globale (Lpar1-/-). Ces animaux présentent un défaut de croissance ainsi que des anomalies osseuses sévères. Cependant, en raison de l'expression ubiquitaire du récepteur LPA1, ce modèle ne permet pas de déterminer l'effet spécifique du LPA dans cellules ostéoblastiques dont l'action est majoritaire au cours de la croissance. L'objectif de mon travail de thèse a été d'étudier le rôle spécifique du LPA et de son récepteur LPA1 dans la lignée ostéoblastique, afin de déterminer son importance pendant le modelage de l'os. Pour ce faire, j'ai étudié des souris Lpar1-ΔOb, générées au laboratoire, et dont l'expression du récepteur LPA1 a été spécifiquement supprimée dans la lignée ostéoblastique. Ces souris ont présenté une baisse de la minéralisation osseuse et une réduction de l'épaisseur de l'os corticale, ainsi qu'une augmentation de la porosité osseuse. In vitro, les ostéoblastes primaires Lpar1-ΔOb et cl1-Ob-Lpar1-/- immortalisés ont révélé une prolifération cellulaire réduite, une altération de la différentiation et une activité de minéralisation réduite. De plus, j'ai mis en évidence chez les souris Lpar1-ΔOb une nette altération de la fonction des ostéocytes. Enfin, j'ai pu montrer in vitro, à la fois dans les ostéoblastes primaires Lpar1-ΔOb et immortalisés cl1-Ob-Lpar1-/-, que l'absence du récepteur LPA1 induit une altération importante de la formation des dendrites, processus précoce et déterminant dans leur différenciation en ostéocyte (ostéocytogenèse). Ces résultats suggèrent un nouveau rôle pour le LPA dans le contrôle de la masse osseuse via la minéralisation osseuse et la fonction des ostéocytes. Ils représentent une piste intéressante à explorer en physiopathologies pour résoudre des problématiques de minéralisation. Ils pourraient également ouvrir des perspectives dans l'exploration de certaines anomalies d'acquisition de masse osseuse comme la scoliose idiopathique de l'adolescent, qui est une pathologie rare dans laquelle des défauts de fonction ostéocytaire similaires à ceux des souris Lpar1-ΔOb ont été rapportésBone is a complex and dynamic organ that is constantly renewing by the coordinated activity of osteoblasts and osteocytes which form the new bone matrix, and osteoclasts responsible for bone resorption. During normal childhood and adolescence, the skeleton undergoes rapid growth, mediated by intense bone-forming activity, also called bone modeling. This acquisition of bone mass requires the proper interaction of numerous systemic and local factors. Lysophosphatidic acid (LPA) is a natural lipid mediator whose biological functions affect multiple organs and multiple cell types, including bone cells. The action of LPA on bone tissue was demonstrated for the first time in our laboratory, in a global Lpar1-knockout mice. These animals present a growth defect as well as severe bone abnormalities. However, due to the large expression of LPA1 in the cells, including bone cells, the Lpar1-/- mice are not suitable to understand the specific effect of LPA in osteoblastic cells, that have the predominant action during growth. The objective of my thesis work was to study the specific role of LPA and its receptor LPA1 in the osteoblastic lineage, in order to determine its importance during bone modeling. Thus, I studied the osteoblast-specific Lpar1 knockout mice (Lpar1-ΔOb) that we generated in the laboratory. These mice revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone cortical porosity. In vitro, primary Lpar1-ΔOb and immortalized cl1-Ob-Lpar1-/- osteoblasts revealed a reduced cell proliferation associated with alterations in differentiation markers, and reduced mineralization activity. Furthermore, I highlighted in Lpar1-ΔOb mice a markedly impaired osteocyte specification. Finally, I was able to show in vitro, both in primary Lpar1-ΔOb and immortalized cl1-Ob-Lpar1-/- osteoblasts that the absence of LPA1 receptor leads to a significant alteration in the dendrites formation, an early and decisive process in their differentiation into osteocytes (Osteocytogenesis). These results suggest a new role for LPA in the control of bone mass via bone mineralization and osteocyte function. They will certainly be helpful in pathophysiology to solve mineralization problems. They could also open perspectives in the exploration of certain abnormalities in bone mass acquisition such as adolescent's idiopathic scoliosis, which is a rare pathology in which defects in osteocyte function similar to those in Lpar1-ΔOb mice have been reported
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Spruth, Wilhelm G. "Enterprise Computing." Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-126859.
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Das vorliegende Buch entstand aus einer zweisemestrigen Vorlesung „Enterprise Computing“, die wir gemeinsam über viele Jahre als Teil des Bachelor- oder Master-Studienganges an der Universität Leipzig gehalten haben.
Das Buch führt ein in die Welt des Mainframe und soll dem Leser einen einführenden Überblick geben. Band 1 ist der Einführung in z/OS gewidmet, während sich Band 2 mit der Internet Integration beschäftigt. Ergänzend werden in Band 3 praktische Übungen unter z/OS dargestellt.
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Jones, Joanna L. "The involvement and regulation of ARF6 in agonist-induced internalization of the β₂-adrenoceptor and the LPA2 and LPA3 receptors." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422551.
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David, Marion. "Rôle de l'axe Autotaxine (ATX)- Acide Lysophosphatidique (LPA) et récepteur LPA1 dans la dissémination métastatique des cancers du sein." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00878970.
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Les métastases sont des conséquences dramatiques lors de la progression des cancers. Malgré les traitements actuels la médiane de survie de patients atteints de métastases osseuses n'est que de 24 mois. Donc l'identification de nouvelles cibles thérapeutiques dans le traitement ou la prévention des métastases revêt un caractère crucial. L'objectif de ce travail de thèse est d'étudier le rôle de l'acide lysophosphatidique (LPA) et de l'autotaxine (ATX) dans la dissémination métastatique des cancers du sein. Notre laboratoire a montré que le LPA contrôle la croissance tumorale et la progression des métastases osseuses dans le contexte des cancers du sein. On sait depuis peu qu'en raison de son activité lysophospholipase D, ATX produit du LPA à partir de la lysophosphatidylcholine et contrôle les niveaux de LPA dans la circulation sanguine. ATX est une protéine sécrétée présentant des propriétés métastatiques. Les travaux présentés dans cette thèse montrent que l'expression d'ATX par les cellules tumorales contrôle les événements précoces de la dissémination métastatique des cancers du sein ainsi que le processus plus tardif de formation et de progression des métastases osseuses en agissant sur la fonction ostéoclastique. Il existe un grand nombre de récepteurs capables de transmettre l'activation cellulaire par le LPA (LPA1-6). Ce travail de thèse montre également que le niveau d'expression du récepteur LPA1 au niveau de la tumeur primaire est un facteur prédictif de la rechute métastatique chez les patientes ayant un cancer du sein. D'autre part dans un modèle animal préclinique, nous avons observé que le ciblage thérapeutique précoce de LPA1 par le DEBIO-0719 bloque efficacement la dissémination métastatique des cellules de cancer du sein. En conclusion, nos résultats montrent que le ciblage de l'axe ATX/LPA/LPA1 présente un haut potentiel thérapeutique chez des patientes atteintes d'un cancer du sein à fort risque métastatique
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Sahay, Debashish. "Identification of genes activated and biological markers involved in lysophosphatidic acid (LPA)-induced breast cancer metastasis through its receptor LPA1." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10012/document.
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L'acide lysophosphatique est un biolipide naturel actif capable de réguler diverses fonctions biologiques et d'agir en tant que facteur de croissance, via l'activation de six différents récepteurs de surfaces couplées aux protéines G (LPA1-6). Notre laboratoire a montré que le ciblage thérapeutique du récepteur LPA1 bloque de façon remarquable la dissémination métastatique des cellules de cancer du sein. Les mécanismes moléculaires et génétiques impliqués dans ce processus sont cependant encore inconnus. De plus, la plupart des cellules de mammifères co-expriment plusieurs formes de récepteurs du LPA. La réponse cellulaire est la résultante de l'activation de multiples voies de signalisation, parfois synergiques ou opposées, compromettant la validation chez le patient de l'efficacité des thérapies ciblant ces récepteurs. Au cours de cette thèse, nous avons dans un premier temps montré que HB-EGF est un marqueur spécifique de l'activité de LPA1. Le blocage pharmacologique de ce récepteur via des antagonistes des récepteurs LPA1-3 (Ki16425/Debio0719) ou l'invalidation de son expression par une technique d'ARN interférence entraine une inhibition de la surexpression en HB-EGF. Le ciblage thérapeutique de LPA1 via l'antagoniste Ki16425, dans notre modèle animal préclinique de xénogreffe de cancer de la prostate PC3, conduit également à une diminution de l'expression en ARNm de HB-EGF au niveau de la tumeur primaire et à une diminution des concentrations en HB-EGF humain circulants dans le sérum. Dans un deuxième temps, nous nous sommes intéressé au rôle des miRNAs, qui sont impliqués dans la régulation de l'expression de gènes. Grâce à l'analyse de 1488 patients atteins de cancers du sein référencés sur des bases de données publiques, nous avons pu établir une corrélation entre le gène LPA1 et le gène ZEB1. Nous avons également trouvé que le coefficient de corrélation entre ZEB1 et LPA1 était supérieur au niveau des tumeurs mammaires basalesLysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA1-6). It has been demonstrated that blocking LPA1 activity in vivo inhibits breast cancer cell metastasis, however, activated genes involved in LPA-induced metastasis have not been defined yet. In addition most mammalian cells co-express multiple LPA receptors, resulting in the co-activation of multiple intracellular signaling pathways with potential redundant or opposite effects impairing the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. In the first part of this thesis I found that HB-EGF is a specific biomarker of LPA1 activity. HB-EGF upregulation was inhibited by LPA1-3 antagonists (Ki16425, Debio0719) and by stably silencing LPA1. Using a human xenograft prostate tumors mouse model with PC3 cells, we found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. In the second part of experimental work, we focused our attention on miRNAs that are master gene regulators. We carried out correlation studies in 1488 human primary breast tumors from publically available databases and found ZEB1 as the most correlated gene with LPAR1. The coefficient of correlation between ZEB1 and LPAR1 was higher in human basal tumors than in non basal tumors. In three different basal cell lines LPA up-regulated ZEB1 through an LPA1/Phosphatidylinositol-3-Kinase (Pi3K)/AKT-dependent pathway. Based on microarray and real-time PCR analyses we found that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/AKT/ZEB1-dependent mechanism. MirVana miR-21 inhibitor, silencing LPA1 or silencing ZEB1 totally blocked in vitro LPA-induced cell migration and invasion, and in vivo tumor cell bone colonization. In all cases, basal breast cancer cell functions were rescued with mirVana miR-21 mimic. All together our results identify HB-EGF as a new and relevant biomarker with potentially high value in quantifying LPA1 activation state in patients receiving anti-LPA1 therapies
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Urs, Nikhil Mahabir. "The regulation of cellular trafficking of the human lysophosphatidic acid receptor 1: identification of the molecular determinants required for receptor trafficking." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/16177.
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The following thesis research was undertaken to gain a better understanding of the mechanisms that regulate the cellular trafficking and signaling of the endothelial differentiation gene (EDG) family of G-protein coupled receptors, LPA1, LPA2, and LPA3. This thesis will specifically focus on the regulation of the trafficking of the LPA1 Lysophosphatidic acid receptor, which is the most widely expressed and has been shown to be a major regulator of migration of cells expressing it.
The initial studies undertaken in this project were aimed at understanding the endocytic pathway followed by the LPA1 receptor. Lysophosphatidic acid (LPA), an abundant serum phospholipid, stimulates heterotrimeric G protein signaling by activating three closely related receptors, termed LPA1, LPA2 and LPA3. In the first part of the project we show that in addition to promoting LPA1 signaling, membrane cholesterol is essential for the association of LPA1 with β-arrestin, which leads to signal attenuation and clathrin dependent endocytosis of LPA1.
The second phase of the project was aimed at elucidating the different structural motifs required for the trafficking and signaling of the LPA1 receptor and helping us gain a more mechanistic view of the processes involved in its regulation. In the second part of the project we show that agonist-independent internalization of the LPA1 receptor is clathrin adaptor, AP-2 dependent and PKC-dependent and that it requires a distal dileucine motif, whereas agonist-dependent internalization of the LPA1 receptor is β-arrestin and clathrin-dependent and requires a cluster of serine residues in the tail region, which is upstream of the dileucine motif.
These studies collectively vastly enhance our understanding of mechanisms that regulate LPA1 trafficking and signaling. These studies can also be applied to other G-protein coupled receptors making the task easier for other scientists to understand this vast family of receptors.
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Murph, Mandi Michelle. "A characterization of the human G protein-coupled receptor, lysophosphatidic acid1 its intracellular trafficking and signaling consequences on the tumor suppressor, P53 /." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-03222005-105717/unrestricted/murph%5Fmandi%5Fm%5F200505%5Fphd.pdf.
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Thesis (Ph. D.)--Biology, Georgia Institute of Technology, 2005.Merrill, Alfred, Committee Member ; Mills, Gordon, Committee Member ; McCarty, Nael, Committee Member ; Kubanek, Julia, Committee Member ; Radhakrishna, Harish, Committee Chair. Includes bibliographical references.
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SÃ, Samy Soares Passos de. "Uma aplicaÃÃo para a LPR." Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=8878.
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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoSistemas automatizados de apoio à decisÃo lidam com a representaÃÃo de conhecimento atravÃs de sistemas formais que permitam cÃlculo de inferÃncias, e atravÃs deste, a possibilidade de tirar conclusÃes de uma base de conhecimento. LÃgicas nÃo-monotÃnicas vÃm sendo discutidas como soluÃÃo para contornar os limites de expressividade da lÃgica clÃssica quanto à representaÃÃo de bases de conhecimento. A LPR (Logic of Plausible Reasoning) à uma proposta recente, que sugere uma estrutura de regra nÃo monotÃnica atravÃs do conceito de generalizaÃÃo e um cÃlculo de extensÃes prÃprio como soluÃÃo capaz de lidar com alguns dos principais problemas e limites expressivos dos formalismos que a antecederam. O presente trabalho à um dos primeiros a explorar o poder expressivo e potencial para a utilizaÃÃo dessa tÃcnica como ferramenta de modelagem de bases de conhecimento para sistemas de apoio à decisÃo. Introduzimos as regras de um jogo enquanto sistema formal adequado à anÃlise e ilustramos o funcionamento do raciocÃnio modelado pela LPR sobre o conhecimento corrente em vÃrios momentos do mesmo, permitindo modelar aspectos do pensamento tais como a formulaÃÃo de conjecturas, avaliaÃÃo de cenÃrios e mudanÃa de idÃia em decorrÃncia de novas descobertas. Apresentamos, ainda, um programa PROLOG que implementa o modelo descrito com regras LPR como instrumento de corretude do mesmo, utilizando uma tÃcnica de divisÃo do programa para formular na linguagem regras baseadas em quantificadores e equivalÃncia de variÃveis.
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Sá, Samy Soares Passos de. "Uma aplicação para a LPR." reponame:Repositório Institucional da UFC, 2008. http://www.repositorio.ufc.br/handle/riufc/18648.
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SÁ, Samy Soares Passos de. Uma aplicação para a LPR. 2008. 141 f. Dissertação (Mestrado em ciência da computação)- Universidade Federal do Ceará, Fortaleza-CE, 2008.Submitted by Elineudson Ribeiro (elineudsonr@gmail.com) on 2016-07-12T17:22:42Z No. of bitstreams: 1 2008_dis_sspsa.pdf: 2115584 bytes, checksum: d4deacd5a3b3ddf9d60b718c6fc45ca9 (MD5)
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Sistemas automatizados de apoio à decisão lidam com a representação de conhecimento através de sistemas formais que permitam cálculo de inferências, e através deste, a possibilidade de tirar conclusões de uma base de conhecimento. Lógicas não-monotônicas vêm sendo discutidas como solução para contornar os limites de expressividade da lógica clássica quanto à representação de bases de conhecimento. A LPR (Logic of Plausible Reasoning) é uma proposta recente, que sugere uma estrutura de regra não monotônica através do conceito de generalização e um cálculo de extensões próprio como solução capaz de lidar com alguns dos principais problemas e limites expressivos dos formalismos que a antecederam. O presente trabalho é um dos primeiros a explorar o poder expressivo e potencial para a utilização dessa técnica como ferramenta de modelagem de bases de conhecimento para sistemas de apoio à decisão. Introduzimos as regras de um jogo enquanto sistema formal adequado à análise e ilustramos o funcionamento do raciocínio modelado pela LPR sobre o conhecimento corrente em vários momentos do mesmo, permitindo modelar aspectos do pensamento tais como a formulação de conjecturas, avaliação de cenários e mudança de idéia em decorrência de novas descobertas. Apresentamos, ainda, um programa PROLOG que implementa o modelo descrito com regras LPR como instrumento de corretude do mesmo, utilizando uma técnica de divisão do programa para formular na linguagem regras baseadas em quantificadores e equivalência de variáveis.
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Belemezova, Emilia. "Die späte Blockade von CCR1 mit BX471 verbessert die Lupusnephritis bei MRL lpr/lpr Mäusen." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-51011.
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Lee, Peilun. "BIOLOGICAL FUNCTIONS OF THE NOVEL LYSOPHOSPHATIDIC ACID (LPA) RECEPTOR, LPA4/p2y9/GPR23." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1676.
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Lysophosphatidic acid (LPA), a naturally occurring phospholipid present in serum and malignant effusions, elicits diverse biological functions through binding and activating specific cell surface G-protein coupled receptors. In addition to the conventional LPA1/Edg2, LPA2/Edg4 and LPA3/Edg7 receptors of the endothelial differentiation gene (Edg) family, LPA4/p2y9/GPR23 of the purinergic receptor family and the related LPA5/GPR92 and LPA6/p2y5 have been identified as novel LPA receptors. These newly identified LPA receptors are structurally distant from the Edg LPA1-3 receptors and couple to Gq, G12/13 and probably Gs subunits. However, the roles of the LPA4-6 receptors in LPA signal transduction and physiology are poorly understood. This project has used biochemical and genetic approaches to study biological functions of LPA4. In the first part of the study, we confirmed that LPA4 is indeed a functional LPA receptor mediating some cellular and biochemical responses to LPA including stimulation of neurite retraction, protein tyrosine phosphorylation. LPA4 also physically binds to LPA when ectopically expressed in cell lines. Mammalian cells usually express multiple LPA receptor subtypes and respond to LPA, making it difficult to link LPA receptors to specific responses. Targeted deletion has become a necessary approach to probe functions of individual LPA receptors. We therefore disrupted LPA4-encoding gene (lpa4/p2y9/gpr23) in mice. LPA4-deficient mice were born at the expected frequency and displayed no apparent abnormalities at least at early ages, indicating that LPA4 is not required for fertility, embryonic development or normal physiology. This is similar to knockouts of other LPA receptors. The backup and/or redundant receptor subtypes of LPA may suffice to compensate for the loss of individual LPA receptors in vivo. Alternatively, LPA may not be the only or rate-limiting mediator physiologically required in vivo. LPA signaling may be more critical in pathophysiological conditions when levels of the lipid mediator are locally and temporally altered. The availability of LPA4-null mice provides a valued model to analyze the roles of LPA4 in pathophysiological processes. Despite the lack of apparent phenotypes in mice, we took advantage of the LPA4- negative mouse embryonic fibroblasts (MEFs) to evaluate the effects of lpa4 deletion on cellular responses to LPA. Strikingly, LPA4-deficient MEFs were hypersensitive to LPA induced migration. Consistent with negative modulation of the phosphatidylinositol 3 kinase (PI3K) pathway by LPA4, LPA4 deficiency potentiated AKT and Rac but decreased Rho activation induced by LPA. Reconstitution of LPA4 converted LPA4-negative cells into a less motile phenotype. In support of the biological relevance of these observations, ectopic expression of LPA4 strongly inhibited migration and invasion of human cancer cells. When coexpressed with LPA1 in B103 neuroblastoma cells devoid of endogenous LPA receptors, LPA4 attenuated LPA1-driven migration and invasion, indicating functional antagonism between the two subtypes of LPA receptors. These results provide genetic and biochemical evidence that LPA4 is a suppressor of LPA-dependent cell migration and invasion. LPA4 may thus play a role in negative regulation of LPA signal transduction and specific cellular responses.
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Shuyu, E. "Role of the LPA2 receptor in protecting against apoptosis." View the abstract Download the full-text PDF version, 2008. http://etd.utmem.edu/WORLD-ACCESS/E/2008-046-E.pdf.
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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on January 7, 2009). Research advisor: Gabor Tigyi, M.D., Ph.D. Document formatted into pages (xiv, 105 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 90-105).
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Ma, Wei. "Detection of anti-neutrophil cytoplasmic antibodies in MRL/Mp-lpr/lpr mice and analysis of their target antigens." Kyoto University, 2001. http://hdl.handle.net/2433/151461.
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Mirzoyan, Koryun. "The role of LPA in kidney pathologies." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30073/document.
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Les maladies rénales chroniques (MRC) et l'insuffisance rénale aiguë (IRA) sont des problèmes essentiels de santé publique en raison de l'augmentation continue de leur fréquence et du manque de solutions thérapeutiques contre ces maladies. L'acide lysophosphatidique (LPA) est un lysophospholipide bioactif qui induit un large éventail de réponses cellulaires par le biais de récepteurs membranaires spécifiques (LPA1 à LPA6) couplés aux protéines G. Dans ce travail, nous nous sommes intéressés aux effets biologiques et au métabolisme du LPA dans les MRC et l'IRA. Des travaux antérieurs de l'équipe avaient montré que le LPA contribuait, via le récepteur LPA1, au développement de la fibrose tubulointerstitio (TIF) dans un modèle de MRC chez la souris : l'obstruction urétérale. Dans la première partie de la thèse nous avons étudié l'implication du LPA dans un modèle plus avancé de MRC: la néphrectomie subtotale (SNX) chez la souris. Nos travaux ont montré que 5 mois après chirurgie les souris (SNX) développaient une albuminurie massive associée à une TIF sévère et à une hypertrophie glomérulaire. Chez ces souris la concentration en LPA mesurée par chromatographie liquide en spectrométrie de masse en tandem était augmentée dans l'urine et étroitement corrélée à l'albuminurie et à la TIF. En parallèle, nous avons observé une diminution de l'expression rénale des Lipid-Phosphate Phosphatases (LPP 1, 2 et 3) responsables de l'inactivation du LPA. Nous avons également observé que l'expression rénale des récepteurs LPA1, 2, 3 et 4 était diminuée chez les souris Snx. Nous avons conclu que les effets délétères éventuels du LPA dans le développement de la MRC chez les souris SNX était vraisemblablement lié à une augmentation de sa production rénale plutôt qu'à une sensibilité accrue du rein au LPA. Des travaux antérieurs avaient montré que l'injection de LPA protégeait contre l'apparition des lésions rénales induites par ischémie/reperfusion chez la souris. Une autre étude avait montré que le LPA permettait d'atténuer l'inflammation systémique et les dommages aux organes induits par un choc septique. Dans la deuxième partie de la thèse, nous avons étudié l'influence du LPA sur l'IRA induite par une endotoxémie au LPS (lipopolysaccharide) chez la souris. Nous avons observé que l'injection de LPA permettait d'atténuer l'élévation d'urée et de créatinine plasmatiques, ainsi que l'augmentation d'expression rénale de cytokines inflammatoires (IL-6, TNFa, MCP-1) induites par le LPS. Le LPA a également empêché la baisse d'expression rénale du facteur PGC1a ainsi que les altérations ultra-structurales des mitochondries rénales induites par le LPS. In vitro, le LPA atténue l'augmentation d'expression des cytokines pro-inflammatoires (TNFa et MCP-1) induite par le LPS dans les macrophages RAW264. Enfin, nos travaux ont montré que l'endotoxémie au LPS chez la souris entrainait une réduction de la concentration urinaire de LPA associée à une réduction des enzymes anaboliques LPA (autotaxine et acylglycérol kinase) et une élévation de l'expression de de LPP2, dans le cortex rénal. Nous en avons conclu que l'IRA associée à l'endotoxémie pourrait être liée, au moins en partie, à une réduction de la production rénale de LPA et, par voix de conséquence, de ses effets anti-inflammatoires protecteurs de la fonction rénale. En conclusion, notre travail montre que les variations de production rénale de LPA pourraient jouer un rôle important dans le développement des maladies rénales. L'augmentation du LPA dans les MRC favoriserait ses effets délétères (fibrose, inflammation). Sa réduction dans l'IRA réduirait ses effets anti-inflammatoires. Cibler le catabolisme LPA pourrait donc être une approche intéressante dans le traitement des maladies rénalesBoth chronic kidney diseases (CKD) with consecutive development of end stage renal disease (ESRD) and acute kidney injury (AKI) represent worrying problems for healthcare system due to its increased frequency and the lack of efficient treatments. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that elicits a wide range of cell responses (proliferation, migration, transformation, contraction etc.) through the activation of specific G protein-coupled receptors (LPA1 to LPA6). In this work we were interested in involvement of the LPA and changes in its metabolism in CKD and AKI. Previous works showed that LPA exerts pro-fibrotic activity and contributes to development of tubulointerstitioal fibrosis (TIF) after ureteral obstruction through activation of LPA1 receptors. In the first part of the thesis we were interested whether LPA signalization is involved in more advanced model of the disease. We found that 5 months after subtotal nephrectomy (SNX) mice develop massive albuminuria, TIF and glomerular hypertrophy compared to control animals. LPA concentration measured by liquid chromatography tandem mass spectrometry was increased in urine but not in plasma of animals. That increase in LPA significantly correlated with albuminuria and TIF. In addition we found a decreased renal expression of lipid phosphate phosphatases (LPP1, 2 and 3) that are responsible for the degradation of LPA by dephosphorylation. Moreover, the expression of LPA1-LPA4 receptors is down-regulated, whereas LPA5 and LPA6 are unchanged. We concluded here that the possible deleterious effect of LPA in the development of CKD in SNX mice was likely related to its increased production rather than an increased sensitivity of the kidney to LPA. Since LPA was reported previously to protect kidney damage in the course of ischemia/reperfusion injury, and that it was able to mitigate the systemic inflammation and organ damage in sepsis, we were interested in second part of the thesis to determine whether exogenous and/or endogenous LPA might protect against sepsis-associated AKI. C57BL/6 mice were treated with exogenous LPA 18:1 1 hour before being injected with the lipopolysaccharide (LPS) and AKI was analyzed after 24h. LPA pre-treatment significantly mitigated the LPS-induced elevation of plasma urea and creatinine, lessened the up-regulation of inflammatory cytokines (IL-6, TNFa, MCP-1) and completely prevented the down-regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) in kidney. LPA also prevented LPS-mediated alterations of renal mitochondria ultrastructure. In vitro, pre-treatment with LPA 18:1 (10 µM) significantly attenuated LPS-induced up-regulation of the pro-inflammatory cytokines (TNFa and MCP-1) in RAW264 macrophages. In addition we found that LPS led to the reduction of urinary LPA concentration that was associated with a reduction in LPA anabolic enzymes (autotaxin and acylglycerol kinase), and an elevation in LPA catabolic enzyme (lipid phosphate phosphatase 2) expression in kidney cortex. We concluded hereby that exogenous LPA exerts protection against endotoxemia-induced kidney injury. Moreover, the observation that LPS reduces the renal production of LPA suggests that sepsis-associated AKI could be mediated, at least in part, by alleviation of the protective action of endogenous LPA. In general our work shows that LPA local metabolism is altered in both forms of kidney diseases. In course of sepsis-induced AKI LPS leads to increased local catabolism of LPA leading to low availability of the phospholipid and alleviating its protective effect whereas in advanced CKD the local catabolism of the phospholipid is decreased with subsequent increase of urine LPA that favors development of the disease. Targeting LPA catabolism can be an interesting approach in treatment of kidney diseases
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Lai, Yun-Ju. "Role of TRIP6 in LPA-induced cell migration." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/lai.pdf.
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Weiner, Joshua A. "Lysophosphatidic acid (LPA) and its G protein-coupled receptor LPA₁/VZG-1 : a novel signaling system in neuronal and glial development /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9944214.
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Aguilar, Salvador Daniel Isui. "Characterization of the role of lpaA on the cytoskeletal anchorage of Shigella flexneri." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7144.
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Shigella envahit les cellules de l'épithélium intestinal en injectant des protéines effectrices via un système de sécrétion de type III (T3SS). L’effecteur de type III IpaA se lie à la taline et à la vinculine par l’intermédiaire de trois sites de liaison à la vinculine (VBS), favorisant ainsi l’ancrage cytosquelettique ainsi que l’internalisation des bactéries. Contrairement à d'autres bactéries invasives, Shigella ne montre pas d'activité de liaison cellulaire constitutive mais déclenche une adhésion transitoire par l'activation de T3SS. IpaA VBS3 s'est avéré être structurellement analogue à l'hélice de la taline H5, qui, avec H1-H4, forme le faisceau de taline R1. L'analyse fonctionnelle identifiée IpaA VBS3 est nécessaire au recrutement de la taline dans les foyers d'entrée de Shigella et à la formation d'adhérences naissantes et de filopodes. IpaA VBS3 stimule également la capture filopodiale des bactéries et stabilise les adhérences cellulaires dans les cellules envahies. D'autre part, les modèles structurels des interactions IpaA VBS ⁄ Vinculin indiquent un nouveau mode d'activation de la vinculine, impliquant des changements conformationnels dans le domaine de la tête de la vinculine, conduisant à la trimérisation et à la stabilisation des adhérences focales. IpaA a également été observé comme étant injecté par une bactérie "s'embrassant et courant", facilitant des événements supplémentaires de liaison bactérienne et d'invasion. Cet amorçage dépendant d'IpaA dépendait d'IpaA VBS3 mais pas d'IpaA VBS1-2. Une fois injecté, IpaA, forme des grappes apposées sur le côté apical de la cellule pour induire une grappe d'intégrines. Globalement, les résultats indiquent que l’IpaA provoque des modifications générales des propriétés adhésives des cellules et favorise un mécanisme coopératif d’invasion de ShigellaShigella invades cells of the intestinal epithelium by injecting effector proteins through a Type III Secretion System (T3SS). The type III effector IpaA binds to talin and vinculin through three Vinculin Binding Sites (VBSs), promoting cytoskeletal anchorage to promote bacterial internalization. As opposed to other invasive bacteria, Shigella does not show constitutive cell binding activity but triggers transient adhesion through T3SS activation. IpaA VBS3 was found to be structurally analogous to talin H5 helix, which, together with H1-H4, forms the R1 talin bundle. Functional analysis identified IpaA VBS3 is necessary for talin recruitment to Shigella entry foci and formation of nascent adhesions and filopodia. IpaA VBS3 also stimulates filopodial capture of bacteria and stabilizes cell adhesions in invaded cells. On the other hand, structural models of IpaA VBSs/Vinculin interactions indicate a novel mode of vinculin activation, involving conformational changes in vinculin head domain that leads to trimerization and stabilization of focal adhesions. IpaA was also observed to be injected by "kissing-and-running" bacteria, facilitating additional bacterial binding and invasion events. This IpaA-dependent priming was dependent on IpaA VBS3 but not on IpaA VBS1-2. Injected IpaA was observed to form clusters apposed to the cell apical side and to induce integrin clustering. Overall, the results indicate that IpaA triggers general changes in cell adhesive properties and promotes a cooperative mechanism of Shigella invasion
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Kaminski, Debra Ann. "Cellular abnormalities seen in the autoimmune MRL-lpr mouse strain." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/27494.
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The MRL-+ and MRL-/pr mouse strains spontaneously develop autoimmune disease similar to human SLE. The autosomal recessive Ipr gene causes extensive lymphoproliferation of a unique DN T cell. The transfer of the Ipr gene to non-autoimmune mice [B6- lpr] has revealed other functions of the Ipr gene, among them autoAb production. The study of disease in MRL and Ipr mouse models affords an opportunity to determine the cellular basis of immune dysregulation seen in ensuing disease. The observation that Ipr mice elicit a decreased ability to respond to mitogen or alloantigen activation was initially investigated. Coincident with the age-dependent hyporesponsiveness, an increase in the number of cells bearing the tumour-specific marker recognized by the YE19.1.3 McAb was demonstrated. These YE19.1.3+ cells were separated from cells not bearing the marker, and those bearing the marker were unable to respond to conA activation. The YE19.1.3- cells could respond to conA, but demonstrated an age related decrease in responsiveness. These results were demonstrated in both MRL- lpr and B6- lpr mice. Lastly, the involvement of thymus education in the development of lymphadenopathy was investigated by making B6- lpr ->B6- lpr and ->B6 chimeras. The percent of YE19.1.3+ cells and mitogen reactivity of these cells and the YE19.1.3- cells were comparable to B6- lpr controls in ->B6- lpr mice; the percent of YE19.1.3+ cells for ->B6 mice was greatly reduced, but mitogen responsiveness had not changed for these cells, hence the cells could not respond, demonstrating an intrinsic defect in YE19.1.3+ cells that cannot be overcome by education in a normal thymus. No age related hyporesponsiveness to conA was seen for the YE19.1.3- cells from ->B6 mice. Several aspects of certain APCs in Ipr mice were examined. The assays used demonstrated both qualitative and quantitative abnormalities seen in MRL-+, MRL- lpr and B6- lpr mice. First of all, quantification by esterase staining implied that with age, MRL-lpr PECs contained very high numbers of 1710s which resulted in less than optimal conditions for responder T cells to proliferate to conA or alloAg presentation. B6- lpr PECs had normal numbers of esterase positive PECs. When B6- lpr mice were old, their PECs augmented T cell responses, suggesting a qualitative rather than a quantitative defect in these mice when compared to MRL-lpr mice. Unfortunately, quantification using the McAb F4/80 could not support or refute the above results. ‖1 production from either Ipr animal strain did not appear to be much different from H-2 compatible controls. The studies performed on DC-enriched populations suggested that peculiar differences between MRL-lpr and B6- lpr DCs exist. MRL-lpr mice were tested for in vitro TsC function. It had previously been shown that preculture allowed for responsiveness by MRL-lpr NWT, thus experimentation was done and confirmed earlier results. Mixing experiments suggested that there may be some in vitro TsC function, but culture with a McAb specific for TsCs and TsFs [B16G] could not support those results. The above observations were not seen with B6- lpr NWT. Lastly, in vivo TsC function with respect to auto a-DNA production was assessed. MRL-+, MRL- lpr and B6- lpr mice were treated once, at the age of two months, with the immunotoxin B16G-HP to remove TsCs. Control CBA and B6 mice were also treated. This treatment led to elevated auto a-DNA production in all experimental mice; due to the variability in autoAb production for individual mice, significant differences between the treated and untreated groups could only be shown for B6- lpr mice, one
week after treatment. The same treatment in control mice failed to induce auto α-DNA IgG.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Choukaife, Ala Eldin. "Variations biologiques de la LpAI des apolipoprotéines : apport de l'électrophorèse bidimensionnelle en biologie clinique." Nancy 1, 1990. http://www.theses.fr/1990NAN10551.
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Pradère, Jean-Philippe. "Etude de la régulation et du rôle de l'autotaxine et de l'acide lysophosphatidique dans le tissu adipeux et le rein." Toulouse 3, 2007. http://thesesups.ups-tlse.fr/75/.
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Parallèlement à son activité métabolique, le tissu adipeux (TA) possède également une activité sécrétoire intense. L'Autotaxine (ATX) est une protéine soluble sécrétée par le TA qui possède une activité enzymatique de type lysophospholipase D (lysoPLD) responsable de la synthèse d'acide lysophosphatidique (LPA). Le LPA est un phospholipide générant divers effets biologiques (prolifération, motilité. . . ) via l'activation de cinq récepteurs couplés aux protéines G (LPA1-5). Dans un premier temps, nous avons étudié les mécanismes de maturation et de sécrétion de l'ATX par l'adipocyte 3T3F442A in vitro. Nos résultats montrent que l'ATX est une protéine N-glycosylée et que l'inhibition de la N-glycosylation empêche la sécrétion de l'ATX et inhibe son activité lysoPLD. Nous avons aussi démontré que l'ATX suit une mode de sécrétion classique après clivage protéolytique par des signal peptidases. Dans un deuxième temps, nous avons étudié les effets biologiques du LPA au sein du TA. Nos résultats montrent que le LPA est un puissant inhibiteur de la différenciation adipocytaire via la diminution d'expression du récépteur nucléaire PPAR(2. Cet effet anti-adipogénique du LPA est confirmé par l'augmentation de la masse adipeuse des animaux invalidés pour le récepteur LPA1. Ainsi, la production locale de LPA pourrait exercer un effet tonique inhibiteur sur le développement du TA. Dans la troisième partie du travail, nous avons étudié, chez la souris, l'implication potentielle du LPA dans la mise en place de la fibrose tubulointerstitielle rénale (FTI) induite par l'obstruction urétérale unilatérale (OUU). La FTI induite par l'OUU entraîne une augmentation de la libération de LPA par le rein et une augmentation de l'expression rénale du récepteur LPA1. Les animaux LPA1 -/-, comme les animaux traités avec l'antagoniste du récepteur LPA1, le Ki16425, sont protégés des lésions induites par l'UUO. Ce travail permet donc de proposer le récepteur LPA1 comme une nouvelle cible pharmacologique d'intérêt dans le traitement de la fibrose rénaleWhite adipose tissue is now considered as an endocrine organ because of its huge capacity for secreting a large number of factors. Among them is Autotaxin (ATX), a soluble protein possessing a lysophopholipase D activity responsible for synthesis of lysophosphatidic acid (LPA), a bioactive phospholipid able to mediate different cellular responses (proliferation, motility…) via the activation of five distinct G protein coupled receptors (LPA1-5). In the present thesis, we first investigated the mechanisms of maturation and secretion of ATX in 3T3F442A adipocytes in vitro. Our results show that ATX is a N-glycosylated protein and that inhibition of N-glycosylation inhibits both secretion and lysoPLD activity of ATX. We also demonstrated that ATX follows a classical secretion pathway and undergoes a signal peptidase proteolytic cleavage which is required for its secretion. The second part of our work addressed the biological effects of LPA in white adipose tissue. Our data show that LPA is a strong inhibitor of adipogenesis resulting from a down-regulation of the nuclear receptor PPAR\gamma\2. The anti-adipogenic activity of LPA is accompanied by the higher adiposity of LPA1 receptor knockout mice compared to their wild type counterpart
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Jethwa, Susanna Anjali. "Exosomes : vesicular carriers of autotaxin, a novel mechanism of LPA signalling." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608189.
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Muinonen-Martin, Andrew James. "Melanoma cells induce LPA gradients that drive chemotactic dispersal and invasion." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4836/.
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Melanoma is notoriously resistant to immuno- and even targeted chemotherapeutic strategies despite recent advances in drug development. The overall mortality of melanoma correlates with its ability to metastasise. Breslow thickness or the depth of invasion remains the most useful prognostic indicator, thereby linking the ability of the cells to invade with their propensity to metastasise. Invasion occurs early during tumour development, but the factors driving this process remain poorly understood. There is a growing appreciation that chemotaxis plays an important role in driving the migration and invasion of melanoma cells, but the key stimuli are not known. Through the generation and validation of an improved chamber for cancer cell chemotaxis, melanoma cells are shown to create chemotactic gradients that drive or disperse themselves outwards with remarkable efficiency. This process is driven by strikingly positive chemotaxis and depends on the melanoma reaching a critical density to generate the gradient. The principal attractant is the inflammatory signal lysophosphatidic acid (LPA). Unexpectedly, it is active across all stages of melanoma evolution and LPA is both necessary and sufficient for chemotaxis in 2D & 3D assays. Growth Factors were previously considered to play essential roles in driving directed migration, but instead facilitate LPA chemotaxis. Sampling across the margins of melanomas in vivo, gradients of LPA are reliably identified, which are capable of driving accurate chemotaxis. This not only confirms the physiological importance of the results, but also is the first time a chemoattractant gradient has been measured in vivo. The corollary of these findings is that, provided with an external homogenous source of LPA, a large enough melanoma will degrade the local LPA to generate an outward gradient. Therefore it is the ability to degrade the gradient that acts as the signal to drive chemotaxis and invasion rather than the presence of LPA per se. In the chambers, cells are observed dispersing in a wave and in addition to driving efficient melanoma invasion, this may be responsible for the patterning of melanocytes across the skin during embryogenesis. Ultimately, identifying key aspects of and targeting the LPA-axis may prove a novel prognostic indicator and therapeutic target for invasion and metastasis.
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Nguyen, Giang Huong. "A functional analysis of the human LPA₁G protein coupled receptor." Thesis, Available online, Georgia Institute of Technology, 2004:, 2004. http://etd.gatech.edu/theses/available/etd-06072004-131304/unrestricted/nguyen%5Fgiang%5Fh%5F200405%5Fms.pdf.
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Kimura, Yuka. "Functional characterizations of lysophosphatidic acid (LPA) receptor, mouseLPA̳1̳ and Xenopus LPA̳1̳ /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3001262.
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Goldsmith, Zachariah G. "Oncogenic Signaling Pathways Activated by Lysophosphatidic Acid (LPA) in Ovarian Carcinoma." Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/34336.
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Molecular Biology and GeneticsPh.D.
Ovarian cancer is currently the most fatal gynecologic cancer and the fifth leading cause of fatal cancer in women overall. As compared to the better-characterized malignancies, such as such as prostate, breast and colorectal cancers, there have been no major changes in methods of detection or treatment of ovarian cancers since the 1970's. As a result, the incidence and age-adjusted death rates for this disease have improved only marginally since that time. The molecular changes required for ovarian cancer pathogenesis remain poorly defined. Lysophosphatidic acid (LPA) has emerged as a biomarker present in the ascitic fluid and serum of ovarian cancer patients. Subsequent studies have identified LPA as an agonist for G protein coupled receptors (GPCRs). LPA has been well characterized as a pro-migratory factor in ovarian cancer and other cell systems. However, the role of LPA in mediating a proliferative response in ovarian cancer cells has yet to be fully characterized. In addition, the identity of the G protein pathways involved in this proliferative response remains a major unresolved question in the field. To investigate the mitogenic role of LPA in ovarian cancers, a panel of representative human ovarian cancer cells was assembled. A series of immunoblot and RT-PCR analyses was used to profile the LPA receptors and Gα-subunits expressed in these cells. In addition to verifying the migratory effect of LPA in these cells, a series of proliferation assays were used to investigate the potential role for LPA as a mitogen. The results indicate that stimulation with LPA results in a robust and statistically significant proliferative response. This response was quantified using multiple approaches. In addition, the proliferative response was observed in three independent ovarian cancer cell lines using concentrations of LPA within the range found in vivo in the ascitic fluid of ovarian cancer patients. Taken together, these data for the first time validate the role of LPA as a mitogen in ovarian cancer cells. To gain further insight into the oncogenic signaling response stimulated by LPA, activation of the mitogen activated protein kinase (MAPK) modules was determined. Using a series of immunoblot analyses and kinase assays, LPA was found to stimulate ERK as well as JNK modules. To investigate the functional roles of these pathways, a series of proliferation assays were carried out using inhibitors of ERK and JNK signaling. Consistent with the role of ERK as a crucial regulator of growth-factor induced proliferation in other cell systems, the results demonstrated a significantly attenuated growth response to LPA with ERK inhibition. Moreover, additional studies demonstrated for the first time that inhibition of JNK signaling significantly attenuates the proliferative response to LPA. In order to investigate the potential role of Gα12 in mediating the oncogenic response to LPA, the activation status of Gα12 was monitored in ovarian cancer cells stimulated with LPA. These studies demonstrate rapid activation of Gα12 with LPA stimulation. Finally to investigate the functional role of LPA-Gα12 signaling, a series of cell lines was established which express a dominant negative form of Gα12. Expression of this construct induced complete inhibition of Gα12 activation by LPA. These cells were then used to determine the effects of Gα12 inhibition on the oncogenic response to LPA. Consistent with the role of G12 family members in mediating cell migration, these cells demonstrated an attenuated migratory response to LPA. In addition, inhibition of Gα12 resulted in an attenuated proliferative response to serum. Finally, to investigate the role of Gα12 in mediating the proliferative response to LPA, a series of proliferation assays was carried out. The results indicated a significant > 50% inhibition in multiple ovarian cancer cell lines. Taken together, these results, presented here for the first time, establish that LPA is a potent mitogen that induces a proliferative response in human ovarian carcinoma cells. Although LPA had previously been shown to induce a proliferative response in multiple other cell types, it had not been known if LPA activates specific oncogenic pathways. This thesis tested the hypothesis that LPA, which is crucially involved in the pathophysiology of ovarian carcinoma, induces the activation of Gα12. In this context, the data presented here demonstrating a novel role for Gα12- which has been defined as the gep oncogene - in mediating this proliferative response in ovarian carcinoma, represents a major finding in the field.
Temple University--Theses
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Koh, Yvette Wui Hui. "Deciphering the role of LPA and pseudopod machinery during melanoma chemotaxis." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8686/.
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In this thesis, I have applied a complementary and alternative understanding of melanoma chemotaxis by incorporating the role of LPA and through a pseudopod-centred approach. I have demonstrated that pseudopods are self organising actin entities that undergo mainly bifurcation (splitting) from preexisting protrusions rather than through synthesis of de novo pseudopods for melanoma cell chemotaxis. This observation was also extended to mouse melanoblast migration in vivo. These superior split pseudopods influence cell steering by alignment, size and lifetime regulation, and biases retraction. In non-metastatic cells, they are no longer able to form stable split pseudopods in response to external stimuli. LPA signaling is also established as vital for the stability of split pseudopods. Hence, in the event of LPAR1 perturbation, metastatic cells formed more actin protrusions but they adopted pseudopod morphologies similar to the non-metastatic lines. The role of Rac, Ras, Paxillin and Ezrin in split pseudopod regulation was also explored in this thesis. Finally, the increased stability of split pseudopods acting through LPA signalling could emerge as a signature of metastatic cells.
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Wang, Yun. "Host Modifier Genes Affect Mouse Autoimmunity Induced by the lpr Gene." Kyoto University, 2001. http://hdl.handle.net/2433/150546.
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Halpern, Melissa Dale. "The in vivo and in vitro effects of diethyldithiocarbamate on autoimmune New Zealand Black/White F₁ hybrid, MRL/Mp-lpr/lpr and related and normal murine strains." Diss., The University of Arizona, 1989. http://hdl.handle.net/10150/184940.
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New Zealand Black/White F₁ hybrid (NZB/W) and MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop a Systemic Lupus Erythematosus-like autoimmune disease. While the primary immunologic defect in the NZB/W is due to B cells, in the MRL/lpr it is a result of T cell abnormalities. Diethyldithiocarbamate (DTC), an agent suggested to enhance T cell function, was used to treat both strains. Weekly treatment of NZB/W mice with 25 mg/kg DTC had no significant effect upon survival or autoantibody levels but did induce changes in cell surface antigen expression. MRL/lpr mice treated with DTC displayed normalization of cell surface antigen expression (particularly increased expression of Lyt-2, macrophage markers and Lyt-2⁺/L3T4⁺ thymocytes), decreased lymphoproliferation and thymic atrophy, decreased serum autoantibody levels and kidney deposition of C3 and IgM, restored responses to mitogens and significantly prolonged survival. To determine both the influence of MRL background and lpr genes and to better understand on what cell populations DTC effects, changes in cell surface antigen expression were examined in DTC treated MRL-+/+, Balb/c, and Balb/lpr strains. The only consistent similarities observed between all strains tested were DTC induced changes in Mac-1 splenocyte surface antigen expression. In vitro studies showed DTC to have variable effects upon the mitogenic responses of lymphoid cells to phytohemagluttinin, but DTC alone stimulated both MRL/lpr and Balb/lpr lymphocytes. DTC stimulated the null cell population that predominates in lpr gene-bearing mice, but all observed in vitro effects of DTC were dependent upon the adherent cell population included in culture. DTC had no apparent direct effects upon adherent cells alone however. These studies have shown that DTC is capable of positive effects upon one autoimmune murine strain, the MRL/lpr, but not the NZB/W. DTC appears to affect macrophages, but other cell populations are required to obtain full activity of this compound. The variable effects of DTC emphasize the need to define the immunopathology of individual patients with autoimmune disease before initiating treatment with immunomodulative therapy.
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LIMA, Aleide Santos de Melo. "Estudo de alterações moleculares e sua relação com dados clínico-laboratoriais em pacientes adultos com leucemia mieloide aguda." Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/13089.
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Marcadores moleculares, como mutações nos genes FLT3 e NPM1, são ferramentas úteis para a avaliação prognóstica de pacientes com leucemia mieloide aguda (LMA) e, até o momento, não tinham sido estudadas em pacientes com LMA no Estado de Pernambuco. Dessa forma, esse trabalho teve como objetivo caracterizar pacientes adultos com LMA diagnosticados na Fundação HEMOPE de acordo com achados clínico-laboratoriais e as mutações nos genes FLT3 e NPM1. Foram incluídos 115 pacientes com LMA de novo (15 com leucemia promielocítica aguda (LPA) e 100 com outros subtipos LMA). As frequências das mutações FLT3/ITD, FLT3/TKD e NPM1 nos pacientes não-LPA foram de 22%, 2% e 24%, respectivamente. Nos pacientes com LPA, a frequência foi de 40% e 6,7% para as mutações FLT3/ITD e NPM1, respectivamente, não sendo diagnosticado nenhum caso com mutação FLT3/TKD. As mutações FLT3/ITD e no NPM1 foram relacionadas com alta contagem de leucócitos (p=0,021; p=0,012) e mutações no NPM1 foram mais frequentes em pacientes com mais de 60 anos (p=0,01) e no grupo de cariótipo normal (p=0,008). Não foi observada diferença nas sobrevidas global (SG) e livre de doença (SLD) e nas taxas de remissão completa (TRC) e de recaída (TR) entre os grupos com e sem mutação FLT3/ITD e no NPM1 quando avaliados os pacientes não-LPA; entretanto, pacientes LPA com mutação FLT3/ITD apresentaram menores TRC, SG e SLD. Os resultados comprovam o valor preditivo da mutação FLT3/ITD para um curso clínico desfavorável na LPA do adulto, enquanto que, para os pacientes não-LPA, as mutações FLT3/ITD e no NPM1, aparentemente, não apresentaram o mesmo impacto prognóstico.
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Weißbach, Julia [Verfasser]. "Lokalisation und Regulierung der Endothel-Differenzierungs-Gen-Rezeptoren S1P1 und LPA1 in humanen Myokardproben / Julia Weißbach." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2007. http://d-nb.info/1021855693/34.
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Pflumio, Françoise. "La souris doublement immunodeficiente c57bl/6 nu/nu, bg/bg. Construction, caracterisation et utilisation pour l'etude de l'etiologie du syndrome autoimmun et lymphoproliferatif de la souris c57bl/6 lpr/lpr." Université Louis Pasteur (Strasbourg) (1971-2008), 1990. http://www.theses.fr/1990STR13144.
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La souris c57bl/6 nu/nu, bg/bg (b6 nubg) a ete obtenue en 5 generations a partir de croisements effectues entre des souris b6 +/+, bg/bg et b6 nu/nu, +/+ (b6 bg et b6 nu). Elle se caracterise par une duree de vie de 12 semaines, une activite nk faible et elle ne dispose d'aucun lymphocyte t mature. Ses concentrations en immunoglobulines seriques sont equivalentes a celles des souris b6 nu. Dans des experiences de transfert adoptif de cellules lymphoides de souris (b6 lpr/lpr (b6 lpr), les souris receveuses b6 nubg n'ont pas developpe les signes caracteristiques du syndrome autoimmun lpr. Aucune lymphoproliferation n'est apparue. Une autoimmunite a ete detectee peu de temps apres la greffe mais elle a disparu progressivement, rejoignant les taux mesures pour les chimeres controles. En comparaison, plusieurs types de chimeres ont ete construites a partir de receveurs b6 bg. La greffe de cellules spleniques de souris b6 lpr a des souris b6 bg pretraitees par du cyclophosphamide a permis le transfert d'une lymphadenopathie et d'une autoimmunite
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Chen, Xi. "Oxidatively Truncated Ether Phospholipid: Synthesis, Detection in LDL and Biological Activities." online version, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1192974399.
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OLIVEIRA, ANDRE TEIXEIRA DE MIRANDA. "GOVERNMENT GUARANTEES IN PPP PROJECTS: AN APPLICATION OF THE LPVR MODEL TO THE BR-116/324 HIGHWAY PROJECT." PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2008. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=13037@1.
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CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOA partir da década de 90 houve um aumento da participação do setor privado em projetos de infra-estrutura no Brasil. Esta participação deu-se principalmente por meio de concessões tradicionais regidas pela Lei das Concessões. Contudo, para tornar economicamente viáveis projetos de baixa atratividade para o setor privado devido ao seu alto risco, o governo brasileiro passou a analisar formas de redução destes riscos, como as Parcerias Público- Privadas (PPPs), incluindo a flexibilização do prazo de concessão, garantias de tráfego, de risco cambial ou até mesmo garantias de financiamento. Neste trabalho é utilizado o modelo LPVR (Menor Valor Presente das Receitas) de prazo de concessão variável aliado a uma garantia de tráfego mínimo para a avaliação do caso do projeto da rodovia BR-116/324 através da metodologia das Opções Reais. Os resultados indicam que o uso deste modelo permite uma redução dos riscos tanto para o Governo, pela limitação de ganhos excessivos da concessionária, quanto para o investidor privado, pela flexibilidade do prazo e garantia de tráfego concedida. Concluímos que o modelo LPVR associado a uma garantia de tráfego mínimo de 80% aumenta em média o VPL do projeto em mais de 60%. Embora esta garantia represente um custo adicional para o Governo, ela é compensada pelo aumento da atratividade do investimento para o setor privado.
Since the 90`s, there has been an increasing participation of the private sector in infrastructure projects in Brazil. This participation, however, took place mainly through traditional concessions, governed by the Concessions Law. However, to become economically viable projects that would not have attractiveness to the private sector due to its high risks, Brazilian government started to analyze some ways to reduce these risks such as the Public Private Partnerships (PPPs), including the term flexibility, traffic guarantee, guarantee of foreign currency risk or even assurance of funding. In this project it`s used the LPVR model (Least Present Value of Revenue) with variable period concession, ally to a minimum traffic guarantee and applying the case to the BR-116/324 highway project through the Real Options Methodology. The results show that the use of this model allows a reduction on the risks both for the government, avoiding excessive gains by the concessionaire, and for the private investor, either for the term flexibility or the guarantee of the traffic granted. So, we can conclude that the LPVR model associated with a minimum traffic guarantee of 80%, increases the VPL in an average of 60%, although this guarantee represents a further cost to the government which is compensated by the increasing attractiveness of the investment to the private sector.
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Keller, Jeannette. "Effektivität einer PPI-Therapie mit Esomeprazol (40 mg, 1x täglich) bei laryngopharyngealem Reflux (LPR)." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-94809.
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Mourad, Agha Zein [Verfasser]. "Bedeutung von Lysophosphatidsäure (LPA) bei der Insulinresistenz von pankreatischen β-Zellen / Zein Mourad Agha." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1117028348/34.
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Harper, Kelly. "Autotaxin promotes cancer cell invasion via the lysophosphatidic acid receptor 4." Mémoire, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4035.
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Tumor metastasis is a fundamental property of malignant cancer cells and the major cause of death in cancer patients. Recent studies indicate that tumor cell invasion and metastasis may be initiated by the formation of the actin-rich cell protrusions with ECM degradation activity, invadopodia. However, despite extensive research on the biology of invadopodia, very little is known about their specific inducers during tumor progression. Autotaxin (ATX) is a secreted lysophospholipase whose expression levels within tumors correlates strongly with their aggressiveness and invasiveness. ATX produces lyosophosphatidic acid (LPA), a phospholipid with known tumor promoting functions that acts through the G-protein coupled receptors, LPA[subscript 1-6] . Recently, overexpression of ATX and LPA receptors (LPA[subscript 1-3]) has been linked to increased tumor invasion and metastasis in vivo , however, the role of other LPA receptors (LPA[subscript 4-6]) as well as the exact mechanisms by which ATX induces tumor metastasis remain poorly characterized. In order to determine the involvement of ATX and LPA in invadopodia production, we used the fibrosarcoma HT-1080 cells stably transfected with ATX or shRNA targeting ATX in fluorescent matrix degradation assays. Our results demonstrate that ATX is implicated in the production of invadopodia resulting in an increase in both their formation and function. Using LPC or LPA, the substrate and product of ATX, we further show that invadopodia production is dependent on the production of LPA from LPC. Among the LPA receptors, LPA 4 has the highest expression in HT1080 cells. Using LPA[subscript 4] shRNA as well as agonists and inhibitors of the cAMP pathway, we provide evidence that LPA[subscript 4] signaling through the cAMP-EPAC-Rap1 axis, regulates invadopodia formation downstream of ATX. Furthermore, inhibition of Rac1, a known effector of Rap1 and invadopodia formation, abolished EPAC-induced invadopodia production, suggesting downstream participation of Rac1. Finally, results using LPA[subscript 4] shRNA support the requirement of this receptor for in vitro cell invasion and in vivo metastasis formation. Our results suggest that ATX through LPA[subscript 4] is a strong inducer of invadopodia formation that correlates with the ability of the cells to invade and metastasize. This study also revealed an unexpected signaling pathway for cell invasion involving LPA[subscript 4]-driven cAMP production and subsequent activation of the EPAC-Rap1-Rac1 axis.
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SCHNEIDER, SERROUYA NATHALIE. "Place des dosages de lpa1 et de cholesterol hdl2 dans le bilan lipidique : application aux diabetiques non insulino-dependants." Reims, 1993. http://www.theses.fr/1993REIMM016.
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Cheng, Jin [Verfasser]. "Precise somatotopic thalamocortical axon guidance depends on LPA-mediated PRG-2/Radixin signaling / Jin Cheng." Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1124104542/34.
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Moughal, Noreen Akhtar. "S1P,LPA and TRK a receptor expression, activation and signal transduction in various cell types." Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487875.
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Lysophosphatidate (LPA) binds to a family of G-protein coupled receptors (GPCR). Three receptors belong to the endothelial differentiation gene (EDG) family, namely LPA1-3. whereas another two receptors LPA4-5 are evolutionary distant. The LPA1receptor couples to effectors via the heterotrimeric G-protein Gi to stimulate activation of the p42/p44 MAPK pathway.
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Hammond-McKibben, Denise M. "Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity." Diss., This resource online, 1995. http://scholar.lib.vt.edu/theses/available/etd-06062008-162732/.
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Castagna, Diana. "Investigation of LPA₁ receptor antagonism/ATX inhibition by a scaffold hopping aproach and SAR analysis." Thesis, University of Strathclyde, 2016. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=26620.
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The Autotaxin-Lysophosphatidic acid (ATX-LPA) signalling pathway has been implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic disease, inflammation, neurodegeneration, and neuropathic pain, amongst others. Two methods have been pursued in attempts to develop novel targets for this disease state which include: Route A – the development of novel LPA1 receptor antagonist, and Route B – the inhibition of the enzyme ATX required for the production of LPA (Scheme 1). Both of these routes will be pursued within this study with a view to developing novel targets for the inhibition of the LPA-ATX signalling pathway. Scheme 1: Proposed routes for the development of novel LPA-ATX inhibitors. A small compound library was constructed to target Route A, where of the compounds analysed none exhibited LPA1 receptor antagonism. Pleasingly, cross screening against ATX inhibition revealed several hit compounds, indicating the ability of cross-talk between these two signalling pathways. In regards to the second route, an extensive compound library was built based on the development of SAR surrounding a known potent ATX inhibitor by Amira Pharmaceuticals. The designed compounds were screened using a dual assay procedure (LPC and (bis-p-nitrophenyl)phosphate assay) which indicated a range of active compounds, as well as indicating the complexity associated with the binding mode of this particular motif.
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Cunha, Bruno Santos. "Aplicabilidade da lei federal 9.784/99." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/2/2134/tde-11022015-150338/.
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O presente trabalho tem por escopo analisar a aplicabilidade da Lei Federal n. 9.784/99 (Lei de Processo Administrativo Federal LPAF). A partir do exame das expressões doutrinárias do direito e do processo administrativo no Brasil, busca-se investigar a extensão de sua incidência, tendo-se como premissa inicial o fato de a referida Lei representar um verdadeiro quadro ou fonte normativa primordial de ordenação da atuação administrativa, pautando requisitos mínimos para instauração, instrução e decisão relativos à formação e posterior execução da vontade funcional da Administração Pública. Nesse sentido, busca-se discutir a fórmula ou regime geral de incidência da LPAF, tendo como fundamento sua estipulação baseada em normas básicas e sua subsidiariedade em relação às espécies processuais administrativas reguladas por leis específicas. Os critérios legais de aplicabilidade da lei são evidenciados para que se chegue a um escalonamento (ordem de preferência) entre os mesmos, sobretudo a fim de melhor trilhar a extensão da lei entre os entes, entidades e órgãos submetidos a seu quadro normativo. Em vistas disso, o estudo toma como base os caracteres estruturais Administração Pública, alinhando a atividade administrativa e a consequente incidência da LPAF ao quadro de organização administrativa disposto no Anteprojeto de Lei Orgânica da Administração Pública Federal e Entes de Colaboração. Por derradeiro, estuda-se a o alcance federativo da lei, de forma a investigar a possibilidade de sua aplicação e extensão aos entes subnacionais, com a instauração de um patamar de tratamento e atuação unificados perante as diversas facetas e expressões de atividade administrativa em todas as entidades políticas (União, Distrito Federal, Estados e Municípios)The present work aims to analyze the Federal Law n. 9.784/99 applicability (Federal Administrative Procedure Act, also known, in Brazil, as LPAF). From the examination of brazilian experts expressions about administrative law and administrative procedure law, the study seeks to investigate the extension of the LPAF impact, taking into consideration that this Act represents a primary source of normative ordering of the administrative functions and all the acts and decisions taken and made by the Public Administration. In such scope, the aim is thus to discuss a general formula for the impact of the LPAF, mainly based on its basic rules and principles and its subsidiarity in relation to administrative procedural species regulated by specific Acts. Furthermore, the legal criteria for the applicability of the LPAF are highlighted in order to reach an order of preference between them. From this point, the study sets its focus on the structural character of the Public Administration to investigate the impact of the LPAF aligned to regular administrative activity. For the last, the federal state issue is raised in order to discuss its applicability and the possibility of establishing an unified level of administrative procedures and activities through all the political entities in the Federation (Union, Federal District, States and Municipalities).
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Di, Pietro Magali. "Régulation des aquaporines et réponse des racines d'Arabidopsis thaliana à des stimuli abiotiques et nutritionnels." Thesis, Montpellier, SupAgro, 2011. http://www.theses.fr/2011NSAM0038/document.
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La conductivité hydraulique racinaire (Lpr) traduit la facilité du passage de l'eau au travers des racines. Ce paramètre, majoritairement contrôlé par l'activité de canaux hydriques membranaires (aquaporines), est modulable par diverses contraintes environnementales. Ce travail a permis de caractériser, sur un même organisme (Arabidopsis), les effets d'un ensemble de contraintes abiotiques et biotiques, représentatives de situations environnementales, sur la Lpr. Alors que la flagelline n'affecte pas la Lpr, les contraintes osmotiques (NaCl, mannitol), oxydantes (H2O2, NO) et nutritionnelles (carence en phosphate, en nitrate, culture des plantes en nuit prolongée) inhibent la Lpr. Par contre, la réalimentation en phosphate ainsi que l'addition de saccharose à des plantes cultivées en nuit prolongée stimulent la Lpr. Une approche phosphoprotéomique quantitative, basée sur l'analyse par MS de protéines microsomales racinaires purifiées à partir de plantes cultivées dans trois de ces contextes (NaCl, NO, phosphate) a permis de quantifier les variations d'abondance de l'ensemble des aquaporines racinaires ainsi que de leur état de MPT. D'un point de vue qualitatif, 22 aquaporines ont été identifiées dans la racine ainsi que plusieurs types de MPTs, incluant des nouveaux sites de phosphorylation (7), de méthylation (13 à 15), de formylation (4) et de déamidation (25 à 26). D'un point de vue quantitatif, cette étude a permis de conclure que les observations réalisées au niveau de la Lpr sont la résultante de mécanismes multifactoriels incluant l'état de phosphorylation des trois sites de l'extrémité C terminale de PIP2;1/2;2/2;3, l'état de phosphorylation de l'extrémité N terminale de PIP1;1/1;2, ainsi que les aquaporines TIPs. Ce travail permet donc de proposer de nouveaux mécanismes moléculaires impliqués dans la régulation de la Lpr en réponse à des contraintes de l'environnementThe water uptake capacity of plant roots (root hydraulic conductivity, Lpr) is mainly determined by water channels (aquaporins) and is modulated by environmental constraints. The present work characterised, in a unique organism (Arabidopsis), effects on Lpr of abiotic and biotic constraints representative of environmental situations. Whereas flagelline does not affect Lpr, osmotic (NaCl or mannitol), oxidative (H2O2 or NO) and nutritional (phosphate or nitrate starvation, prolonged night) stimuli inhibit Lpr. However, phosphate and sucrose resupply stimulate Lpr. A phosphoproteomics approach based on MS analysis of microsomal proteins extracted from roots of plants cultivated in different environmental constraints (NaCl, NO,phosphate starvation and resupply) allowed to quantify variations of abundance of roots aquaporins and of their PTMs. As a qualitative point of view, 22 aquaporins were identified in roots as well as several post-translational modifications including new sites of phosphorylation (7), methylation (13 to 15), formylation (4) and deamidation (25 to 26). From a quantitative point of view, the present work drove to the conclusion that the modulations of Lpr result from multifactorial mechanisms including the phosphorylation status of the C terminal part of PIP2;1/2;2/2;3 and of the N-terminal part of PIP1;1/1;2 and TIP aquaporins. This study proposes new molecular mechanisms implicated in Lpr regulation in response to various environmental situations
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Morales, Rodrigo Luiz Resende. "Mecanismo LPVR - Least Present Value of Revenues como mitigador de riscos em concessões rodoviárias: uma aplicação a um caso brasileiro." reponame:Repositório Institucional do FGV, 2014. http://hdl.handle.net/10438/13658.
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In recent years the Brazilian govcmmcnt has adopted the posture of encouraging infrastructure projects, mainly road concessions. There is debate about the best way to attract investors in tenns of retum, without, at the same time, users do not havc a high cost and can enjoy good service. This discussion goes primarily by an analysis of traffic risl<, which is entirely allocated to auction's winners today. The methodology used in recent tenders follows a requirement of maximum Internai Rate of Return (IRR), for the Grantor (ANTI), in real terms anda fixcd duration. From the estimated costs and in particular concession investments, ANTT sets a ceiling-rate being charged by the utility to users, through the IRR maximum required in tbe project. This IRR is calculated based on the weighted average cost of capital (WACC) of companies in the sector, which have sbares traded on the Brazilian Excbange (BM&FBovespa), using only domestic data. This paper proposes an alternative model, based on thc Least Present Value of Revenues ( LPVR) mecanism. In this model we obserYe that traffic risk is much lower to the auction 's winners because the grant expires only when a certain levei of revenues required by the concessionaire is rcachcd. A model with tlexible term for such is necessary. Howcver, with less risl< of traffic, the upside and downside in tenns of return, are minor compareci to tbe current model. Using tbis model, the Grantor can also define a winner foa· the auctiou (the dealership tbat offcrs the lowest present valuc of rcvenues) and also uses the proposed simulatiou of traffic for setting a deadline for the grant, if demanded.
Nos últimos anos o governo brasileiro tem adotado a postura de incentivo a projetos de infraestrutura, sendo as concessões rodoviárias um dos principais mecanismos. Muito se discute sobre a melhor forma de remuneração das concessionárias, sem que, ao mesmo tempo, os usuários não tenham um custo elevado e possam usufruir de bons serviçoes prestados.Essa discussão passa, principalmente, por uma análise de risco de tráfego, que hoje é inteiramente alocado as cconcessionárias. A metodologia utilizada nos últimos leilões segue uma exigência de Taxa Interna de Retorno ( TIR ) máxima, pelo Poder Concedente ( ANTT ), em termos reais e um prazo de concessão fixo. A partir de custos e investimentos estimados em determinada concessão, a ANTT define uma tarifa-teto a ser cobrada pela concessionária aos usuários através da TIR máxima exigida no projeto. Esta TIR é calculada com base no custo médio ponderado de capital ( WACC ) de empresas do setor, que tem ações negociadas na BM&F Bovespa, utilizando-se apenas dados domésticos. Neste trabalho é proposto um modelo alternativo, baseado no menor valor presente das receitas ( LPVR - Least Present Value of Revenues ). Neste modelo observamos que o risco de tráfego é bem menor para a concessionária, pois a concessão só se expira quando determinado nível de receitas exigido pela concessionária é atingido. Ou seja, para tal, é necessário um modelo de prazo flexível. Neste mecanismo, entretanto, com menor risco de tráfego, o upside e o downside, em termos de retorno, são menores em comparação com o modelo vigente. Utilizando este modelo, o Poder Concedente pode também definir um vencedor para o leilão ( a concessionária que ofertar o menor valor presente das receitas ) e também se utilizar da proposta de simulação de tráfegos para a definição de um prazo máximo para a concessão, em caso de implementação do mecanismo proposto.
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Krampoťák, Štefan. "Model dopravních situací." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2012. http://www.nusl.cz/ntk/nusl-219706.
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This master thesis deals with analyze of camera system in real traffic, using these system and realization of traffic situation model. Result of this work is fully functional model of traffic situation, which shows the capability of these camera systems in real traffic. It consists of two basic parts, the first is physical model of traffic with semaphore and second part is control program with algorithm for detection of traffic offences. The system contains speed measurement and red light violation. Model has capable of control the speed of cars, control semaphores and configure cameras.
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Kazantzoglou, Avraam. "Flexible Architecture System & Topology License Plate Recognition (FAST LPR) and Concept of Operations in Thailand." Thesis, Monterey, Calif. : Naval Postgraduate School, 2008. http://edocs.nps.edu/npspubs/scholarly/theses/2008/Sept/08Sep%5FKazantzoglou.pdf.
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Thesis (M.S. in Electronic Warfare Systems Engineering and M.A. in Security Studies (Stabilization and Reconstruction))--Naval Postgraduate School, September 2008.Thesis Advisor(s): Sankar, Pat ; McNab, Robert. "September 2008." Description based on title screen as viewed on November 6, 2008. Includes bibliographical references (p. 151-154). Also available in print.
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YAÑEZ, LENDIZABAL ALEJANDRA EMILSEN. "IMPLEMENTACIÓN DE LA NORMA CQI-8 LPA´s, EN EL PROCESO DE INYECCIÓN DE CERA PERDIDA." Tesis de Licenciatura, Universidad Autónoma del Estado de México, 2015. http://hdl.handle.net/20.500.11799/40410.
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La aplicación de la norma CQI-8 LPA´s se llevará a cabo en una empresa automotriz que obtiene sus productos mediante el proceso de fundición a la cera perdida, específicamente en el proceso de inyección de cera. Los datos serán analizados considerando los antecedentes e información para el estudio correspondiente.Las empresas manufactureras industriales, principalmente las automotrices, en su esfuerzo por mantenerse competitivos en el mercado, trabajan para estar en conformidad con los estándares de las certificaciones de los sistemas de gestión: ISO (International Organization for Standardization) 9001:2008, ISO/TS 16949, Norma CQI-8 Layered Process Audit (Auditorías de Procesos por Capas (o niveles)).