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1
Gineste, Aurélie. "Fer et immunité innée : vers une meilleure compréhension des mécanismes développés par l'hôte pour réduire le fer accessible aux pathogènes." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30117/document.
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Le fer est un élément essentiel à de nombreux processus physiologiques fondamentaux. Lors d'une infection, une forte compétition entre l'hôte et l'agent pathogène a lieu ; alors que la bactérie a besoin d'acquérir le fer de l'hôte, pour son développement et sa virulence, l'hôte déploie de nombreux mécanismes pour protéger ses stocks de fer. Il sécrète notamment un peptide capable de moduler l'homéostasie du fer au niveau systémique, l'hepcidine, qui va causer une diminution de la quantité de fer sérique, une rétention intracellulaire du fer et donc une restriction du fer accessible aux pathogènes. Lors d'une inflammation, l'expression de l'hepcidine est décrite dans la littérature pour être principalement induite via l'activation de deux voies de signalisation : la voie STAT3 et la voie BMP/SMAD, l'altération de chacune de ces voies conduisant à un défaut d'induction d'hepcidine. Cependant, nos précédentes observations publiées ont infirmé le rôle de l'IL6, ligand de la voie STAT3, dans la régulation de l'hepcidine en réponse au LPS, et ont suggéré l'implication d'un peptide appartenant à la famille du TGFb, l'activine B, dans la régulation de l'hepcidine via l'activation de la voie BMP/SMAD in vivo. Dans cette étude, nous nous sommes intéressés au rôle de l'activine B dans la régulation de l'hepcidine in vivo, lors d'une infection. Grâce à l'utilisation de souris invalidées pour le gène codant l'activine B (Inhbb-/-), nous avons confirmé que l'activine B était un ligand endogène de la voie BMP/SMAD dans le foie, puisqu'elle induit la phosphorylation des effecteurs SMAD en réponse au LPS. Cependant, nous avons pu clairement démontrer que l'activine B, et donc l'augmentation de la phosphorylation des effecteurs SMAD, ne participaient pas à la régulation de l'hepcidine in vivo, en réponse à l'infection. Nous nous sommes alors intéressés à l'implication de l'IL6 dans la régulation de l'hepcidine. Alors que l'absence d'Il6 n'altère pas l'induction de l'hepcidine in vivo en réponse au LPS, cette cytokine semble jouer un rôle clé pour la réponse de l'hôte lors d'une infection par une bactérie. Dans ce contexte, la littérature décrit l'importance de l'IL6 pour une réponse immunitaire protectrice de l'hôte lors d'une infection. Lors d'une infection, nous proposons donc l'implication d'une nouvelle voie de signalisation dans l'expression de l'hepcidine. De plus, nous suggérons un rôle important de l'IL6, non pas dans la régulation transcriptionnelle de l'hepcidine, mais pour la protection de l'hôte lors d'une infection bactérienne. Enfin, nos résultats montrent qu'un niveau d'activation basal de la voie BMP/SMAD est requis pour une induction d'hepcidine lors d'inflammation, et que l'augmentation de la phosphorylation des effecteurs SMAD observée en réponse à l'inflammation ne participe pas à cette régulationIron is essential for several fundamental metabolic processes. During infection, a strong competition between the host and the pathogen occurs; while the bacteria needs to acquire iron from the host, for its growth and virulence, hosts have developed several mechanisms to protect its iron stores. In particular, the host produces a peptide in order to modulate systemic iron homeostasis, hepcidin. Hepcidin decreases the amount of circulating iron, causes intracellular iron retention and thus a restriction of accessible iron to pathogens. During inflammation, hepcidin expression is described in the literature to be mainly mediated through activation of two signaling pathways: the STAT3 and the BMP/SMAD pathways. Impairment of one of these pathways leads to an impaired hepcidin induction. However, our previous published observations did not support the role of IL6, the major ligand of STAT3 pathway, in the regulation of hepcidin in response to LPS, but suggested the involvement of another protein, that belongs to the TGFb family, activin B, in the regulation of hepcidin via the activation of the BMP/SMAD pathway in vivo. In this study, we investigated the role of activin B in the regulation of hepcidin in vivo, during infection. By using knockout mice for the gene encoding activin B (Inhbb-/-), our results suggest that activin B is not involved in the regulation of hepcidin in vivo in response to infection. We then investigated the function of IL6 in the regulation of hepcidin. Although the absence of IL6 does not affect the induction of hepcidin in vivo in response to LPS, this cytokine appears to play a key role in the host response during bacterial infection. Indeed, the literature describes the importance of IL6 for a protective immune response of the host during infection. During infection, we hypothesize that another signaling pathway regulates hepcidin expression. In addition, we suggest an important role of IL6, not in the transcriptional regulation of hepcidin, but for the host protection during a bacterial infection. Finally, our results also show that basal level of BMP/SMAD pathway is required for an appropriate induction of hepcidin during inflammation
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Mahmoud, Abady Maryam. "Modulation of growth factors and cell cycle regulatory molecules in experimental cardiomyopathy." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210244.
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Background: Different types of cardiomyopathies are associated with variable hypertrophic response. A number of growth factors are thought to play a role in pathologic cardiac remodeling.
Aims: We compared the modulation of the TGF-ƒÒ superfamily and IGF-1 signaling pathways and their target genes, the cell cycle regulatory proteins in tachycardia-induced dilated cardiomyopathy, a model with no detectable hypertrophy and in ischemic cardiomyopathy, a model with a marked hypertrophic reaction.
Methods: In the first study, endomyocardial biopsies were obtained weekly in 15 dogs, during the development of tachycardiomyopaty. Genes involved in the myostatin-TGF-ƒÒ-Activin-A/Smad signaling pathway, p21 and cyclin D were quantified and correlated to echocardiographic measures of hypertrophy. In the second study, myocardial tissue samples were obtained in 8 dogs with a healed myocardial infarction, in 8 dogs with heart failure induced by overpacing and in 7 healthy dogs. We measured gene expression of IGF-1, its receptor (IGF-1R) and cyclins A, B, D1, D2, D3 and E and correlated them to the level of hypertrophy.
Results: Tachycardiomyopathy was characterized by chambers dilation with no identifiable hypertrophy. Ischemic cardiomyopathy was characterized by eccentric hypertrophy. In tachycardiomyopathy, Activin-A mRNA was 4-fold higher than at baseline. Smad7 was overexpressed in severe heart failure; p21, a direct target gene of the Smad pathway was upregulated 8-fold and cyclin D1 was down-regulated. In that model, IGF-1 was overexpressed but neither IGF-1R nor any of the cyclins studied.
In ischemic cardiomyopathy, IGF-1, IGF-R, and cyclins B, D1, D3 and E gene expression were upregulated.
In tachycardiomyopathy, Activin-A and p21 were inversely correlated to the thickness of the interventricular septum. In normal dogs and in the both models of cardiomyopathy, IGF-1R was correlated to the thickness of the interventricular septum and to cyclins.
Conclusions: Taken together, these results agree with the notion that Activin-A, IGF and cyclins are involved in the modulation of hypertrophic response observed in cardiomyopathies.
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished
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Elliott, Robert Jeffery. "Active-site variants of Streptomyces griseus protease B with peptide-ligation activity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0022/NQ51857.pdf.
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Addington, Trevor. "Engineering carbohydrate-active enzymes: specificity and activity remodeled." Doctoral thesis, Universitat Ramon Llull, 2009. http://hdl.handle.net/10803/9285.
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To understand and modify the secondary cell walls of plants the project group Enzyme Discovery in Hybrid Aspen for Fiber Engineering (EDEN) was founded composed of nine laboratories with funding from the European Commission. The main target of EDEN´s research is to genetically engineer fiber structure in order to produce transgenic trees with modified properties for the pulp and paper industries. In this target framework, the Populus tremula x tremuloides xyloglucan endotransglycosylase (PttXET16A) was selected for in-depth study of its transglycosylase activity catalyzing cleavage and reconnection of xyloglucan molecules, which is proposed to be involved in secondary cell wall morphogenesis.
The creation of a family 16 carbohydrate active enzyme -glucanase/XET hybrids were attempted in order to design a chimeric enzyme with one or more of the following altered properties: specificity, activity, and or stability.
The two enzymes, Bacillus licheniformis 1,3-1,4--glucanase and Populus tremula x tremuloides xyloglucan endotransglycosylase, are members of the same enzymatic family and have highly homologous 3-dimensional structures. However, the enzymes exhibit different activities, one a hydrolase the other a transferase; different specificities, one accepts only linear glcosydic substrates while the other branched substrates; and different stabilities.
Hybrid enzyme construction represented an investigational challenge in order to understand what physical characteristics of both enzymes attribute to the specific pattern of activity and specificity observed.
Removal of the 1,3-1,4--glucanase major loop resulted in a folded protein which still maintained some β-glucan hydrolase activity. However, no xyloglucan endotransglycosylase-like activity or specificity was observed. Next, point mutations of the β-sheets forming the enzymatic binding site cleft were mutated to resemble PttXET16A residues. The final chimeric protein neither exhibited XET nor β-glucanase activities. Structural analysis by X-ray crystallography revealed a major unexpected structural rearrangement providing a clear insight for further enzyme engineering.
Amb la finalitat d'entendre i modificar la paret cel·lular secundària de les plantes, es va fundar el grup Enzyme Discovery in Hibrid Aspen for Fibern Engineering (EDEN) composat per nou laboratoris amb la finançament de la Comissió Europea. El principal objectiu de la recerca del grup EDEN és enginyar genèticament l'estructura de fibres per tal de produir arbres transgènics amb propietats modificades per les indústries de la polpa i el paper.
En el marc d'aquest projecte, es va seleccionar el Populus tremula x tremuloides xiloglucà endotransglicosilasa (PttXET16A) per estudiar en profunditat la seva activitat transglicosilasa catalitzant el trencament i la reconnexió de molècules de xiloglucà, el qual sembla estar involucrat en la morfogènesi de la paret cel·lular secundària.
D'aquesta manera, s'intentà crear una família 16 d'híbrids de l'enzim actiu amb carbohidrats -glucanasa/XET per tal de dissenyar un enzim quimèric amb una o més de les propietats següents alterades: especificitat, activitat i/o estabilitat.
Els dos enzims, Bacillus licheniformis 1,3-1,4--glucanasa i Populus tremula x tremuloides xiloglucà endotransglicosilasa, són membres de la mateixa família enzimàtica i tenen una gran homologia en les seves estructures en 3-dimensions. Tot i així, aquests enzims presenten diferents activitats, un presenta activitat hidrolasa i l'altre, transferasa; diferents especificitats, un accepta només substrats glicosílics lineals mentre l'altre, substrats ramificats; i diferents estabilitats.
La construcció d'un enzim híbrid representa un repte en la investigació amb la finalitat d'entendre quines característiques físiques dels dos enzims s'atribueixen al model específic de l'activitat i especificitat observada.
L'extracció del llaç més gran de l'1,3-1,4--glucanasa va resultar en l'obtenció d'una proteïna plegada que encara manté certa activitat hidrolasa del -glucà. Tot i això, no s'observà activitat o especificitat similar a la xiloglucà endotransglicosilasa. A partir d'aquí, es realitzaren mutacions puntuals a diferents punts de les fulles que formen l'escletxa del lloc d'unió de l'enzim per assemblar-se als residus del PttXET16A. La proteïna quimèrica final tampoc presentava activitat XET ni -glucanasa. L'anàlisi de l'estructura per cristal·lografia de raigs X revelà una major reorganització estructural de l'esperada proveint el nou enzim d'un clar espai intern que obra moltes més portes a l'enginyeria de l'enzim.
Con la finalidad de entender y modificar la pared celular secundaria de las plantas, se fundó el grupo Enzyme Discovery in Hibrid Aspen for Fibern Engineering (EDEN) compuesto por nueve laboratorios con la financiación de la Comisión Europea. El principal objetivo de la búsqueda del grupo EDEN es ingeniar genéticamente la estructura de fibras para producir árboles transgénicos con propiedades modificadas para las industrias de la pulpa y el papel.
En el marco de este proyecto, se seleccionó el Populus tremula x tremuloides xiloglucán endotransglicosilasa (PttXET16A) para estudiar en profundidad su actividad transglicosilasa catalizando la rotura y la reconnexión de moléculas de xiloglucán, el cual parece estar involucrado en la morfogénesis de la pared celular secundaria. De esta forma, se intentó crear una familia 16 de híbridos de la enzima activa con carbohidratos -glucanasa/XET con la finalidad de diseñar una enzima quimérica con una o más de las propiedades siguientes alteradas: especificidad, actividad y/o estabilidad.
Las dos enzimas, Bacillus licheniformis 1,3-1,4--glucanasa y Populus tremula x tremuloides xiloglucà endotransglicosilasa, son miembros de la misma familia enzimática y tienen una gran homología en sus estructuras en 3-dimensiones. Aún así, estas enzimas presentan diferentes actividades, una tiene actividad hidrolasa y la otra, transferasa; diferentes especificidades, una acepta sólo sustratos glicosílicos lineales mientras la otra, sustratos ramificados; y diferentes estabilidades.
La construcción de una enzima híbrida representa un reto dentro de la investigación con la finalidad de entender qué características físicas de las dos enzimas se atribuyen al modelo específico de la actividad y especificidad observada. La extracción del lazo más grande de la 1,3-1,4--glucanasa resultó en la obtención de una proteína plegada que todavía mantiene cierta actividad hidrolasa del -glucán. Aún así, no se observó actividad o especificidad similar a la xiloglucán endotransglicosilasa. A partir de este punto, se realizaron mutaciones puntuales a diferentes puntos de las hojas que forman la brecha del lugar de unión de la enzima por asemejarse a los residuos del PttXET16A. La proteína quimérica final tampoco presentaba actividad XET ni -glucanasa. El análisis de la estructura por cristalografía de rayos X reveló una mayor reorganización estructural de la esperada proveyendo la nueva enzima de un claro espacio interno que obre muchas más puertas a la ingeniería de la enzima.
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Gretton, Heather Margaret. "Platelet monoamine oxidase type B (MAO-B) activity in psychopathy." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30619.
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Studies of platelet MAO-B activity have revealed a link between low platelet activity and psychiatric syndromes characterized by an inability to control impulses and to anticipate future consequences of behavior (Oreland, 1980; Gottfries, von Knorring, & Oreland, 1980). These characteristics are fundamental to the construct of psychopathy, and we might therefore expect that psychopathy is associated with low MAO activity. Indeed, some investigators have suggested that low platelet MAO-B activity is a potential marker for vulnerability to psychopathy (Schalling, Asberg, Edman, & Oreland, 1987). However, no study to date has directly examined the association between platelet MAO activity and psychometrically-sound indices of psychopathy. The present study measured platelet MAO-B activity in a sample of 54 male offenders, assessed with the Psychopathy Checklist-Revised (PCL-R; Hare, 1991). PCL-R scores were not significantly related to level of platelet MAO activity. The results are discussed in terms of methodological issues involved in conducting biochemical research.Arts, Faculty of
Psychology, Department of
Graduate
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Malicorne, Gilles. "Thiéno (2,3-b) et (3,2-b) pyridines synthèse et activité antibactérienne /." Grenoble 2 : ANRT, 1987. http://catalogue.bnf.fr/ark:/12148/cb376075729.
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Malicorne, Gilles. "Thiéno (2,3-b) et (3,2-b) pyridines : synthèse et activité antibactérienne." Montpellier 2, 1987. http://www.theses.fr/1987MON20277.
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DESMARTIN, VINCENT. "Synthese et activite cholinergique d'imidazo(1,2-b)pyridazines." Strasbourg 1, 1994. http://www.theses.fr/1994STR15050.
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Ludlow, Helen. "Novel and improved immunoassays for Activin B and Inhibin B and their clinical applications." Thesis, Oxford Brookes University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493408.
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The functional roles of inhibin and activin and clinical applications of measuring them in serum have been reported in a large number of publications. Commercial enzyme-linked immunosorbent assays (ELISAs) for inhibin A, inhibin B and activin A are already available on the market globally.
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Czor, Mathias. "Angoisse et activité ludique." Doctoral thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/25891.
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Dans cette thèse qui traite du rapport entre l'angoisse et l'activité ludique, nous reprenons les grands thèmes de l'angoisse : existentielle, morale, absurde. Nous explorons ses nombreux traits : la condition humaine, la mortalité, l'absurdité, l'inconnu, le possible, le néant. Nous abordons la liberté qui en constitue une des composantes essentielles. S'y ajoutent des émotions proches de l'angoisse. Cette thèse trace, dans les grandes lignes, la description de ce que le jeu implique, requiert, accomplit, la forme qu'il prend et la place que cette activité, que nous considérons souvent comme à l'opposé du sérieux, occupe dans notre quotidien. Nous offrons différents points de vue sur ses caractéristiques, notamment l'esthétique, l'irréel, le passif, l'actif et le subjectif. Nous faisons également une description de plusieurs jeux, ce qui nous permet d'analyser les différentes attitudes possibles du joueur, qui impliquent sa subjectivité, sa maturité et son besoin de se dépenser dans des circonstances peu dangereuses. Enfin, nous mettons en relation ces deux concepts, angoisse et jeu, qui l'un comme l'autre demandent la liberté. Ce travail s'inspire et partage les écrits d'auteurs anciens et récents qui traitent de ces sujets, dont les incontournables Buytendijk, Caillois, Fink, Gadamer, Heidegger, Huizinga, Kierkegaard et Sartre. Nous y abordons d'importantes facettes de la vie qui amèneront le lecteur à développer et à prendre position sur ses propres définitions de l'angoisse et du ludique. Notre objectif est de mettre en évidence le rôle indispensable du jeu, de ses effets dans la vie humaine et de démontrer son influence sur l'angoisse.This thesis written about the relation between angst and play, gives the main definitions of angst : existentialism, culpability, absurdity. We explore the traits of angst : human condition, mortality, absurdity, unknown, possibilities and void. We explain many feelings close to angst. This thesis traces wide lines to describe what play implies, requires, achieves, what forms it takes and where this activity that we often consider the opposite of serious takes place in everyday's existence. Also, we describe many characteristics of play, mainly esthetic, unreal, passive, active, subjective. Many games are also explained. We touch different theories about the player, which imply his subjectivity, maturity and his need to spend energy in non-dangerous activities. Then, we show the relation between play and angst, two concepts that require liberty. Inspired by great authors, old and modern, of those we have to mention Buytendijk, Caillois, Fink, Gadamer, Heidegger, Huizinga, Kierkegaard and Sartre ; we describe important parts of life, which will bring the reader to develop and take position on his view of play and angst. This is to show the irreplaceable role of play and its attributes in the human life but even more to push the limits of knowledge on play, and show play's influence on angst.
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駱淑芳 and Suk-fong Anna Lok. "Replication of hepatitis B virus in Chinese patients with chronic hepatitis B virus infection." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1990. http://hub.hku.hk/bib/B31981392.
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Wu, Kechun. "Solubility and manipulation of disulfides in puroindoline-b: Recombinant puroindoline-b shows antifungal activity." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/27083.
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Wheat (Triticum aestivum) kernel texture (hardness) is the most important determinant of milling and end-product quality. Recent data indicate that the only difference between soft and hard textured wheat is a single amino acid mutation in one protein, puroindoline-b (PIN-b). A rare tryptophan-rich domain in this protein consists of five tryptophan residues among a stretch of seven amino acid residues. To understand how this single mutation makes hard wheat possible, thus enabling bread making, it is crucial to have a high-resolution three-dimensional structure of this protein. The prerequisite for structural elucidation of any protein is the high-quality sample preparation.
In this thesis PIN-b from a diploid wheat (Triticum monococcum ) was chosen as the model system because its grain is soft and it has the simplest genome of all wheats. The coding sequence of PIN-b was amplified from the diploid wheat using PIN-b specific primers. It was cloned into a protein expression vector. PIN-b was expressed as a protein behind the thioredoxin (TRX-a) tag. The TRX-a-PIN-b fusion protein was purified using nickel chelating chromatography. The immunological identity of the fusion protein was confirmed by Western blot. The PIN-b was released from the fusion protein by enterokinase proteolysis and purified using ion exchange chromatography. After glutathione treatment to facilitate full formation of the potential five disulfide bonds, PIN-b demonstrated higher fungicidal activity when compared to the non-treated PIN-b.
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Patel, Pratiq A. "Functionalization of Nitrogen-Containing Heterocycles in the Synthesis of Biologically Active Molecules." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1382064973.
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Gautier, Nicolas. "Contribution de la vaccination spécifique chez les patients atteints d'hépatite virale B chronique active : à propos d'un cas." Bordeaux 2, 1999. http://www.theses.fr/1999BOR2M164.
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Lefebvre, Haidee. "B-boy (dance) cipher: an innovative knowledge community's shared activity." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106265.
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My study focuses on b-boying, the archetype of hiphop dance, to better understand the informal teaching and learning processes embodied in the freestyle or raw b-boy cipher (improvisational dance circle). I draw from an ethnographic approach to investigate how hiphop aesthetic practices influence people's ways of doing and habits of mind. In particular, participant observation structures my activities at 13 hiphop events. These observations are complemented by an in-depth interview with Buddha, co-founder of the Canadian Floor Masters, Canada's oldest b-boy dance crew. The theoretical framework uses Lave and Wenger's concept of situated learning in tandem with Nonaka's organizational theory of knowledge creation. By analyzing the cipher as a potential site for dancers to experience a conscious readiness to change I find that 1) situated learning and knowledge creation are closely related; 2) knowledge creation and hiphop practices are connected; 3) b-boy culture resembles an innovative knowledge community that shares personal knowledge to create and advance communal knowledge. The research approach I practice may help educators better understand how a neighbourhood activity created over 30 years ago by and for some South Bronx youth has developed into a global practice produced and consumed by many of today's youth and adults.Mon étude porte sur le b-boying (break boy, danseur), archétype de la danse hip-hop, pour dégager l'enseignement et les procédés d'apprentissage informels inhérents aux cercles de danse improvisée – création libre (freestyle ou raw cipher). Ma méthodologie intègre certains aspects d'observation participante selon la trajectoire de recherche s'intéressant à l'influence des pratiques hip-hop sur les façons de faire et de penser. Ceci oriente mon observation participante de 13 événements et mon entrevue en profondeur avec Buddha, de la plus ancienne troupe de breaking du Canada, Canadian Floor Masters. Mon cadre théorique s'appuie sur l'apprentissage situé de Lave et Wenger, et la création du savoir de Nonaka. J'analyse le cercle de danse comme lieu permettant de s'ouvrir consciemment au changement, constatant que : 1) il existe une corrélation entre l'apprentissage situé et la création du savoir; 2) la création du savoir et les pratiques hip-hop sont interreliées; 3) la culture b-boy évoque une communauté de savoir novatrice partageant des connaissances personnelles pour générer et faire progresser un savoir collectif. Mon approche aiderait les éducateurs à mieux comprendre comment cette activité de quartier créée il y a trente ans, par et pour des jeunes du South Bronx, s'est transformée en pratique réalisée et consommée à l'échelle du globe par les jeunes et les adultes contemporains.
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Saohin, Wipawee. "Studies on the stability and activity of polymyxin B solutions." Thesis, Robert Gordon University, 1997. http://hdl.handle.net/10059/606.
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The correlation between the chemical stability and the microbiological activity of polymyxin B in phosphate buffer pH 6.0 and in proprietary eye drops was evaluated. High Performance Liquid Chromatography (HPLC) was used to quantify the amount of the main components in samples stored at 43,50,55 and 60°C for a period of 500 h. The data indicated that there are significant differences in chemical stability among the different proprietary eye drops. The accurate decomposition rate constants and shelf-lives (~o) at 4°C of two of the six formulated eye drops and the standard polymyxin B solution stored in glass containers at pH 6.0 were established. It was concluded that microbiological assay by agar diffusion was unsuitable for determining the activity of control polymyxin B in phosphate buffer and polymyxin B in eye drops. Killing time determinations for polymyxin B against cell suspensions of P. aeruginosa NCTC 6750 were consequently used. Thioglycollate broth containingp- aminobenzoic acid (PABA) 0.16 %w/v and magnesium sulphate 1 %w/v was used as an inactivating recovery medium. The effect of preservatives and of second antibacterials contained in the eye drops were tested individually and combined with polymyxin B. Thiomersal 0.001 %w/v, trimethoprim 0.02 %w/v and thiomersal 0.001 %w/v plus trimethoprim 0.02 %w/v did not have an effect on the activity of polymyxin B 2000 U/ml. Neomycin was an exception and at the concentrations in the range 0.0192 to 0.16 %w/v exhibited an antagonistic effect. Chemical interaction between polymyxin B and neomycin could not be detected and it was considered that the inhibitory effect of neomycin may be the result of competition between polymyxin B and neomycin for the same binding sites on the cell surface. Gentamicin is active against P. aeruginosa NCTC 6750 and at concentrations of 0.075 and 0.036 %w/v it exhibited an additive effect with polymyxin B 2000 U/ml against the test organism. The results obtained with the samples stored at 55°C for a period of 500 h demonstrated the critical effect of pH. At a pH of 6.0 microbiological activity and chemical stability appeared optimal. The chemical stability data of five eye drop samples correlated with microbiological activity data. Exceptions were polymyxin B in one eye drop sample and control polymyxin B. These extensively decomposed samples showed good antibacterial activity which appeared to result from the activity of decomposition products. Chemical stability data for standard polymyxin B solution at pH 6.0 also correlated to microbiological activity data over the temperature range of 92 - 115°C. The polymyxin B retained detectable microbiological activity when the amount of PB1 was greater than 20%. It is suggested that the decomposition products which occurred at these higher temperatures did not possess antibacterial activity.
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Wu, Kwan-I. "NF kappa B expression and matrix metalloproteinase activity in hypertension." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1467958.
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Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed September 17, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 42-47).
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Mbongo, Nicolas. "Activite, mode d'action de complexes organometalliques et mecanismes de resistance a l'amphotericine b chez les leishmanies." Paris 11, 1997. http://www.theses.fr/1997PA114816.
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Saint-Auret, Sarah. "Synthèse totale de mycolactone A/B et d'analogues ciblés pour l'étude mécanistique de l'ulcère de Buruli." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF049.
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L’ulcère de Buruli est une maladie nécrotique de la peau présente dans plus de trente pays dans le monde, et affectant principalement le continent africain et l’Océanie. L’infection est due à Mycobacterium ulcerans (M. ulcerans), un micro-organisme qui sécrète une exotoxine appelée mycolactone, représentant le premier polycétide isolé d’un pathogène humain. La maladie est caractérisée par la formation progressive de lésions nécrotiques combinée à une absence de réponse immunitaire et de sensation de douleur ; la mycolactone est connue pour être directement impliquée dans ce mécanisme biologique. A ce jour, aucun traitement totalement performant et spécifique contre l’ulcère de Buruli n’a été développé, ce qui révèle le manque crucial de connaissances sur les mécanismes chimique et biologique. Dans ce contexte, le projet développé s’intéresse à l’élucidation du mécanisme d’action des mycolactones en utilisant la synthèse totale comme outil principal. Pour cela, notre équipe a mis au point une voie de synthèse modulaire permettant la préparation de la toxine naturelle et de ses différents analogues en vue de les tester biologiquement et d’affiner ainsi notre compréhension mécanistique de cette infectionBuruli ulcer is a necrotizing skin disease present in more than thirty countries in the world, located mainly in West and Central Africa but also in Australia and in Japan. This infection is caused by Mycobacterium ulcerans (M. ulcerans) that secretes a macrolide toxin called mycolactone, which is the first polyketide isolated from a human pathogen. The disease is characterized by the formation of painless progressive necrotic lesions combined with a lack of acute inflammatory response, and mycolactone is known to be directly involved in the biological mechanism. To date no specific and completely efficient treatment of Buruli ulcer has been developed which correlates with the dramatic lack of understanding of the associated chemical and biological mechanisms. In this context, this research project aims at a better understanding of mycolactone A/B molecular interactions by using total synthesis as main tool. To this end, our research team has developed an efficient synthetic pathway allowing the preparation of the natural toxin and its differents analogues for purposes of their biological evaluation and fine-tuning our mechanical understanding of this infection
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Batisse, Cornélie. "Targeting strategies using B-subunit of Shiga toxin : innovative drug-delivery systems." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB220.
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Les stratégies thérapeutiques mises en place contre le cancer ont de nos jours besoin de nouveaux médicaments, à la fois plus actifs que ceux déjà existants et induisant moins d’effets secondaires. Ces nouvelles stratégies visent à cibler spécifiquement les cellules cancéreuses. Parmi ces stratégies, ces travaux de thèse concernent la vectorisation active, à l’aide d’un vecteur protéique dérivé de la toxine de Shiga, STxB. STxB reconnait spécifiquement son récepteur biologique Gb3, surexprimé à la surface des cellules cancéreuses humaines. Ce projet de recherche porte sur la conception et la synthèse de conjugués, combinant STxB et un agent cytotoxique. Le linker chimique, qui relie ces deux espèces, a été soigneusement conçu pour respecter les deux critères suivants : être suffisamment stable et néanmoins pouvoir être clivé pour libérer l’agent cytotoxique une fois les cellules cancéreuses atteintes. Un premier linker a été construit autour du motif mercaptoethanol, lié au vecteur STxB par une liaison disulfure. La libération de l’agent cytotoxique peut donc être initiée par un réducteur biologique comme le glutathion, puis par une étape d’auto-immolation. Ce linker a été appliqué à deux composés cytotoxiques très puissants, dérivés de l’auristatine, et a conduit à des résultats prometteurs in vitro. La labilité de la liaison ester à pH acide a également été mise à profit dans l’élaboration de deux linkers, conçus autour de motifs glutamate et thréoninate. L’utilisation d’un agent cytotoxique modérément puissant a été l’occasion de développer une stratégie de multivalence, consistant à augmenter la charge d’agents cytotoxiques sur STxB. Une autre option a été de considérer les nano-batônnets d’or comme une plate-forme nanométrique multimodale, capable de lier plusieurs milliers d’agents cytotoxiques et STxB. Enfin l’incorporation d’une séquence peptidique, connue pour être substrat d’une protéase, a donné lieu à une troisième étude, reposant sur un linker clivable plus sélectivement. Plusieurs linkers ont été étudiées, selon qu’ils libèrent l’agent cytotoxique sous sa forme native ou nonWe need new therapeutic strategies to treat cancerous patients by the discovery of new drugs that would be more active than those existing and especially assigning fewer side effects. These new therapies aim to specifically target cancer cells. Among the strategies for cancer targeting, we investigated drug-targeted strategies using a proteic carrier, STxB, derived from Shiga toxin. This protein recognizes specifically its biological receptor Gb3, which is over-expressed on human cancer cells. This work consisted in the design and synthesis of conjugates combining STxB and a cytotoxic drug. The chemical linker binding these two moieties was carefully designed in order to fit requirements of both stability and ability to trigger a drug-delivery. A first linker was designed around a mercaptoethanol core, able to be conjugated to STxB by a disulfide bond. This constitutes a drug-delivery trigger, activated by a biological reducing agent such as glutathion, and followed by a self-immolative step. Two highly potent conjugates of auristatin derivatives were obtained and showed promising results in vitro. The ester bonds lability in acidic pH was exploited for the design of two amino acid based linker. With the aim of increasing the ratio of drug on STxB, we investigated several multivalent linkers. Another option was to consider gold nanorods as a nanometric platform, able to carry thousands of drugs and STxB. The incorporation of a protease substrate to produce an enzyme-cleavable linker was investigated. Several spacers, which induced release of the drug under native form or under prodrug form, were designed and tested
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Svedendahl, Maria. "Exploring Conjugate Addition Activity in Pseudozyma antarctica Lipase B." Licentiate thesis, KTH, Skolan för bioteknologi (BIO), 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-11598.
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Multifunctional enzymes have alternative functions or activities, known as “moonlighting” or “promiscuous”, which are often hidden behind a native enzyme activity and therefore only visible under special environmental conditions. In this thesis, the active-site of Pseudozyma (formerly Candida) antarctica lipase B was explored for a promiscuous conjugate addition activity. Pseudozyma antarctica lipase B is a lipase industrially used for hydrolysis or transacylation reactions. This enzyme contains a catalytic triad, Ser105-His224-Asp187, where a nucleophilic attack from Ser105 on carboxylic acid/ester substrates cause the formation of an acyl enzyme. For conjugate addition activity in Pseudozyma antarctica lipase B, replacement of Ser105 was assumed necessary to prevent competing hemiacetal formation. However, experiments revealed conjugate addition activity in both wild-type enzyme and the Ser105Ala variant. Enzyme-catalyzed conjugate additions were performed by adding sec-amine, thiols or 1,3-dicarbonyl compounds to various α,β-unsaturated carbonyl compounds in both water or organic solvent. The reactions followed Michaelis-Menten kinetics and the native ping pong bi bi reaction mechanism of Pseudozyma antarctica lipase B for hydrolysis/transacylation was rerouted to a novel ordered bi uni reaction mechanism for conjugate addition (Paper I, II, III). The lipase hydrolysis activity was suppressed more than 1000 times by the replacement of the nucleophilic Ser105 to Ala (Paper III).
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CHIEUX, VINCENT. "Proteine mxa : activite antivirale et interet medical." Lille 2, 2000. http://www.theses.fr/2000LIL2T003.
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Feldhahn, Niklas. "Mimicry of a constitutively active pre-B cell receptor in BCR-ABL1-transformed pre-B leukemia cells." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=979851769.
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Kahi, Sandrine. "Activité lymphocytaire spécifique au cours de la toxoplasmose congénitale humaine." Lyon 1, 1999. http://www.theses.fr/1999LYO1T126.
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Mehrvarzi, Christopher Omid. "Active Transport in Chaotic Rayleigh-Be?nard Convection." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/51806.
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The transport of a species in complex flow fields is an important phenomenon related to many areas in science and engineering. There has been significant progress theoretically and experimentally in understanding active transport in steady, periodic flows such as a chain of vortices but many open questions remain for transport in complex and chaotic flows. This thesis investigates the active transport in a three-dimensional, time-dependent flow field characterized by a spatiotemporally chaotic state of Rayleigh-Be?nard convection. A nonlinear Fischer-Kolmogorov-Petrovskii-Piskunov reaction is selected to study the transport within these flows. A highly efficient, parallel spectral element approach is employed to solve the Boussinesq and the reaction-advection-diffusion equations in a spatially-extended cylindrical domain with experimentally relevant boundary conditions. The transport is quantified using statistics of spreading and in terms of active transport characteristics like front speed and geometry and are compared with those results for transport in steady flows found in the literature. The results of the simulations indicate an anomalous diffusion process with a power law 2 < ? < 5/2 a result that deviates from other superdiffusive processes in simpler flows, and reveals that the presence of spiral defect chaos induces strongly anomalous transport. Additionally, transport was found to most likely occur in a direction perpendicular to a convection roll in the flow field. The presence of the spiral defect chaos state of the fluid convection is found to enhance the front perimeter by t^3/2 and by a perimeter enhancement ratio r(p) = 2.3.Master of Science
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Tian, Wen. "Etude phytochimique de Zanthoxylum unifoliolatum T. G. Hartley, ined. : synthèse et activité biologique de dérivés aminés et d'aza-analogues de la benzo[b]acronycine." Paris 5, 2004. http://www.theses.fr/2004PA05P617.
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Les benzo[c]phénanthridines sont des alcaloïdes largement présents dans les plantes de la famille des Rutaceae(genre Zanthoxylum et Toddalia). Ces composés présentent des activités antileucémiques, antiinflammatoires et antimicrobiennes. La première partie de ce travail porte sur l’étude phytochimique d’une nouvelle espèce, Zanthoxylum unifoliolatum T. G. Hartley, ined. , Rutaceae endémique de la Nouvelle Calédonie. A partir des écorces de tronc une coumarine et douze alcaloïdes ont été isolés, deux furoquinoléines et dix benzo[c]phénanthridines dont, deux nouveaux composés dérivés de l’avicine et de la nitidine. L’acronycine (3,12-dihyro-6-méthoxy-3,3,12-triméthyl-7H-pyrano[2,3-c]acridin-7-one) alcaloïde isolé d’Acronychi baueri Schott (Rutaceae) possède un large spectre d’activité sur des tumeurs expérimentales animales mais son évaluation clinique n’avait connu qu’un succès limité en raison de son insolubilité dans les solvants biocompatibles et de sa faible puissance. Des produits plus puissants ont déjà été synthétisés dans notre laboratoire d’accueil et l’un d’entre eux, la (±)cis-1,2-diacétoxy-6-méthoxy-1,2,3,14-tétrahydro-3,3,14-triméthyl-7H-benzo[b]pyrano[3,2-h]acridin-7-one est actuelle-ment en essais clinique de phase I, sous la référence S23906-1. Dans la deuxième partie de ce travail deux séries de composés d’hydrosolubilité accrue ont été préparés, des dérivés aminés et des aza-analogues de série benzo[b]acronycine. Leur activité cytotoxique, in vitro, a été évaluée sur des cultures de cellules leucémiques murines L1210 et de tumeur humaine du côlon HT 29. Leur cytotoxicité reste comparable à celle des dérivés de la série benzo[b]acronycine et les composés les plus actifs ont été sélectionnés et font actuellement l’objet d’une évaluation in vivo chez la Souris vis-à-vis du carcinome du côlon 38The first part of this work describes the chemical investigation of a new neocaledonian endemic species of Zanthoxylum, Zanthoxylum unifoliolatum. From the bark of Zanthoxylum unifoliolatum T. G. Hartley, ined, were isolated one coumarin and twelve alkaloids, two furoquinolines and ten benzo[c]phenanthridines. Two compounds of the benzo[c]phenanthridine series are new and were determined on the basic of the spectral data as the 6-methoxynoravicine and the 6-methoxynornitidine. The alkaloid acronycine ( 6-methoxy-3,3,12-trimethyl-3,12-dihydro-7H-pyrano-[2,3-c]acridin-7-one ), first isolated from Acronychia baueri Schott (Rutaceae), was subsequently shown to exhibit a broad spectrum of activity against numerous experimental tumors models. Neverthless, clinical trials gave only poor results, probably due to the moderate potency of this alkaloid. Further on, structural analogues with an additional aromatic ring linearly fused on the natural alkaloid skeleton were developed, and several cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one diesters proved even more potent. Among them, the cis-1,2-diacetate, currently under preclinical development under the code S 23906-1, and two series of amino derivatives have been prepared. Their in vitro cytotoxic activities have been evaluated against the murine L1210 leukemia cell line and the human colon tumor HT29, and are shown to exhibit cytotoxic activities comparable to those of their benzo[b]acronycine counterparts. One of the compounds is currently evaluating in vivo against the tumors colon 38 in mice
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Motalli, Rita Nadia. "GABA[subscript]B receptors and epileptiform activity in the juvenile rat hippocampus." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0025/MQ50840.pdf.
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Zerbini, Francesca <1982>. "Polymerizing activity and regulation of group B Streptococcus pilus 2a sortase C1." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6480/.
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Group B Streptococcus [GBS; Streptococcus agalactiae] is the leading cause of life-threatening diseases in newborn and is also becoming a common cause of invasive diseases in non-pregnant, elderly and immune-compromised adults. Pili, long filamentous fibers protruding from the bacterial surface, have been discovered in GBS, as important virulence factors and vaccine candidates. Gram-positive bacteria build pili on their cell surface via a class C sortase-catalyzed transpeptidation mechanism from pilin protein substrates. Despite the availability of several crystal structures, pilus-related C sortases remain poorly characterized to date and their mechanisms of transpeptidation and regulation need to be further investigated. The available three-dimensional structures of these enzymes reveal a typical sortase fold except for the presence of a unique feature represented by an N-terminal highly flexible loop, known as the “lid”. This region interacts with the residues composing the catalytic triad and covers the active site, thus maintaining the enzyme in an auto-inhibited state and preventing the accessibility to the substrate. It is believed that enzyme activation may occur only after lid displacement from the catalytic domain. In this work we provide the first direct evidence of the regulatory role of the lid, demonstrating that it is possible to obtain in vitro an efficient polymerization of pilin subunits using an active C sortase lid mutant carrying a single residue mutation in the lid region. Moreover, biochemical analyses of this recombinant mutant reveal that the lid confers thermodynamic and proteolytic stability to the enzyme. A further characterization of this sortase active mutant showed promiscuity in the substrate recognition, as it is able to polymerize different LPXTG-proteins in vitro.
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Zhang, Liying. "NF-[kappa]B induces rat androgen receptor promotor activity in Sertoli cells." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080805.
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Grundy, Martin. "Activity of the aurora kinase B inhibitor AZD1152 in acute myeloid leukaemia." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12758/.
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Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies including those of leukaemic origin. Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells whose prognosis is particularly poor and where standard induction therapy has changed little over the past thirty years. This thesis evaluated the effects of AZD1152-hQPA (barasertib-hQPA), a highly selective inhibitor of aurora-B kinase, in AML cell lines and primary samples. Inhibition of phospho-Histone H3 (pHH3) on serine 10 can be used as a biomarker for AZD1152-hQPA activity and an assay was optimized to measure pHH3 in our cell lines and primary samples. AZD1152-hQPA inhibited pHH3 in our cell lines resulting in polyploid cells, apoptosis, and cell death, irrespective of cellular p53 status. Over-expression of the ATP-binding cassette (ABC) drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in AML. A cell line which over-expresses Pgp was developed by selecting for daunorubicin (DNR) resistance in OCI-AML3 cells. Pgp and also BCRP expressing AML cell lines were found to be resistant to AZD1152-hQPA and it was found that AZD1152-hQPA is effluxed by these transporters. pHH3 inhibition by low dose AZD1152-hQPA was seen in all of the primary samples tested with Pgp and BCRP positive samples being less sensitive. However, 50% inhibition of pHH3 by AZD1152-hQPA was achieved in 94.6% of these samples. The FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines were particularly sensitive to AZD1152-hQPA. Internal tandem duplications (ITDs) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. It was demonstrated that AZD1152-hQPA directly targets phosphorylated FLT3 in the FLT3-ITD cell lines along with inhibiting its downstream target pSTAT5. FLT3-ITD primary samples were particularly sensitive to clonogenic inhibition and pSTAT5 down-regulation after treatment with AZD1152-hQPA compared with FLT3 wild-type (WT) samples.
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Peltekian, Cécile. "Activité antivirale de la protéine MxA contre le virus de l'hépatite B." Paris 7, 2004. http://www.theses.fr/2004PA077139.
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Hodge, Mathis. "Synthesis and Antiproliferative Activity of C3' and B-ring Modified Paclitaxel Analogs." Thesis, Virginia Tech, 2007. http://hdl.handle.net/10919/30940.
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The natural product, paclitaxel, has made tremendous contributions in supplying the arsenal of anticancer therapeutics, and was FDA approved for clinical use in 1992. In order to design simplified analogs, the conformation that paclitaxel adopts when binding to tubulin has been the subject of ongoing studies. Much evidence has led to a T-taxol proposal and a C3' constrained analog has been designed and synthesized as a test of this conformation. In the search for more active analogs, a number of modifications have been made to paclitaxel by other researchers. However, the nature of the alterations, and combinations thereof, have not been exhausted. To this end, synthesis of northern hemisphere B-ring analogs is underway.Master of Science
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Nusair, Arwa Y. "Comparison of Aspartate Transcarbamoylase Activity Between Pseudomonas Aeruginosa Which Has One Chromosome and Burkholderia Cepacia Which Has Three Chromosomes." Thesis, University of North Texas, 2012. https://digital.library.unt.edu/ark:/67531/metadc149646/.
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The pyrimidine biosynthetic pathway is essential and similar in all bacteria. The pathway from Pseudomonas is regulated by nucleotides which bind to the upstream region of the pyrBC’ gene complex. Work in our lab mapped the genes and showed that the pyrB and pyrC’ were part of an overlap complex. The Pseudomonas aeruginosa has one circular chromosome. A former Pseudomonas now called Burkholderia cepacia is similar to P. aeruginosa except that it contains three circular chromosomes (CI, CII, CIII) and one large plasmid. The primary chromosome named CI contains the pyrBC’. To our knowledge there has been no report of the activity of ATCase in Pseudomonas and contrasted with that of Burkholderia. Here, we compare the activity of ATCase in P. aeruginosa and B .cepacia. Cells of both organisms were grown in Pseudomonas minimal medium and in Enriched medium. The ATCase was extracted and partially purified from each sample. It is hypothesized that the B. cepacia has greater activity for ATCase than do the Pseudomonas.
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Whitted, Crystal L. "Pharmacokinetics, Tissue Distribution, Synergistic Activity, and Antitumor Activity of Two Isomeric Flavones." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3167.
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Flavonoids are polyphenolic secondary metabolites found in plants that have bioactive properties including antiviral, antioxidant, and anticancer. Two isomeric flavone were extracted from Gnaphalium elegans and Achyrocline bogotensis, plants used by the people from the Andean region of South America as remedies for cancer. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5, 7–dihydroxy- 3, 6, 8 trimethoxy flavone/ flavone A) and 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3, 5–dihydroxy-6, 7, 8–trimethoxy flavone/ flavone B) have shown antineoplastic activity against colon cancer cell lines dependent upon their differentiation status. Pharmacokinetic studies reported herein were used to determine dosing for antitumor assays, as well as determine target tissue concentration. These included the development of methods to extract the flavones from plasma or colon tissue and reverse phase high performance liquid chromatography methods for quantification. Quantification methods were linear (r2 ≥ 0.99) with plasma calibration curves ranging from 250 - 2,500 ng/mL and 2,500 - 100,000 ng/mL for both flavones and colon calibration curves ranging from 250 – 100,000 ng/g (flavone A) and 1,000-25,000 ng/g (flavone B). Intravenous administration of a 20 mg/kg dose in rats yielded half-lives of 83.68 ± 56.61 and 107.45 ± 53.31 minutes with clearance values of 12.99 ± 13.78 and 80.79 ± 35.06 mL/min/kg for flavones A and B, respectively. Analysis of colon tissue yielded concentrations of 1639 ± 601 ng/g (flavone A) and 5975 ± 2480 ng/g (flavone B), suggesting both may be good candidate for individual or adjunct therapy for colon cancer due to distribution to the target tissue. Preliminary studies in colon cancer cells CaCo 2 and HCT 116 using either flavone in combination with 5-fluorouracil (5-FU) suggested synergistic activity of these compounds. The combination treatment increased induction of apoptosis by enhancing the DNA damaging mechanism of 5-FU. In vivo, preliminary xenograft experiments using HCT 116 cells showed smaller tumors in mice dosed with flavone B as compared to the 5-FU or combination treatment. Further experiments are warranted to confirm these observations.
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Kanamori, Yohei. "Transcriptional regulation of hepcidin by molecules mediating inflammatory responses." Kyoto University, 2018. http://hdl.handle.net/2433/232336.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第21135号
農博第2261号
新制||農||1057(附属図書館)
学位論文||H30||N5109(農学部図書室)
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 松井 徹, 教授 久米 新一, 教授 廣岡 博之
学位規則第4条第1項該当
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Schob, Stefan, Jonas Meyer, Matthias Gawlitza, Clara Frydrychowicz, Wolf Müller, Matthias Preuss, Lionel Bure, Ulf Quäschling, Karl-Titus Hoffmann, and Alexey Surov. "Diffusion-weighted MRI reflects proliferative activity in primary CNS lymphoma." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-210909.
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Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples.
Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several
previously published studies—indicate an increased cellularity within the tumor.
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Jourand, David. "Etude théorique du mécanisme réactionnel de la neuraminidase d'Influenza B : conception d'un algorithme de Drug Design." Université Joseph Fourier (Grenoble), 1997. http://www.theses.fr/1997GRE10158.
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Deux types de recherches complementaires concernant la neuraminidase du virus influenza sont presentes : d'une part l'etude theorique de son mecanisme catalytique et d'autre part la conception d'un algorithme de drug design theoriquement capable de creer des ligands interagissant avec son site actif. Des etudes experimentales et cristallographiques de la neuraminidase d'influenza b, qui hydrolyse un acide sialique terminal de glycoproteines, de glycolipides, ou d'oligosaccharides ont permis d'identifier le site actif et de proposer des mecanismes reactionnels possibles. Cette reaction se realise en deux etapes successives : - formation d'un oxocarbonium, intermediaire reactionnel a partir du substrat (sialilactose), - formation de l'acide sialique a partir de l'oxocarbonium. Le systeme a ete modelise par un potentiel mixte combinant mecanique quantique et mecanique moleculaire. Le site actif est ainsi traite en mecanique quantique tandis que le reste du systeme est traite en mecanique moleculaire. Puis le chemin a ete determine pour quatre modeles differents par un algorithme dedie, chain. Les resultats obtenus permettent de modifier le chemin propose, en montrant que certaines hypotheses faites quant a la stabilisation de l'oxocarbonium par le site actif sont erronees. Ils montrent egalement que plusieurs mecanismes sont possibles, mais avec des probabilites de realisation differentes. Alors que la plupart des algorithmes de drug design existants (grid, mcss) utilisent des ligands/inhibiteurs connus et proposent des derives de ceux-ci afin de bloquer/occuper le site actif, celui decrit dans ce travail se propose de creer des ligands de novo ne dependant d'aucune bibliotheque pre-existante. Pour cette raison, l'algorithme a ete teste sur deux systemes modeles simples avant d'etre applique a la structure minimisee de la neuraminidase complexee a l'oxocarbonium, un ligand initial (dana) plus ou moins modifie etant neanmoins fourni. Malgre le fait que le ligand obtenu a tendance a etre le plus grand possible, la superposition des structures observees montre clairement la faisabilite d'un tel algorithme. De plus, les temps de calculs relativement courts le rendent plus souple, permettant de generer de nombreuses solutions. Un tel algorithme, mene a terme, serait tres prometteur.
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Gordien, Nerville Emmanuel. "Activite antivirale de la proteine mxa inductible par le systeme interferon de type 1 sur le virus de l'hepatite b." Paris 5, 2000. http://www.theses.fr/2000PA05N124.
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Gadd, Samantha. "Acetaminophen-induced proliferation of estrogen-responsive breast cancer cells is associated with increased c-mcy RNA expression and NF-kB activity." Morgantown, W. Va. : [West Virginia University Libraries], 2001. http://etd.wvu.edu/templates/showETD.cfm?recnum=2016.
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Thesis (Ph. D.)--West Virginia University, 2001.Title from document title page. Document formatted into pages; contains xi, 147 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 128-143).
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Tzellos, Stelios. "Mechanism of superior B cell immortalisation activity of type 1 Epstein-Barr virus." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/23223.
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Epstein-Barr virus (EBV) establishes lifelong latent infections in humans. EBV isolates worldwide are classified as type 1 or type 2 based on their EBNA-2 gene sequence. Type 1 EBV is more efficient at B cell transformation, a property previously mapped to the EBNA-2 locus. Previous work using EREB2.5 cells in a trans-complementation assay showed that the superior ability of type 1 EBNA-2 to sustain B cell proliferation is mostly determined by its C-terminal region. In this study, conversion of a single amino acid in the transactivation domain (TAD), from serine in type 2 EBNA-2 to the aspartate residue in the type 1 protein (S442D), was remarkably found to confer the type 1 growth-promoting phenotype in the EREB2.5 growth assay. The mechanism of the greater transformation efficiency of type 1 EBV appears to involve differential regulation of EBNA-2 target genes. The superior growth properties of type 1 EBNA-2 correlate with the greater induction and activation of viral LMP-1 and cellular CXCR7, compared to type 2 EBNA-2. 5' RACE was used to identify the transcription start site (TSS) of the CXCR7 promoter transcribed in response to EBNA-2. In chromatin immunoprecipitation (ChIP) assays, type 1 EBNA-2 was found to associate more strongly than the type 2 protein with EBNA-2 binding sites near the LMP-1 and CXCR7 genes. D442 was shown to increase binding of type 2 EBNA-2 to some sites at differentially regulated genes. Unbiased motif searching identified an ETS-interferon regulatory factor (IRF) composite element (EICE) that closely resembles the sequence known to mediate EBNA-2 regulation of the LMP-1 promoter. This element may therefore confer the differential effects of type 1 and type 2 EBNA-2 on both LMP-1 and cell gene activation resulting in superior immortalisation by type 1 EBV.
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ARPINI, R. H. "A Framework to Support the Assignment of Active Structure and Behavior in Enterprise Modeling Approaches." Universidade Federal do Espírito Santo, 2012. http://repositorio.ufes.br/handle/10/4260.
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Previous issue date: 2012-08-31The need to relate the various architectural domains captured in partial descriptions of an enterprise is addressed in virtually all enterprise modeling approaches. One of these domains, namely that of organizational behavior, has received significant attention in recent years in the context of business process modeling and management. Another important domain, that of organizational structure is strongly inter-related with the process domain. While the process domain focuses on how the business process activities are structured and performed, the organizational structure domain focuses on who performs these activities, i.e., which kinds of entities in an organization are capable of performing work. Given the strong connection between the organizational behavior and organizational resources, we argue that any comprehensive enterprise modeling technique should explicitly establish the relations between the modeling elements that represent organizational behavior, called here behavioral elements, and those used to represent the organizational resources (organizational actors) involved in these activities, called here active structure elements. Despite the importance of the relations between these architectural domains, many of the current enterprise architecture and business process modeling approaches lack support for the expressiveness of a number of important active structure allocation scenarios. This work aims to overcome these limitations by proposing a framework for active structure assignment that can be applied to enterprise architecture and business process modeling approaches. This framework enriches the expressiveness of existing techniques and supports the definition of precise active structure assignments. It is designed such that it should be applicable to a number of enterprise architecture and business process modeling languages, i.e., one should be able to use and apply different (enterprise and business process) modeling languages to the framework with minor changes.
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Xiong, Siyuan. "The role of Activin B and TGFb1 in regulating endometrial cancer cell adhesion and migration." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58581.
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Endometrial cancer is the fourth most common female cancer and the most common gynecological malignancy. Although it comprises only ~10% of all endometrial cancers, the serous histological subtype accounts for ~40% of deaths due to its aggressive behavior and propensity to metastasize. Moreover, the number of endometrial cancer related deaths keeps rising, which can be attributed to the increased incidence of advanced-stage tumor and high risk histologies. Histopathological studies suggest that in non-endometrioid endometrial cancers (type II, mostly serous), elevated expression of activin/inhibin βB subunit is associated with reduced survival and TGFβ signalings are closely associated with the neoplastic transformation of human endometrium and the initiation of invasion of endometrial cancer. However, little is known about the specific roles and mechanisms of activin B (βB dimer) and TGFβ1 in type II endometrial cancer cell progression. We hypothesized that integrin αvβ3, E-cadherin, and PTEN play critical roles in activin B or TGFβ1 induced endometria cancer cell adhesion or migration. Type II endometrial cancer cell lines KLE, HEC-1B and HEC-50 were used as study models. Cancer cell adhesion was assessed by extracellular matrix coated 96 well adhesion assays. Cancer cell migration or invasiveness was assessed by transwell assays without or with coated matrigel following exposure to recombinant human activin B or TGFβ1. Small interfering RNA (siRNA)-mediated knockdown or vector-mediated overexpression approaches were used to investigate the molecular determinants of activin B or TGFβ1-mediated functions. In summary, our results demonstrate that SMAD-mediated integrin β3 up-regulation by activin B promotes type II endometrial cancer cell adhesion and migration while ERK1/2-SNAIL-mediated E-cadherin down-regulation by activin B plays important roles in cancer migration. Moreover, TGFβ1 induces type II endometrial cancer cell migration via ERK1/2 mediated-up-regulation of integrin αvβ3. TGFβ1 also promotes cancer cell migration by down-regulating PTEN via both SMAD-dependent and independent pathways. Our findings provide important insights into the molecular mechanisms underlying the effects of activin and TGFβ on endometrial cancer cell migration and suggest novel therapeutic targets for treating type II endometrial cancer.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Cruickshank, Mark. "Analysis of CR2/CD21 transcriptional regulation by chromatin structural variation and notch activity in human cell models." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0115.
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[Truncated abstract] Human complement receptor 2 (CR2/CD21) is a cell surface glycoprotein detected on specific cells involved in immunity, which binds complement C3 cleavage fragments, cellular ligands IFN-? and CD23 as well as the EBV coat protein, gp350/220. During the early stages of B-cell development CR2/CD21 is silenced. Expression is initiated on immature B-cells escaping negative selection. During peripheral maturation CR2/CD21 is up-regulated with B-cell sub-populations showing distinctive surface levels (comparatively low, intermediate or high). CR2/CD21 is silenced upon terminal plasmacytic differentiation. Appropriate timing and expression level of CR2/CD21 is important for the development of a healthy B-cell repertoire. Previous studies have identified sequences within the proximal promoter and first intron of CR2/CD21 that cooperate within native chromatin to control cell-specific silencing. Further, analysis of cultured human cells has revealed chromatin structural variation causing DNase I hypersensitivity at these regulatory sites in a CR2/CD21-expressing mature B-cell line (Raji) which are absent in a non-lymphoid cell type (K562). The primary focus of the present study involved characterising chromatin structural variation over previously recognized DNase I hypersensitive regions at the CR2/CD21 locus in human cells to understand how chromatin structure might regulate developmental expression of CR2/CD21. ... These studies provide evidence that notch signaling influences CR2/CD21 expression in human cell lines. First, in vivo binding of CBF1 to CR2/CD21 sequences in the proximal promoter and CRS implies that CR2/CD21 is a direct target of notch activation. Second, the effect of exogenous notch signalling molecules on CR2/CD21 proximal promoter activity was modulated by factors binding tandem E-boxes near the transcriptional start site suggesting that the notch pathway may also influence CR2/CD21 expression via control of HLH molecules. Third, initiation of CR2/CD21 expression was observed in a nonexpressing pre-B cell line (Reh) by co-culture with stromal cells expressing a notch ligand (OP9-DL) but not control stroma (OP9-GFP). Together, these findings support a role for notch regulation of B-cell maturation and invite speculation that initiation of CR2/CD21 expression following negative selection of immature B-cells involves crosstalk between HLH transcriptional regulators and the notch pathway. Furthermore, the Reh/OP9-DL co-culture system may provide a model to directly study the relationship between cell signalling molecules, transcription factor regulation, chromatin structural variation and differentiation of B-cells.
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BROSSART, MARC. "Traitement des hepatites chroniques actives a virus b par la vidarabine." Aix-Marseille 2, 1988. http://www.theses.fr/1988AIX20448.
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Torres, Alba Fabiola Costa. "AÃÃo antibacteriana antifÃngica e antiparasitÃria de veneno de serpentes do gÃnero Bothrops e suas fraÃÃes fosfolipase A2 e L-AminoÃcido oxidase." Universidade Federal do CearÃ, 2009. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=3129.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorOs venenos de serpentes contem substÃncias biologicamente ativas, primariamente consistindo de proteÃnas (90-95%). Algumas delas apresentam atividade enzimÃtica como as fosfolipases A2 e L-aminoÃcido oxidase. O presente estudo verificou a aÃÃo dos venenos de Bothrops leucurus (BleuVT) e Bothrops marajoensis (BmarVT), e suas fraÃÃes PLA2 (BleuPLA2 e BmarPLA2) e LAAO (BleuLAAO e BmarLAAO) sobre cepas de bactÃria, C. albicans, Leishmania sp e T. cruzi, bem com sua toxicidade sobre macrÃfagos murinos. A susceptibilidade das cepas bacterianas e fÃngica foi analisada atravÃs do mÃtodo de difusÃo em Ãgar, para determinaÃÃo do potencial antimicrobiano; e microdiluiÃÃo em caldo, para determinaÃÃo da CIM e CLM, com modificaÃÃes. A atividade antiparasitÃria foi avaliada atravÃs do tratamento das culturas de parasitos com diferentes concentraÃÃes dos venenos ou de suas fraÃÃes. As formas promastigotas de Leishmania sp. foram cultivadas, durante 72h, em meio NNN/Schneider a 28ÂC; e as formas epimastigotas de T. cruzi foram cultivadas em meio LIT, durante 5 dias, a 28ÂC. Os macrÃfagos foram cultivados em meio RPMI 1640, em presenÃa de diferentes concentraÃÃes dos venenos e fraÃÃes, durante 24h, e submetidos ao ensaio com MTT. Os resultados foram estatisticamente analisados atravÃs do teste t ou ANOVA seguida do teste Bonferroni, quando apropriado, com p<0.05. A BmarLAAO foi capaz de inibir o crescimento bacteriano do Gram-negativo P. aeruginosa, da levedura C. albicans e do Gram-positivo S. aureus; e o BleuTV inibiu o crescimento de S. aureus, sendo a inibiÃÃo dose-dependente. A ordem de susceptibilidade dos microorganismos testados com BmarLAAO foi S. aureus > C. albicans > P. aeruginosa. Por outro lado o BmarTV, BmarPLA2, BleuPLA2 e BleuLAAO nÃo apresentaram nenhum grau de inibiÃÃo sobre as cepas em estudo. O potencial inibitÃrio foi mais significante sobre S. aureus apresentando CIM= 50Âg/mL e CLM=200Âg/mL para BmarLAAO, e CIM=CLM=25Âg/mL para BleuTV. Em concentraÃÃes maiores que 1.56Âg/mL a BmarLAAO foi capaz de inibir o crescimento de formas promastigotas de L. chagasi e L.amazonensis, sendo os valores de IC50, apÃs 72h de cultivo, para L. amazonenis, 2.55Âg/mL e 2.86 Âg/mL para L. chagasi. BmarTV e BleuTV tambÃm apresentaram significante inibiÃÃo sobre o crescimento parasitÃrio, sendo os valores de IC50 86.56 Âg/mL para L. amazonensis e 79.02Âg/mL para L. chagasi, quando tratado com BmarTV; e 5.49Âg/mL para L. amazonensis e 1.94Âg/mL para L. chagasi, quando tratado com BleuTV. Os venenos e BmarLAAO mostraram efeito inibitÃrio sobre formas epimastigotas de T. cruzi. Os valores de IC50 para BleuTV, BmarTV e BmarLAAO foram, respectivamente, 1.14Âg/mL, 24.19Âg/mL e 0.89Âg/mL. As fraÃÃes BmarPLA2, BleuPLA2 e BleuLAAO nÃo foram capazes de promover nenhum efeito inibitÃrio sobre os parasitos em estudo. O BmarLAAO , BmarTV e BleuTV apresentaram baixa toxicidade sobre macrÃfagos nas concentraÃÃes estudadas. Em conclusÃo, os veneno de B. leucurus e de B. marajoensis, bem como a L-aminoÃcido oxidase de Bothrops marajoensis mostraram ser capazes de interferir no crescimento de diferentes microorganismos como S.aureus, C. albicans, P. aeruginosa, Leishmania sp. e T. cruzi.
Snakes venoms contain biologically active substances primarily consisting of proteins (90-95%). Some of these present enzymatic activities, such as phospholipases A2 and the L-amino acid oxidases. In this study we verify the action of Bothrops leucurus (BleuTV) and Bothrops marajoensis (BmarTV) venoms, and fractions PLA2 (BleuPLA2 and BmarPLA2) and LAAO (BleuLAAO and BmarLAAO) on strains of bacteria, yeast, Leishmania sp and T. cruzi. The susceptibility of bacterial and yeast strains was analyzed through disc-diffusion assay, for determination of antimicrobial potential; and the microdilution method, for determination of MIC and MLC, with modifications. The antiparasitic activity was evaluated through of the culture treatment of parasites with different concentrations of venoms or their fractions. The forms promastigotes of Leishmania sp. had been cultived, during 72h, in NNN/Schneider media, 28ÂC; and the forms epimastigotes of T. cruzi had been cultived in LIT media, during 5d, 28ÂC. The macrophages were cultured in RPMI 1640 media, during 24h, 37ÂC and 5% of CO2, with different concentrations of venoms or fractions. After, they were analyzed by MTT method. The results was statistically analyzed with t test or ANOVA followed the Bonferroniâs test, when appropriated, with p<0.05. The BmarLAAO was able to inhibit the growth of gram negative P. aeruginosa, of yeast C. albicans and of gram positive S. aureus; and the BleuTV inhibited the growth of S. aureus, being the inhibitions dose-dependent. The order of susceptibility of microorganisms tested against BmarLAAO was S. aureus > C. albicans > P. aeruginosa. On the other hand the BmarTV, BmarPLA2, BleuPLA2 and BleuLAAO had not provided any degree of inhibition on strains in study. The inhibitory effect was more significant on S. aureus presenting CIM= 50Âg/mL and CLM=200Âg/mL for BmarLAAO, and CIM=CLM=25Âg/mL for the BleuTV. In concentrations greater than 1.56Âg/mL BmarLAAO was able to inhibit the growth of promastigotes forms of L. chagasi and L.amazonensis, after 72h of culture. The IC50 values were 2.55Âg/mL for L. amazonenis, and 2.86 Âg/mL for L. chagasi. BmarTV and BleuTV also provided significant inhibition of the parasitic growth, with an IC50 value of 86.56 Âg/mL for L. amazonensis and 79.02 Âg/mL for L. chagasi, when treated with BmarTV; and 5.49Âg/mL for L. amazonensis and 1.94Âg/mL for L. chagasi, when treated with BleuTV. The venoms and BmarLAAO showed inhibitory effect on epimastigotes forms of T. cruzi. The IC50 value for BleuTV, BmarTV and BmarLAAO where, respectively 1.14Âg/mL, 24.19Âg/mL and 0.89Âg/mL.This effects presented behavior dose-dependent. The fractions BmarPLA2, BleuPLA2 and BleuLAAO had not been capable to promote any inhibition on the growth of these parasites. The BmarLAAO, BmarTV and BleuTV presented low toxicity in studied concentrations. In conclusion, the whole venoms as well as the L-amino acid oxidase from Bothrops marajoensis showed to be capable to interfere in the growth of several microorganisms as S.aureus, Candida albicans, Pseudomonas aeruginosa, Leishmania sp. and T. cruzi.
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Chebil, Latifa. "Acylation des flavonoides par les llipases de Candida antarctica et Pseudomonas cepacia : études cinétique, structurale et conformationnelle." Thesis, Vandoeuvre-les-Nancy, INPL, 2006. http://www.theses.fr/2006INPL097N/document.
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Ce travail a pour objectif d'étudier les perfomances et la régiosélectivité de deux lipases lors de l'acylation de flavonoïdes en milieu organique. Cette étude a permis de montrer que la solubilité dans l'acétonitrile, l'acétone et le tert-amyl alcool dépend de la nature du flavonoïde. La solubilité la plus élevée a été obtenue avec la naringénine et l'hepéritine et la plus faible pour la rutine et l'isoquercitrine. Les propriétés thermophysiques sont également affectées par la nature du flavonoïde. Ainsi, les flavonoïdes glycosylés possèdent un point de fusion moins élevé et une enthalpie de fusion plus élevée que ceux des aglycones. Du point de vue cinétique d'acylation, des rendements de conversion de 99% ont été obtenus avec la quercétine. Ces rendements varient en fonction de la nature du flavonoïde et du donneur d'acyle, du rapport molaire (vinyle acétate/ flavonoïde) et de la nature du solvant. Le rendement le plus faible a été obtenu avec l'hespéritine. La modélisation moléculaire de flavonoïdes dans le vide et dans des solvants a permis d'étudier le rôle de la conformation sur la solubilité et de dégager des relations structure-activité pour un certain nombre de descripteurs moléculaires. Enfin des modèles OPLS tout atomes ont été construits pour étudier par dynamique moléculaire la quercétine dans des phases condensées de solvants organiquesThis work aims to study the performances and the regioselcetivity of two lipases throughout the acylation of flavonoids in organic medium. This study showed that the solubility in acetonitrile, acetone and tert-amyl alcohol depends on the nature of the flavonoid. The highest solubility, in actonitrile, was obtained with the naringenin and hesperitin and the lowest with rutin and isoquercitrin. The thermophysical properties are also affected by the nature of flavonoids. Thus glycosylated flavonoids are characterized by a low melting point and a high enthalpy of fusion compared to the aglycon ones. From the kinetic acylation data, the highest conversion yields of 99% were obtained with quercetin. These conversion yields vary according to the nature of the flavonoid and the acyl donor, the molar ratio (vinyl acetate/flavonoid) and the nature of the solvent. The lowest conversion yield was obtained with hesperitin. Molecular modeling of flavonoids in vacuum and solvents allows to study the role of conformation structure on solubility and to release the structure-activity relationship with many electronic descriptors. Finally, OPLS all atoms were built to study, by molecular dynamics, quercetin in condensed phases of organic solvents
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Reimann, Sven [Verfasser]. "Regulation of the activity of the Escherichia coli ABC transporter haemolysin B / Sven Reimann." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1135382239/34.
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Williams, Edward Spencer. "Dysregulation of nuclear factor kappa B activity and osteopontin expression in oxidant-induced atherogenesis." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/175.
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NF-κB activity is critical in the regulation of atherosclerotic vascular smooth muscle cell (vSMC) phenotypes induced following oxidative injury by allylamine. The present studies were designed to detail dysregulation of NF-κB activity in these altered phenotypes, and to assess the importance of NF-κB in the regulation of osteopontin, a cytokine which modulates atherosclerosis. Increased degradation of IκBα was observed in allylamine-induced atherosclerotic vSMC phenotypes (henceforth referred to as allylamine cells). Enhanced phosphorylation of I-κ-kinases was observed by Western immunoblotting. NF-κB DNA binding activity as assessed by electrophoretic mobility shift assay demonstrated changes in the kinetics and magnitude of induction of binding. Enhancement of NF-κB binding activity was evident in allylamine cells compared to controls when seeded on plastic, fibronectin, and laminin, but not collagen I. Posttranscriptional alterations in Rel protein expression and nuclear localization partly account for changes in NF-κB DNA binding activity. Promoter-specific NF-κB binding profiles suggest altered dimer prevalence as a consequence of the changes in Rel protein expression. The expression of NF-κB regulated genes osteopontin and MMP-2 was enhanced in allylamine-treated aortas, while cyclin D1 and MMP-9 were unchanged. As the importance of osteopontin in atherosclerosis has been described in several models, subsequent studies were designed to assess osteopontin promoter activity. Activity of the osteopontin promoter was significantly reduced in allylamine cells compared to controls as assessed using a luciferase reporter. Deletion analysis suggested the presence of inhibitory cis-acting elements in the regulatory region of the gene. Mutation of these elements, including VDRE, AP-1, NF-κB, and USF1, indicated that NF-κB and USF1 mediate suppression of osteopontin promoter activity in allylamine cells. Decreased serine phosphorylation of immunoprecipitated RelA/p65 was observed in allylamine cells, indicating decreased ability of this protein to transactive gene promoters. NF-κB was found to play a role in suppression of osteopontin promoter activity by collagen I-mediated integrin signaling. These findings suggest that enhancements in NF-κB activity suppress osteopontin promoter activity in oxidant-activated vSMC cultures. Dysregulation of NF-κB activity occurs as a result of altered matrix and intracellular signaling upstream of the nucleus and possibly differential dimer assembly leading to cell-specific profiles of NF-κB-dependent gene regulation.
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Hu, Jiancheng. "Regulation of Lsc activity and role in B cell migration and antigen receptor signaling /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 103-118). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Wells, Greggory M. "Synthesis and Biological Activity of N-Acyl Aziridines." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1450458169.
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