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Thullberg, Minna. "The cell cycle regulators p15, p16, p18 and p19 : functions and regulation during normal cell cycle and in multistep carcinogenesis /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4432-6/.
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Quesnel, Bruno. "Gene p16 ink4a , p15 ink4b, et hemopathies malignes." Lille 2, 1997. http://www.theses.fr/1997LIL2T009.
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文偉倫 and Wai-lun Matthew Man. "p15 and p16 genes in head and neck carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31224945.
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Man, Wai-lun Matthew. "P15 and p16 genes in head and neck carcinoma /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk:8888/cgi-bin/hkuto%5Ftoc%5Fpdf?B23436001.
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Bourassa, Nancy. "Étude des gènes p16 et p15 dans la prédisposition au cancer colorectal héréditaire sans polypose." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq33581.pdf.
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Le, Frère-Belda Marie-Aude. "Les inhibiteurs de la transition G1-Sp14arf, p15 et p16 dans le cancer de vessie." Paris 11, 2002. http://www.theses.fr/2002PA11T063.
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Chicano, Lavilla María. "Estudio de metilación en los genes CDH1, P15, P16 y BIK en pacientes afectos de mieloma múltiple." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458532.
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El Mieloma Múltiple (MM) es una neoplasia hematológica, que en la gran mayoría de casos, la enfermedad viene precedida de una alteración de células plasmáticas (CP) asintomática, la Gammapatía monoclonal de significado incierto (GMSI). Así mismo se ha descrito un estadio intermedio entre GMSI y MM denominado Smoldering Multiple Myeloma (SMM). Se desconoce por qué solo algunas GMSI progresan a MM. Se han elaborado guías de estratificación de los pacientes con marcadores de progresión clínico-biológicos, como los niveles de componente monoclonal, el tipo de cadenas ligeras libres y el porcentaje y atipias de las CP. Sin embargo, y debido a la gran heterogeneidad que presenta esta enfermedad, no existen marcadores de progresión fiables.
La inactivación por metilación de los promotores de genes supresores de tumor podría estar implicada en la progresión y/o evolución de la enfermedad. Estudios de metilación global en MM de la literatura describen un aumento del porcentaje de pacientes con metilación, en algunos de estos genes a lo largo de la evolución de la enfermedad. El estudio del patrón de metilación de determinados genes supresores de tumor podría ayudar a comprender los mecanismos implicados en la evolución del MM.
En el presente estudio se ha analizado la presencia de metilación en el promotor de los genes supresores de tumor CDH1, P15, P16 y BIK en una serie de 103 pacientes afectos de MM, GMSI o SMM. El análisis de metilación se ha realizado mediante MS-PCR con DNA obtenido del cultivo celular de médula ósea tras fijación con Carnoy, siendo el primero en MM que utiliza este tipo de muestras. Se ha establecido la frecuencia de casos con metilación en estadios asintomáticos y en MM. Se ha comparado la frecuencia de metilación en pacientes con MM estudiados al diagnóstico con la de pacientes estudiados durante el seguimiento y resistentes al tratamiento o en recaída. Asimismo se ha evaluado la posible relación entre la metilación de estos genes y variables clínico-biológicas para establecer su posible valor pronóstico.
Las frecuencias de casos con metilación en P15 y P16 mostraron diferencias significativas entre estadios premalignos y MM. Es de destacar que en cuatro de los pacientes, de los que se disponían muestras en dos estadios diferentes de la enfermedad, se observó metilación en BIK únicamente en aquellas correspondientes a la enfermedad resistente a tratamiento. Ello sugiere que la metilación de algunos genes supresores de tumor podría tener un papel importante en la progresión de determinados clones de CP resistentes a tratamiento.
Al analizar la relación entre las variables clínico-biológicas y metilación, solamente se encontró correlación en toda la cohorte de pacientes (pre-MM y MM) entre metilación en P15 y niveles elevados de LDH así como entre P16 y niveles elevados de b2-microglobulina y porcentaje elevado de CP. Además la presencia de tres o cuatro genes metilados estaba asociada a una supervivencia inferior en los pacientes. Ello sugiere que la metilación de varios genes supresores de tumor podría conferir un fenotipo más agresivo. Es de destacar que la metilación concomitante en P16 y BIK en pacientes afectos de MM tenía un impacto más adverso en la SG que roza la significación como factor pronóstico independiente. Éste hecho apoyaría la hipótesis de que la metilación de determinados genes supresores de tumor podría tener un papel importante en la supervivencia de determinados clones de CP porque serían resistentes al tratamiento.Multiple Myeloma is a hematologic neoplasm included in the called plasma cell (PC) dyscrasias. In most of the cases the disease is preceded by an asymptomatic premalignant entity, the MGUS, an intermediate stage called Smoldering Multiple Myeloma (SMM) has also been described. Only some of the MGUS progress to MM, but the reason is unknown. The research of progression markers in MM has brought to the incorporation of some clinical variables in stratification guides as monoclonal component levels, free light chain type and PC percentage and atypia. However, due to the heterogeneity of the MM, there is no clear progression marker, specifically in the context of MGUS to MM progression. Promoter methylation of tumour suppressor genes could lead to an inactivation and could have an effect in the progression and/or evolution of the disease. Global methylation studies in MM have observed an increase in the methylation of some of these genes all along the evolution of the disease. For that reason, changes in methylation pattern of some genes could help into a better comprehension of the evolution of the disease. In this study the presence of promoter methylation in tumour suppressor genes CDH1, P15, P16 and BIK has been analysed in 103 patients of MM, SMM or MGUS. The frequency of methylation has been compared between asymptomatic stages and MM, as well as in MM patients at diagnostic or in the follow up of the disease. Additionally, the relation between methylation of these genes and clinical variables has been evaluated in order to observe a possible implication in the prognosis. Methylation analysis has been done by MS-PCR with DNA obtained from bone marrow cell culture after fixation with Carnoy. Only methylation frequencies in P15 and P16 showed significant differences between asymptomatic stages and MM, however, they did not show a correlation with adverse prognosis variables. In relation to methylation and the evolution of the disease, a tendency to a greater BIK methylation frequency in the follow up MM patients compared to the diagnostic patients was observed. Likewise, the presence of BIK gene methylation in refractory samples of four patients which didn’t showed methylation in a previous study, could suggest that methylation of certain genes could play a role in the progression of drug resistant PC clones. In the analysis of the relation between clinical variables and methylation, just a correlation of P15 methylation and high levels of LDH as well as a correlation of P16 methylation and high levels of b2-microglobulin and CP were found. This results were observed only in the total of the series but not when only MM patients were analysed. In overall survival analysis, the presence of methylation in three or more genes showed lower survival than the rest of the group, which would suggest that hypermethylation could confer a more aggressive phenotype. A tendency to a lower survival was observed in refractory or relapsed patients which showed methylation in P16. The combined methylation in P16 and BIK had an adverse impact on overall survival in MM patients that was near the significance when was studied as an independent prognosis factor. This result would sustain the hypothesis that methylation in certain genes could have an important paper in the survival of some PC clones resistant to treatment.
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Patel, Shyamal. "MC1R and p15/RB pathways in melanocyte differentiation and melanoma progression." Thesis, St George's, University of London, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677181.
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Skin melanocytes are cells that produce pigment in melanosomes and protect us from the damaging effects of UV radiation. This project covered two facets of melanocyte biology: melanocyte differentiation and transformation. Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder, is characterised by oculocutaneous albinism, a bleeding diathesis and other variable symptoms due to impaired formation of lysosome-related organelles, including melanosomes. We showed that cAMP agonists modestly restore pigmentation in HPS-mutant melanocytes and that this effect correlates with pigment formation in lysosomes instead of melanosomes, shown for the first time by colocalisation studies. These findings build upon our current understanding of melanosomal protein trafficking in HPS-mutant melanocytes and may have important implications for the treatment of hypopigmentation in patients with HPS or other forms of albinism. The other section of this project focused on melanoma. The majority of cancer cells have centrosome numerical abnormalities including extra or supernumerary centrosomes. This correlates with aneuploidy and genetic instability and may affect tumour aggressiveness and clinical outcome. The tumour suppressors p 15INK4B and p16INK4A (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p 16INK4A and its downstream regulators are also associated with suppressing centrosome overduplication; however, the role of p15INK4B in centrosome amplification is unknown. We showed that normal human melanocyte lines did not exhibit centrosome number abnormalities whereas those from later stages of melanoma did. Additionally, under conditions of S-phase block, p 15INK4B and p 16INK4A status determined whether centrosome overduplication would occur. Indeed, removal of p 151NK4B from p 161NK4A negative cells from various stages of melanoma progression changed lines that previously would not overduplicate their centrosomes into cells that did. These data suggest that, during melanoma progression, sequential loss of p15INK4B and p16INK4A provides the conditions to deregulated centrosome duplication with consequences for genome instability,
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Hussey, Damian J. "An investigation of the (4;11)(q21;p15) translocation in acute lymphocytic leukaemia /." Title page, contents and abstract only, 2000. http://web4.library.adelaide.edu.au/theses/09PH/09phh9725.pdf.
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Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2000.Copies of author's previously published articles inserted. Errata pasted onto verso of back end-paper. Bibliography: leaves 163-189.
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Wadsworth, Santiago. "Genetic and biochemical study of P15, the RNA silencing suppressor of Peanut clump virus." Strasbourg, 2010. http://www.theses.fr/2010STRA6233.
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Le RNA silencing est un mécanisme de régulation négative de l’expression des gènes, retrouvé chez la plupart des organismes eucaryotes et basé sur des interactions d’ARN séquence-spécifiques. Il est déclenché par de l’ARN double brin qui est découpé par Dicer en de petits ARNs de 21 ‡ 24nt, nommés short-interfering (si)RNAs ou microRNAs. Un brin du duplex est incorporé dans un complexe appelé RNA-induced silencing complex (RISC), pour guider le clivage endonucléolytique ou l’inhibition traductionnelle d’ARNm présentant une homologie de séquence. Chez les plantes, le RNA silencing joue un rôle important dans la défense antivirale, le développement et l’adaptation aux stress biotiques et abiotiques. Pour contrer ce mécanisme de défense, les virus de plantes ont élaboré des protéines dites suppresseurs de RNA silencing. Au cours de cette thèse, nous avons analysé les interactions entre le RNA silencing et le Peanut clump virus (PCV). Nous avons démontré que les siRNA dérivés de PCV sont produits par Dicer-like 4 (DCL4) et dans une moindre mesure par DCL2, se traduisant par l’accumulation de siRNA de 21 et 22nt respectivement. La P15, suppresseur de RNA silencing du PCV, provoque une réduction drastique des niveaux de siRNA provenant des molécules d’ARN exogène de type tige-boucle ; et stabilise le brin non incorporé dans RISC. Dans une deuxième partie, nous avons étudié les interactions de P15 et ces protéines cibles. Nous avons ainsi identifié DCL1 parmi les protéines co-immunoprécipitées par P15 et montré que P15 affecte le niveau d’accumulation de DCL1, suggèrant ainsi que P15 pourrait déclencher une régulation négative DCL1-dépendante du système antiviralRNA silencing refers to a set of RNA-based eukaryotic processes that regulate gene expression in a sequence-specific manner. It initiates with the processing of dsRNA by Dicer (RNase type III) proteins into small molecules of dsRNA of 21- to 24-nt in length, generally referred as short-interfering (si)RNAs or microRNAs, depending on their origin. One brand of the small duplex is incorporated into an effector complex, the RNA-Induced Silencing Complex, to guide the regulation of gene expression through different mechanisms, including endonucleolytic cleavage, translational repression or histone- and DNA-modifications. In plants, siRNAs and miRNAs are involved in viral defense, development and adaptation to biotic and abiotic stresses. As natural targets of RNA silencing, plant viruses have produced highly diverse proteins called silencing suppressors. First, we have studied the genetic requirements of Peanut clump virus (PCV) viral-si(vs)RNA production in Arabidopsis and shown that PCV RNA is primary processed by Dicer-like 4 (DCL4) to produce 21-nt vsRNAs, with DCL2 playing a minor role in the production of 22-nt PCV viRNAs. We also observed that P15, the PCV-encoded silencing suppressor, drastically reduces the accumulation of siRNAs derived only from transgenic hairpins of perfect dsRNA and stabilizes the non-incorporated brand of the miRNA duplex. Another part of this work consisted in the identification of plant proteins that may interact with P15. Among others, we identified DCL1 as P15 co-immunoprecipitated protein and showed that P15 alters the level of DCL1, suggesting that P15 may mediate a DCL1-dependent negative regulation of the antiviral plant defense
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Amiot-Chaussade, Laure. "Etude du statut du gène p15 dans les carcinomes neuroendocrines bronchopulmonaires : rôle de la méthylation." Université Joseph Fourier (Grenoble), 2001. http://www.theses.fr/2001GRE10001.
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La proteine p15 active l'arret du cycle cellulaire en phase g1 en inhibant le complexe cdk4-cycline d1 qui active la phosphorylation de la proteine rb, provoquant l'entree en phase s. P15 est donc de la meme famille que p16. Nous avons etudie le gene p15 et les deux isoformes proteiques (p15 et p15,5) dans une serie de tumeurs neuroendocrines du poumon. Nous avons compare par western blot l'expression proteique dans 3 types de tissus : 8 poumons de patients sans cancer (temoins, pn), 15 poumons normaux associes aux tumeurs (pna) et 24 tumeurs neuroendocrines (tn). Nous avons observe une expression variable de p15 et p15,5 dans les pn, dans les pna et dans les tn. Il semble que p15,5 est touchee par la carcinogenese car, dans les tn, son expression est plus anarchique que dans les pn. Cette deregulation s'observe deja dans les pna, temoin du champ de cancerisation d'ou l'importance de l'etude sur les pn. Nous avons essaye d'etablir un lien entre une anomalie du gene et l'heterogeneite d'expression. Aucune mutation de p15 n'est detectee. Nous avons recherche les methylations en 5 du gene p15 par pcr based assay et la methylation specific pcr , chacune permet l'etude d'une region differente de l'ilot cpg. Par pcr-ba, nous observons 7 tn, 5 pna et 7 pn methyles. Par msp, tous sont methyles. Nous n'observons donc aucune correlation entre methylation et expression proteique. Aucune mutation de cdk4 n'est detectee. Nous avons regarde par western blot le statut proteique de rb dans les tn. Rb est : majoritairement hyperphosphoryle dans les tn de haut grade et, soit hypo soit hyperphosphoryle, dans les tn de bas grade de malignite. La forme hyperphosphorylee existe quand rb est exprime or p16 est peu inactive dans les tn. Si p15
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Draney, Carrie. "Overexpression of HDAC1 Induces Functional β-cell Mass." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6573.
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Type 2 diabetes is a metabolic disorder that results in β-cell dysfunction and ultimate destruction, and leads to impaired glucose homeostasis. High rates of proliferation and differentiation of pancreatic β-cells occurs mostly during neonatal development. However, research shows these mechanisms remain intact as β-cell proliferation has been observed during pregnancy and obesity. We have shown that overexpression of the β-cell transcription factor Nkx6.1 is sufficient to induce β-cell proliferation. Exploration of the transcriptional targets of Nkx6.1 has identified histone deacetylase 1 (HDAC1) as a down-stream target of Nkx6.1. Here we demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation, enhance β-cell survival upon exposure to apoptotic stimuli and maintains glucose stimulated insulin secretion (GSIS). Our data suggests overexpression of HDAC1 leads to p15/INK4b suppression, a cell cycle inhibitor, potentially explaining the mechanism behind these observed effects. These data demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation and enhance cell survival while maintaining glucose stimulated insulin secretion.
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Tanaka, Tomoyuki. "High incidence of allelic loss on chromosome 5 and inactivation of p15^{INK4B} and p16^{INK4A} tumor suppressor genes in oxystress-induced renal cell carcinoma of rats." Kyoto University, 1999. http://hdl.handle.net/2433/181736.
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Ferro, Daniel Giberne. "Estudo clínico da aplicação de peptídeo sintético de adesão celular (PepGen-P15®) em lesões periodontais graves de cães." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/10/10137/tde-29092006-195735/.
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Este estudo teve como objetivo avaliar clinica e radiograficamente a resposta de dentes com perda do nível clínico de inserção (NCI), bolsa periodontal, retração gengival e exposição de furca graus II e III após três e seis meses da intervenção cirúrgica de implante com um peptídeo sintético de adesão celular (PepGen P-15®). Vinte e um cães apresentados ao atendimento do Hospital Veterinário da FMVZ-USP foram anestesiados para tratamento periodontal e um total de 91 faces de dentes com perda do nível clínico de inserção foram tratadas, sendo que 45% (41 faces) receberam PepGen P-15® e 55% (50 faces) formaram o grupo controle, que recebeu tratamento convencional (raspagem e aplainamento radicular a céu aberto). Além destes, oito dentes estavam com exposição de furca dental, sendo que cinco receberam o peptídeo e três receberam tratamento convencional. Foram feitas radiografias de todos os procedimentos, além de exploração sub-gengival com sonda periodontal. Os animais foram novamente anestesiados após três meses e após seis meses, sendo submetidos às mesmas radiografias, sondagens e fotografias. Dos cinco dentes com exposição de furca que receberam o PepGen P-15®, dois apresentaram redução do grau de exposição, dois não apresentaram alteração do quadro e um teve seu grau de exposição aumentado. No caso dos três dentes que receberam tratamento convencional, um mostrou redução do grau de furca, dois não apresentaram alteração e nenhum apresentou aumento do grau. Das 41 faces de dentes com perda do nível clínico de inserção e tratadas com o peptídeo, observou-se, em média, uma taxa de recuperação do nível clínico de inserção de 40% aos seis meses. As faces que receberam tratamento convencional não apresentaram, em média, alteração nas mensurações dos níveis clínicos de inserção. A face que apresentou o melhor resultado frente à aplicação do PepGen P-15® foi a palatina (40% de recuperação) e os dentes que melhor responderam ao tratamento foram os caninos (57,14%) e os molares (65%). Não se observaram sinais pós-operatórios de infecção relacionados à falta de higiene oral destes animais. Somente um dos proprietários (4,76%) relatou escovação diária em seu animal. Pode-se concluir que a aplicação do peptídeo sintético PepGen P-15® favorece a recuperação das estruturas que compõem o periodonto de sustentação, inclusive osso alveolar. Sua aplicação é relativamente simples e prática e a incidência de complicações pós-operatórias é baixa. Há a necessidade, porém, de se realizar outros estudos para avaliação da qualidade e da quantidade do osso formado, bem como do ligamento periodontal relacionadoThe aim of this study was to evaluate the attachment loss, periodontal pocket, gingival ressection and II and III furcation lesion response in teeth after 3 and 6 month with collagen cell-binding peptide (PepGen P-15®) graft application. Twenty one dogs from the FMVZ-USP Veterinary Hospital were anesthetized in order to accomplish periodontal treatment and 91 tooth faces with attachment loss were treated, with 45% (41 faces) receiving PepGen P-15® and 55% (50 faces) constituting the control group that received conventional treatment (muco-gingival flap and root planning). Eight teeth showed furcation lesions. Five received the peptide and three did not. The procedure was documented by radiography and all periodontal probing were photographed. After 3 and 6 month, the animals were re-anesthetized in order to accomplish new photography, radiography and periodontal probing exams. In the furcation exposure of teeth treated with PepGen P-15®, two exhibited reduction of furcation degree, two did not change their conditions and one had the furcation enhanced after 6 month. The conventional treatment group presented one tooth with furcation reduction and no changes in two teeth. The 41 attachment loss faces that received graft material exhibited 40% of regeneration rate after 6 month. The control faces did not change their attachment level. The palatal face presented the better regeneration rates (40%) and the canines and molars teeth showed the better responses (57,14% and 65%, respectively). There was no post-surgical infection related to absence of oral home care. One owner (4,76%) reported daily teeth brushing on his pet. It can be concluded that the PepGen P-15® helps a more rapidly periodontal structure re-attachment and regeneration, including alveolar bone. Its application is easy and practical and the post-surgical complications incidence is low. Nevertheless, more studies and researches are necessary to evaluate the amount and the quality of formed bone and periodontal ligament
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Barrera, Vilarmau Susana. "Actividad de la proteina intrínsecamente desordenada p15(PAF) en el replisoma o cómo el desorden orquesta la replicación celular." Doctoral thesis, Universitat de Barcelona, 2022. http://hdl.handle.net/10803/673908.
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La abrazadera deslizante eucariota (PCNA), juega un papel esencial como componente del replisoma. PCNA, de forma toroidal, rodea el DNA y ata las polimerasas y otros factores a la plantilla genómica para una síntesis rápida y procesiva. PCNA puede deslizar bidireccionalmente a lo largo del dúplex de DNA rastreando su columna vertebral mediante un mecanismo de «rueda dentada» basado en interacciones polares efímeras que mantienen la orientación de la pinza invariante en relación con la doble hélice. La mutación de residuos en esta interfaz de interacción PCNA-DNA hace desfavorable el inicio de la síntesis de DNA por Pol δ, por lo tanto, es necesaria una pinza orientada correctamente en el DNA para el ensamblaje de una holoenzima pol δ-PCNA competente en replicación.
La cara del interior del anillo de PCNA, además de ser crucial para la función de PCNA como factor de procesividad durante la replicación, está altamente regulada para controlar la resistencia al daño en el DNA. Se puede modular (i) a través de la acetilación de su lisina 20, lo que estimula la reparación por recombinación homóloga, o (ii) mediante la unión de p15PAF, lo que desactiva el baipás de lesión en el DNA.
p15PAF es una proteína intrínsecamente desordenada que atraviesa el canal del anillo de PCNA, uniendo su dominio PIP-box al bolsillo hidrofóbico de la cara frontal de la pinza y estableciendo contactos también con la superficie deslizante de la abrazadera para asomar su cola N-terminal por la cara trasera. Cuando dos moléculas de p15PAF ocupan dos subunidades del homotrímero de PCNA, el DNA dentro del canal del anillo se une a la subunidad que queda desocupada y no desplaza a p15PAF de la pared del anillo interno de PCNA. Cuando p15PAF está unida a PCNA, se reduce la superficie deslizante disponible de la abrazadera, así que p15PAF puede estar funcionando como un cinturón que abrocha el DNA a PCNA durante la síntesis por la polimerasa replicativa Pol δ. Esta restricción de la superficie deslizante, sin embargo, necesita ser eliminada para un baipás eficaz de la lesión del DNA por parte de la polimerasa de síntesis translesión Pol η.
PCNA es estable en forma de anillo cerrado y, por lo tanto, debe cargarse activamente en las uniones cebador/plantilla del DNA, colocándose exactamente en el lugar y posición correctas para una replicación procesiva. La apertura y carga de PCNA la lleva a cabo el cargador de la pinza RFC. Una vez en el DNA, PCNA se vuelve a sellar alrededor del DNA y entonces el cargador de la pinza es expulsado. Cuando PCNA ya no es necesaria anclada en el DNA, el complejo RFC es el encargado de retirarla abriéndola y soltándola fuera de la doble hebra. Pero la flexibilidad intrínseca de PCNA hace que tenga cierta predisposición a estar en estado abierto separando dos de sus subunidades a través de su interfaz. Esto, que favorece la apertura del anillo por parte de RFC para lograr el ensamblado alrededor del DNA, puede ser un problema para mantenerla cerrada en la unión cebador/plantilla. De hecho, la estabilidad de las interfaces entre subunidades de PCNA disminuye cuando se une al DNA después de ser cargada por RFC, y dicha estabilidad solo la ve recuperada cuando p15PAF se ancla por su dominio PIP-box a sus bolsillos hidrofóbicos, grapando así las subunidades de la pinza e impidiendo su salida prematura del complejo con el DNA. Además de estabilizar la forma cerrada del anillo de PCNA, cuando p15PAF está anclada a su cara frontal, impide que RFC se aproxime, se una a ella y la desenganche de la unión cebador/plantilla.The eukaryotic sliding clamp (PCNA) is an essential replisome's component. PCNA, with a toroidal shape, surrounds DNA and binds polymerases and other factors to the genomic template for rapid and processive synthesis. PCNA can slide bi-directionally along the DNA duplex using a "cogwheel" mechanism based on ephemeral polar interactions that maintain the orientation of the clamp invariant relative to the double helix. However, mutations in the PCNA-DNA interaction interface render unfavourable the initiation of DNA synthesis by Pol δ. Therefore, a correctly oriented clamp on the DNA is necessary to assemble a competent pol δ-PCNA holoenzyme. Tight regulation of the inner face of PCNA, which is crucial for PCNA function as a processivity factor during replication, controls the DNA damage resistance. The inner PCNA ring face can be regulated (i) through acetylation of its lysine 20, which stimulates repair by homologous recombination, or (ii) by p15PAF binding, which deactivates the bypass of DNA damage. p15PAF is an intrinsically disordered protein that crosses the channel of the PCNA ring, attaching its PIP-box domain to the hydrophobic pocket on the front face of the clamp and establishing contacts with the sliding surface to show its N-terminal tail through the rear face. When two p15PAF molecules occupy two subunits of the PCNA homotrimer, the DNA within the ring channel binds to the unoccupied subunit and does not displace p15PAF from the inner ring wall of PCNA. When p15PAF is bound to PCNA, the available slip surface of the clamp is reduced, so p15PAF may be functioning as a belt that binds DNA to PCNA during synthesis by the replicative polymerase Pol δ. This sliding surface restriction, however, needs to be removed for efficient bypass of DNA damage by the translesion synthesis polymerase Pol η. PCNA is a stable closed ring and must be actively loaded onto the primer/template junctions of DNA, getting precisely in the right place and position for processive replication. RFC clamp loader opens and loads PCNA onto the DNA. Once in the DNA, PCNA reseals around the DNA and RFC is then ejected. When PCNA is no longer needed around the DNA, the RFC complex opens and unloads it. But the local flexibility of PCNA's subunits interfaces makes it have a certain predisposition to be in the open state. This local flexibility, which favours the RFC opening of the ring to achieve assembly around the DNA, can be a problem in keeping it closed at the primer/template junction. Furthermore, the stability of the interfaces between PCNA subunits decreases further when it binds to DNA. Interestingly, the PCNA homotrimer interfaces stability recovers when p15PAF is anchored by its PIP-box domain to PCNA's hydrophobic pockets, thus stapling the clamp subunits and preventing their premature exit from the complex with DNA. In addition, when p15PAF is anchored to PCNA front face, it prevents RFC from approaching, binding to, and unloading PCNA from the primer/template junction.
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Dodge, Jonathan Eldon. "Selective variegated methylation of the p15/INK4B CpG island is a high frequency event in acute myeloid leukemia (AML)." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284143.
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We attempted to define target genes that were inactivated in acute myeloid leukemia (AML) by DNA methylation. We hypothesized that hypermethylation of 51 CpG islands is associated with transcriptional silencing of the corresponding gene and participates in either the emergence of drug resistance or the conversion of normal cells to cancer cells. To test this hypothesis the DNA methylation status of the 5' CpG islands of dCK containing 49 CpGs, p15 containing 80 CpGs, and p16 containing 53 CpGs was determined by sodium bisulfite sequencing of normal human peripheral blood lymphocytes (PBL) and bone marrow (NBM), human leukemia cell lines, and cytosine-arabinoside (ara-C)-resistant adult acute myeloid leukemia (AML) patients. In PBL and NBM dCK, p15, and p16 were all unmethylated. dCK was unmethylated in the paired ara-C-sensitive (/S) ara-C-resistant (/R) leukemia cell lines HL60/S & /R and K562/S & /R, and in the 8 AML patients analyzed. p16 was unmethylated in KG-l and KG-1a and both had detectable p16 mRNA and protein. None of the 8 AML patients had aberrant methylation of p16. For p15, a variegated pattern of aberrant methylation was found in KG-1, and complete methylation of p15 was found in KG-1a. The variegated pattern of p15 methylation seen in KG-1 and the complete methylation seen in KG-1a were both associated with no detectable p15 mRNA or protein. p15 was aberrantly methylated in 6 of the 8 AML patients, 5 had a variegated pattern of methylation, and 1 showed complete methylation. We next introduced ectopic p15 and p16 into the p15 and p16 negative human T-cell lymphocytic leukemia cell line Jurkat. The p15 positive clones grew at a slower rate than the parent cell or p16 positive clones as measured by growth in liquid culture and MTS assay. cDNA microarray expression analysis differentiated p15 and p16 positive subclones from the parent cell line but not from each other. This suggests that despite the selective methylation of p15 but not p16 in AML, p15 and p16 are functionally similar.
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Incarbone, Marco. "In vivo study of the suppression of cell-autonomous and systemic RNA silencing by the Peanut clump virus protein P15." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ090/document.
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Chez les plantes, le RNA silencing (RNAi) est le principal mécanisme de défense antivirale. Il est opéré par de petites molécules d’ARN (siRNA), de 21-22nt de long, générées à partir de l’ARN viral par DCL4 et DCL2, respectivement. Ces siRNA confèrent la séquence-spécificité des réactions de défense intracellulaire et peuvent se déplacer à longue distance pour immuniser les cellules saines. En conséquence, les virus ont développé des protéines (VSRs) capables de supprimer ces deux aspects du RNAi. Au cours de cette thèse, j’ai pu démontrer in vivo que la protéine P15 du Peanut clump virus (PCV) est capable de séquestrer les siRNA de 21 et 22nt et qu’elle bloque le mouvement de ces derniers plus efficacement que ceux de 21nt. Pour compenser cette faiblesse, au cours de l’infection par le PCV, P15 est transportée à l’intérieur des peroxisomes en association avec les siRNA qu’elle séquestre. Le confinement des siRNA mobiles de 21nt à l’intérieur de ces organelles conduit à une inhibition du RNAi systémique et stimule fortement la propagation du PCV à travers la plante. Ces travaux définissent une nouvelle stratégie de pathogénèse virale au cours de laquelle une organelle est utilisé pour neutraliser des molécules de défense produites par l’hôteIn plants, RNA interference (RNAi) is the main antiviral defense mechanism. It is initiated through the processing of viral RNA into 21-22nt long siRNA by DCL4 and DCL2, respectively. These siRNA can mediate sequence-specific local defense reactions (cell-autonomous RNAi) or move to distant tissues to prime defenses in naive cells (systemic RNAi). Consequently, viruses have evolved proteins (VSRs) to suppress both aspects of RNAi. In this in vivo study, I show that P15, the VSR of Peanut clump virus (PCV), binds and sequesters both 21nt and 22nt siRNA. Importantly, it stops the movement of 22nt siRNA more efficiently than 21nt siRNA. During infection, P15 is shuttled into peroxisomes, and is able to « piggyback » siRNA into these organelles. By confining mobile DCL4-dependent antiviral 21nt siRNA within peroxisomes, P15 is able to shut down systemic RNAi and strongly promote PCV movement. This work describes a novel pathogenic strategy in which an organelle is used to neutralize host defensive molecules
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Abu-Nasir, Mohammed [Verfasser], and Andreas [Akademischer Betreuer] Schlegel. "Biofunktionalisierung von Implantatoberflächen mit einem synthetisch hergestellten Peptid (P15) bei diabetischen Versuchstieren gegenüber gesunden Versuchstieren / Mohammed Abu-Nasir. Gutachter: Andreas Schlegel." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2014. http://d-nb.info/1076120180/34.
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Suaid, Flavia Adelino. "Avaliação do potencial regenerativo da matriz óssea bovina inorgânica/P15 particulada em lesão de bifurcação grau III. Estudo histomorfométrico em cães." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/58/58132/tde-23012009-165328/.
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Introdução: A falta de previsibilidade no tratamento periodontal regenerativo de defeito de furca grau III, têm estimulado o estudo de alternativas para melhorar os resultados, através do emprego de diferentes técnicas e biomateriais. Um novo enxerto ósseo enriquecido com peptídeos - Matriz óssea bovina inorgânica/P15 (PepGen P15) - foi desenvolvido recentemente e, segundo a literatura, mostrou resultados significantes em relação à neoformação tecidual nos defeitos infra-ósseos testados. Assim, o presente estudo teve como objetivo verificar o potencial regenerativo da matriz óssea inorgânica/P15 particulada, no tratamento de defeitos de furca grau III em cães associado ou não ao uso de membrana de PTFE-e Material e Métodos: Foram utilizados seis cães, nos quais defeitos de furca grau III nos pré-molares inferiores foram confeccionados, sendo que no grupo teste foi utilizado a membrana de PTFE-e e a matriz óssea inorgânica/P15, no grupo controle foi utilizada somente a membrana e no grupo controle negativo, nos 2° prémolares, não foi colocado biomaterial. Os defeitos foram confeccionados e preenchidos com material de impressão (Impregum F) e após 21 dias foram debridados, as raízes aplainadas com cureta Gracey (Hu-friedy) e os dentes submetidos à profilaxia semanal com ultra-som e limpeza diária com digluconato de clorexidina a 0,12% durante 15 dias. Na segunda fase cirúrgica, foram realizadas marcações do nível ósseo nas raízes mesial e distal dos dentes P2, P3 e P4, colocação das membranas e do enxerto ósseo nos respectivos defeitos. Os dentes P3 e P4 foram aleatoriamente escolhidos para ser o grupo teste ou controle. Quatro semanas após a colocação das membranas, estas foram retiradas e, doze semanas após a remoção, os animais foram sacrificados. Os dentes e seus tecidos periodontais de proteção e suporte foram removidos, fixados em formalina tamponada a 10%, descalcificados em ácido tricloroacético a 10%, desidratados e seccionados no plano mésio-distal em cortes semi-seriados com 7m de espessura cada. Os cortes foram corados com hematoxilina e eosina (HE) ou tricrômico de Mallory (TM) sendo selecionados para a análise histomorfométrica 5 cortes representativos da porção central da bifurcação. Foram realizadas medidas da área total da bifurcação (AT), área de novos tecidos formados (ANT), área de epitélio (AE), área de tecido conjuntivo (ATC), área de novo osso (ANO) e medidas lineares da extensão representativa da altura do defeito (ED), extensão do novo tecido extensão (ENT), extensão do novo osso (EO), extensão da bifurcação (EB) e extensão do novo cemento (EC). Resultados: A análise histológica demonstrou características morfológicas similares entre os grupos avaliados. Adicionalmente, o grupo teste apresentou grânulos do enxerto ósseo, envoltos por uma matriz óssea imatura, aprisionado entre os tecidos neoformados. Os resultados das médias das medidas lineares (mm) e das medidas de área (mm2) foram respectivamente os seguintes para o grupo teste: 14,11 ± 1,74 (EF) e 17,62 ± 2,39 (ATF); 8,61 ± 3,24 (EC) e 14,66 ± 3,73 (ANT); 4,71 ± 0,54 (ED) e 0,90 ± 0,80 (AE); 3,78 ± 0,85 (ENT) e 5,36 ± 2,41 (ATC); 1,77 ± 1,54 (EO) e 6,52 ± 5,69 (ANO); 4,82 ± 2,98 (DO). As seguintes médias lineares e de área para o grupo controle respectivamente: 13,19 ± 2,03 (EF) e 15,11 ± 3,29 (ATF); 8,52 ± 3,54 (EC) e 11,88 ± 2,09 (ANT); 4,59 ± 0,65 (ED) e 0,95 ± 0,71 (AE); 3,54 ± 0,61 (ENT) e 5,19 ± 2,17 (ATC); 1,64 ± 1,06 (EO) e 4,17 ± 3,40 (ANO); 2,58 ± 1,71 (DO). E as seguintes médias lineares e de área para o grupo controle negativo respectivamente: 13,54 ± 1,41 (EF) e 14,99 ± 3,13 (ATF); 6,56 ± 2,11 (EC) e 11,13 ± 3,25 (ANT); 4,62 ± 0,47 (ED) e 0,95 ± 0,78 (AE); 3,59 ± 0,28 (ENT) e 5,89 ± 0,87 (ATC); 0,98 ± 0,48 (EO) e 2,88 ± 2,49 (ANO); 2,35 ± 2,00 (DO). A análise estatística dos dados, realizada através da aplicação do teste de Friedman Test (< 0,05), demonstrou haver diferenças estatisticamente significantes entre o grupo teste e controle negativo no parâmetro referente à ANO. Conclusão: Pode-se concluir que a matriz óssea inorgânica/P15 apresentou resultados semelhantes aos outros grupos em relação à regeneração periodontal do defeito. No entanto, quando a matriz óssea permaneceu no defeito, apresentou resultados satisfatórios através da formação óssea que circunscreveu as partículas.Background: The aim of this study was to verify the regenerative potential of particulate ABM/Synthetic Peptide in class III furcation defects associated or not with ePTFE membranes. Material and Methods: Six dogs were used and class III furcation defects were produced in the lower pre-molars and filled with impression material. After 21 days, the membranes and the bone grafts were inserted and P3 and P4 were randomized to form the test and control groups. P2 was the negative control. The animals were sacrificed 3 months post-treatment. Results: Comparisons between groups by the Friedman Test (<0.05) showed statistically significant differences between the test and negative control groups, based on NBA parameter. In the negative control group, a new bone area (NBA) of 20% was observed. In the test group, a new bone area of 37% was observed. There was no statistically significant difference between the groups to the others parameters. Conclusions: The statistical analysis using Friedman Test (<0.05) showed statistically significant differences between the test and negative control groups, based on NBA parameter. Furthermore, when the Inorganic Bone Matrix/P15 remained inside the defects, it could be clearly observed that new bone formation not only circumscribed the particles but formed above the level of the particles.
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Dunoyer, Patrice. "Etude des stratégies mises en oeuvre par le Peanut clump virus pour assurer l'amplification de son génome : rôle de la protéine P15." Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13139.
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Kubina, Julie. "Étude de l'export nucléaire des ARNm du virus de la mosaïque du chou-fleur (CaMV) chez Arabidopsis thaliana." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ052.
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Chez les métazoaires et leurs virus la majorité des ARNm est exportée du noyau par les exportines TAP-p15 et le complexe TREX-1, alors qu’une minorité est exportée par CRM1. Chez les plantes ce processus fondamental reste peu décrit voir inconnu pour les phytovirus comme le CaMV et ses ARNm 19S et 35S. Notre objectif a été de clarifier cette étape primordiale mais jamais étudiée du cycle de CaMV et de l'utiliser pour mieux comprendre l'export nucléaire des ARNm chez la plante modèle Arabidopsis thaliana. Nos principaux résultats montrent que le CaMV utilise les deux voies d’export, celle de TREX-1 et celle de CRM1, pour exporter ses ARN 35S et que le précurseur de sa protéase et transcriptase inverse, P5, est important pour l’export par TREX-1. Nous avons également démontré que la région leader de ces ARN viraux, et en particulier sa structure secondaire, est un élément reconnu par la machinerie d’export nucléaireIn metazoa most of the mature cellular and viral mRNAs are exported out of the nucleus via the TAP-p15 export receptors and their associated TREX-1 complex while a minority is exported by the exportin CRM1. In plants, this fundamental process is poorly known and even unknown for DNA phytoviruses such as CaMV and its 19S and 35S mRNAs. Our aim was to clarify this important but never studied step in CaMV life cycle in order to decode the mechanisms of mRNAs nuclear export in the model plant Arabidopsis thaliana. Our main results show that CaMV uses both the TREX-1 complex pathway as well as CRM1 to export its 35S mRNAs, and that the precursor of the viral proteinase and retrotranscriptase, P5, is important for the nuclear export by TREX-1. We also demonstrated that CaMV 35S RNA leader region and especially its highly structured stem-loop is a cis-acting element recognized by the mRNAs nuclear export machinery
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Ko, Rose Marie. "The effect of the AML1-ETO translocation on cell cycle tumor suppressor gene function." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/ko.pdf.
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Cahen-Fourot, Louison. "The social relation to the environment in contemporary capitalism: theoretical reflections and empirical explorations." WU Vienna University of Economics and Business, 2019. http://epub.wu.ac.at/6957/1/WP_26.pdf.
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This paper analyses the socio-economic context into which environmental policies and ecological sentiments emerge through empirically studying the relation to the environment of different kinds of capitalism. The association and interaction of the relation to the environment with other key social relations, e.g. the labour-capital relations, are studied and discussed. To achieve this, I draw from Regulation Theory and augment its analytical framework with an explicit environmental dimension. I then conduct an empirical analysis of the diversity of contemporary capitalism including the social relation to the environment for a sample of thirty-seven OECD and BRICS countries. Five kinds of capitalism are identified: the Northern-continental European, the Southern-central European, the Anglo-Saxon and Pacific, the Emerging Countries and the Two Giants. A main result is the correspondence between ecology-prone social relations to the environment, labour oriented capital-labour relations and welfare-oriented states. However, the results show that countries that are the most ecology-prone are also the ones that have the most relocated their environmental impact, an observation consistent with the critical literature on the Environmental Kuznets Curve.Series: Ecological Economic Papers
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Lindberg, Daniel. "Molecular Genetic Studies of Sporadic and MEN1-Associated Endocrine Pancreatic Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7595.
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Cabral, Vinicius Duarte. "Expressão imuno-histoquímica dos supressores tumorais p53, p16 e p14 em neoplasias epiteliais ovarianas." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/148115.
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Introdução: Anormalidades nos supressores tumorais p14, p16 e p53 são relatadas em diversos tipos de câncer em humanos. Na carcinogênese ovariana, p16 e p53 foram extensivamente estudados, mas p14 foi analisado somente em carcinomas. Objetivo: O estudo visa determinar a expressão imuno-histoquímica de p14, p16 e p53 em tumores ovarianos epiteliais benignos, borderline e malignos. Método: Estudo transversal utilizando imuno-histoquímica em amostras de tumores epiteliais ovarianos emblocados em parafina do Hospital de Clínicas de Porto Alegre. Resultados: p14 foi positivo em 93% dos tumores benignos, 94% dos borderline e 60% dos malignos. A perda de expressão foi estatisticamente associada com carcinomas. p16 foi positivo em 94,6% dos carcinomas, 75% dos tumores borderline e 45,7% dos benignos. p53 foi positivo em 29,7%, 16,7% e 2,9% dos tumores malignos, borderline e benignos, respectivamente. Os subtipos de carcinoma não mostraram diferenças de expressão. Conclusão: Nosso estudo foi o primeiro a descrever a expressão de p14 em tumores benignos e borderline. Ela permanece estável nos benignos e borderline, enquanto os carcinomas exibem uma perda de expressão significativa. Isso pode indicar que anormalidades de p14 acontecem tardiamente na carcinogênese. As taxas de expressão de p16 e p53 foram semelhantes a estudos anteriores. Estudos futuros devem investigar anormalidades genéticas nas sequencias codificadoras de p14 e incluir todos os tipos de tumor epitelial ovariano.Background: Abnormalities in tumor suppressors p14, p16 and p53 are reported in several human cancers. In ovarian carcinogenesis, p16 and p53 have been extensively studied, but p14 was only analyzed in carcinomas. Aim: This study seeks to determine p14, p16 and p53 immunohistochemical expression in benign, borderline and malignant ovarian epithelial tumors and correlate them with survival and clinical variables. Methods: Cross-sectional study utilizing immunohistochemical staining of p14, p16 and p53 in paraffin-embedded tissue samples from ovarian epithelial tumors obtained from Hospital de Clinicas de Porto Alegre. Results: p14 was positive in 93% of benign, 94% of borderline and 60% of malignant tumors. Loss of expression was statistically associated with carcinomas. p16 was positive in 94.6% of carcinomas, 75% of borderline and 45.7% of benign tumors. p53 was positive in 29.7%, 16.7% and 2.9% of malignant, borderline and benign tumors, respectively. Carcinoma subtypes showed no difference in expression. Conclusions: To our knowledge, this is the first description of p14 expression in benign and borderline tumors. It remains stable in benign and borderline tumors, while carcinomas show a significant absence of staining. This may indicate p14 abnormalities occur later in carcinogenesis. p16 and p53 expression rates show similar results to previous reports. Future studies should investigate genetic abnormalities in p14 coding sequences and include all types of ovarian epithelial tumors.
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Li, Junan. "Structural and functional studies on Tumor Suppressor INK4 Proteins P16(INK4A) and P18(INK4C) /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488194825665461.
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Chevillard, Christophe. "Cartographie physique et transcriptionnelle de la région p11. 2-p12 du chromosome 17 humain." Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX22073.
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Plusieurs pathologies ont ete localisees au niveau de la region juxtacentromerique (17p11. 2-p12) du bras court du chromosome 17 humain: le syndrome de smith-magenis (sms) la maladie de charcot-marie-tooth de type 1a (cmt 1a) la neuropathie tomaculaire (hnpp). Les buts de ce travail etaient les suivants: 1) construire une carte physique a l'aide de chromosomes artificiels de levure (yac). 2) construire et/ou localiser de nouveaux marqueurs a des fins fondamentales ou appliquees (diagnostic). 3) isoler de nouveaux genes localises dans ces regions. 4) preciser la localisation et l'etendue des regions critiques cmt 1a et sms, ainsi qu'une possible relation mecanisme commun) entre ces deux pathologie impliquant des remaniements chromosomiques. L'ensemble de ces travaux nous a conduit aux resultats suivants: 1) construction d'un contig de yacs de 5,5 mb, couvrant entierement la region cmt 1a. 2) isolement de yacs couvrant les bornes proximales de la region cmt 1a. 3) localisation de 5 microsatellites dans la region sms et de 4 dans la region cmt 1a. Ces marqueurs seront utiles en diagnostic. 4) caracterisation de diverses sequences transcrites. L'une sn u3, prealablement connue mais non localisee, est situee dans la region sms. Il s'agit de la premiere sequence transcrite, deletee chez des patients sms. La deuxieme sequence transcrite (884g12 b7), isolee par selection directe d'adnc, est situee dans la region dupliquee chez des patients cmt 1a
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Ekström, Alexander. "Förutsättningar för ökad livslängd av sandlåsöverhettare." Thesis, Uppsala universitet, Strukturkemi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-343511.
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Superheaters suffer large material loss during combustion of waste and biomass, causing a short life time for these expensive components. During combustion, corrosive ash particles are formed and erosion is caused by circulating bed material and sand particles, all contributing to the material loss. This study examines whether corrosion or erosion has the largest effect on this material loss by investigating two superheaters in loop seal during biomass and waste combustion of an 85 MW, Circulating Fluidized Bed (CFB) boiler in Händelö. The samples were investigated by SEM/EDX and XRD with regard to material loss and corrosion products. The superheaters have different thermal conditions since the material temperature in the first superheater that the steam passes is lower than in the one that comes after. In this report, a model to determine the tube temperature in steam boiler superheaters is also described due to the fact that the local tube temperature is of great importance of condensation of corrosive gases such as KCl and NaCl. Material loss was significantly greater on the cooler superheater compared with the warmer. The material temperatures on the outside of the tubes, were calculated to be about 574 °C for the cooler superheater and about 617°C for the warmer superheater. Overall, all analyzes showed low levels of corrosive substances, although there was a certain corrosion tendency, which indicates that material loss of the superheaters is caused by corrosion-assisted erosion. Lower material temperature of the superheater resulted in a higher degree of condensation of corrosive species such as alkali chlorides, which might have accelerated the erosion. The conclusion is that the dominant mechanism of material loss on the superheaters is erosion.
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Camós, Guijosa Mireia. "Caracterización biológica de la leucemia mieloide aguda con translocación t(8;16)(p11;p13) y reordenamiento MYST3-CREBBP." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/2220.
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INTRODUCCIÓN. La leucemia mieloide aguda (LMA) es una enfermedad heterogénea desde el punto de vista clínico y biológico. En los últimos años se vienen reconociendo diversas alteraciones moleculares que definen entidades específicas. En este contexto, la LMA con translocación t(8;16)(p11;p13) y reordenamiento MYST3 (MOZ)/CREBBP (CBP) es una variedad infrecuente mal caracterizada desde el punto de vista biológico. HIPÓTESIS Y OBJETIVOS. La proteína quimérica MYST3-CREBBP, resultante de la translocación t(8;16)(p11;p13), podría conferir a este subtipo de LMA una individualidad biológica propia, con rasgos diferenciados respecto al resto de leucemias. Para confirmar esta hipótesis general los objetivos de la presente tesis doctoral fueron: 1) diseñar una técnica de PCR para el diagnóstico rápido y específico del reordenamiento MYST3-CREBBP; 2) caracterizar el punto de ruptura de los genes implicados en la translocación en una serie de pacientes y 3) estudiar el perfil de expresión génica de las LMA con reordenamiento MYST3-CREBBP y compararlo con el de otros subtipos bien definidos de LMA.
PACIENTES Y MÉTODOS. Se estudió una serie de pacientes con LMA y reordenamiento MYST3-CREBBP (n=7) y se compararon sus características biológicas con otros casos de LMA. Para ello se diseñó una técnica de PCR nueva para la detección del reordenamiento MYST3-CREBBP, mientras que los puntos de ruptura de los genes implicados en la translocación se estudiaron mediante secuenciación directa. El estudio del perfil de expresión génica de la LMA con reordenamiento MYST3-CREBBP se abordó utilizando microarrays de oligonucleótidos (Affymetrix HU133A). La diferencia entre la expresión génica entre diferentes subtipos de leucemia se analizó con diversas técnicas estadísticas (ANOVA, t-test), utilizando diferentes programas informáticos. Los resultados de este análisis se validaron en una serie independiente de pacientes estudiados mediante RT-PCR cuantitativa utilizando arrays de baja densidad.
RESULTADOS. Los pacientes afectos de LMA con reordenamiento MYST3-CREBBP presentaron un inmunofenotipo característico (CD34-, HLA-DR-, CD117-, CD56+, expresión de marcadores mielomonocíticos). Por otro lado, el análisis molecular reveló que el tránscrito tipo I del gen quimérico MYST3-CREBBP es el más común en estos pacientes. Por otra parte, el análisis sobre el perfil de expresión génica mostró una firma característica para las LMA con reordenamiento MYST3-CREBBP, consistente en la sobreexpresión de determinados genes HOX (HOXA9, HOXA10), de los oncogenes RET y PRL y la infraexpresión de genes como CCND2, STAT5 y WT1. Por otro lado, se observó una similitud en la expresión de algunos genes entre las leucemias MYST3-CREBBP y las LMA con reordenamiento de MLL, lo que sugiere un mecanismo de leucemogénesis parcialmente compartido por los dos tipos de leucemia.
CONCLUSIONES. La técnica de RT-PCR implementada es útil para la detección rápida del reordenamiento MYST3-CREBBP. El denominado tránscrito tipo I del gen quimérico MYST3-CREBBP es el más común en la LMA con t(8;16). La LMA con reordenamiento MYST3-CREBBP posee un perfil de expresión característico, con sobreexpresión de diversos oncogenes como RET y PRL y la presencia de un patrón específico de expresión de los genes homeobox.
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Shapla, Tanweer J. "INFERENCE OF ATTRIBUTABLE RISK FOR MULTIPLE EXPOSURE LEVELS UNDER CROSS-SECTIONAL SAMPLING DESIGN." Bowling Green State University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1148489335.
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Song, Jin. "TNFR2/p75 and TNFR1/p55 interactions in delayed non-targeted effects of radiation in bone marrow derives EPCs." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12229.
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Thesis (M.A.)--Boston UniversityThe central dogma of radiation has been that all biological effects of ionizing radiation occur through direct damage of DNA in the nucleus. There is however evidence dating back to as early as 1950’s which suggests that radiation can cause damage in unirradiated “bystander” cells through mechanisms currently unknown at low dose exposures (Parsons, 1954). This radiobiological bystander effect has since been observed in numerous studies involving microbeam experiments and media transfer experiments, where the observed DNA damage was significantly higher than the amount of cells directly traversed by radiation (Zhou, 2001; Mothersill, 1998). Elevation in the levels of IL-8, TNF-α, FASL, nitric oxide, and reactive oxygen species have been associated with low dose irradiation and are implicated as potential mediators of bystander effect (Narayanan, 1999; Burr, 2010; Rastogi, 2012). TNF-α has two types of receptors p55 and p75 that are part of the mechanism involving NF-κB gene transcription. In our study, we invested the role of TNF-α receptors in the induction of p-H2AX foci (marker of DNA double strand breaks-DBS) in unirradiated mice endothelial progenitor cells (EPCs) post irradiation (IR). One set of EPCs were irradiated with low dose γ-radiation and the media of the cells transferred to corresponding unirradiated EPCs of wild type (WT), p55 knock out (KO), and p75KO mice. Our data showed that at 24 hours, control WT EPCs had the highest p-H2AX foci/cell and gradually decreased 3 and 5 days post media transfer. In contrast, p75KO and p55KO EPCs had lowest count of p-H2AX foci at 24 hours and increased at 3 days. At 5 days post conditioned media (CM) transfer, p55KO continued to have higher p-H2AX foci in an increasing trend whereas p75KO decreased in p-H2AX foci. Our findings showed that in comparison to WT EPCs, the expression of TNFR1/p55 and TNFR2/p75 greatly influenced the pattern of p-H2AX induction over time. ELISA analysis of the γ-irradiated WT and p55KO EPC conditioned media at different time points of the experiment showed that several cytokines and chemokines such as IL-1α, IL-1β, MCP-1, Rantes, and MIP-1α are associated with the increasing trend of p-H2AX foci in p55KO EPCs. Our in vitro mouse recombinant cytokine treatment of p55KO EPCs, using the concentrations of cytokines determined in the ELISA analysis confirmed the ability of TNF-α to induce p-H2AX foci and identified IL-1α as one of the main inducers.
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Mas, Herrero Sergi. "Metilación en p16(INK4a), p14(ARF) y hMLH1 en cáncer colorectal: influencia de la dieta y el genotipo MTHFR." Doctoral thesis, Universitat de Barcelona, 2004. http://hdl.handle.net/10803/673087.
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Los tumores que presentan alteraciones en los patrones de metilación podrían constituir un subtipo molecular de cáncer colorectal (CRC) con entidad etiológica y clínicopatológica propia. Los conocimientos recientes en la biología del CRC han permitido diferenciar distintos subtipos moleculares de CRC, que en los próximos años podrían incorporar nuevos conocimienos en metilación aberrante y las posibles causas ambientales relacionadas.
Además, estas alteraciones epigenéticas que suprimen la expresión génica son potencialmente reversibles, lo que ofrece una oportunidad única para el desarrollo de nuevas terapias; además pueden ser el punto de partida de estrategias preventivas. Sidransky, Baylin, Hermán y otros autores, han demostrado recientemente que la metilación de p16(INK4a) puede ser detectada en suero de pacientes de CRC con tumores metilados, lo que abre posibilidades adicionales para monitorizar las recidivas o incluso el diagnostico precoz.
Nuestra hipótesis es que la etiología de dichos subtipos moleculares podría estar fundamentada en factores genéticos y/o dietéticos.
Por lo tanto, dada la importancia de los problemas de metilación en la patogenia del CRC y la escasez de datos respecto a sus posibles causas, proponemos un estudio focalizado en factores de riesgo genéticos y metabólico-dietéticos para el CRC que presente alteraciones de metilación.
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AZZI, LYAMINE. "Regulation du cycle cellulaire : interaction entre p9#c#k#s#h#s#2 et p34#c#d#c#2. caracterisation de la p15#c#d#k#-#b#p, une nouvelle proteine interagissant avec p34#c#d#k#4 et p33#c#d#k#5." Rennes 1, 1994. http://www.theses.fr/1994REN10063.
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Le cycle cellulaire est constitue de deux phases majeures, la phase s (replication de l'adn) et la phase m (division cellulaire). Celles-ci sont separees par deux periodes gap(g1 and g2). Le cycle cellulaire est hautement regule par les kinases cycline-dependantes (les cdk). La transition g2/m est declenchee par un facteur universel, le mpf m-phase promoting factor, identifie comme un complexe constitue d'au moins deux sous-unites, la p34#c#d#c#2 et la cycline b#c#d#c#1#3. L'entree de la cellule en phase m est caracterisee par une activation de la kinase cdc2 suite a une dephosphorylation sur les residus thr14 et tyr15. Cette dephosphorylation est catalysee par la phosphatase cdc25. Parmi les proteines regulant la formation et l'activation du complexe p34#c#d#c#2/cycline b, la p13#s#u#c#1/p9#c#k#s#h#s semble jouer un role fondamental. La p9#c#k#s#h#s interagit avec la p34#c#d#c#2 a travers deux sites cooperatifs conduisants a la formation d'un complexe p9#c#k#s#h#s/p34#c#d#c#2 tres stable. In vitro, la p9#c#k#s#h#s peut s'assembler en une structure hexamerique impliquant une possible oligomerisation de la p34#c#d#c#2 in vivo. Nous avons purifie une proteine de 15 kda, la p15#c#d#k#-#b#p, qui interagit fortement avec les kinases cdk4/cycline d (impliquee en g1) et cdk5/p25 (preferentiellement exprimee dans les tissus nerveux). La p15cdk-bp retient une kinase active envers les proteines chromosomales hmg i/y et p1 et la mbp myelin basic protein. Immobilisee sur des billes de sepharose, la p15#c#d#k#-#b#p peut constituer un outil important pour etudier la regulation du cycle cellulaire ainsi que la fonction et la pathologie du cerveau
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Brown, Victoria Lissa. "The role of p16'I'N'K'4'a and p14'A'R'F tumour suppressor genes in the pathogenesis of cutaneous squamous cell carcinoma." Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423542.
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Mabrouk, Kamel. "Synthèse peptidique en phase solide : contribution à l'étude de relations structure-fonction des protéines P18, P25, TAT ET REV DU VIH-1." Aix-Marseille 2, 1992. http://www.theses.fr/1992AIX22072.
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La synthese des peptides en phase solide est d'un interet considerable dans de multiples domaines d'etude de molecules biologiquement actives. Dans ce travail deux applications menees a l'aide de peptides synthetiques sont presentees: l'etude de la reponse humorale dirigee contre les proteines de structure interne p25 et p18 du virus de l'immunodeficience humaine (vih); l'etude de l'activite neurotoxique des proteines de regulation tat, et rev des virus vih, siv, visna et htlv. Une analyse fine de la specificite de la reponse humorale dirigee contre la proteine p25 (capside) du vih a ete effectuee a l'aide de 37 peptides synthetiques de taille variable de 9 a 48 residus d'acides amines. Cette etude a ete entreprise d'une part, chez l'homme et le chimpanze infectes ainsi que chez le chimpanze immunise avec le virus entier inactive et d'autre part, chez le lapin et le chimpanze immunises avec le proteine soluble. Les resultats montrent une specificite des epitopes b en fonction de l'immunogene utilise: particules virales ou proteines solubles. L'antigenicite de la proteine p18 (matrice) a ete analysee a l'aide de 20 peptides synthetiques courts et longs couvrant la totalite de la structure primaire de la proteine. Cette etude a ete realisee sur des serums d'individus infectes ou de chimpanzes immunises. Apres analyse des structures secondaires des 21 peptides synthetiques par dichroisme circulaire, notre etude semble montrer contrairement aux hypotheses largement admises, l'absence de relation evidente entre l'antigenicite d'un peptide (epitopes b et t) et sa capacite a adopter une structure secondaire bien determinee. Nous avons etudie l'activite neurotoxique in vitro et in vivo des proteines de regulation tat et rev des virus vih, siv, htlv. A l'aide de peptides synthetiques, nous avons montre que cette activite est associee a la region basique de ces proteines
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Nilsson, Lisa. "The cell cycle regulators p18Ink4c and p19Ink4d : in vivo studies of their roles in tumorigenesis and development." Doctoral thesis, Umeå University, Molecular Biology (Faculty of Science and Technology), 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1357.
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Progression through the G1, S, G2 and M phases of the cell cycle is controlled by cyclin-dependent kinases (Cdks) and cyclins. These proteins form active Cdk:cyclin complexes that phosphorylate specific substrates. The Cdk:cyclin complexes of the G1/S transition regulate the progression of cells into the S phase by phosphorylating the retinoblastoma protein (Rb). This prevents Rb from sequestering E2F, a transcription factor that induces expression of genes required for DNA synthesis. This process is in part regulated by a family of Cdk inhibitors (CKIs) called the Ink4 family (Inhibitors of Cdk4). The Ink4 family of CKIs consists of four members; p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, and they bind specifically to Cdk4 and Cdk6, thereby negatively regulating their kinase activities and cell cycle progression. Because of its cell cycle inhibitory role, p16Ink4a is frequently mutated or deleted in human cancer, whereas the other Ink4 genes are only occasionally altered in cancer. The overall aim of this thesis was to study the roles of p18Ink4c and p19Ink4d using in vivo models of cancer and embryonic development. In paper I, we analyzed the tumor spectrum in mice lacking p53, Ink4c and Ink4d. p53 is a tumor suppressor and one of the most frequently mutated genes in human cancer. Mice carrying mutated p53 alleles are highly tumor-prone but develop predominantly lymphomas. However, the combined loss of p53 and Ink4c (but not Ink4d) caused a shift in the tumor spectrum to increased incidences of hemangiomas and hemangiosarcomas, as well as appearance of medulloblastomas, a tumor of the cerebellum. These data, revealed in the absence of p53, suggest a cell-type specific tumor suppressing role for p18Ink4c. In paper II, loss of Ink4c was evaluated in another tumor-prone mouse model; the Eµ-Myc mouse. This is a transgenic mouse overexpressing c-Myc in B cells causing clonal B cell lymphomas. Surprisingly, precancerous B cells and lymphomas from Eµ-Myc mice exhibited elevated levels of p18Ink4c mRNA and protein despite high rates of proliferation. Moreover, loss of Ink4c in this model did not affect the rate of cell proliferation or the onset of tumor development. We conclude from these studies that Ink4c is not an important tumor suppressor of Myc-induced lymphomas. To gain insight into the role of Ink4 genes in early vertebrate development, the African clawed frog, Xenopus laevis, was analyzed for the presence of Ink4 homologs. Paper III describes the cloning and characterization of a gene homologous to Ink4d, Xl-Ink4d. This CKI is expressed throughout frog embryo development, making Xl-Ink4d the only CKI present during the cleavage stages of X. laevis. Antisense morpholino oligonucleotides directed against Xl-Ink4d were used to knock down the protein level of Xl-Ink4d during development. This resulted in defects in head tissues and reduced expression of Twist, a gene important for neural crest cell migration. We therefore propose that Xl-Ink4d is important for proper neural crest differentiation in the frog.
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Renaud-Rougier, Marie-Bénédicte. "Apport des potentiels évoqués visuels précoces (P45 et P75) à la compréhension de l'organisation du système visuel: mise en évidence de processus cognitifs sous-corticaux." Bordeaux 2, 1998. http://www.theses.fr/1998BOR28600.
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Carvalho, Acacia Fernandes Lacerda de [UNIFESP]. "Estudo Citogenético-molecular e Clínico de uma família com onze portadores de monossomia 5p ou trissomia 5p em decorrência de uma translocação (5;15)(p13;p12)." Universidade Federal de São Paulo (UNIFESP), 2008. http://repositorio.unifesp.br/handle/11600/9497.
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Publico-10861c.pdf: 1168973 bytes, checksum: 52297e627ce7149b800b96678eafb89a (MD5)Introdução: A monossomia parcial 5p (síndrome de cri-du-chat) e a trissomia parcial 5p são síndromes bem caracterizadas clinicamente com vários casos descritos na literatura. No entanto, este é o primeiro estudo citogenético -molecular e clínico com as duas síndromes presentes em uma mesma família. No presente estudo existe onze afetados vivos com a monossomia ou trissomia parcial 5p. decorrente de uma translocação equilibrada t(5;15)(p13;p12) parental. Objetivos: Este trabalho teve como objetivos: realizar a identificação citogenética e clínica dos casos com monossomia e trissomia 5p na família e dos indivíduos portadores da translocação na forma equilibrada; produzir subsídios para o aconselhamento genético da família; avaliar as variações fenotípicas intra-familial e a correlação genótipo-fenótipo na monossomia 5p e trissomia 5p e determinar o ponto de quebra envolvido na translocação; . Casuística e métodos: Quatro gerações de uma família. A avaliação citogenética foi realizada por culturas de linfócitos e posterior bandamento G TG e NOR. A técnica de Hibridação in situ por fluorescência (FISH) utilizando clones de BACs foi utilizada para a determinação do ponto de quebra em 5p. Resultados: Foram identificados seis indivíduos com a monossomia parcial 5p e cinco com a trissomia parc ial 5p, apresentando cariótipos: 46,XX ou XY,der(5)t(5;15)(p13;p12) e cariótipo 46,XX ou XY,der(15)t(5;15)(p13;p12), respectivamente , além de sete portadores da translocação equilibrada, seis deles com filhos afetados. Após a utilização de 12 clones de BACs o ponto de quebra foi mapeado na região correspondente ao BAC RP11 -1079N14 em 5p13.3, resultando em deleção ou duplicação de cerca de 32 Mb nos pacientes em questão. A avaliação clínica intrafamilial dos portadores da monossomia 5p demonstrou que estes pacientes apresentam a maioria das características descritas na síndrome de cri-du-chat, enquanto que nos pacientes com a trissomia 5p existe uma maior heterogeneidade clínica, comparado aos casos da literatura, decorrente da região em triplicata presente na família estudada. Conclusões: O estudo identificou os indivíduos com monossomia ou trissomia 5p e os possíveis portadores da translocação na forma equilibrada possibilitando o aconselhamento genético da família. Por haver vários indivíduos afetados e, por ter sido identificado o ponto de quebra, foi possível uma melhor caracterização clínica das duas síndromes e uma maior correlação do segmento cromossômico em desequilíbrio com as alterações fenotípicas.
Introduction: Partial monosomy 5p (Cri du Chat syndrome) and partial trisomy 5p are clinically well characterized syndromes, with several cases described in the literature. This, however, is the first molecular-cytogenetic and clinical study with both syndromes present in the same family. We describe eleven alive affected individuals with partial 5p monosomy or trisomy resulting from a parental balanced translocation t(5;15)(p13;p12). Objectives: The objectives of this work were to identify cytogenetically and clinically the 5p monosomy and trisomy cases and the carriers of the balanced translocation in the family, to determine molecularly the breakpoint involved in the translocation, to evaluate the intrafamilial phenotypic variations, to establish a genotype-phenotype correlation in 5p monosomy and trisomy, and to provide genetic counseling to the family. Casuistic and methods: Four generations of a family were studied. Cytogenetic evaluation was performed on G- and NOR-banded cultured lymphocytes. The fluorescence in situ hybridization (FISH) technique with bacterial artificial chromosome (BAC) probes was used to determine the breakpoint on 5p. Results: Six individuals with partial 5p monosomy and five with partial 5p trisomy were identified, presenting the karyotypes 46,XX or XY,der(5)t(5;15)(p13;p12) and 46,XX or XY,der(15)t(5;15)(p13;p12), respectively. Seven carriers of the balanced translocation were identified, six of them with affected children. After using 12 BAC probes, the breakpoint was mapped to the region corresponding to BAC RP11-1079N14, at 5p13.3, resulting in a deletion or duplication of about 32 Mb in the studied patients. The intrafamilial clinical evaluation of the patients with 5p monosomy showed that they presented most of the characteristics described in the cat eye syndrome, whereas the patients with 5p trisomy displayed a greater clinical variability, compared to the cases from the literature. Conclusions: The study identified the individuals with 5p monosomy and trisomy and the carriers of the balanced translocation, thus enabling to provide genetic counseling to the family. The determination of the breakpoint and of the unbalanced chromosome segment made it possible to establish a more precise karyotype-phenotype correlation and to better characterize the partial 5p monosomy and trisomy syndromes.
TEDE
BV UNIFESP: Teses e dissertações
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Ng, Kung Yau. "ANKRA2 interacts with p35 and is a substrate for Cdk5/p35 /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BICH%202006%20NG.
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Mönch, Dina [Verfasser], and German [Akademischer Betreuer] Ott. "Identifizierung von Zielmolekülen für die innovative Therapie pleuraler Mesotheliome : Untersuchung von Tyrosinkinasen sowie Komponenten der NF2/mTOR- und p14/p16-Signalwege / Dina Mönch ; Betreuer: German Ott." Hohenheim : Kommunikations-, Informations- und Medienzentrum der Universität Hohenheim, 2020. http://d-nb.info/1220774723/34.
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Hleibieh, Kamal. "Etude des propriétés biologiques de la protéine p25, de l'ARN3 et de la protéine p14 du Beet necrotic yellow vein virus : vers de nouvelles stratégies de luttes antivirales." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/HLEIBIEH_Kamal_2010.pdf.
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Le virus des nervures jaunes et nécrotiques de la betterave (BNYVV) est responsable de la rhizomanie de la betterave sucrière. La prolifération racinaire, les symptômes foliaires et le mouvement à longue distance viral sont liés à l’ARN3 viral. Si l’infection systémique du virus nécessite une séquence nucléotidique de l’ARN3 de 20 nts appelée coremin, les symptômes foliaires et racinaires sont induits par l’expression de la protéine p25. Mes recherches ont été consacrées à l’étude des modifications post traductionnelles de la protéine p25, et plus précisément l’incidence des phosphorylations sur ses propriétés connues, pour rechercher un éventuel mutant dominant négatif utilisable dans la lutte antivirale. Cette étude a montré un rôle de la phosphorylation de la protéine p25 dans la modulation de ses propriétés. J’ai recherché les partenaires cellulaires et viraux de la protéine p25 par co-immunoprécipitation et double hybride de levure et montré que la protéine p25 forme un complexe avec les composants de SCF (F-box-Kelch•ASK2•Cul1). Nos recherches concernant la séquence coremin de l’ARN3 indispensable pour l’infection systémique chez Beta macrocarpa ont révélé l’interaction spécifique entre cette petite séquence et la protéine p14, le suppresseur de RNA silencing codé par l’ARN2. La protéine p14 et la séquence d’ARN3 sont nécessaires au mouvement à longue distance. Leur interaction favorise mais n’apparaît pas essentielle au mouvement viral à longue distance sur B. Macrocarpa et Nicotiana benthamiana. La présence de la séquence coremin complémente directement ou indirectement la fonction de la protéine p14 dans l’inhibition de la mort cellulaire et dans la multiplication viraleThe Beet necrotic yellow vein virus (BNYVV) is responsible for the rhizomania syndrome of sugar beet. Root proliferation, leaf symptom expression and long distance movement are directly linked to the viral RNA3. If the systemic spread of the virus requires the 20 nts long coremin sequence on the RNA3, the leaf (yellowing) and root (proliferation) symptoms are induced by the expression of the p25 protein. My researches were dedicated to study the post translational modifications of p25 protein, more precisely the incidence of phosphorylations on p25 properties, looking for a possible dominant negative mutant to be used in antiviral fights. This study showed that p25 phosphorylation modulates its properties. I’ve searched for cellular and viral partners of the p25 protein using coimmunoprecipitation and yeast two-hybrid and showed that the p25 protein forms a complex with the components of a SCF (F-box-Kelch•ASK2•Cul1). Our researches concerning the RNA3 coremin sequence responsible for the systemic spread on Beta macrocarpa, evidenced a specific interaction between this RNA3 sequence and the RNA2- encoded p14 silencing suppressor protein. Both p14 and the coremin sequence are required for viral systemic spread. Their interaction favors but appear not essential for the long distance movement of the virus on B. Macrocarpa and Nicotiana benthamiana. The coremin sequence can directly or indirectly complement the p14 function in symptom manifestation and in the viral multiplication
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Valentino, Francesca. "“Caratterizzazione funzionale di p65(-1), nuova isoforma di p65 del complesso NF-kB e preparazione di un clone per l'ingegnerizzazione di un topo p65(-1) -/-“." Doctoral thesis, Università degli Studi di Palermo, 2014. http://hdl.handle.net/10447/91282.
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NF-kB è un fattore di trascrizione eucariotico e ubiquitario che regola l’espressione di geni coinvolti in molteplici processi cellulari come la risposta immunitaria, la flogosi, l’apoptosi, la crescita cellulare e lo sviluppo embrionale.
Le proteine appartenenti alla famiglia di NF-kB sono p65, c-Rel, RelB, p50 e p52. Tali proteine svolgono la funzione di fattori trascrizionali legando specifiche consensus del DNA (consensus kB) sotto forma di omo - eterodimeri.
Ogni membro della famiglia di NF-kB è caratterizzato dalla presenza di un dominio, altamente conservato, il “Rel Homology Domain” (RHD). Nel RHD sono stati mappati i sottodomini di dimerizzazione, interazione con gli inibitori (IkB), traslocazione nucleare e legame al DNA.
In condizioni basali i dimeri di NF-kB sono mantenuti nel citoplasma dagli inibitori IkB. La presenza di uno stimolo specifico induce il rilascio di NF-kB e la traslocazione al nucleo, dove lega sequenze promotrici e regola l’espressione dei geni target.
Tra i diversi complessi di NF-kB, il p65/p50 è sicuramente il più abbondante nelle cellule e conseguentemente anche il più studiato.
In uomo e in topo è stata scoperta un’isoforma di p65, chiamata p65(-1). Questa variante di splicing contiene un nuovo esone (chiamato esone -1), localizzato a monte del primo esone (esone 0) ad oggi conosciuto del gene RelA, codificante per p65.
La trascrizione dell’esone -1 induce un evento di splicing tra gli esoni -1 e 1, determinando la contemporanea escissione dell’esone 0,
Conseguentemente la p65(-1) presenta un RHD più piccolo rispetto a quello della controparte wild type.
Numerose analisi hanno evidenziato differenze funzionali tra le proteine p65 e p65(-1), in alcuni meccanismi cellulari come l’attività trascrizionale sulle consensus kB, la regolazione dell’apoptosi e l’attivazione del recettore dei glucocorticoidi (GR).
Pertanto l’obiettivo di questa tesi è di caratterizzare il ruolo di p65(-1) attraverso tre approcci: il primo in vitro, il secondo ex vivo e il terzo in vivo.
Allo scopo di analizzare il ruolo come fattore trascrizionale di p65(-1), sono stati realizzati saggi luciferasi, usando alcuni promotori artificiali e naturali come NF-kB-Luc (nuclear factor kB) CRE-Luc (elementi di risposta all’cAMP), AP1-Luc (elementi di risposta di AP1), SRE-Luc (elementi di risposta al siero), HSE-Luc (elementi di risposta alle proteine da shock termico), pANXA-1-Luc (annessina 1) e pIL-6-Luc (interleuchina 6). Inoltre, le attività di p65(-1) sono state analizzate sia in termini di omodimero sia in termini di eterodimero con le proteine p65 o p50.
Un’ulteriore analisi di espressione è stata condotta sulle cellule del sangue periferico umano (PBMC), in cui si dimostra che l’espressione del messaggero è sempre presente nei campioni analizzati. Inoltre i nostri dati dimostrano la presenza di profili di espressione differenti tra gli individui considerati.
Infine per identificare le funzioni biologiche della nuova isoforma, vogliamo ingegnerizzare un topo KO per p65(-1). In particolare in questa sede presentiamo le possibili strategie analizzate e la realizzazione di un clone per la ricombinazione omologa per ingegnerizzare un topo transgenico caratterizzato dalla mancata espressione di p65(-1), senza alterare le funzioni di p65.Nuclear Factor-κB (NF-κB) are ubiquitous transcription factors that in mammals regulate many biological process including inflammation, immunoregulation, apoptosis, cell growth and cell proliferation. NF-kB family members include RelA (p65), c-Rel, RelB, p50 and p52. These proteins exert their functions by binding as homodimers or heterodimers to specific DNA target sites (kB consensus). NF-kBs are defined by an highly conserved amino acid domain the Rel Homology Domain (RHD), in which lie sequences for dimerization, binding to inhibitors (IkB), nuclear translocation and DNA binding. In basal conditions, NF-kB is localized in the cytoplasm complexed with its inhibitor IkB. Upon receipt of a specific signal, NF-kB is released from IkB and translocates to the nucleus to control gene expression. A new isoform of p65, named p65(-1), have been discovered in human and mouse. This isoform contains an unknown exon (named exon –1) located upstream to the first known exon of RelA, coding for p65. Transcription of the exon -1 leads to an alternative splicing between exon -1 and exon 1, thus skipping exon 0. By consequence p65(-1) has a smaller RHD than p65. Many evidences show that p65(-1), compared to p65, has different biochemical properties in some cellular mechanism like transcriptional activity on kB consensus, apoptosis and regulation of the glucocorticoid receptor (GR) activation. Therefore the aim of this study is to characterize the function of p65(-1) by an in vitro, ex vivo and an in vivo approach. In order to test the transcriptional role of p65(-1) we have analyzed the transactivation of p65(-1) using both artificial and natural promoter regions, linked with the pathway of NF-kB. We have performed luciferase assays with NF-kB-Luc (nuclear factor kB) CRE-Luc (cAMP response element), AP1-Luc (AP1 response element), SRE-Luc (serum response element), HSE-Luc (heat shock protein response element), pANXA-1-Luc (annexina 1) e pIL-6-Luc (interleuchin 6) to study the activity of p65(-1) and we have also analized p65(-1) activity with p65 or p50 under the same conditions. We have also studied p65(-1) expression on human peripheral blood mononuclear cells (PBMC); it is shown that the expression of mRNA is always present in the analyzed samples. In addition, our data demonstrate different expression profiles between individuals considered. We are also engineering a mouse p65(-1)-/-. Here we show the strategy we used to engegnire the homologous recombination vector to knock out p65(-1) expression without affecting p65 functions
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Salehi, Amir Hassan. "Characterization of NRAGE, a p75 neurotrophin receptor interacting protein and a mediator of p75 initiated apoptosis." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102163.
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The neurotrophins are a family of growth factors involved in the survival, development, and apoptosis of specific populations of neurons and non-neuronal cells. The pro-apoptotic action of neurotrophins is, at least partially, carried out by the p75 neurotrophin Receptor (p75NTR). However the mechanism employed by p75NTR to mediate apoptosis is poorly defined.We used a yeast two-hybrid screen to find proteins involved in p75NTR apoptotic signaling. This screen led to the identification NRAGE (for neurotrophin receptor-interacting M AGE homologue), as a p75NTR interacting molecule. NRAGE is a novel member of the MAGE family of proteins, a group of molecules with ill-defined function, sharing a ∼200 amino-acid region of homology. We found that NRAGE binds p75NTR in vitro and in vivo, and that the ectopic expression of NRAGE promotes p75NTR-dependent death in cells normally insensitive to p75NTR signaling. Furthermore, physical and functional assays indicated that the interaction of p75NTR with NRAGE, or that of p75NTR with its co-receptor TrkA, are mutually exclusive.
To further dissect the mechanism of NRAGE mediated apoptosis, we developed an inducible recombinant NRAGE adenovirus. Induced NRAGE expression resulted in robust activation of the JNK pathway, cytosolic accumulation of Cytochrome c, activation of Caspases-3, -7 and -9 and caspase-dependent cell death. Accordingly, inhibition of the JNK pathway suppressed NRAGE-mediated caspase activation and NRAGE-induced cell death.
The well-characterized activation of JNK-dependent cell death by NRAGE or p75NTR was then used as a model system to determine the mechanism-of-action of a novel anti-apoptotic pharmaceutical, AEG3482. Our studies revealed that AEG3482 almost completely blocks JNK-dependent apoptosis induced by p75NTR or NRAGE. The apoptotic inhibitory activity of AEG3482 was attributed to its ability to induce the expression of Heat-Shock Protein-70 (HSP70), which acts as a direct inhibitor of JNK activity. Therefore AEG3482 blocks cell death through an indirect inhbition of JNK. The identical sensitivity of p75NTR- and NRAGE-initiated signaling to AEG3482 or its analogues, provides further support for NRAGE as a mediator of p75NTR-induced apoptotic signaling.
In summary, our results show that NRAGE contributes to p75NTR-dependent cell death via JNK-dependent activation of the mitochondrial death pathway.
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Bell, Lonnie David. "Textual stability and fluidity exhibited in the earliest Greek manuscripts of John : an analysis of the second/third-century fragments with attention also to the more extensive papyri (P45, P66, P75)." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/11768.
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This thesis is an assessment of the character of textual transmission reflected in the pre-fourth century Greek manuscripts of the Gospel of John. Since John is the most attested New Testament book among the early papyri, has the highest number of papyri that share overlapping text, and is the best attested Christian text in the second century, it serves well as a case study into the level of fluidity and stability of the New Testament text in its earliest period of transmission. The transmission of New Testament writings in this period has been characterized by a number of scholars as error-prone, free, wild and chaotic. This thesis is an inquiry into the validity of this characterization. I contend that our earliest extant manuscripts should serve as the most relevant evidence for addressing this issue, both for the period in which they were copied and for inferences about the preceding period for which we lack manuscript evidence. My treatment of the earliest Greek manuscripts of John primarily involves a fresh and full assessment of the level of fluidity and stability exhibited in the 14 smaller fragments (P5, P22, P28, P39, P52, P90, P95, P106, P107, P108, P109, P119, P121, 0162) by identifying on the basis of internal evidence the character of variants and unique readings attested. Additionally, I compare the number, character and significance of the singular/sub-singular readings of each early fragmentary manuscript with those in the same portion of text in the major majuscule manuscripts up through the seventh century that share complete overlap. The unique readings of P66 and P75 are added to this comparison where they fully overlap with the smaller fragments. Since P45 and P66 have been particularly identified with a “free” manner of transmission, I include an extended discussion in my introductory section in which I engage with research on the character of transmission exhibited in these two witnesses. My analysis of these early manuscripts based on the internal evidence of readings allows for a more in-depth and accurate characterization of the freedom and/or care exhibited. The comparison of singular and sub-singular readings with those of the later majuscules facilitates a diachronic comparison of the number and nature of readings most likely to have been generated at the time in which each respective manuscript was transcribed. This latter step allows us to test, by way of these passages, whether or not the manuscript tradition can be fairly characterized as freer and more prone to corruption in the second and third centuries than in subsequent centuries. From these data, and in conjunction with observations made on any relevant physical features of the manuscripts themselves, I conclude that the copying of John during the second and third centuries was characterized largely by stability and by continuity with the later period. These conclusions serve the broader purpose of providing a window on the character of New Testament textual transmission in the earliest centuries.
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Harrington, Anthony W. "Mechanism and consequence of P75 Signaling." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1110476306.
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Samrani, George. "Histone upregulation may contribute to cytotoxicity in spinal muscular atrophy : Examination of smn1 knockdown in the P19 cell line." Thesis, Umeå universitet, Biomedicinsk laboratorievetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-58533.
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Tep-Cullison, Chhavy R. "Distinct roles of p75 regulation on myelination in the peripheral nervous system and central nervous system." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299179635.
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Foulkes, T. "The role of p11 (S100A10) in nociception." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445486/.
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The S100-family protein p11 (S100A10) is involved in a variety of physiological processes, including channel trafficking and angiogenesis. In this thesis, we used genetic approaches to investigate the functional roles of p11. p11 modulates the plasma membrane trafficking of the sensory neuron-specific voltage-gated Na" channel Nay 1.8 and numerous other proteins. Since Nav1.8 performs a specialised function in the detection of noxious stimuli (nociception), we investigated the role of p11 in peripheral pain pathways. We used the Ctq-IoxP system to delete p11 exclusively from nociceptive neurons, allowing the examination of this aspect of p11 function without confounding effects from roles of p11 in other tissues, p11-null neurons showed deficits in the functional expression of Nav1.8. Noxious coding in wide-dynamic range neurons in the dorsal horn was compromised in p11-null animals. Acute mechanical pain behaviour was attenuated, but no deficits in inflammatory pain were observed. Reduced neuropathic pain behaviour was apparent in nociceptor-specific p11-null mice. While certain effects of p11 deletion can be explained by reduced Nav1.8 trafficking. Nav1.8 is not required for neuropathic pain, p11 therefore acts through both Nay1.8-dependent and alternative mechanisms to control nociceptive thresholds. This suggests it is a potential therapeutic target. Given the importance of p11-dependent modulation of Nav1.8. we investigated the p11-binding site on the Nav1.8 N-terminus. In vitro fluorescence resonance energy transfer (FRET) assays were used to examine this interaction. In contrast to previous studies, we found the interaction to be complex, involving two distinct binding sites and an autoinhibitory domain. The p11-Nav1.8 interaction is therefore not well-suited to small molecule-based inhibition. p11 has been reported to play an important role in processes required for angiogenesis. In assays of angiogenesis-dependent tumour growth, global p11 deletion resulted in increased tumour volume and altered vascular morphology. This may have implications for novel anti-cancer therapies targeting p11.
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Carpentier, David Cyriel Jermain. "The baculovirus P10 protein; exploring an enigma." Thesis, Oxford Brookes University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496053.
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After over 30 years of research the role of the baculovirus P10 protein during infection remains a mystery. Believed to be non-essential during infection both in cell culture and in its natural caterpillar host the tiny P10 protein of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) has been associated with a number of intracellular structures and functions. Roles in the formation and release of the baculovirus occlusion bodies have been suggested. This thesis describes a number of studies aimed at further elucidating the role and function of the P10 protein A screen of all available ; baculovirus genome sequences revealed that P10 is evolutionarily conserved within the Alphabaculoviruses. Bioinformatics of all identified P10 homologues revealed an overall structural conservation and a high degree of sequence conservation within the N-terminal 14- amino acids. A number of putative modification sites have been identified thought to play an important role in controlling P10 function.
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Mason, Sarah Louise. "Regulation of E2F activity by p14'A'R'F." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368592.
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