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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
331

Método de clasificación ABC para optimizar la gestión de los inventarios en la empresa acabados Marcelino E.I.R.L en Chiclayo 2022

Yajahuanca Cuzque, Maria Elva January 2024 (has links)
La presente investigación tiene como título “método de clasificación ABC para optimizar la gestión de los inventarios en la empresa acabados Marcelino E.I.R.L en Chiclayo 2021, teniendo como principal objetivo aplicar el método de clasificación ABC para la mejora de la gestión de inventarios en la empresa Acabados Marcelino E.I.R.L. Así mismo la investigación esta abordada desde el enfoque tipo mixta (cuantitativa y cualitativa). A la vez se aplicó una entrevista al encargado del almacén para poder conocer la gestión de los inventarios de empresa e identificar cuáles son las deficiencias para el orden del almacén y poder desarrollar el método ABC. Por lo cual se obtuvo los resultados que la empresa no cuenta con un método para controlar sus inventarios, no conocen la rotación de sus productos, todas las revisiones lo hacen bajo un sistema de facturación y no conocen el stock real ni que productos están por agotarse ocasionado pérdidas de ventas puntuales y costos por almacenaje innecesarios. Finalmente se concluye que la metodología ABC optimizara la gestión de la empresa en relación a sus inventarios dado que contara con un detalle más exacto sobre qué y que cantidad pedir en cada reposición de productos, dentro la categorización ABC. / The title of this research is “ABC classification method to optimize inventory management in the Marcelino E.I.R.L. finishing company in Chiclayo 2021, with the main objective of applying the ABC classification method to improve inventory management in the Finishing company. Marcelino E.I.R.L. Likewise, the research is approached from a mixed approach (quantitative and qualitative). At the same time, an interview was carried out with the warehouse manager in order to learn about the management of company inventories and identify the deficiencies in the order of the warehouse and to be able to develop the ABC method. Therefore, the results were obtained that the company does not have a method to control its inventories, they do not know the rotation of their products, all reviews are done under a billing system and they do not know the real stock or which products are about to run out. caused specific sales losses and unnecessary storage costs. Finally, it is concluded that the ABC methodology will optimize the company's management in relation to its inventories given that it will have more exact detail about what and what quantity to order in each product replacement, within the ABC categorization.
332

Therapie der experimentellen autoimmunen Enzephalomyelitis mit Mitoxantron - Vergleichende Analyse von C57BL/6J- mit Abcg2-knock-out-Mäusen / Therapeutic effect of mitoxantrone in experimental autoimmune encephalomyelitis - Comparative analysis of the effect on C57BL/6J- and abcg2-knock-out-mice

Huber, Bastian 12 March 2012 (has links)
No description available.
333

A análise da produção imobiliária residencial do Grande ABC entre 2000 e 2013

Virgens, Felipe Dias das January 2016 (has links)
Orientador: Prof. Dr. Jeroen Johannes Klink / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Planejamento e Gestão do Território, 2016. / O impulsionamento dos lançamentos residenciais no mercado formal a partir da última década revela-se de grande expressividade dado o grande volume de novas unidades habitacionais produzidas neste período. As relações imbricadas entre o mercado financeiro e o setor imobiliário explicam em grande parte o alavancamento de novos lançamentos apoiados em medida que transformaram e modificaram as características do complexo imobiliário-financeiro. Na Região Metropolitana de São Paulo, maior concentrador do número de lançamentos, o Grande ABC se destaca com participação efetiva como agente de absorção do transbordamento da produção imobiliária do município de São Paulo. Os lançamentos residenciais neste período foram estudados em termo dos valores aplicados, as características construtivas, a relação com o entorno, os agentes financeiros envolvidos e a dinâmica do uso do solo na região. Os sete municípios que compõem o Grande ABC apresentaram características específicas nos lançamentos estudados diferenciados pelo modo de atuação do setor imobiliário-residencial, seja no tempo de resposta ao boom imobiliário, ou, no perfil construtivo e locacional utilizados pelas incorporadoras-construtoras. A estruturação do setor imobiliário e a capacidade na transformação do território ressaltou a falta de suporte do setor público no enfrentamento de mudanças e transformações do espaço urbano, principalmente pela ausência de mecanismos de planejamento multiescalares capazes de absorver rapidamente novas tendências e atuar em um território que perpassem os limites municipais. / The growth of residential launches in the formal market since the last decade is very expressive given the large volume of new housing units produced in this period. The imbricated relations between the financial market and the real estate sector largely explain the leverage of new launches supported as they have transformed and modified the characteristics of the financial-real estate complex. In the Metropolitan Region of São Paulo, which is the largest concentrator of the number of launches, Grande ABC stands out with effective participation as an agent to absorb the overflow of real estate production in the city of São Paulo. The residential launches in this period were studied in terms of the values applied, the constructive characteristics, the relation with the neighborhoods, the financial agents involved and the dynamics of the land use in the region. The seven municipalities that make up the Grande ABC presented specific characteristics in the launches studied, differentiated by the real-estate sector, either in the response time to the real estate boom or in the constructive and locational profile used by the real estate developers. The structuring of the real estate sector and the capacity for territory transformation underscored the lack of support from the public sector facing the changes and transformations in the urban space, mainly due to the absence of multi-scale planning mechanisms capable of rapidly absorbing new trends and acting in a territory that cross the Municipal boundaries.
334

Estudo do desenvolvimento floral em espécies arbóreas da família Meliaceae / Floral development in woody species of the Meliaceae family

Gouvêa, Cantídio Fernando 08 1900 (has links)
A família Meliaceae compreende cerca de 51 gêneros e 550 espécies distribuídas principalmente na região Neotropical. Incluídas nesta família, estão espécies de elevado interesse comercial para a produção de madeiras nobres. Há carência de informações quanto à biologia floral dessas espécies, que aliada a problemas silviculturas dificulta a elaboração de programas efetivos de melhoramento genético das espécies de interesse econômico da família. O presente trabalho visa contribuir para o entendimento do desenvolvimento floral na família Meliaceae, com destaque para sete espécies de interesse econômico e/ou ecológico: Cedrela fissilis L., Cedrela odorata L., Swietenia macrophylla R. A. King, Trichilia claussenii C. DC., Guarea guidonea (L.) Sleumer, Toona ciliata M. J. Roem e Melia azedarach L. Para os estudos morfo-anatômicos utilizaram-se técnicas de microscopia óptica e microscopia eletrônica de varredura. Analisou-se igualmente o padrão de expressão de genes do modelo ABC, relacionados ao desenvolvimento floral, via hibridização in situ. Os estudos morfo-anatômicos permitiram caracterizar o desenvolvimento dos primórdios dos órgãos florais e o estabelecimento de estágios arbitrários de desenvolvimento, auxiliando na caracterização da expressão gênica. Estes resultados permitiram ainda a identificação de flores funcionalmente femininas ou masculinas em S. macrophylla C. fissilis, C. odorata e T. ciliata, as quais apresentam dimorfismo sexual. O padrão de expressão dos homólogos dos genes: APETALA1 (AP1), APETALA3 (AP3) e AGAMOUS (AG) foram diferentes daqueles previstos pelo modelo ABC. A expressão dos homólogos de AP1 foi verificada em todo o meristema floral nos estágios iniciais de desenvolvimento, em todas as espécies estudadas. O sinal de expressão concentrou-se nos primórdios das sépalas e pétalas em estágios mais avançados do desenvolvimento, porém um fraco sinal de hibridização de AP1 foi verificado em todos os verticilos. A expressão dos homólogos de AP3 foi verificada nas regiões previstas pelo modelo ABC, correspondentes ao segundo e terceiro verticilos. Porém um fraco sinal de AP3 foi também observado no quarto verticilo, o que não é previsto pelo modelo teórico. A expressão dos homólogos de AG foi restrita à região central do meristema floral, correspondente ao terceiro e quarto verticilos, em todos os estágios do desenvolvimento floral de todas as espécies estudadas. Entretanto, sinais adicionais de hibridização dos homólogos de AG foram visualizados na região abaxial dos primórdios de sépalas e pétalas em C. fissilis, C. odorata e T. ciliata. Os estudos da expressão dos genes do modelo ABC em Meliaceae revelaram padrões de expressão que não concordam com o modelo teórico vigente do controle molecular da determinação da identidade dos órgãos florais._________________________________________________________________________________________ ABSTRACT: The Meliaceae family comprises approximately 51 genus and 550 species mainly distributed in the Neotropical region. In this family there are many species of commercial interest for the production of noble wood. The lack of information on the floral biology associated with silvicultural problems limits the elaboration of effective breeding programs with species of economic interest. The present work aims to contribute with the understanding of floral development in Meliaceae, focusing in seven species of economical or ecological interest: Cedrela fissilis L., Cedrela odorata L., Swietenia macrophylla R. A. King, Trichilia claussenii C. DC., Guarea guidonea (L.) Sleumer, Toona ciliata M. J. Roem e Melia azedarach L. Morpho-anatomical analyses were done by light and scannning electron microscopy. The expression pattern of the ABC model genes, which are related to floral development, was analyzed by in situ hybridization. The characterization of the development of floral organ primordia and the establishment of arbitrary stages of floral development was done and was important for the characterization of gene expression. These results allowed for the identification of functionally female and male flowers in Swietenia macrophylla, Cedrela fissilis, Cedrela odorata and Toona ciliata, characterizing sexual dimorphism. The patterns of gene expression of the homologous of APETALA 1, APETALA 3 and AGAMOUS were different from those predicted by the ABC model. AP1 expression was observed in the entire floral meristem in the initial stages of development, in all seven species. The expression signal was more concentrated in sepal and petal primordia in further stages of development, although a weak hybridization signal of AP1 was verified in all four whorls. The expression of AP3 homologs was observed in the second and third whorls, as predicted by the ABC model. However, a weak signal of AP3 was also observed in the forth whorl, which was not predicted by the ABC model. AG homolog expression was restricted to the central region of the floral meristem, corresponding to the third and forth whorls, in all stages of development of all seven species. However, additional hybridization signal of AG homologs were seen in the abaxial region of sepal and petal primordia in Cedrela fissilis, Cedrela odorata and Toona ciliata. The analyses of the ABC model genes in Meliaceae revealed that the expression patterns do not agree with the theoretical currently accepted model that determines the molecular control of the identity of the floral organs.
335

No crepúsculo da mudança: um estudo sobre a formação continuada dos professores da Universidade Federal do ABC na confluência de uma prática pedagógica inclusiva e intercultural

Santos, Sandra Rosa Gomes dos 25 October 2017 (has links)
Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-02-02T13:17:28Z No. of bitstreams: 2 Sandra Rosa Gomes dos Santos.pdf: 2171892 bytes, checksum: 2905698530c093c7607eeac0cb11caae (MD5) Sandra Rosa Gomes dos Santos VOL II.pdf: 752330 bytes, checksum: fe8ca974c4c0661452be97386cb2fcf6 (MD5) / Made available in DSpace on 2018-02-02T13:17:29Z (GMT). No. of bitstreams: 2 Sandra Rosa Gomes dos Santos.pdf: 2171892 bytes, checksum: 2905698530c093c7607eeac0cb11caae (MD5) Sandra Rosa Gomes dos Santos VOL II.pdf: 752330 bytes, checksum: fe8ca974c4c0661452be97386cb2fcf6 (MD5) Previous issue date: 2017-10-25 / The object of this research is focused on the continuing education of UFABC professors at the confluence of an inclusive and intercultural pedagogical practice. The research problem results from the fact that the inclusion of new historically marginalized publics and cultures from the right to higher education requires new pedagogical-didactic skills from the professors and that these competences can be acquired through continuous training. In this sense, higher education professors, in addition to continuing education in the scientific field, specifically linked to research projects, must also have training in the pedagogical-didactic field that allows them to work with students on issues related to themes of social, cultural and epistemological inclusion, interculturality and interdisciplinarity. The question of research resulting from the problem that was set forth and which guided us was as follows: taking the sources the documents and the professor’s speeches, how is the continuous training of UFABC professors organized in the confluence of an inclusive and intercultural pedagogical practice? We define as a general objective of the research, as a result of the stated nuclear issue, the following: analyze the way in which the continuous formation of professors is organized, in the confluence of an inclusive and intercultural pedagogical practice. We follow a theoretical-epistemological model according to post-critical and post-colonial theories. From the methodological point of view, the approach was qualitative using the analysis of international and institutional documents and the analysis of interviews with professors. The conclusions of the study point to the lack of an institutional model of continuing education and to the existence of substantial ruptures between UFABC's institutional discourse and the discourse of regulatory agencies, especially with regard to the issues of social inclusion and the organizational proposal of institution. They also point to a contradiction between the institutional principles and the practice of their professionals. Professor’s work generically on cultural diversity but the problem of interculturality is not only worked out in pedagogical practice, not is it alluded to in institutional documents. The research findings also reveal that professors attach importance to the dimension of research and its relation to teaching and the need for continuing education that allows them to improve pedagogical and didactic issues and to promote interculturality as a complement social inclusion. / El objeto de esta investigación se centra en la formación continuada de los profesores de la UFABC en la confluencia de una práctica pedagógica inclusiva e intercultural. El problema de la investigación es el resultado de la inclusión en la universidad de nuevos públicos y culturas históricamente marginados del derecho a la educación superior, hecho que exige por parte de los profesores nuevas competencias pedagógicas-didácticas y la conciencia de que dichas competencias podrán ser adquiridas a través de una formación continuada. En este sentido, se impone que los profesores de la educación superior, además de la formación continuada en el ámbito científico, ligada específicamente a proyectos de investigación, tengan también formación en el ámbito pedagógico-didáctico que les permita trabajar con los estudiantes las cuestiones relacionadas a las temáticas de la inclusión social, cultural y epistemológica, interculturalidad e interdisciplinariedad. La cuestión de la investigación resultante del problema enunciado y que nos orientó fue la siguiente: tomando como fuentes los documentos y los discursos de los profesores, cómo se organiza la formación continuada de los profesores de la UFABC en la confluencia de una práctica pedagógica inclusiva e intercultural? Definimos como objetivo general de la investigación, derivado de la cuestión nuclear enunciada, el siguiente: analizar el modo como se organiza la formación continuada de los profesores, en la confluencia de una práctica pedagógica inclusiva e intercultural. Seguimos un modelo teórico-epistemológico de acuerdo con las teorías post-críticas y postcoloniales. Desde el punto de vista metodológico, el enfoque fue cualitativo con el análisis de los documentos internacionales e institucionales y el análisis de entrevistas hechas con los profesores. Las conclusiones del estudio apuntan a la inexistencia de un modelo institucional de formación continuada y la existencia de rupturas sustanciales entre el discurso institucional de la UFABC y el discurso de las agencias reguladoras, sobre todo en lo que se refiere a las problemáticas de la inclusión social y de la propuesta organizativa de la institución. También apuntan a una contradicción entre los principios institucionales y la práctica de sus profesionales. Los profesores trabajan, genéricamente, la diversidad cultural pero la problemática de la interculturalidad no sólo no se trabaja en la práctica pedagógica como ni siquiera se hace alusión a ella en los documentos institucionales. Las conclusiones de la investigación revelan además que los profesores atribuyen importancia a la dimensión de la investigación y a su relación con la enseñanza y la necesidad que sienten de una formación continuada que les permita el perfeccionamiento de las cuestiones de naturaleza pedagógica y didáctica bien como la promoción de la interculturalidad como complemento obligatorio de la inclusión social. / O objeto desta pesquisa incide sobre a formação continuada dos professores da UFABC na confluência de uma prática pedagógica inclusiva e intercultural. O problema de pesquisa resulta do fato de considerarmos que a inclusão de novos públicos e culturas historicamente marginalizadas do direito à educação superior exige, da parte dos professores, novas competências pedagógico-didáticas e que essas competências poderão ser adquiridas por meio de uma formação continuada. Neste sentido, impõe-se que os professores da educação superior, para além da formação continuada no âmbito científico, ligada, especificamente, a projetos de pesquisa, tenham também formação no domínio pedagógico-didático que lhes permita trabalhar com os estudantes as questões ligadas às temáticas da inclusão social, cultural e epistemológica, interculturalidade e interdisciplinaridade. A questão de pesquisa resultante do problema enunciado, e que nos orientou, foi a seguinte: tomando como fontes os documentos e os discursos dos professores, como se organiza a formação continuada dos professores da UFABC na confluência de uma prática pedagógica inclusiva e intercultural? Definimos como objetivo geral da pesquisa, decorrente da questão nuclear enunciada, o seguinte: analisar o modo como se organiza a formação continuada dos professores, na confluência de uma prática pedagógica inclusiva e intercultural. Seguimos um modelo teórico-epistemológico de acordo com as teorias pós-críticas e pós-coloniais. Do ponto de vista metodológico, a abordagem foi qualitativa com recurso à análise dos documentos internacionais e institucionais e à análise de entrevistas com os professores. As conclusões do estudo apontam para a inexistência de um modelo institucional de formação continuada e para a existência de rupturas substanciais entre o discurso institucional da UFABC e o discurso das agências reguladoras, sobretudo no que diz respeito às problemáticas da inclusão social e da proposta organizativa da instituição. Apontam, também, para uma contradição entre os princípios institucionais e a prática dos seus profissionais. Os professores trabalham, genericamente, a diversidade cultural, mas a problemática da interculturalidade, não só não é trabalhada na prática pedagógica, como nem sequer se faz alusão a ela nos documentos institucionais. As conclusões da pesquisa revelam ainda que os professores atribuem importância à dimensão da pesquisa e à sua relação com o ensino, e à necessidade que sentem de uma formação continuada que lhes permita o aperfeiçoamento das questões de natureza pedagógica e didática, e a promoção da interculturalidade como complemento obrigatório da inclusão social.
336

A model for material handling improvements when using automated storage systems: A case study / En modell för förbättringar av materialhantering genom användandet av automatiserade lagersystem: En fallstudie

Thongmal Larsson, Marie January 2010 (has links)
<p>The purpose of this thesis is to create a model of how to organize the placements of articles in an automated storage system in order to reduce time and cost related to the extractions. The model was developed during an investigation at a case company, and a comprehensive study of the material handling identified bottlenecks, whereof one was chosen to be further investigated: the automated storage system. The automated storage system is newly installed equipment, which required new working methods to be incorporated to the already existing working environment. The ABC-analysis was used in order to motivate how the articles should be placed in the automated storage. The goal for the new way of handling material was to put as little effort as possible on time related to the extraction of material. This due to the realization of material handling processes being a huge contributor to waste activities. This resulted in the development of the model and the suggestion that is given to the case company is to place the most frequent extracted articles close to the users. However, advantages must be held against disadvantages of rearrangements since the material handling will not be eliminated totally due to smaller improvements.</p> / <p>Syftet med denna uppsats är att skapa en modell för hur man ska organisera artikelplaceringar i ett automatiserat lagersystem för att reducera tid och kostnad relaterat till uttag av material. Modellen skapades genom en undersökning på ett fallföretag, en omfattande studie av materialhanteringen identifierade flaskhalsar, varav en valdes för fortsatt undersökning: det automatiserade lagersystemet. Det automatiserade lagersystemet är en nyinstallerad utrustning, som kräver att nya arbetsmetoder ska inkorporeras till den redan existerande arbetsmiljön. ABC-analysen användes för att motivera hur artiklarna ska placeras i det automatiserade lagret. Målet för det nya sättet att hantera material på var att så få insatser som möjligt skulle användas för uttag av material. Detta pågrund av insikten utav att materialhanteringsprocesser är en stor bidragande slöserifaktor. Detta resulterade i modellen och förslagen som ges till fallföretaget är att placera de mest frekvent använda artiklarna nära användaren. Emellertid så måste man väga fördelar mot nackdelar av en förändring eftersom materialhanteringen inte kommer att elimineras helt pågrund av mindre förbättringar.</p>
337

Fettsäuretransport in die peroxisomale Matrix von <i>Arabidopsis thaliana</i> / Fatty acid transport into the peroxisomal matrix of <i>Arabidopsis thaliana</i>

Struß, Annett 03 May 2007 (has links)
No description available.
338

Déterminants historiques et sélectifs des échanges génétiques au cours de la spéciation chez la souris domestique : patrons de coalescence et introgression en zone hybride. / Historical and selective determinants of genetic exchanges during house mouse speciation : coalescence patterns and introgression in a hybrid zone.

Duvaux, Ludovic 18 November 2010 (has links)
Afin de comprendre le processus de spéciation, il est nécessaire d'appréhender les patrons de flux géniques entre espèces naissantes et le rôle de la sélection dans leur détermination. C'est ce que tente d'aborder cette thèse en utilisant comme modèle deux sous-espèces de la souris domestique, Mus musculus. Nous avons reconstitué l'histoire de leur différenciation sur la base du polymorphisme de séquence à 60 locus autosomaux. La simulation du coalescent de ces locus sous plusieurs scenarios historiques nous a permis d'inférer, via une méthode ABC (Approximate Bayesian Computation), une divergence ancienne des sous-espèces (1,5Ma). Elle fut suivie d'une longue phase d'isolement (1,2Ma) précédant une phase d'échanges génétiques débutant bien avant la formation de la zone hybride européenne actuelle. La phase d'isolement a été assez longue pour expliquer une grande partie des incompatibilités génétiques observées actuellement. Les flux génétiques anciens et prolongés pourraient avoir favorisé le renforcement comportemental de l'isolement reproductif. Nous étudions aussi la relation entre le mode d'évolution de 77 régions génomiques autosomales et leur comportement d'introgression à travers une zone hybride. Le taux de recombinaison locale semble déterminer en partie les introgressions symétriques et limitées de certains locus. Toutefois tel n'est pas le cas pour 40% des locus, qui présentent une introgression asymétrique dans l'une ou l'autre direction. Nous proposons que l'introgression coté musculus soit majoritairement contrôlée par la sélection et que l'introgression coté domesticus soit influencée par un déplacement de la zone hybride vers le territoire musculus. / Understanding the speciation process requires to appraise patterns of gene flow between incipient speices as well as the role of selection in their determination. This thesis attempts to do so using two subspecies of the house mouse, Mus musculus, as a model. We inferred the history of their differentiation based on sequence polymorphism data at 60 autosomal loci. By simulating the coalescent of these loci under several historical scenarios we were able to infer, using an ABC (Approximate Bayesian Computation) method, an ancient divergence of the subspecies (1.5 MY). This was followed by a long period of isolation (1.2 MY) preceding a phase of genetic exchanges that started well before the formation of the present European hybrid zone. The isolation phase lasted long enough to explain a majority of the present genetic incompatibilities. Ancient and lasting gene flow could have favoured a behavioural reinforcement of reproductive isolation. We a lso studied the relationship between the mode of evolution of 77 autosomal genomic regions and their introgression patterns across a hybrid zone. Local recombination rates variations seem to partly account for the patterns observed at some loci with limited and symmetrical introgression. However such is not the case for 40% of the the loci showing asymmetrical introgression in on direction or the other. domesticus results from a movement of the hybrid zone from domesticus to musculus.
339

Le transporteur ABCG2 de multiples drogues : rôle d’une séquence spécifique et recherche d’inhibiteurs sélectifs / The multidrug transporter ABCG2 : role of a specific sequence and research of selective inhibitors

Macalou, Sira 11 December 2009 (has links)
Au cours de chimiothérapies, les cellules cancéreuses parviennent fréquemment à échapper aux effets toxiques des médicaments en développant des mécanismes de chimiorésistance qui résultent souvent de la présence d’un système d’efflux de ces médicaments. Cette chimiorésistance est corrélée à un phénomène appelé « phénotype MDR » pour (MultiDrug Resistance) et associé à la surexpression d’ATPases membranaires appartenant aux transporteurs ABC (ATP Binding Cassette). Le transporteur ABCG2 fait partie de cette grande famille de protéines. Un alignement de séquence a permis l’identification chez ABCG2 une séquence spécifique (LSGGE) très semblable à la séquence signature (VSGGE) de tous les transporteurs ABC. La mutation ponctuelle des résidus de cette séquence en alanine a produit une perte importante de fonction des mutants L352A et S353A, observée au niveau du transport et de l’activité ATPasique. Des relations structure-activité établies à partir de différents composés de la famille des flavonoïdes ont permis d’identifier MBLI 97, boéravinone G, MHT et ABI comme des composés puissants et spécifiques, capables d’abolir la résistance à de multiples drogues et chimiosensibiliser la croissance cellulaire. Le ciblage de séquences spécifiques et l'utilisation d'inhibiteurs spécifiques de ces transporteurs constituent des stratégies destinées à contrer la chimiorésistance et augmenter l’efficacité des traitements chimiothérapeutiques. / During chemotherapy, cancer cells frequently succeed to escape the toxic effects of drugs by developing mechanisms of chemoresistance which often result from the presence of an efflux system of these drugs. Such a chemoresistance is correlated to the MDR (MultiDrug Resistance) phenotype and associated to overexpression of membrane ATPases belonging to the ABC (ATP-Binding Cassette) transporters. The ABCG2 transporter belongs to this large family of proteins. Sequence alignment allowed the identification of a specific (LSGGE) sequence in ABCG2, which is quite similar to the canonical sequence signature (VSGGE) of all ABC transporters. Point mutation of these residues into alanine produced a loss of function in L352A and S353A mutants, as observed in transport and on ATPase activity. Structure-activity relationships drawn from some compounds among the family of flavonoids allowed the identification of MBLI 97, boeravinone G, MHT and ABI as potent and ABCG2-specific inhibitors, able to revert multidrug resistance and chemosensitize cell growth. The study of specific sequences and use of specific inhibitors of these transporters constitute strategies to abolish cancer cell chemoresistance and to increase the efficiency of chemotherapeutic treatments.
340

Étude fonctionnelle de la région intracellulaire d’ABCG2 et modulation d’ABCG2 et ABCB1 humains par des petidomimétiques non compétitifs / Functional study of ABCG2 intracellular loops and human ABCG2 and ABCB1 modulation by non competitive peptidomimetics

Arnaud, Ophélie 09 June 2011 (has links)
La surexpression de pompes d’efflux par les cellules cancéreuses permet l’élimination d’agents cytotoxiques, induisant alors une résistance à la chimiothérapie. Trois transporteurs ABC sont principalement impliqués dans cette résistance : ABCB1 (aussi appelé P-gp), ABCC1 (ou MRP1) et ABCG2 (ou BCRP, MXR, ABCP). Du fait de leur implication dans le phénotype de « MultiDrug Resistance », il est essentiel de mieux comprendre le fonctionnement de ces transporteurs. Une étude par mutagenèse dirigée a montré que les boucles intracellulaires, ICL0 et ICL1 sont impliquées dans le transport des substrats. Deux résidus sont particulièrement intéressants : W379 qui agirait comme un filtre des substrats ; et H457 qui participerait à la reconnaissance ou à la fixation des substrats. Par ailleurs, il est important de moduler cette chimiorésistance. Dans ce contexte nous avons développé une nouvelle classe d’inhibiteurs d’ABCB1 et ABCG2 non compétitifs basés sur un motif dipeptidique. Les composés les plus efficaces, CT1347 pour ABCB1 et CT1364 pour ABCG2, s’avèrent, d’une part peu ou pas cytotoxiques à fortes concentrations, abolissent d’autre part la résistance induite par ABCB1 ou ABCG2 et se comportent comme des inhibiteurs non compétitifs du Hoechst 33342 et de la daunorubicine. De plus, CT1364 inhibe l’activité ATPasique d’ABCG2 et induit une diminution rapide de l’expression de la protéine. Enfin, les 1ers tests in vivo de ce composé montrent que l’association avec l’irinotécan ralentit la croissance des xénogreffes de petite taille chez des souris / Resistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane which prevent the accumulation of anticancer drugs in the tumour cells. Three human ATP-binding Cassette (ABC) transporters are particularly involved in this phenotype: P-gp/ABCB1, MRP1/ABCC1, and the last discovered BCRP/ABCG2. Because of their involvement in chemoresistance, it is critical to understand the mechanism by which those ABC transporters recognize and transport drugs. The mutagenesis study of the intracellular loops, ICL0 and 1 shows that these loops are involved in this mechanism. Two amino acids were particularly remarkable: W379 which act as a substrate filter and H457 which can be involved in substrate recognition and binding. In order to restore the cancer cell sensitivity to chemotherapeutic drugs, we have developed a new class of peptide inhibitors, specific to one transporter. A structure-activity relationship study has been performed and made it possible to develop a second generation of molecules. The most efficient compound inhibiting ABCB1 (CT1347) or ABCG2 (CT1364) have none or limitated cytotoxic effects. These compounds restore the activity of chemotherapeutic drugs and act as non competitive inhibitors. Moreover, CT1364 inhibits the ATP hydrolysis activity and lead to a rapid reduction of ABCG2 expression. Initial in vivo tests that have been carried out with CT1364 associated with irinotecan allow to observe a growth reduction of small mice xenografts

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