Résumé L’approvisionnement en cholestérol est un facteur limitant la stéroïdogenèse ovarienne. Pour cette raison, la majorité du cholestérol requis pour la synthèse des stéroïdes est importé de la circulation via les récepteurs des lipoprotéines de haute (HDL) et de basse densité (LDL) nommés scavenger receptor (SR-BI) et low-density lipoprotein receptor (LDLr). L’ARN messager de SR-BI est exprimé dans les ovaires de porcs durant toutes les étapes de la folliculogenèse ainsi que dans le corps jaune (CL). L’expression de la protéine SR-BI a également été détectée dans les follicules de souris lors du cycle œstral. Chez les deux espèces, l’expression est concentrée dans le cytoplasme et en périphérie des cellules du follicule. Les gonadotrophines induisent l'expression de SR-BI dans les cellules de la granulosa porcines, avec une expression cytoplasmique qui augmente durant la période périovulatoire, et avec une migration aux périphéries cellulaires durant la maturation du CL. Une conformation de 82 kDa de SR-BI est fortement exprimée dans le CL porcin, avec une conformation moins abondante de 57 kDa. Les différences entre les conformations sont attribuables à la glycosylation. La culture in vitro de follicules porcins avec des gonatrophines chorioniques humaines (hCG) a induit une hausse de régulation dépendante du temps du SR-BI de 82 kDa dans les cellules du granulosa. SR-BI et LDLr ont été exprimés réciproquement, avec LDLr étant le plus élévé dans les cellules folliculaires du granulosa et diminuant précipitamment avec la formation du CL. Pour explorer plus en détail les mécanismes d’approvisionnement en cholestérol de la stéroïdogenèse ovarienne, nous avons examiné des souris soumis à un traitement de désaccouplement de l'ovulation, et des souris portant la mutation nulle du gène Scarb1 (SR-BI-/-). Les résultats ont démontré que des ovocytes enfermés dans des structures lutéinisées expriment SR-BI. Les souris SR-BI-/ - présentaient de petits CLs, et de large follicules avec des cellules de thèque hypertrophiées et des kystes folliculaires avec des cavités remplies de sang et une diminution de 50% du niveau de progestérone dans le sérum. Les souris SR-BI-/ - traitées avec une combinaison de 20 g / g de mevinoline et 100  g / g de chloroquine ont démontré une diminution de 43% du niveau de progestérone sérique chez le type sauvage et de 30% chez les souris SR-BI-/ -. L’expression protéique de l’enzyme limitant pour la synthèse du cholestérol, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), a augmenté chez les souris SR-BI-/-. Nous avons présenté des preuves démontrant que les cellules des follicules expriment le SR-BI durant la stéroïdogenèse et que la lutéinisation augmente l’expression de SR-BI. La maturation post-transcriptionelle est caractérisée par la glycosylation. Sous des conditions normales, l’expression de LDLr est arrêtée durant la lutéinisation. Ainsi SR-BI devient le facteur principal pour l’importation du cholestérol extracellulaire. En plus, la perturbation extracellulaire du cholestérol synthétisé de novo et l’absorption par les LDLr chez les souris SR-BI-/- diminuent la fonction lutéal. L’homéostasie du cholestérol ovarien est très importante pour une lutéinisation adéquate et sa perturbation mène à une réduction, mais non à un blocage complet, de la fonction lutéal. En conclusion, l’expression de SR-BI est un facteur important, mais non essentiel, pour maintenir l’homéostasie du cholestérol ovarien et la synthèse des stéroïdes, et la lutéinisation. Un réseau de mécanismes complémentaires et compensatoires d’approvisionnement en cholestérol agit en concert pour assurer la synthèse des stéroïdes ovariens. / Abstract Ovarian cholesterol supply is rate limiting to ovarian steroidogenesis. For this reason, the majority of cholesterol required for steroid synthesis is imported via scavenger receptor-BI (SR-BI) and the low-density lipoprotein (LDL) receptor from circulating HDL and LDL. SR-BI mRNA is expressed in pig ovaries at all stages of folliculogenesis and in the corpus luteum (CL). SR-BI protein expression in mouse ovary during estrous cycle was also detected. In both species, expression is concentrated in cytoplasm and periphery of follicular cells. Gonadotropins induce SR-BI expression in pig granulosa cells, with cytoplasmic expression increasing through the periovulatory period, with migration to the cell periphery as the CL matured. An 82-kDa form of SR-BI is strongly expressed in the pig CL, with the less abundant 57-kDa form, differences between forms are attributable to glycosylation. In vitro culture of pig follicles with human chorionic gonadotropin (hCG) induced time-dependent upregulation of 82-kDa SR-BI in granulosa cells. SR-BI and LDL receptor were reciprocally expressed, with the latter highest in follicular granulosa cells, declining precipitously with CL formation. To further explore mechanisms of cholesterol supply to ovarian steroidogenesis, we examined mice treated to uncouple ovulation and mice bearing null mutation of the Scarb1 gene (SR-BI-/-). Results show entrapped oocytes in luteinized structures expressed SR-BI. SR-BI-/- mice displayed small corpora lutea, large follicles with theca cells hypertrophied, follicular cysts with blood filled cavities and 50% decreased in plasma progesterone. In SR-BI-/- mice, treatment with a combination of 20 g/g of mevinolin and 100 g/g of chloroquine (CHLORO) was employed to disturbed cholesterol sources. Serum progesterone was reduced by 43% in wild type and 30% in SR-BI-/- mice. The protein expression of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) increased in SR-BI-/- mice. It was concluded that follicular cells express SR-BI during follicle development and luteinization causes upregulation of SR-BI expression. Posttranslational maturation is characterized by glycosylation. Under normal conditions expression of the LDLr (low density lipoprotein recepors) is extinguished during luteinization such that SR-BI becomes the principal means of importation of extracellular cholesterol. Further, perturbation of cholesterol de novo synthesis and uptake from LDLr in SR-BI-/- mice leads to a reduction of luteal function. Ovarian cholesterol homeostasis is central to adequate luteinization, and its perturbation leads to reduction, but not to complete impairment, of luteal function. We conclude that SR-BI expression is an important but not essential factor in maintaining ovarian cholesterol homeostasis, steroid synthesis and luteinization. A network of complementary and compensatory cholesterol supply mechanisms act in concert to assure ovarian steroid synthesis. / Studies were funded by Colegio de Postgraduados, México. CONACyT, México. SRE, México. Ministère de l’Éducation du Québec, University of Montreal and an Operating Grant to B.D. Murphy from the Canadian Institutes of Health Research.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

名古屋大学年代測定総合研究センターシンポジウム報告

L’splicing és el mecanisme pel qual els introns són eliminats del pre-mRNA per generar un trànscrit madur. Aquest procés és dut a terme per un complex macromolecular anomenat spliceosoma i requereix el reconeixement dels senyals d’splicing al pre-mRNA. Aquests senyals no són sempre identificats correctament, el que permet la producció de trànscrits diferents a partir d’un únic pre-mRNA mitjançant un procés anomenat splicing alternatiu. Aquest procés pot ser regulat mitjançant factors proteics específics o per altres mecanismes que alteren el reconeixement dels senyals d’splicing com l’estructura secundària adoptada pels pre-mRNAs. En aquesta tesi hem investigat els mecanismes de regulació de l’splicing en eucariotes mitjançant tècniques computacionals. També hem estudiat la relació existent entre les proteïnes que intervenen en la regulació de l’splicing i els senyals d’splicing, i com han coevolucionat en diferents espècies. Finalment, i tenint en compte les possibilitats que l’splicing alternatiu ofereix des del punt de vista evolutiu, també hem analitzat l’impacte de l’splicing alternatiu en l’evolució gènica. / Splicing is the mechanism by which introns are removed from the pre-mRNA to create a mature transcript. This process is performed by a macromolecular complex, the spliceosome, and involves the recognition of the splicing signals in the premRNA. These signals are not always perfectly recognized, which allows the production of different mature transcripts from a single pre-mRNA through a process called alternative splicing. This process can be regulated by specific protein factors or by other mechanisms that affect the recognition of the splicing signals, such as the secondary structure adopted by the pre-mRNA. In this thesis we have investigated the mechanisms of splicing regulation in eukaryotes using computational approaches. Moreover, we have also studied the relationship that exists between protein factors involved in splicing regulation and splicing signals, and how they have co-evolved across species. Finally, and considering the possibilities that alternative splicing can offer from the evolutionary point of view, he have also analyzed the impact of alternative splicing in gene evolution.

Le virus de l’hépatite C (VHC) est l’une des causes majeures de cirrhose du foie et de carcinome hépatocellulaire. Au courant de la première partie de ma thèse, nous nous sommes intéressés à caractériser plus en détail le rôle de SR-BI dans l’infection par le VHC. Bien que les mécanismes impliquant SR-BI dans la liaison du virus à l’hépatocyte aient été partiellement caractérisés, le rôle de SR-BI dans les étapes suivant la liaison du VHC reste encore largement méconnu. Afin de mieux caractériser le rôle de l’interaction VHC/SR-BI dans l’infection par le VHC, notre laboratoire à généré une nouvelle classe d’anticorps monoclonaux anti-SR-BI inhibant l’infection virale. Nous avons pu démontrer que SR-BI humain jouait un rôle dans le processus d’entrée du virus à la fois lorsde l’étape de liaison du virus à la cellule hôte mais aussi au cours d’étapes suivant cette liaison. Ainsi il serait intéressant de cibler cette fonction de SR-BI dans le cadre d’une stratégie antivirale pour lutter contre l’infection parle VHC. Dans la seconde partie de ma thèse, nous avions pour but de caractériser les mécanismes moléculaires intervenant dans la réinfection du greffon lors de la transplantation hépatique (TH). Nous avons ainsi identifiés 3 mutations adaptatives dans la glycoprotéine d’enveloppe E2 responsables de l’entrée virale augmentée du variant hautement infectieux. Ces mutations influent sur la dépendance au récepteur CD81 du VHC résultant en une entrée virale accrue. L’identification de ces mécanismes va nous permettre une meilleure compréhension de la pathogénèse de l’infection par le VHC, et est un premier pas pour le développement d’une stratégie préventive antivirale ou vaccinale. / Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. In the first part of my PhD, we aimed to further characterize the role of scavenger receptor class B type I (SR-BI) in HCV infection. While the SR-BI determinants involved in HCV binding have been partially characterized, the post-binding function of SR-BI remains remained largely unknown. To further explore the role of HCV-SR-BI interaction during HCV infection, we generated a novel class of anti-SR-BI monoclonal antibodies inhibiting HCV infection. We demonstrated that human SR-BI plays a dual role in the HCV entry process during both binding and post-binding steps. Targeting the post-binding function of SR-BI thus represents an interesting antiviral strategy against HCV infection. In the second part of my PhD, we aimed to characterize the molecular mechanisms underlying HCV re-infection of the graft after liver transplantation (LT). We identified threeadaptive mutations in envelope glycoprotein E2 mediating enhanced entry and evasion of a highly infectious escape variant. These mutations markedly modulated CD81 receptor dependency resulting in enhanced viral entry. The identification of these mechanisms advances our understanding of the pathogenesis of HCV infection and paves the way for the development of novel antiviral strategies and vaccines.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os granitoides do Domínio Cambuci, na região limítrofe entre os estados do Rio de Janeiro e Espírito Santo, foram separados em quatro principais grupos: (1) Complexo Serra da Bolívia (CSB) - Ortogranulitos e Ortognaisses Heterogêneos; Ortognaisse Cinza Foliado; e charnockitos da Região de Monte Verde (2) Leucogranitos/leucocharnockitos gnaissificados da Suíte São João do Paraíso (SSJP) (3) Granito Cinza Foliado (4) Leucogranito isotrópico. O CSB é caracterizado pelo magmatismo de caráter calcioalcalino do tipo I, oriundo em ambiente de arco vulcânico (Suíte Monte Verde) e retrabalhamento crustal (ortogranulitos leucocráticos). O Ortogranulito esverdeado fino, é considerado no presente estudo como rocha do embasamento para o Terreno Oriental, cristalizada durante o paleoproterozoico - Riaciano (2184,3 21 Ma) e recristalizada durante o evento metamórfico Brasiliano no neoproterozoico - Edicariano (607,2 1,5 Ma), cuja idade TDM é de 2936 Ma. O Ortogranulito leucocrático médio cristalizou-se no neoproterozoico Edicariano (entre 592 e 609 Ma) e idade TDM ca. 2100 Ma, ao qual apresenta registro de herança no paleoproterozoico. A Suíte Monte Verde caracteriza-se por um magmatismo calcioalcalino e a Suíte Córrego Fortaleza, por um magmatismo calcioalcalino de alto K, ambas com assinatura de arco magmático. Registram dois pulsos magmáticos, em no Neoproterozoico - Edicarano: um em 592 2 Ma, idade do charnoenderbito, com idade TDM 1797 Ma, e outro em 571,2 1,8 Ma (injeção de um charnockitoide). Para todas as rochas do CSB são registradas feições protomiloníticas, miloníticas e localmente ultramiloníticas. Os dados geoquímicos indicam que os granitoides da SSJP são da série calcioalcalina de alto K, gerados no Neoproterozoico (idades que variam desde 610,3 4,7 Ma até, 592,2 1,3 Ma. As idades TDM revelam valores discrepantes para duas amostras: 1918 Ma e 2415 Ma, sugerindo que tenham sido geradas de diferentes fontes. O Granito Cinza Foliado é da Série Shoshonítica, metaluminoso do tipo I e, de ambiência tectônica de granitos intraplaca. Entretanto, poderiam ter sido fomados em ambiente de arco cordilheirano, havendo contaminação de outras fontes crustais. Fato este pode ser confirmado pelas as idades TDM calculadas ≈ 1429 1446 Ma. O Leucogranito isotrópico ocorre em forma de diques de direção NW, possui textura maciça e é inequigranular. Dados geoquímicos revelam que são granitoides metaluminosos do tipo I da série shoshonítica, e, de acordo com a ambiência tectônica, são granitos intraplaca. O Leucogranito Isotrópico representa o magmatismo pós-colisional ao qual ocorreu entre 80 a 90 Ma de anos após o término do evento colisional na região central da Faixa Ribeira. O Leucogranito Issotrópico cristalizou-se no cambriano (512,3 3,3 Ma e 508,6 2,2 Ma) e com idades TDM ca. 1900 / The granitoids of Cambuci Domain, situated between Rio de Janeiro and Espírito Santo states, were divided into four main groups: (1) Serra Bolivia Complex (CSB) - Heterogeneous Orthogranulites and Orthogneisses; Grey Fine grained Orthogneiss; and charnockites of Monte Verde Region (2) leucogranites / leucocharnockites gness of the São João do Paraíso Suite (SSJP) (3) Grey Foliated Granite (4) Isotropic Leucogranite. The CSB is characterized by type I calc character of magmatism, generate in volcanic arc environment (Monte Verde Suite) and crustal reworking (Leucocratic ortogranulites). The Fine grained Greenish, is considered in this research as the embasement rock for the Oriental Terrain, crystallized during the Paleoproterozoic - Riacian (2184.3 21 Ma) and recrystallized during in the metamorphic event in the Neoproterozoic - Edicarian (607.2 1.5 Ma), whose TDM age is 2936 Ma. The Medium grained Leucocratic Ortogranulite was crystallized in the Neoproterozoic - Edicarian (between 592 and 609 Ma) and its TDM age is ca. 2100 Ma, which features heritage record in the Paleoproterozoic. The Monte Verde Suite is characterized by a magmatism calcialcalin and the Córrego Fortaleza Suite, magmatism calc-alkaline high K, both show magmatic arc signature. Records two magmatic pulses in a sample (JP-RM-08A) in the Neoproterozoic - Edicaran: the first one in 592 2 Ma, and TDM age 1797 Ma, and the second one in 571.2 1.8 Ma (injecting a charnockitoids). For all CSB rocks, protomylonítics, Mylonitic and locally ultramilonítics features were portrayed. Geochemical data show these SSJP granitoids are the calc-alkaline series of high-K, crystallyzed in Neoproterozoic (ranging from 610.3 4.7 Ma to 592.2 1.3 Ma). TDM ages show outliers in two samples: 1918 Ma and 2415 Ma, suggesting that have been generated from different sources. The Gray Foliated Granite belongs to the shoshonitic series, type I and metaluminous and are intraplate granites. However, could have been formed into arc cordilheirano, with crustal contamination of other sources. This fact would be confirmed by the TDM ages calculated ≈ 1429 - 1446 Ma. The Isotropic Leucogranite occurs in the form of dykes, NW direction, has massive texture and is inequigranular. Geochemical data show these granitoids are metaluminous the type I shoshonitic series. They are intraplate granites. The Isotropic Leucogranite represents the post-collisional magmatism which took place between 80 and 90 Ma years after the collisional event in central sector of Ribeira Belt. It is crystallized in the Cambrian (512.3 3.3 Ma e 508.6 2.2 Ma) and TDM ages, ca. 1900 Ma

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os granitoides do Domínio Cambuci, na região limítrofe entre os estados do Rio de Janeiro e Espírito Santo, foram separados em quatro principais grupos: (1) Complexo Serra da Bolívia (CSB) - Ortogranulitos e Ortognaisses Heterogêneos; Ortognaisse Cinza Foliado; e charnockitos da Região de Monte Verde (2) Leucogranitos/leucocharnockitos gnaissificados da Suíte São João do Paraíso (SSJP) (3) Granito Cinza Foliado (4) Leucogranito isotrópico. O CSB é caracterizado pelo magmatismo de caráter calcioalcalino do tipo I, oriundo em ambiente de arco vulcânico (Suíte Monte Verde) e retrabalhamento crustal (ortogranulitos leucocráticos). O Ortogranulito esverdeado fino, é considerado no presente estudo como rocha do embasamento para o Terreno Oriental, cristalizada durante o paleoproterozoico - Riaciano (2184,3 21 Ma) e recristalizada durante o evento metamórfico Brasiliano no neoproterozoico - Edicariano (607,2 1,5 Ma), cuja idade TDM é de 2936 Ma. O Ortogranulito leucocrático médio cristalizou-se no neoproterozoico Edicariano (entre 592 e 609 Ma) e idade TDM ca. 2100 Ma, ao qual apresenta registro de herança no paleoproterozoico. A Suíte Monte Verde caracteriza-se por um magmatismo calcioalcalino e a Suíte Córrego Fortaleza, por um magmatismo calcioalcalino de alto K, ambas com assinatura de arco magmático. Registram dois pulsos magmáticos, em no Neoproterozoico - Edicarano: um em 592 2 Ma, idade do charnoenderbito, com idade TDM 1797 Ma, e outro em 571,2 1,8 Ma (injeção de um charnockitoide). Para todas as rochas do CSB são registradas feições protomiloníticas, miloníticas e localmente ultramiloníticas. Os dados geoquímicos indicam que os granitoides da SSJP são da série calcioalcalina de alto K, gerados no Neoproterozoico (idades que variam desde 610,3 4,7 Ma até, 592,2 1,3 Ma. As idades TDM revelam valores discrepantes para duas amostras: 1918 Ma e 2415 Ma, sugerindo que tenham sido geradas de diferentes fontes. O Granito Cinza Foliado é da Série Shoshonítica, metaluminoso do tipo I e, de ambiência tectônica de granitos intraplaca. Entretanto, poderiam ter sido fomados em ambiente de arco cordilheirano, havendo contaminação de outras fontes crustais. Fato este pode ser confirmado pelas as idades TDM calculadas ≈ 1429 1446 Ma. O Leucogranito isotrópico ocorre em forma de diques de direção NW, possui textura maciça e é inequigranular. Dados geoquímicos revelam que são granitoides metaluminosos do tipo I da série shoshonítica, e, de acordo com a ambiência tectônica, são granitos intraplaca. O Leucogranito Isotrópico representa o magmatismo pós-colisional ao qual ocorreu entre 80 a 90 Ma de anos após o término do evento colisional na região central da Faixa Ribeira. O Leucogranito Issotrópico cristalizou-se no cambriano (512,3 3,3 Ma e 508,6 2,2 Ma) e com idades TDM ca. 1900 / The granitoids of Cambuci Domain, situated between Rio de Janeiro and Espírito Santo states, were divided into four main groups: (1) Serra Bolivia Complex (CSB) - Heterogeneous Orthogranulites and Orthogneisses; Grey Fine grained Orthogneiss; and charnockites of Monte Verde Region (2) leucogranites / leucocharnockites gness of the São João do Paraíso Suite (SSJP) (3) Grey Foliated Granite (4) Isotropic Leucogranite. The CSB is characterized by type I calc character of magmatism, generate in volcanic arc environment (Monte Verde Suite) and crustal reworking (Leucocratic ortogranulites). The Fine grained Greenish, is considered in this research as the embasement rock for the Oriental Terrain, crystallized during the Paleoproterozoic - Riacian (2184.3 21 Ma) and recrystallized during in the metamorphic event in the Neoproterozoic - Edicarian (607.2 1.5 Ma), whose TDM age is 2936 Ma. The Medium grained Leucocratic Ortogranulite was crystallized in the Neoproterozoic - Edicarian (between 592 and 609 Ma) and its TDM age is ca. 2100 Ma, which features heritage record in the Paleoproterozoic. The Monte Verde Suite is characterized by a magmatism calcialcalin and the Córrego Fortaleza Suite, magmatism calc-alkaline high K, both show magmatic arc signature. Records two magmatic pulses in a sample (JP-RM-08A) in the Neoproterozoic - Edicaran: the first one in 592 2 Ma, and TDM age 1797 Ma, and the second one in 571.2 1.8 Ma (injecting a charnockitoids). For all CSB rocks, protomylonítics, Mylonitic and locally ultramilonítics features were portrayed. Geochemical data show these SSJP granitoids are the calc-alkaline series of high-K, crystallyzed in Neoproterozoic (ranging from 610.3 4.7 Ma to 592.2 1.3 Ma). TDM ages show outliers in two samples: 1918 Ma and 2415 Ma, suggesting that have been generated from different sources. The Gray Foliated Granite belongs to the shoshonitic series, type I and metaluminous and are intraplate granites. However, could have been formed into arc cordilheirano, with crustal contamination of other sources. This fact would be confirmed by the TDM ages calculated ≈ 1429 - 1446 Ma. The Isotropic Leucogranite occurs in the form of dykes, NW direction, has massive texture and is inequigranular. Geochemical data show these granitoids are metaluminous the type I shoshonitic series. They are intraplate granites. The Isotropic Leucogranite represents the post-collisional magmatism which took place between 80 and 90 Ma years after the collisional event in central sector of Ribeira Belt. It is crystallized in the Cambrian (512.3 3.3 Ma e 508.6 2.2 Ma) and TDM ages, ca. 1900 Ma

Submitted by Neusa Fagundes (neusa.fagundes@unioeste.br) on 2018-03-06T19:28:50Z No. of bitstreams: 2 Giovane_Zanin2014.pdf: 3169659 bytes, checksum: ca4852dea2558da8d3c74260c79fc413 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-06T19:28:50Z (GMT). No. of bitstreams: 2 Giovane_Zanin2014.pdf: 3169659 bytes, checksum: ca4852dea2558da8d3c74260c79fc413 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014-09-26 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The polyvinyl acetate is a polymer used in the development of formulations for sustained release of drugs. Hyaluronic acid (HA) can interact with receptors on the plasma membrane, especially CD44 that overexpressed in tumor cells. This paper presents a pre-formulation study of isolated polyvinyl acetate films with the addition of HA to the application perspective in pharmaceutical dosage forms destined to modified drug release. The films were prepared using the solvent evaporation method and evaluated according to macroscopic and morphologic characteristics, thickness, Fourier transform infrared spectroscopy (FTIR), thermal analyses (thermogravimetry and differential scanning calorimetry), scanning electron microscopy, water vapor transmission, and swelling index. Addition of HA enabled the formation of isolated films, influencing transparency, flexibility, and thickness. FTIR spectra demonstrated that only physical mixing occurred. TG and DSC curves indicated that films are thermally stable up to 200C. Electron micrographs showed modifications in the polymer mesh structure in samples (85:15 and 80:20) previously immersed in simulated gastric fluid and more pronounced after immersion in simulated intestinal fluid. The HA concentration also influenced water vapor permeability and swelling increasing these indices. We propose that films with 95:05 and 90:10 compositions can be used for modified drug release, as they were similar to a reference film and maintained targeted delivery. / O acetato polivinílico (AcPV) é um polímero utilizado no desenvolvimento de formulações para liberação sustentadas de fármacos. O ácido hialurônico (AH) possui a habilidade de interagir com receptores nas membranas plasmáticas celulares, em especial o CD44 que esta super-expresso em células tumorais. O objetivo deste trabalho foi realizar um estudo de pré-formulação em filmes isolados de acetato polivinílico (AcPV) adicionados de AH na perspectiva de aplicação em formas farmacêuticas destinadas à liberação modificada de fármacos. Os filmes foram produzidos pelo método de evaporação do solvente e avaliados quanto as características macroscópicas e morfológicas, espessura, espectroscopia no infravermelho (FT-IR), análises térmicas (TG e DSC), microscopia eletrônica de varredura, transmissão de vapor de água e índice de intumescimento. Os resultados demonstraram que adição de AH permitiu a formação de filmes isolados adequados influenciando na transparência, flexibilidade e espessura. Espectro no FT-IR evidenciaram ocorrência apenas de mistura física entre os constituintes. As curvas TG e DSC indicaram que os filmes são termicamente estáveis até a temperatura de 200 ºC. Nas micrografias eletrônicas foi possível observar alterações na estrutural da malha polimérica nas composições 85:15 e 80:20 para as amostras previamente imersas em fluido de simulação gástrica, sendo ainda mais pronunciado após imersão em fluído de simulação intestinal. A concentração do AH também influenciou diretamente permeabilidade ao vapor de água e o intumescimento, aumentando estes índices. Na perspectiva de aplicação dos filmes avaliados, destacamos as composições 95:05 e 90:10, as quais sugerem maior potencial para aplicação em formas farmacêuticas para liberação modificada de fármacos uma vez que foram os mais semelhantes ao filme padrão e que mantiveram a possível capacidade de sítio alvo especificidade.

The North Atlantic Caledonides are a continent-continent collision type orogeny found in WesternScandinavia, Svalbard, Greenland and the British Isles. They are thought to have formed as a result of a complex history consisting of repeated ocean opening and closure. The tectonostratigraphy of the Scandinavian Caledonides consists of four allochthons that overlay the crystalline, autochthonous basement. The allochthons are thought to have been transported hundreds of kilometers eastward during the Scandian collision.To investigate the complex history of the Scandinavian Caledonides, a scientific drilling initiative called the Collisional Orogeny in the Scandinavian Caledonides (COSC) project began in 2014. The first phase of the project was to drill a borehole to approximately 2500m depth, to sample a thick section of the Lower Seve Nappe of the Middle Allochthon, as well as the underlying thrust zone.The current hypothesis is that the Middle Seve Nappe has been juxtaposed with the Lower Seve Nappe while still in the subduction channel. Both Seve nappes were emplaced onto the underlying units somewhat later. To test this hypothesis, Rb-Sr dating and Ar-Ar dating has been conducted on white and dark mica found in samples taken from the shear zones. Rb-Sr dating yielded an age of 413 ± 12 Ma and Ar-Ar dating yielded an average age of 424.1± 2.9 Ma. Since the Rb-Sr and Ar-Ar ages overlap, it is interpreted that the crystallization age of the samples is recorded in both cases. Likely, the rocks cooled rather quickly, resulting in a negligible difference in Rb-Sr and Ar-Ar ages. Comparing these results to previous age dating work completed in the same area illustrate a complex subduction/exhumation history. At c. 455 Ma, the Middle and Lower Seve nappes were subducted beneath an island arc and peak pressure metamorphic conditions were reached. Shortly afterwards,exhumation of the subducted sheet began, as a result of the buoyancy of the subducted crust, as well as tectonic under pressure caused by wedge extraction. At c. 424 Ma, the Middle Seve was juxtaposed over the Lower Seve while still in the subduction channel, and at c. 424 - 421.2 Ma both the Middle and Lower Seve nappes were exhumed and transported eastward, where they were thrust above the underlying Särv Nappe and Lower Allochthon, creating the lower shear zone which is the focus of this study. Data from this study will help to establish a coherent model of mid-Palaeozoic mountain building, and provide insight on how this mountain chain, as well as its Himalaya-Tibet analogue have formed. / Den kaledoniska bergskedjan är en kontinent-kontinent kollison orogenes som återfinns i västra Skandinavien, Svalbard, Grönland och på de brittiska öarna. Bergskedjan har formats som ett resultat av en komplicerad historia av repeterad öppning och stängning av Iapetushavet. Skandinaviska kaledoniderna består av fyra allochthoner som täcker urberggrunden. Allochthonerna tros ha blivit transporterade hundratals kilometer i östlig riktning under den Skandiska kollisionen.För att kunna utreda den komplicerade historia som de skandinaviska Kaledoniderna har så har ett borrningsprojekt tagits fram under år 2014 med namnet “Collisional Orogeny in the Scandinavian Caledonides” (COSC). Det första skedet i projektet var att borra ett 2500 meter djupt borrhål för att ta prover från den undre Seveskollan som belägen i den mellersta allochthonen, samt den underliggande överskjutningszonen.Hypotesen är att den mellersta Seveskollan har placerats intill den undre Seveskollan då de befann sig i en subduktionskanal. Både mellersta och undre Seveskollan har placerats uppepå den underliggande bergsenheten något senare. För att testa hypotesen har Rb-Sr och Ar-Ar datering utförts på prover med vitt glimmer som tagits från skjuvzonen. Kompositionskartor av vitt glimmer påvisar inga uppenbara tecken på zonation, vilket innebär att glimmerkornen nyligen bildats eller omkristalliserats under skjuvning. Rb-Sr dateringen gav en ålder på 413 ± 12 miljoner år och Ar-Ar dateringen gav en ålder på424.1 ± 2.9 miljoner år. Detta tolkas som åldern på de omkristalliserade glimmerkornen.Resultatet har jämförts med tidigare åldersdateringar i samma område och påvisar en komplicerad subduktionshistoria. För 460 miljoner år sedan subducerade mellersta och undre Seveskollan under en öbåge. För ungefär 440 miljoner år började upplyftandet av de subducerade skollorna som ett resultat av bärkraften av den subducerande jordskorpan, även av tektoniska rörelser orsakad av en kilutdragning. För 424 miljoner år sedan blev mellersta Seveskollan placerad ovanpå undre Seveskollan när de befann sig i subduktionskanalen. Slutligen, för cirka 415 miljoner år sedan blev både den mellersta och undre Seveskollan upplyfta och transporterade i östlig riktning där de skjuvade över den underliggande Särvskollan och den undre allochthonen.Data från denna studie kommer att bidra till skapandet av en följdriktig modell av den mitt-Paleozoiskabergskedjebildningen  och

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.