Le cancer colorectal (CCR) représente un problème majeur de Santé publique. Des facteurs de risque environnementaux, ainsi que l'apparition séquentielle d'altérations génétiques et épigénétiques corrélant avec la progression tumorale ont été extensivement décrites. Cependant, les variations épigénétiques préexistant dans le tissu sain, potentiellement responsables de différences notoires de susceptibilité au CCR, sont restées élusives jusqu'à ce jour. Afin de répondre à cette problématique, la lignée murine Apcd14 (porteuse d'une mutation hétérozygote constitutive au niveau du gène Adenomatous polyposis coli) a servi de modèle au cours de ce projet. Les individus de cette lignée comportent une expressivité très variable, au sens qu'ils développent spontanément un nombre plus ou moins important de tumeurs intestinales, impactant sur leur survie. Cette hétérogénéité est observée en dépit de conditions d'élevage et de génomes considérés identiques. L'analyse exhaustive de cette lignée a conduit à y caractériser deux groupes de souris, présentant une gravité différente de phénotype. La variation d'expression génétique dans le tissu sain (i.e en amont de la tumorigenèse) a ensuite été analysée dans le but de comprendre l'établissement de cette hétérogénéité. Ceci a mené à la découverte d'une signature de gènes différemment exprimés entre les deux groupes, permettant de corréler de façon parfaite données moléculaires et phénotype. La potentielle héritabilité de cette signature a par la suite conduit à remettre en cause le statut considéré syngénique de la lignée. Les approches expérimentales effectuées ont déjà permis de cibler une région chromosomique, ce qui mènera à court terme à la caractérisation d'un nouvel acteur impliqué dans la tumorigenèse intestinale. De manière plus générale, les expériences développées durant ce projet ouvrent la voie à la notion de susceptibilité individuelle face au cancer dépendante de la variation d'expression génétique. / Colorectal cancer (CRC) is a major public health concern. Environmental clues, as well as sequential genetic and epigenetic alterations correlating with tumor progression have been extensively described. Meanwhile, pre-existing epigenetic variations in the healthy intestinal mucosa, potentially leading to differences in CRC suceptibility, have generally been overlooked. In order to answer to this question, we have made use of the Apcd14 mouse model (carrying a heterozygous mutation in the Adenomatous polyposis coli gene). Although all Apcd14 mice apparently share the same genome and are raised in the same environmental conditions, they exhibit a huge phenotypic variability at the individual level, spontaneously developping a few or numerous intestinal tumors, that ultimately results in differences in survival rates. Through detailed analysis of this strain, two groups have been characterized, exhibiting several phenotypic specificities. Gene expression analysis in the healthy intestinal tissue was then performed in order to understand the differences already existing, prior to tumorigenesis. This led to the identification of a group-specific gene expression signature, allowing a correlation between macroscopic phenotype and molecular data. Consideration of the hereditary potential of this signature led to reconsider the syngeneic status of the Apcd14 strain. Several experimental data already targeted a specific genomic region, and this will allow to identify the genetic alteration involved. More generally, this project opens the way to discover a link between individual susceptibility to intestinal tumorigenesis and gene expression variability.

Os Mollicutes causam doenças em várias espécies animais de importância econômica, inclusive em bovinos. Neste estudo, foi avaliada por concentração inibitória mínima (CIM) e citometria de fluxo, a atividade de oito agentes antibacterianos (enrofloxacina, ciprofloxacina, gentamicina, claritromicina, cloranfenicol, oxitetraclina, tiamulina e tilosina) contra Ureaplasma diversum. Foram analisadas 24 amostras de isolados de campo oriundas da mucosa genital de fêmeas bovinas. As amostras foram confirmadas por crescimento em caldo, placa e por PCR. Os inóculos foram submetidos à analise de suscetibilidade aos antibióticos pelo método da microdiluição em microplaca e posteriormente analisados pelo citômetro de fluxo a fim de avaliar a atividade antimicrobiana nas células. A claritromicina apresentou os maiores índices de inibição in vitro, sendo a gentamicina considerada o antibiótico de menor espectro de ação nesse estudo. De acordo com as análises do citômetro, a gentamicina apresentou o menor número de células viáveis enquanto a tiamulina apresentou o maior número. Embora haja resultados destoantes entre as técnicas utilizadas, o citômetro de fluxo pode ser utilizado como uma boa ferramenta para auxiliar a avaliação da suscetibilidade desses microrganismos a antibióticos. / The Mollicutes cause disease in several economically important species, including cattle. In this study, was evaluated by minimum inhibitory concentration (MIC) and flow cytometry, the activity of eight antibacterial agents (enrofloxacin, ciprofloxacin, gentamicin, clarithromycin, chloramphenicol, oxitetraclina, tiamulin and tylosin) against Ureaplasma diversum. We analyzed 24 samples of field isolates originating from the genital mucosa of cows. The samples were confirmed by growth in broth, plate, and PCR. The inoculations were subjected to analysis of susceptibility to antibiotics by the method of micro-dilution plate and then analyzed by flow cytometry to assess the antimicrobial activity in cells. Clarithromycin showed the highest levels of inhibition in vitro, the antibiotic gentamicin considered lower spectrum of action in this study. According to the analysis of the flow cytometer, gentamicin showed the lowest number of viable cells as tiamulin showed the greatest number. Although there are divergent results between the techniques used, flow cytometry can be used as a good tool even help assess the susceptibility of microorganisms to antibiotics.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2018-03-14T10:52:27Z No. of bitstreams: 2 Dissertação - Andressa Santana Santos - 2018.pdf: 1959070 bytes, checksum: d90ba29af15d78161810fe1b557cd44c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-03-14T10:53:11Z (GMT) No. of bitstreams: 2 Dissertação - Andressa Santana Santos - 2018.pdf: 1959070 bytes, checksum: d90ba29af15d78161810fe1b557cd44c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-14T10:53:11Z (GMT). No. of bitstreams: 2 Dissertação - Andressa Santana Santos - 2018.pdf: 1959070 bytes, checksum: d90ba29af15d78161810fe1b557cd44c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-02-28 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Introduction:Vulvovaginal candidiasis (VVC) is characterized as the second most common infection among infections affecting this region. Candida yeasts, such as C. albicans, C. parapsilosis, C. topicalis, C. glabrata, C. krusei and C. guilliermondii, are the main causes of this pathology and can be identified by phenotypic and molecular methods. Objectives:This study determines the predictive value (PPV) of the clinical diagnosis of VVC in comparison to the culture, characterizes Candida species isolated from the vaginal mucosa through phenotypic and molecular methods, and verifies the production of hydrolytic enzymes and the susceptibility profile in vitro to antifungal agents used in VVC therapy. Methods: the phenotypic methods used were based on morphological and biochemical aspects, while molecular tests were performed using the polymerase chain reaction with primes specific for each species. In order to verify the activity of the enzymes protease, phospholipase and hemolysin, yeast growth was carried out in media containing bovine albumin, egg yolk and blood, and the reading was determined by the precipitation zone (PZ). Adherence of Candida to epithelial cells was determined by light microscopy by counting the number of cells adhered to 100 epithelial cells. In vitro susceptibility of Candida isolates to fluconazole, itraconazole, voriconazole, nystatin, and amphotericin B was performed using the broth dilution assay to determine the minimum inhibitory concentration (MIC) of the antifungal. Results: the VPP of clinical diagnosis against the gold standard of 61.8% (34/55). Among the 55 samples collected, 36 isolates identified as C. albicans(27), C. glabrata (5) and C. topicalis (4) were obtained. All isolates were enzyme producers with average adherence to 100 oral epithelial cells for the C. albicans, C. glabrata and C. tropicalis species were respectively 402.5, 236.2 and 58. High resistance to fluconazole (38.8%), high susceptibility to amphotericin B (94.4%) and low MIC values for nystatin (8 μg / mL at > 16 μg/mL) were observed for the isolates. Conclusions: the culture is essential for the diagnosis of CVV and confirm that C. albicans continues the predominant species as CVV agent. All species presented a high pathogenic power. Hydrolytic enzymes were produced by all the isolates. This study allow suggest to the clinician that the in vitro susceptibility tests prior to antifungal prescription would bring higher therapeutic success. / Introdução: a candidíase vulvovaginal (CVV) é caracterizada como a segunda infecção mais comum entre as infecções que acometem esta região. As leveduras do gênero Candida, como C. albicans, C. parapsilosis, C. topicalis, C. glabrata, C. krusei e C. guilliermondii são as principais causadoras desta patologia, podendo ser identificadas por métodos fenotípicos e moleculares. Objetivos: determinar o valor preditivo (VPP), do diagnóstico clínico de CVV em comparação à cultura, realiza a caracterização das espécies de Candida isoladas da mucosa vaginal através de métodos fenotípicos e moleculares, verifica a produção de enzimas hidrolíticas e o perfil de suscetibilidade in vitro aos antifúngicos usados na terapia da CVV. Metódos: Os métodos fenotípicos usados foram baseados em aspectos morfológicos e bioquímicos, enquanto os testes moleculares foram realizados usando–se a reação em cadeia da polimerase com oligonucleotídeos específicos para cada espécie. Para a verificação da atividade das enzimas proteinase, fosfolipase e hemolisina, foi realizado respectivamente, o crescimento das leveduras em meios contendo albumina bovina, gema de ovo e sangue, sendo a leitura determinada pela zona de precipitação (PZ). A aderência de Candida às células epiteliais foi determinada por microscopia óptica pela contagem do número de células aderidas a 100 células epiteliais. A suscetibilidade in vitro dos isolados de Candida para fluconazol, itraconazol, voriconazol, nistatina e anfotericina B foi realizada usando-se o teste de diluição em caldo visando á determinação da concentração inibitória mínima (CIM) do antifúngico. Resultados: o VPP do diagnóstico clínico frente ao padrão-ouro de 61,8% (34/55). Dentre as 55 amostras coletadas foram obtidos 36 isolados identificados como C. albicans (27), C. glabrata (5) e C. tropicalis (4). Todos os isolados foram produtores de enzimas, a média de aderência à 100 células epiteliais bucais para as espécies de C. albicans, C. glabrata e C. tropicalis foi respectivamente de 402,5, 236,2 e 58. Alta resistência ao fluconazol (38,8%), elevada suscetibilidade a anfotericina B (94,4%) e baixos valores de MIC para nistatina (8 μg/mL a > 16 μg/mL) foram observados para os isolados.Conclusões: a cultura é fundamental para o diagnóstico de CVV e confirmam que C. albicans continua a espécie predominante como agente de CVV. Todas as espécies apresentam um alto poder patogênico visto a liberação de enzimas por todos os isolados. Este estudo permite sugerir ao clínico que a realização de testes de suscetibilidade in vitro anterior a prescrição do antifúngico traria maior êxito terapêutico.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A coccidioidomicose e a histoplasmose sÃo micoses sistÃmicas que acometem o homem e animais, causadas por espÃcies de fungos dimÃrficos, com Ãnfase para Coccidioides posadasii e Histoplasma capsulatum var. capsulatum, respectivamente. SÃo consideradas doenÃas profundas importantes, podendo culminar em diversas complicaÃÃes secundÃrias. Nos Ãltimos anos, a melhoria dos mÃtodos de diagnÃstico micolÃgico e o aumento da ocorrÃncia de doenÃas imunossupressoras causaram grande impacto na incidÃncia das micoses profundas e oportunistas no mundo. Apesar da existÃncia de terapias eficazes com antifÃngicos contra a coccidioidomicose e a histoplasmose, a busca por novas drogas para o tratamento destas doenÃas se faz necessÃria. Ciprofloxacina à uma droga antibacteriana clÃssica do grupo das fluoroquinolonas, que inibe a atividade catalÃtica da DNA girase e topoisomerase IV, essenciais na replicaÃÃo e transcriÃÃo do DNA bacteriano. Estudos verificaram que ciprofloxacina pode atuar na DNA girase dos fungos. Assim, o presente estudo visou avaliar o efeito inibitÃrio in vitro de ciprofloxacina (CIP) isolada e em combinaÃÃo com os antifÃngicos anfotericina B (AMB), itraconazol (ITC), voriconazol (VRC) e caspofungina (CAS) frente à C. posadasii e Histoplasma capsulatum var. capsulatum. Foram utilizados 16 cepas de C. posadasii na fase filamentosa, 16 cepas de H. capsulatum var. capsulatum na fase filamentosa e 9 cepas de H. capsulatum var. capsulatum na fase leveduriforme. O estudo foi conduzido em ensaio de macrodiluiÃÃo e microdiluiÃÃo em caldo, descritos nos documentos M-38A e M-27A2, padronizados pelo Clinical Laboratory Standards Institute (CLSI), sendo utilizados para C. posadasii e Histoplasma capsulatum var. capsulatum, respectivamente. A interaÃÃo das drogas foi analisada atravÃs do cÃlculo do Ãndice da ConcentraÃÃo InibitÃria FracionÃria (FICI), definido como a soma das relaÃÃes entre a concentraÃÃo inibitÃria mÃnima (CIM) de cada droga em combinaÃÃo e a CIM da mesma droga isolada, considerando os valores menores ou iguais a 0,5 indicativos de sinergismo. Com relaÃÃo Ãs cepas de C. posadasii, foram observadas interaÃÃes sinÃrgicas em todas as combinaÃÃes, com destaque para as associaÃÃes de CIP (3,125≤CIM≤12,5 ug mL-1) com ITC (0,0078≤CIM≤0,125 ug mL-1) (n=13/16), CIP (3,125≤CIM≤12,5 ug mL-1) com VRC (0,0078≤CIM≤0,0312 ug mL-1) (n=13/16) e CIP (3,125≤CIM≤12,5 ug mL-1) com CAS (2≤CIM≤8 ug mL-1) (n=14/16). Para as cepas de H. capsulatum na fase filamentosa, tambÃm foram observadas interaÃÃes sinÃrgicas em todas as combinaÃÃes, com destaque para as associaÃÃes de CIP (3,906≤CIM≤62,5 ug mL-1) com ITC (0,00006≤CIM≤0,0078 ug mL-1) (n=14/16) e CIP (31,25≤CIM≤125 ug mL-1) com VRC (0,0156≤CIM≤0,125 ug mL-1) (n=16/16). No tocante Ãs cepas de H. capsulatum na fase leveduriforme, foram observadas poucas interaÃÃes sinÃrgicas nas combinaÃÃes de drogas testadas. Nenhuma das associaÃÃes de drogas testadas apresentou antagonismo. Os dados obtidos apontam uma nova alternativa para o tratamento da coccidioidomicose e da histoplasmose, sendo necessÃrios novos estudos que visem investigar os mecanismos de aÃÃo dessas combinaÃÃes de drogas no metabolismo celular fÃngico, bem como o delineamento de experimentos in vivo para confirmar a significÃncia desses achados. / Coccidioidomycosis and histoplasmosis are systemic mycoses that occur in humans and other animals and are caused by the dimorphic fungi Coccidioides posadasii and Histoplasma capsulatum var. capsulatum, respectively. They are considered important deep mycoses that can lead to several secondary complications. In the past years, the improvement of the techniques applied in mycological diagnosis and the increase in the occurrence of immunocompromising diseases have caused a great impact in the incidence of deep and opportunistic mycoses in the world. In spite of the existence of effective antifungal therapy against coccidioidomycosis and histoplasmosis, the pursue of new drugs to treat theses diseases is necessary. Ciprofloxacin is a classic antibacterial drug that belongs to the group of fluoroquinolones, which inhibit the catalytic activity of DNA gyrase and topoisomerase IV, which are essential in bacterial DNA replication and transcription. Some studies have shown that ciprofloxacin can act on fungal DNA gyrase. Thus, the present study aimed at evaluating the in vitro inhibitory effect of ciprofloxacin (CIP), when associated with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC) or caspofungina (CAS), on C. posadasii and H. capsulatum var. capsulatum. Sixteen strains of C. posadasii in the filamentous phase and 16 and 9 strains of H. capsulatum in the filamentous and yeast-like phase, respectively, were used. Broth macrodilution and microdilution assays were performed, as described in the documents M38-A and M27-A2, respectively, of the Clinical Laboratory Standards Institute (CLSI). Drug interaction was analyzed by calculating the fractional inhibitory concentration index (FICI), which is defined as the sum of the ratios between the minimal inhibitory concentration (MIC) of each combined drug and the MIC of the same drug isolatedly. Values of FICI smaller or equal to 0.5 indicate the occurrence of synergy. Concerning the isolates of C. posadasii, synergistic interactions were observed for all combinations, especially for the associations of CIP (3.125≤CIM≤12.5 ug mL-1) with ITC (0.0078≤CIM≤0.125 ug mL-1) (n=13/16), CIP (3.125≤CIM≤12.5 ug mL-1) with VRC (0.0078≤CIM≤0.0312 ug mL-1) (n=13/16) and CIP (3.125≤CIM≤12.5 ug mL-1) with CAS (2≤CIM≤8 ug mL-1) (n=14/16). For the isolates of H. capsulatum in the filamentous phase synergistic interactions were also observed for all combinations, with emphasis to the associations of CIP (3.906≤CIM≤62.5 ug mL-1) with ITC (0.00006≤CIM≤0.0078 ug mL-1) (n=14/16) and CIP (31.25≤CIM≤125 ug mL-1) with VRC (0.0156≤CIM≤0.125 ug mL-1) (n=16/16). For H. capsulatum in yeast-like phase, few synergistic interactions were observed for the tested drug combinations. None of the tested combinations presented antagonism. The obtained data may point at a new alternative for the treatment of coccidioidomycosis and histoplasmosis. Thus, it is necessary to investigate the mechanisms of action of these drug combinations on the fungal cellular metabolism and to perform in vivo experiments to confirm the relevance of these findings.

A química mineral e de rocha e determinações de susceptibilidade magnética (SM) de granitóides sin- e tardi orogênicos (610- 600 Ma) localizados na porção oriental do batólito Agudos Grandes (porção central do Cinturão Ribeira, SE do Brasil) foram utilizadas para determinar as condições de cristalização e as implicações em sua petrogênese. Os granitos sin-orogênicos são metaluminosos e têm índice de cor (IC) entre 8 e 15, dado por hornblenda, biotita, titanita e magnetita (unidade HBgd). As temperaturas liquidus obtidas pelo geotermômetro de saturação em apatita decrescem de 1000 a 950º C com o fracionamento. As temperaturas solidus obtidas pelo geotermômetro hornblenda-plagioclásio, variam de 720 a 800º C e mostram aumento sistemático em direção a leste, refletindo diminuição da a(H2O) dos magmas. As pressões obtidas por geobarometria de Al em hornblenda variam muito pouco (3,6 a 4,5 kbar) mostrando não haver variações significativas no nível de exposição do batólito. Esses granitos cristalizaram sob condições fortemente oxidantes (DNNO ³ + 2), como revelado pela alta SM, pelas composições da biotita e da ilmenita reliquiar e pelo consumo da ilmenita sob fO2 acima do buffer TMQA. Os granitóides tardi-orogênicos (maciço Piedade) variam de metaluminosos a marginalmente peraluminosos. A unidade metaluminosa portadora de titanita e magnetita (BmgT; IC=8) cristalizou sob condições comparáveis às dos granitos sin-orogênicos. As demais unidades são formadas por granitos com biotita e ilmenita (± muscovita e magnetita) e IC variável entre 15 e 5. Essas rochas em geral cristalizaram sob condições mais reduzidas (QFM a DNNO = + 2), como revelado pela SM mais baixa e pela composição de biotita e ilmenita, mas localmente foram afetadas por processos de oxidação pós-magmática. As temperaturas liquidus obtidas a partir do geotermômetro de saturação em apatita para todas as rochas do maciço Piedade são tão elevadas quanto as dos granitos sin-orogênicos. Estimativas de pressão são precárias, mas as composições de muscovitas sugerem valores da ordem de 4 kbar. Os dados obtidos no presente trabalho são consistentes com modelos que admitem um vínculo genético entre os granitos sin- e tardi-orogênicos do batólito Agudos Grandes. Em particular as tendências de variação química contínua das biotitas, com aumento progressivo do componente siderofilita para os granitos com muscovita, paralelas com a diminuição de SM e diminuição de fO2, podem sugerir que diferenças observadas refletem processos de contaminação de magmas metaluminosos por rochas metassedimentares mais reduzidas. / Magnetic susceptibility (MS) measurements and mineral and rock chemistry were used to infer crystallization conditions of syn- to late-orogenic (610-600 Ma) granites of the eastern portion of the Agudos Grandes batholith (central Ribeira Belt, SE Brazil). The syn-orogenic granites are metaluminous and have color indices (IC) of 8 to 15 given by hornblende, biotite, titanite and magnetite (unit HBgd). Liquidus temperatures obtained by apatite saturation thermometry decrease slighlty, from 1000 to 950°C with fractionation. Solidus temperatures, derived from hornblende-plagioclase thermometry, raise eastwards in the batholith from 720 to 800° C, reflecting decreasing a(H2O) of the magmas. Pressures derived from Al-in-hornblende barometry are nearly invariable (3.6 to 4.5 kbar), showing that the batholith is exposed at approximately the same level of intrusion along the studied section. These granites crystallized under strongly oxidizing conditions (DNNO ³ + 2), as revealed by high MS, by the compositions of biotite and relict ilmenite, and by ilmenite consumption due to fO2 above the TMQA buffer. The late-orogenic granites (Piedade massif) are metaluminous to marginally peraluminous. The metaluminous unit (BmgT; IC=8) bears titanite and magnetite, and crystalized under conditions comparable to those shown by the syn-orogenic massifs. The remaining units are made up of biotite + ilmenite (± muscovite and magnetite) granites with variable IC (15 to 5). These rocks crystallized mostly under more reduced conditions (QFM to DNNO = + 2), as revealed by lower MS and by the compositions of biotite and ilmenite, but were locally affected by post-magmatic oxidation processes. The liquidus temperatures obtained from apatite saturation thermometry in all granites from the Piedade massif are as high as those of the syn-orogenic massifs. Pressure estimates, based on muscovite compositions, are less reliable, but yield values around 4 kbar. The data obtained in this work are consistent with models which admit a genetic link between the syn-orogenic and the late-orogenic granites of the Agudos Grandes batholith. Continuous chemical variation of biotites, with the siderophyllite component increasing steadily towards the muscovite-bearing granites, and parallel decreasing of MS and fO2 suggest that contamination of metaluminous magmas by more reduced metasediments could explain most of the variation observed.

Static techniques to measure different magnetic properties of coupled magnetic nanostructured systems is researched and documented with an extensive analysis of the tunnel diode oscillator (TDO). The VSM was used to obtain the major hysteresis loop for the samples and the TDO was used to measure the magnetic susceptibility. The magnetic susceptibility was employed to conceive the static critical curve. The thesis describes both equipments, VSM and TDO, that were used to obtain data for our experiments. Albeit a more comprehensive outlook on the TDO is provided. The theoretical functionality of TDO, previous successful applications for experiments, and the physical setup in the laboratory is explored. The novel addition of the double Helmholtz coil in this setup is described. The viability of replacement of the big electromagnet and the advantages of the Helmholtz coil are discussed. Magnetization dynamics in a series of FeCoB/Ru/FeCoB synthetic antiferromagnetic samples were investigated via reversible susceptibility measurements acquired through the TDO. The major hysteresis loop generated by the VSM were used to calculate the coercivity and magnetic saturation of the sample. The VSM and TDO were subsequently used to explore the magnetization switching in a di_erent coupled magnetic system, the exchange bias samples. A range of NiFe/FeMn samples were studied with varying thickness of the antiferromagnetic layer.

Chikungunya is a mosquito-transmitted disease caused by Chikungunya virus (CHIKV). Symptoms of Chikungunya include debilitating joint pain and swelling, fever and rash. CHIKV was first discovered in 1953 in Tanzania, and has since caused periodic outbreaks of disease. The virus reemerged recently in 2004 and has since spread around the world affecting more than 3 million people. The different strains of CHIKV have been grouped into three phylogenetic clades: West African, Asian and East/Central/South African (ECSA). There are no FDA approved medicines or vaccines used to treat or prevent CHIKV infection. The antiviral drug, T-705 (commercially known as Favipiravir), has recently been shown to have activity against CHIKV. T-705 has already been approved in Japan for the treatment of influenza and is currently going through clinical trials in the US. Since there may be phenotypic differences between the clades of CHIKV, it is important to first characterize distinctions between the strains and determine the susceptibility of these strains to treatment. To do this, we obtained two different CHIKV strains from each of the three phylogenetic groups. These CHIKV strains displayed differences in their ability to replicate in cell culture and exhibited only slight differences in susceptibility to T-705 treatment. However, more profound differences were observed in mouse models where differences in disease severity and response to T-705 treatment were observed.

De nos jours, la modélisation de la compatibilité électromagnétique est devenue une étape importante de la conception des circuits intégrés permettant un gain sur les délais de validation et les coûts de production. Dans ces travaux de thèse, une contribution à la caractérisation et à la modélisation de la susceptibilité conduite des circuits intégrés est présentée. D’abord, une évolution substantielle de la technique RFIP est élaborée. Cette technique permet de caractériser la susceptibilité conduite des circuits intégrés. Nous avons montré les différentes étapes de caractérisation de la sonde de mesure développée ainsi que du banc de mesure en vue d’une extraction des paramètres d’immunité d’un circuit intégré soumis à des perturbations électromagnétiques. Le principe de la mesure RFIP a été validé par simulation et par mesure notamment lors de la caractérisation de l’immunité d’un convertisseur analogique-numérique embarqué dans un microcontrôleur. Ensuite, la méthodologie de construction de macromodèles d’immunité électromagnétique appliqués aux circuits intégrée est présentée. Le macromodèle construit du convertisseur est basé sur la structure du modèle ICIM-CI et ses paramètres sont extraits à partir des résultats de mesure RFIP. Les différentes approches de construction des blocs du macromodèle sont discutées. La technique RFIP s’est avérée avantageuse pour l’amélioration de la compréhension, la caractérisation et la modélisation de l’immunité des circuits intégrés. / Nowadays, electromagnetic compatibility modeling has become an importantstep during integrated circuits design which allows time-to-market and production costsreduction. In this PhD thesis, we present a contribution to the characterization and modelingof integrated circuits susceptibility to electromagnetic interferences. First, a substantialevolution of the RFIP technique, which represents a measurement technique of integratedcircuits conducted susceptibility, is presented. Different characterization steps of thedeveloped measurement probe as well as the measurement test bench are shown. RFIPmeasurement principle is validated through simulation and measurement, especially on ananalog-to-digital converter (ADC) embedded in a microcontroller. Then, the methodology ofthe extraction of the ADC’s immunity macromodel is explained according to the ICIM-CImodel structure. Macromodel’s parameters are deduced from RFIP measurement results.Different approaches for the construction of the macromodel’s blocks are discussed. RFIPtechnique shows many advantages leading to enhance understanding, characterization andmodeling of integrated circuits immunity.

<p>In this thesis, I experimentally investigate feeding selectivity in fallow deer (Dama dama), with respect to plant secondary compounds, especially tannins, which can decrease the quality of foods. I found that fallow deer avoided foods with higher amounts of tannic acid and Quebracho tannin, even though the deer ate some high-tannin food. The food choice was strongly dependent on the context in which the food was presented, so that the food choice in relation to tannin content was relative rather than absolute. When high-tannin food occurred at low frequency, the deer ate proportionally less from this type of food, at least when the difference in tannin content between the two foods was large. A basic implication is that an unpalatable plant type could benefit from its unpalatability, especially when occurring at low frequency. In experiments with two patches, the finding of a stronger within- than between-patch selectivity was mirrored in associational effects. First, low-tannin, palatable food was more eaten when occurring in a high-tannin patch, which corresponds to neighbour contrast susceptibility. Second, high-tannin, unpalatable food in a less defended patch was less eaten, which corresponds to neighbour contrast defence. A proximate cause of the associational effects can be the presence of a simultaneous negative contrast, which was experimentally demonstrated in an additional study. Individual differences in selectivity were present early in life and were consistent over five years, and selectivity was correlated with foraging exploratory behaviour. The results from this thesis suggest that fallow deer are selective in their food choice with respect to tannins from the beginning, and that the frequency of occurrence of different foods, but also the distance between foods and the complexity of presentation, influence the food choice. It is also suggested that a foraging behavioural syndrome is present in mammalian herbivores.</p>

Magnetic resonance imaging is an essential tool for assessing soft tissues. The desire for increased signal-to-noise and improved tissue contrast has spurred development of imaging systems operating at magnetic fields exceeding 3.0 Tesla (T). Unfortunately, traditional imaging methods are of limited utility on these systems. Novel imaging methods are required to exploit the potential of high field systems and enable innovative clinical studies. This thesis presents methodological advances for human brain imaging at 4.7 T. These methods are applied to assess sub-cortical gray matter in multiple sclerosis (MS) patients. Safety concerns regarding energy deposition in the patient precludes the use of traditional fast spin echo (FSE) imaging at 4.7 T. Reduced and variable refocusing angles were employed to effectively moderate this energy deposition while maintaining high signal levels; an assortment of time-efficient FSE images are presented. Contrast changes were observed at low angles, but images maintained a clinically useful appearance. Heterogeneous transmit fields hinder the measurement of transverse relaxation times. A post-processing technique was developed to model the salient signal behaviour and enable accurate transverse relaxometry. This method is robust to transmit variations observed at 4.7 T and improves multislice imaging efficiency. Gradient echo sequences can exploit the magnetic susceptibility difference between tissues to enhance contrast, but are corrupted near air/tissue interfaces. A correction method was developed and employed to reliably produce a multitude of quantitative and qualitative image sets. Using these techniques, transverse relaxation times and susceptibility field shifts were measured in sub-cortical nuclei of relapsing-remitting MS patients. Abnormalities in the globus pallidus and pulvinar nucleus were observed in all quantitative methods; most other regions differed on one or more measures. Correlations with disease duration were not observed, reaffirming that the disease process commences prior to symptom onset. The methods presented in this thesis enable efficient qualitative and quantitative imaging at high field strength. Unique challenges, notably patient safety and field variability, were overcome via sequence implementation and data processing. These techniques enable visualization and measurement of unique contrast mechanisms, which reveal insight into neurodegenerative diseases, including widespread sub-cortical gray matter damage in MS.