Nesta dissertação investigamos como a ficção envolve o leitor. Para isso, partimos da rejeição a Homero declarada por Calímaco, observando que a suposta diferença entre a literatura preferida pelo público e a literatura preferida pela crítica depende de dois fatores distintos. O primeiro é o simples fato de a crítica ler profissionalmente e o público ler por prazer. O segundo está relacionado à distinção entre recepção e uso da literatura proposta por C.S. Lewis. Na recepção, a obra tende a ser admirada por si; no uso, tende a ser instrumentalizada como suporte para um devaneio em que os desejos do próprio leitor são vicariamente satisfeitos. Observamos que essa devaneio, que Lewis chama de construção egoísta de castelos, e que inclui uma variante mórbida, tem um paralelo na noção girardiana do duplo angélico. Contudo, o devaneio depende da simpatia como definida por Adam Smith, a qual por sua vez depende de certa aprovação moral. Investigamos portanto o tipo de personagem que conquista a aprovação moral do leitor, contrastando os heróis homéricos com os cavaleiros cristãos a fim de verificar como o cristianismo dirige a aprovação moral para as vítimas, fazendo com que os heróis da ficção sejam pessoas perseguidas ou marginalizadas. / In this dissertation we investigate how fiction involves the reader. Starting Callimachuss rejection of Homer, we note that the supposed diference between the literature favoured by the public at large and the literature preferred by critics is actually twofold. First, critics read for business and the public reads for pleasure. Second, as proposed by C.S. Lewis, there is a distinction between the reception and use of literature. In reception, a work tends to be admired in itself, whereas in use it becomes a mere support for a sort of daydreaming in which the readers own desires are vicariously satisfied. We discuss this daydreaming called egotistic castle-building by Lewis, highlighting its morbid variant, which finds a parallel in the Girardian notion of the angelic double, developed from a reading of Proust. Now, as egotistic castle-building in its turn depends on sympathy as defined by Adam Smith, a concept which includes moral approval, we investigate the types of characters who obtain the moral approval of readers, contrasting the warriors from Homers poems with Christian knights in order to show that Christianity directs moral approval towards the victims. In a Christian society, fictional heroes must be people who are persecuted or at least marginalised.

CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / FAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas Gerais / Na presente tese foram desenvolvidas três plataformas para a construção de biossensores visando o diagnóstico molecular da hepatite C, hepatite B e artrite reumatoide, por técnicas eletroquímicas, ópticas e microscópicas, usando amostras reais. Os genossensores para hepatites C e B foram desenvolvidos sobre a superfície de um eletrodo de ouro modificado com nanomateriais, sendo esses o óxido de grafeno e o óxido de grafeno reduzido, respectivamente. Em todos os biossensores propostos a interação da sonda com o alvo foi efetivamente verificada pelas diferentes técnicas. No caso do genossensor para hepatite C, o óxido de grafeno foi modificado quimicamente com etilenodiamina e apresentou limites de detecção e quantificação de 1:483 (v/v) e 1:145 (v/v), respectivamente, usando amostras de soro de pacientes positivos. A interação da sonda específica do HCV: gRNA causou uma redução na amplitude de resposta de corrente de cerca de 2,9 vezes quando comparada ao controle negativo, usando a VPD. O genossensor para a hepatite B a sonda foi imobilizada sobre eletrodo de ouro contendo óxido de grafeno reduzido, ouro descoberto e nanoparticulas de ouro. A análise usando VPD indica que a adição de DNA genômico de HBV provocou um aumento de cerca de 1,4 vezes na amplitude de corrente de pico quando comparado ao controle negativo. Em adição, análises de SPR mostraram que as amostras positivas de HBV resultaram em uma alteração de cerca de 15 vezes em comparação com as amostras negativas. No biossensor desenvolvido para o diagnóstico da artrite reumatoide foi utilizado um eletrodo de grafite modificado com um filme poli(3-hidroxibenzóico), no qual foi imobilizado um peptídeo mimético que reconhece o anticorpo anti-CAIII. O sensor mimético desenvolvido permitiu a distinção entre amostras positivas e negativas para a artrite reumatóide, uma vez que apresentou uma diminuição expressiva no sinal de corrente de cerca de 2,2 vezes, quando comparado ao soro negativo. Assim, foi possível desenvolver plataformas analíticas, seletivas e específicas fornecendo novas abordagens para o diagnóstico clínico e aplicações point-of-care para o monitoramento de doenças inflamatórias e infecciosas. / In the present thesis, three biosensing platforms aiming the molecular diagnosis of hepatitis C, hepatitis B and rheumatoid arthritis were developed by electrochemical, optical and microscopic techniques using real samples. The genosensors for the diagnosis of hepatitis C and B were developed on a gold electrode modified with nanomaterials, being these graphene oxide and reduced graphene oxide, respectively. In all proposed biosensors the interaction of the probe with the target was effectively verified by the different techniques. In the case of the genossensor for hepatitis C, graphene oxide was chemically modified with ethylenediamine and showed limits of detection and quantification of 1:483 (v/v) and 1:145 (v/v), respectively, using serum samples from positive patients. The interaction of the HCV probe and the gRNA caused a reduction in current response amplitude of about 2.9 fold as compared to the negative control, using the DPV. The genossensor for hepatitis B probe was immobilized on a gold electrode containing reduced graphene oxide, gold disks and gold nanoparticles. Analysis using DPV indicates that the addition of HBV gDNA caused an increase of about 1.4 times in peak current amplitude, when compared to the negative control. In addition, SPR analyzes showed that positive samples of HBV resulted in a change of about 15- fold compared to negative samples. In the biosensor developed for the diagnosis of rheumatoid arthritis, a graphite electrode modified with a poly (3-hydroxybenzoic) film was used, in which a mimetic peptide that recognizes the anti-CAIII antibody was immobilized. The developed mimetic sensor allowed the distinction between positive and negative samples for rheumatoid arthritis, since it presented an decrease in the current signal of about 2.2 times, when compared to the negative serum. Thus, it was possible to develop analytical, selective and specific platforms, providing new approaches for clinical diagnosis and point-of-care applications, for the monitoring of inflammatory and infectious diseases. / Tese (Doutorado)

Made available in DSpace on 2016-03-15T19:32:52Z (GMT). No. of bitstreams: 1 Vinicius Jose Ribeiro de Carvalho.pdf: 508933 bytes, checksum: 35f5bc3268f8eb84a3d4d15678926b51 (MD5) Previous issue date: 2015-02-03 / This study seeks to understand the utilization of EBITDA by Brazilian market professionals. EBITDA, which emerged in the 1970s in the United States as a tool to measure the operating performance of companies with heavy capital investments and / or highly leveraged companies, due to its success quickly spread throughout the world as an important proxy for cash flows. However, over the years the academic and professional community, as well as regulators and standard-setting bodies, raised a number of criticisms and warnings on its use, possibly greater than its virtues. Thus, was born the motivation of this work: why and how highly skilled and qualified professionals continue utilizing EBITDA in their daily work, despite its conceptual weaknesses? Additionally, there was the motivation to discuss an issue lacking depth in Brazil. This is a qualitative and exploratory study, conducted through interviews with a sample of professionals selected by convenience and the data analyzed by the content analysis technique, with ATLAS.ti software support. The results show that the professionals of the sample continue using EBITDA mainly for ease of use and calculation, and deem it a good measure of operating performance. However, in addition to several criticisms, also showed us that they continue to utilize EBITDA due to the lack of a good proxy for cash flow that has a similar cost-benefit relation. Finally, we identified that one of the probable reasons for its mass utilization lies in Mimetic Isomorphism, as analyzed by the New Institutional Sociology, or Neo-institutionalism. / Este trabalho buscou entender a utilização do EBITDA por profissionais atuantes no mercado profissional brasileiro. O EBITDA, que despontou na década de 1970 nos Estados Unidos da América como uma ferramenta para medir o desempenho operacional de empresas com pesados investimentos em capital intensivo e/ou empresas altamente alavancadas, devido ao seu sucesso rapidamente se disseminou por todo o mundo como uma importante proxy para fluxos de caixa. No entanto, ao longo dos anos a comunidade acadêmica e profissional, assim como órgãos reguladores e normatizadores, levantaram uma série de críticas e ponderações quanto ao seu uso, possivelmente maiores que suas virtudes. Assim, nasceu a motivação deste trabalho: por que e como profissionais tão gabaritados continuam utilizando o EBITDA em seu dia a dia, apesar de suas fragilidades conceituais? Também teve-se a motivação de discutir um tema pouco aprofundado no Brasil. Trata-se de um trabalho de cunho qualitativo e exploratório, realizado através de entrevista com amostra de profissionais selecionados por conveniência e com os dados analisados pela técnica de análise de conteúdo, com suporte do software ATLAS.ti. Os resultados apontaram que os profissionais da amostra continuam utilizando o EBITDA principalmente pela facilidade de uso e de cálculo, além de entenderem ser uma boa medida de desempenho operacional. No entanto, além das diversas críticas tecidas, apontam também que o utilizam devido a falta de uma boa proxy para fluxo de caixa que tenha custo benefício de utilização semelhante. Por fim, identificamos que uma das razões para sua utilização reside no Isomorfismo Mimético, conforme analisado pela Nova Sociologia Institucional, ou Neo-institucionalismo.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-05-04T19:26:38Z No. of bitstreams: 1 lucasfagundesesteves.pdf: 10750065 bytes, checksum: 8871e6f0092a5a329a1cc8099f9a0382 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T13:33:34Z (GMT) No. of bitstreams: 1 lucasfagundesesteves.pdf: 10750065 bytes, checksum: 8871e6f0092a5a329a1cc8099f9a0382 (MD5) / Made available in DSpace on 2017-05-17T13:33:34Z (GMT). No. of bitstreams: 1 lucasfagundesesteves.pdf: 10750065 bytes, checksum: 8871e6f0092a5a329a1cc8099f9a0382 (MD5) Previous issue date: 2016-02-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Esta tese propõe uma investigação teórica do mecanismo de quebra hidrolítica de um modelo para diésteres de fosfato, o íon BDNPP [bis(2,4-dinitrofenil)fosfato], catalisada por um complexo dinuclear de cobre(II) (R1). Esse complexo metálico foi originalmente planejado para mimetizar a estrutura e as propriedades catalíticas do sítio ativo das catecóis oxidases (COs), revelando um caso interessante de promiscuidade catalítica em sistemas biomiméticos. As possibilidades de mecanismo foram cuidadosamente avaliadas através de cálculos de Teoria do Funcional da Densidade (DFT) em fase gás e em fase aquosa com cálculos no ponto dentro do modelo contínuo polarizável (PCM). Dois mecanismos principais foram encontrados. O Mecanismo 1 (Concertado) corresponde a uma reação do tipo SN2 que envolve o ataque da ponte µOH, situada entre os íons Cu(II), ao centro fosfórico da molécula de BDNPP, enquanto que o Mecanismo 2 (Associativo) ocorre através de sucessivas transferências de próton entre o átomo de oxigênio desta mesma ponte com o átomo de oxigênio terminal do grupo fosfato, passando pela formação de um intermediário pentacoordenado estável. O Mecanismo 1 envolve dois possíveis caminhos reacionais para a liberação do íon DNPP [(2,4-dinitrofenil)fosfato] gerado após a quebra hidrolítica. O primeiro caminho reacional (p1) envolve uma transferência de próton – que ocorre entre o átomo de oxigênio que compunha a ponte µ-OH e o átomo de oxigênio terminal do grupo fosfato – imediatamente após a quebra hidrolítica, seguido pela entrada de duas moléculas de água, sendo a etapa de transferência de próton determinante da velocidade. O segundo caminho reacional (p2) envolve a entrada de duas moléculas de água imediatamente após a quebra hidrolítica sem que haja a reação de transferência de próton, sendo a etapa de quebra hidrolítica a etapa determinante da velocidade. Dentre as propostas de mecanismo estudadas o caminho reacional p2 dentro do Mecanismo 1 corresponde ao mais provável, uma vez que possui a menor barreira de reação (ΔG‡ = 23,7 kcal mol-1, em solução aquosa). A constante de velocidade observada experimentalmente, Kobs, vale 1,7 × 10-5 s-1, indicando que o valor calculado teoricamente (K1 = 2.6 × 10-5 s-1) está em excelente acordo com o valor experimental. O efeito isotópico cinético (KIE) foi avaliado para o caminho reacional p2 dentro do Mecanismo 1 com o intuito de entender as alterações estruturais envolvidas na formação do TS1-i (Estado de transição para o Mecanismo 1), caracterizando perfeitamente o mecanismo descrito. O efeito explícito da inclusão de moléculas do solvente foi avaliado de maneira preliminar para apenas uma estrutura do ciclo catalítico para a quebra hidrolítica de ésteres de fosfato, através da utilização do método de Monte Carlo. Os resultados permitem uma análise detalhada da organização das moléculas de solvente ao redor do complexo, podendo servir de ponto de partida para uma análise mais elaborada dos mecanismos reacionais utilizando modelos explícitos para o solvente. O mecanismo de oxidação de catecóis – representado pelo substrato modelo, o 3,5-di-tercbutilcatecol (DTBC) – no sítio ativo do complexo R1 foi avaliado através de cálculos quanto-mecânicos. Embora não tenham sido obtidos resultados conclusivos acerca da cinética da reação, os aspectos estruturais das principais espécies envolvidas no ciclo catalítico foram analisados. / In this thesis the theoretical investigation of the hydrolytic cleavage mechanism of a phosphate diester, BDNPP [bis(2,4-dinitrophenyl)phosphate] in the active site of the dinuclear copper complex, labelled as R1, has been proposed. The metal complex was originally designed to mimic the active site structure as well the catalytic properties of catechol oxidase, revealing an interesting case of catalytic promiscuity in biomimetic systems. The mechanistic possibilities have been carefully evaluated through Density Functional Theory (DFT) calculations in gas phase and in aqueous solution using continuum solvation models with single point calculations within the Polarizable continuum model (PCM). Two reaction mechanisms have been proposed. The Mechanism 1 (Concerted) is a SN2 type mechanism which involves the direct attack of the µ-OH bridge between the two copper(II) ions towards the phosphorus center whereas, the Mechanism 2 (Associative) occurs through two successive proton transferences between the oxygen atom of the bridging hydroxo ligand and another oxygen atom of the phosphate model forming a stable pentacoordinate intermediate. There are two reactions paths for Mechanism 1 to release the DNPP (2,4-dinitrophenylphosphate) ion generated after the hydrolytic cleavage. The first reaction path (p1) involves a proton transfer immediately after the hydrolytic cleavage, being the proton transfer the rate-determining step, followed by the entry of two water molecules. The second reaction path (p2) comprises the entry of two water molecules just after the hydrolytic cleavage without any proton transfer, being the hydrolytic cleavage the rate limiting step. The most probable catalytic path occurs via Mechanism 1, following the second reaction path (p2) once it involves the lowest free energies activation barrier (ΔG‡ = 23.7 kcal mol-1, in aqueous solution). The experimental rate constant, Kobs is 1.7 × 10-5 s-1, indicating that the calculated value, (K1 = 2.6 × 10-5 s-1) is in a very good accordance with the experimental value. Kinetic Isotope Effect (KIE) analysis for the second reaction path (p2) within the Mechanism 1 has also been considered in order to understand the changes taking place in TS1-i (transition state of Mechanism 1) and perfectly characterize the mechanism here described. The solvent effect using explicit water molecules were evaluated in a preliminary fashion for one structure within the catalytic cycle of hydrolytic cleavage of phosphate ester, using the Monte Carlo method. The obtained results allows a detailed analysis of the water molecules organization around the complex, serving as a starting point for an more elaborated study of the reaction mechanisms by using explicit solvent models. The oxidation of catechols – represented herein by the model substrate, 3,5-di-tercbuthylcatechol (DTBC) – in the active site of the R1 complex were evaluated by using quantum-mechanical calculations. The results are not conclusive for the kinetic, but the structural aspects for the main species in the catalytic cycle were studied.

Bio-inspired or biomimetic chemistry deals with the replication of the nature’s fundamental processes, which can help in understanding the functioning of biological systems and develop novel applications. Although a large number of researchers worked towards the replication of natural synthetic pathways through biogenetic syntheses, enzyme mimicry by the small organic molecules and inorganic complexes emerged in leaps and bounds over the years. The development of biomimetic chemistry then continued in designing the molecules that can function like enzymes. And now, with the advent of nanotechnology, nanostructured materials have been shown to exhibit enzyme-like activities (nanozymes). Interestingly, the two distinct fields, biology and materials science, have been integrated to form an entirely new area of research that has captured a great attention. Along with the pronounced application of nanomaterials as drug delivery vehicles, anticancer agents, antimicrobials, etc., research is also focused on designing nanomaterials for the biomimetic applications. The thesis consists of five chapters. The first chapter provides a general overview of the recently discovered nanozymes that mimic heme-peroxidase, oxidase, superoxide dismutase, catalase, haloperoxidase and phosphatase. This chapter also deals with the nanozymes’ application in sensing and immunoassay, and as antioxidants, neuroprotective agents. The factors affecting the nanozymes’ activity and the challenges associated with them is also covered in this chapter. Chapter 2 is divided into two parts and it deals with the biomimetic properties of graphene-based materials. In part A, the remarkable peroxynitrite (PN) reductase and isomerase activities of hemin-functionalized reduced graphene oxide (rGO) is discussed. In part B, the activity of graphene oxide (GO) as peroxide substrate for the glutathione peroxidase (GPx) enzyme is discussed. In chapter 3, the oxidant material, V2O5, is shown to exhibit significant GPx-like antioxidant activity in its nano-form. Chapter 4 deals with the oxidase-like activity of MnFe2O4 nanooctahedrons for the antibody-free detection of major oxidative stress biomarker, carbonylated proteins. In chapter 5, the phosphotriesterase mimetic role of vacancy engineered nanoceria is discussed. instead of H2O2 for glutathione peroxidase (GPx) enzyme. As partial reduction of GO was observed when treated with GPx enzyme due to the fact that large sheet-like structures cannot be accessible to the active site, we studied the reaction with some GPx mimetics (Fig. 2). Varying the concentration of cofactor glutathione (GSH) required for the reaction, GPx mimic, ditelluride, could accomplish the reduction of GO following Michaelis-Menten kinetics. As the structure of GO is elusive and under active investigation, our study highlights the presence of peroxide linkages as integral part of GO other than hydroxyl, epoxy and carboxylic groups. This study also highlights an important fact that the modification of GO by biologically relevant compounds such as redox proteins must be taken into account when using GO for biomedical applications because such modifications can alter the fundamental properties of GO. Figure 2. The GO reductase and decarboxylase activities of GPx mimetic ditelluride compound, suggesting the presence of peroxide linkages on GO. In chapter 3, we have discussed about the novel antioxidant nanozyme that combats oxidative stress. During our attempts in the investigation of antioxidant nanozymes, we surprisingly noticed that the oxidant material, V2O5, shows significant GPx-like antioxidant activity in its nano-form. The Vn readily internalize in the cells and exhibit remarkable protective effects when challenged against reactive oxygen species (ROS). Although Vn has been shown to protect cells from ROS-induced damage, cells treated with bulk V2O5 and few vanadium complexes resulted in generation of ROS and severe toxicity. Detailed investigation on the mechanism of this interesting phenomenon Chapter 4 deals with the development of novel methodology for detection of biomarkers. Inspired by the use of antibodies and enzymes for detection of a specific antigen, we have shown for the first time that the nanozymes can entirely replace antibodies and enzymes in Enzyme-linked Immunosorbent Assays (ELISA). As a specific example, we focused on the antibody-free detection of chief oxidative stress biomarker, carbonylated proteins, as our target. To achieve this, we designed MnFe2O4 nanooctahedrons that can function as oxidase enzyme and form signaling point of detection. We functionalized MnFe2O4 nanooctahedrons with hydrazide terminating groups so that carbonylated proteins can be linked to nanozymes by hydrazone linkage (Fig. 4a). Treatment of various carbonylated proteins (hemoglobin (Hb), Myoglobin (Mb), Cytochrome c (Cyt c), RNase and BSA) coated in well plate with hydrazide-terminated MnFe2O4 nanooctahedrons and then with 3,3’,5,5’-tetramethylbenzidine substrate, resulted in instantaneous detection by well plate reader (Fig. 4b). Considering the challenges and difficulties associated with the conventional methods used to detect such modified proteins, this methodology opens up a new avenue for the simple, cost-effective, instantaneous and entirely antibody-free ELISA-type detection of carbonylated proteins. Our results provide a cumulative application of nanozymes’ technology in oxidative stress associated areas and pave a new way for direct early detection of post translational modification (PTM) related diseases. Figure 4. a) Nanozyme linked to the carbonylated protein coated on a plate through hydrazone linkage. b) General bar diagram showing detection of oxidized (carbonylated) proteins by nanozymes. Synopsis Figure 5. a) A cartoon view of surface of ceria showing vacancy. b) Zoomed portion of high resolution transmission electron microscopic image showing few vacancies on the surface of nanoceria. c) Catalytic mechanism of detoxification of paraoxon at the defect site. In the final chapter, chapter 5, we have discussed about the nanomaterial that can function as phosphotriesterase enzyme. Phosphotriesterase enzyme is a bacterial enzyme that is involved in the rapid hydrolysis of sarin gas-related deadly nerve agents such as paraoxon, parathion and malathion. When encountered with these orgnaophospatetriesters, living beings tend to undergo nerve shock to cause paralysis by inhibiting an extremely important enzyme called acetylcholine esterase. They are also known to cause severe oxidative stress problems and are associated with neurodegenerative disorders. Therefore, curbing the toxic effects and detoxification of these nerve agents is a world-wide concern and many research teams have focused their attention to address this important problem. Working on the development of nanozymes for important problems, we found that nanoceria, especially the vacancy engineered one (Fig. 5a,b), can serve as active mimic of phosphotriesterase enzyme in the presence of N-methylmorpholine (acting as a distal base histidine). Vacancy engineered nanoceria has been shown to catalyze the hydrolysis of high amounts of paraoxon quiet efficiently and within few minutes with very low activation energy and high kcat. Detailed mechanistic investigation revealed that the presence of both Ce(III) and Ce(IV) is very essential for detoxification activity (Fig. 5b). The vacancies on the surface of nanoceria, were the buried Ce(III) ions are directly exposed to the reaction environment, behave as hotspots or enzyme active sites for detoxification reaction (Fig. 5b).

Actuellement, il est largement reconnu que la décision des cellules souches de maintenir leur caractère souche ou se différencier vers une lignée spécialisée dépend particulièrement de la nature de leur microenvironnement, appelé niche cellulaire. Une des composantes essentielles de cette niche cellulaire est la matrice extracellulaire (MEC), qui au-delà de sa fonction de support cellulaire, détermine le devenir des cellules souches en fonction de sa composition biochimique, sa structure et sa localisation. D’un point de vue rationnel, un biomatériau destiné à remplacer la fonction d’un tissu endommagé doit non seulement jouer le rôle d’échafaudage cellulaire mais également mimer les propriétés de la MEC dans son ensemble. Malheureusement, il est extrêmement difficile de concevoir des biomatériaux mimétiques de la MEC naturelle tenant compte de sa complexité structurelle et fonctionnelle. Pour pallier à cette problématique, il semble nécessaire d’effectuer un travail en amont de déconstruction/reconstruction de la complexité de la MEC en étudiant l’effet individuel puis combiné de ses propriétés sur la différenciation des cellules souches. Ce projet de doctorat rentre dans le cadre de ce travail et vise à déterminer le rôle spécifique ou concomitant de différentes propriétés inhérentes à la MEC sur la différenciation ostéoblastique des cellules souches mésenchymateuses humaines (hCSMs). En effet, nous avons évalué l’effet de la composition biochimique de la MEC et la distribution spatiale des ligands sur la différenciation des hCSMs, en fonctionnalisant la surface d’un matériau modèle avec les peptides RGD et/ou BMP-2, distribués d’une manière aléatoire ou structurée. / Actually, it is well-established that maintaining the stemness character of stem cells or eliciting their lineage-specific differentiation is closely related to the nature of their microenvironment, known as stem cell niche. The extracellular matrix (ECM), a key component of stem cell niche, not only provides a support function for stem cells but also dictates their fate decision. From a rational point of view, a biomaterial intended to replace a damaged tissue should mimic the natural ECM in all its aspects, including its biochemistry, 3D structure, topography, porosity, rigidity…. etc. Unfortunately, the design of biomaterials that fully mimic the natural ECM is still a big challenge, due to its high structural and functional complexity. Towards the development of finely-tuned biomaterials, it seems important to start by deconstructing and then reconstructing the complexity of the ECM. In this context, the thesis project, herein, seeks to evaluate both the individual and the synergistic effect of different properties inherent to the natural ECM on human mesenchymal stem cells (hMSCs) osteogenic differentiation. Indeed, we investigated whether the biochemical composition of the ECM and the spatial distribution of its components modulate hMSCs osteogenesis. This was achieved by creating different artificial ECMs, in vitro, containing RGD and/or BMP-2 mimetic peptides, distributed randomly or as specific micropatterns on the surface of a model material.

Notre étude porte sur les personnages féminins de Marcel Proust à l'aide du « désir » de René Girard, du « don » de Marcel Mauss et des « focalisations » de Gérard Genette. La focalisation variable dans le récit facilite la compréhension de toutes les relations et en particulier des sentiments amoureux du héros pour les femmes. Il croit pouvoir réaliser ses rêves à travers ces femmes et se réjouit à l'idée de posséder les clés qui lui permettent d'entrer dans le monde qu'il recherche. Ce sera le narrateur vieillissant qui démystifiera ce sentiment. En réalité, sa satisfaction ne provient pas des femmes en elles-mêmes, mais de leurs qualités périphériques qu'il peut retrouver chez elles. Girard défend le désir des mauvais procédés, il parle également du mimétisme, de la rivalité et de la violence dans le désir qui relève de l'imagination. Le « désir girardien » définit correctement le désir maladif du jeune héros envers les femmes. Quant à Mauss, il défend une réciprocité de la reconnaissance comme « trois obligations » afin de pouvoir constituer une bonne relation sociale. Il dévoile principalement les bons procédés tels l'amitié, l'amour et l'échange de cadeaux, mais il traite aussi du sujet de la rivalité. Ces deux théories semblent contradictoires, cependant le désir et le don coexistent dans la Recherche, on les retrouve tous deux au fur et à mesure de notre relecture. La poursuite de l'amitié et de la gloire sociale du héros est défaite, pourtant toutes les pages sur l'art nous montrent la philosophie de Proust, ce qui n'est pas possible par l'amour est possible grâce à la littérature. La Recherche parle de la compréhension de la vie ce qui est un don du romancier. / My research focuses on the female characters in In Search of Lost Time by Marcel Proust from the perspective of the "desire" of René Girard, the "gift" of Marcel Mauss and the "focus" of Gérard Genette. The variable focus in the narrative facilitates the comprehension of all relationships, connections and in particular the passion and the varied emotional projections of the hero for these women. He believes that his dreams will come true through these women. It will be the narrator, another "me" of the hero, who will demystify this feeling. In fact, his satisfaction is not in regard to the women themselves, but to the peripheral qualities that he can find from these women. Girard defends the desire of bad processes, he talks about the mimicry, rivalry and violence in desire which is also from the imagination. Girard's theory of mimetic desire composed of envy, jealousy and helpless hatred corresponds exactly to the unhealthy desire of the young hero for these women. The theory of Mauss regarding mutual recognition as being composed of "three obligations" which constitute a good social relationship. He defends not only the good processes like friendship, love and gift exchange, but also the topic of rivalry. It might seem that these two theories are contradictory, but Desire and the Gift coexist in fact in this novel, we can find them in our new interpretation. The hero's pursuit of friendship and social glory is defeated, however all pages on art shows us the philosophy of Proust, which is not possible by love is possible through literature. In Search of Lost Time is a gift of the author, it's a comprehension all about life.

Les pays de l’UEMOA ont recours depuis quelques années aux Partenariats Public-Privé (PPP) pour faire face à une demande en infrastructures publiques loin d’être satisfaite par le seul budget de l’Etat. Au-delà des difficultés financières, il s’avère difficile de construire des modèles de gouvernance durables et socialement acceptables pour conduire ces processus. Ainsi notre problématique concerne l’indentification des modèles adéquats de gouvernance des PPP dans le contexte des pays de l’UEMOA. Le cadre théorique mobilisé à cet effet s’inspire de la théorie des coûts de transaction, de la théorie de l’agence, du nouveau management public et des contributions récentes à l’analyse des modèles de gouvernance de PPP. Ainsi, une grille d’analyse des données empiriques composée de quatre macro-dimensions (exogène, organisationnelle, projet et qualité du service) est déduite. Dans une posture du constructiviste pragmatique, une méthodologie qualitative basée sur deux études de cas a été privilégiée. La collecte des données, effectuée en deux phases séparées d’un an, a permis l’analyse de régularités. 42 entretiens semi-directifs, auprès des acteurs impliqués dans deux processus PPP, ont été réalisés. Il s’agit du Programme de Vérification des Importations- Nouvelle Génération (PVI-NG) au Bénin et du pont Henri Konan Bédié d’Abidjan en Côte D’Ivoire. Le traitement et l’analyse des données sont effectués à l’aide du logiciel N’vivo. Certes, l’analyse des résultats a permis d’identifier trois modèles (coercitif, normatif/mimétique et participatif) de gouvernance de PPP ; mais dans la pratique, c’est à une combinaison, des trois modèles, dosée selon le PPP qu’on assiste. Un système propositionnel de 28 principes relatifs aux trois modèles est déduit pour améliorer le management des processus PPP. / Recently, WAEMU countries have been using PPPs to meet the demand for public infrastructure which is far from being met by the state budget alone. Added to financial difficulties, difficulties in building sustainable and socially acceptable governance models for these public projects are faced. Thus, our problem concerns the identification of adequate models of PPP governance in WAEMU context. The theoretical framework mobilized for this purpose is based on the theory of transaction costs, agency theory, new public management and recent contributions to the analysis of PPP governance models. Thus, an empirical data analysis grid composed of four macro-dimensions (exogenous, organizational, project and quality of service) is deduced. In a pragmatic constructivist posture, a qualitative methodology based on two case studies was favored. The data collection, carried out in two separate phases of one year, allowed the analysis of patterns. 42 semi-directive interviews were conducted with stakeholders involved in two PPP processes. These are the New Generation-Import Verification Program (PVI-NG) in Benin and the Henri Konan Bédié Bridge in Abidjan, Côte d'Ivoire. Data processing and analysis is carried out using the N'vivo software. The results highlight three PPP governance models: coercive, normative / mimetic and participatory; but in practice, it is a combination of the three models, assayed according to the PPP. A propositional system of 28 principles relating to the three models is deduced to improve the PPP processes management.

Mixed association of calix[4]resorcinarene with ethyl sulfonate groups on the lower rim and dimethylaminomethyl groups on the upper rim (CR) and cationic surfactant 4-aza-1-hexadecyl-azoniabicyclo[2.2.2]octane bromide (DABCO-16) is studied by methods of tensiometry, conductometry, potentiometry and NMR spectroscopy at fixed CR concentration and varied surfactant concentration. Beyond ca. 0.4 mM of DABCO-16, mixed aggregates enriched by CR are proved to be formed due to electrostatic forces, while beyond ca. 5 mM, aggregates enriched by surfactant occur due to the hydrophobic effect. Spectrophotometry monitoring of the solubilization of a hydrophobic dye, Orange OT, demonstrated that only the second type of mixed aggregate enriched by DABCO-16 is capable of binding the organic probe, while the mixed system where the surfactant is a minor component shows no binding capacity towards Orange OT. This finding can be used for the design of nanocontainers with controllable binding/release properties. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Nonviral gene delivery, though limited by inefficiency, has extensive utility in cell therapy, tissue engineering, and diagnostics. Substrate-mediated gene delivery (SMD) increases efficiency and allows transfection at a cell-biomaterial interface, by immobilizing and concentrating nucleic acid complexes on a surface. Efficient SMD generally requires substrates to be coated with serum or other protein coatings to mediate nucleic acid complex immobilization, as well as cell adhesion and growth; however, this strategy limits reproducibility and may be difficult to translate for clinical applications. As an alternative, we screened a chemically defined combinatorial library of 20 different extracellular matrix mimetic substrates containing combinations of (1) different sulfated polysaccharides that are essential extracellular matrix glycosaminoglycans (GAGs), with (2) mimetic peptides derived from adhesion proteins, growth factors, and cell-penetrating domains, for use as SMD coatings. We identified optimal substrates for DNA lipoplex and polyplex SMD transfection of fibroblasts and human mesenchymal stem cells. Optimal extracellular matrix mimetic substrates varied between cell type, donor source, and transfection reagent, but typically contained Heparin GAG and an adhesion peptide. Multiple substrates significantly increased transgene expression (i.e. 2- to 20-fold) over standard protein coatings. Considering previous research of similar ligands, we hypothesize extracellular matrix mimetic substrates modulate cell adhesion, proliferation, and survival, as well as plasmid internalization and trafficking. Our results demonstrate the utility of screening combinatorial extracellular matrix mimetic substrates for optimal SMD transfection towards application- and patient-specific technologies.