Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-15T12:20:21Z No. of bitstreams: 1 victoreustaquiotosteszidirich.pdf: 1142000 bytes, checksum: 2b246de219ef265a66f3c21f0381b817 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-07-19T15:50:40Z (GMT) No. of bitstreams: 1 victoreustaquiotosteszidirich.pdf: 1142000 bytes, checksum: 2b246de219ef265a66f3c21f0381b817 (MD5) / Made available in DSpace on 2016-07-19T15:50:40Z (GMT). No. of bitstreams: 1 victoreustaquiotosteszidirich.pdf: 1142000 bytes, checksum: 2b246de219ef265a66f3c21f0381b817 (MD5) Previous issue date: 2011-03-18 / O ácido linoléico conjugado, do inglês “Conjugated Linoleic Acid” (CLA) é uma mistura de isômeros de posição e geométricos do ácido linoléico (C18:2 n-6), comumente encontrado em maiores concentrações na carne bovina e em produtos lácteos de ruminantes. Numerosas atividades biológicas têm sido atribuídas aos isômeros C18:2 cis-9, trans-11(c9t11) e ao C18:2 trans-10, cis-12 (t10c12) dentre as quais destacam-se: propriedades anticarcinogênica, antiaterogênica, antiobesogênica, incluindo aumento da massa magra em animais, retardo do aparecimento de diabetes tipo II e também nas respostas imunes humoral e celular. O presente trabalho focou na utilização do c9t11 na dieta em camundongos da linhagem BALB/c, avaliando efeitos na resposta imune humoral como a produção anticorpos específicos para ovalbumina (OVA), bem como a síntese de citocinas e respostas à hipersensibilidade tardia (HTT). O trabalho mostrou que o CLA na dieta reduziu efeitos nas respostas de HTT em 24 horas nos animais e estes apresentaram altos níveis de Ac anti- IgG1 e supressão no perfil Th1 de citocinas como IFN-γ e TNF-α. Com base nesses resultados foi possível perceber que o CLA foi um importante fator no controle do processo inflamatório do modelo e que seu uso poderia ser considerado como uma importante intervenção profilática para muitas doenças de natureza inflamatória. / Conjugated Linoleic Acid (CLA) is a mixture of positional and geometrical isomers of linoleic acid (C18:2 n-6), commonly found in high concentrations in bovine meat and lacteous products from ruminants. Numerous biological activities have been attributed to C18:2 cis-9, trans-11(c9t11) and C18:2 trans-10, cis-12 (t10c12) isomers, among which anti-carcinogenic, anti-aterogenic, anti-obesity properties must be highlighted, including increase of thin mass in animals, delay in type II diabetes emergence and also in humoral and cellular immune responses. This work focused on the use of c9t11 in the diet of BALB/c mice, evaluating effects on humoral immune response by means of production of ovalbumin (OVA) specific antibodies, cytokine production and responses to delayed type hypersensitivity (DTH). The results showed that using CLA in the diet of BALB/c mice decreased effects on DTH responses in a 24h period after animals had been challenged. They exhibited high levels of Ab anti-IgG1 and suppression of Th1 profile cytokines such as IFN-γ and TNF-α. Based on these results, it was possible to say that CLA was an important factor of control in the inflammatory process of the model and that its use could be considered as an important prophylactic intervention for many diseases of inflammatory nature.

Le système immunitaire est divisé en deux réponses : innée et adaptative. Dans la réponse adaptative, les principaux acteurs sont les cellules T CD8 et CD4, dont l'activation est médiée par le complexe antigène-récepteur (TCR) et la génération de signaux intracellulaires. L'intensité du signal est contrôlée par l'affinité du ligand impliquant la kinase p56lck et la protéine adaptatrice SLP-76. Les souris dépourvues de SLP-76 sont bloquées dans leur développement thymique, ce qui rend difficile l'évaluation de l'importance de l'adaptateur, dans la fonction des cellules T périphériques. Récemment, le laboratoire Rudd a généré une souris knock-in (KI) avec une forme de SLP-76 mutée au niveau d'un seul résidu, K56, ayant des cellules T périphériques normales. Cette mutation empêche SLP-76 de se lier au complexe de pore nucléaire (CPN). L'objectif de ce mémoire est de comprendre le rôle de SLP-76, plus particulièrement du mutant K56E dans le contrôle de certains aspects de la fonction des cellules T périphériques. K56E sur un fond transgénique OT1, a montré une déficience partielle de la fonction et du métabolisme des cellules T en réponse à des ligands peptidiques d'ovalbumine de poulet, de différentes affinités. Plus précisément, les voies de la glycolyse et de la phosphorylation oxydative en ont été altérées. Dans l'ensemble, l'altération des fonctions et du métabolisme des lymphocytes T chez le mutant K56E confirme l'existence d'un lien entre le SLP-76 et le métabolisme des lymphocytes T, ce qui pourrait avoir des implications importantes dans le développement de thérapies ciblant la fonction des lymphocytes T. / The immune system is divided into two responses: innate and adaptive. In the adaptive response, the main players are CD8 and CD4 T-cells whose activation is mediated by ligation of the antigen-receptor complex (TCR) and its generation of intracellular signals. The strength of signal is controlled by the affinity of the ligand in a process that involves upstream kinases such as p56lck and downstream targets such as the adaptor protein SLP-76. Mice lacking SLP-76 are blocked in thymic development, making it difficult to assess the importance of the adaptor in peripheral T-cell function. Recently, the Rudd lab generated a knock-in (KI) mouse with a form of SLP-76 mutated at a single residue K56 which shows a normal peripheral T-cell compartment. The mutant prevents SLP-76 binding to the nuclear pore complex (NPC). The object of this dissertation is to understand role of SLP-76 and specifically the K56E mutant in the control of aspects of peripheral Tcell function. The K56E mutant on an OT1 TCR transgenic background showed a partial impairment of T-cell function and metabolism in response to chicken ovalbumin peptide ligands of different affinities. Specifically, both glycolysis and oxidative phosphorylation pathways were impaired in response to peptide ligand activation. Overall, the impairment of T-cell function and metabolism in the K56E mutant supports a link between SLP-76 and T-cell metabolism which may have important implications in the development of therapies targeting T-cell function.

The main goal in reversing the allergy epidemic is the development of effective prophylactic strategies. Early life events, such as exposures to microbes, have a major influence on the development of balanced immune responses. Due to their ability to interact with host immune system and to modulate host immune responses probiotics, mainly bifidobacteria and lactobacilli have been used with some success in prevention of allergic disease. In order to be referred to as probiotic, bacterial strain has to undergo rigorous testing. We have selected three new Lactobacillus (L.) strains out of 24 human isolates according to their antagonistic activity against pathogenic bacteria, resistance to low pH and milieu of bile salts. Safety of these strains was proven upon intragastric administration to mice; moreover, we have shown their ability to shift cytokine Th1 - Th2 balance towards non-allergic Th1 response in isolated splenic cells. Allergen specific prophylaxis using probiotics as vehicles for mucosal delivery of recombinant allergen is an attractive concept for development of well-tolerated and effective allergy vaccines. We have shown that neonatal mono-colonization of germ-free mice with the L. plantarum NCIMB8826 strain producing the major birch pollen allergen Bet v 1 attenuates the development of...

The aim of this study is to construct a numerical reservoir model for Bal&ccedil / ova geothermal field, which is located in the izmir bay area of the Aegean coast. A commercial numerical simulation program, TOUGH2 was utilized with a graphical interface, PETRASIM to model the Bal&ccedil / ova geothermal field. Natural state modeling of the field was carried out based on the conceptual model of the field, then history matching of production &ndash / injection practices of the field was established for the period of 1996 &ndash / 2008. The final stage of modeling was the future performance prediction of the field by using three different Scenarios. In Scenario-1, production and injection rates in year 2008 were repeated for 20 years. In Scenario-2, production and injection rates in year 2008 were repeated for the first 3 years, then they were increased at every 3 years. In Scenario-3, a new well (BT-1) that is assumed to be drilled to 1000 m depth is added for injecting some portion of water that was injected through BD-8 well. In that scenario, similar to Scenario-2, production and injection rates in year 2008 were repeated during the first 3 years, and then the rates of these wells (except the new well) were increased every three years. Analysis of the results indicated that in Scenario-2, compared to Scenario-1, both the temperatures of deep wells located at the eastern portion of the field (BD-6, BD-2, BD-14, BD-9, BD-11, BD-12) and the temperatures of deep wells located at the western portion (BD-4, BD-15, BD-7, BD-5) decreased more. In Scenario-3, compared to Scenario-1, the deep wells located at the eastern side experienced less temperature drops while the deep wells located at the western side experienced higher temperature drops. Such temperature differences were not encountered in shallow wells. No significant changes in bottom hole pressures of deep wells occurred in all three scenarios. On the other hand, shallow wells, especially B-10 and B-5, responded to Scenario-2 and Scenario-3 as decrease in bottom hole pressures.

Oral tolerance is the state of immunologic non-responsiveness that is established following oral antigen consumption. Failures of oral tolerance can result in food allergy. The mechanisms regulating oral tolerance are not well understood, but similar mechanisms may control tolerance to foods and commensal microbes in the intestine. The specific roles of many pattern recognition receptors (PRRs) and innate cells have not been examined in the context of oral tolerance. Mast cells are innate sentinel cells positioned at mucosal surfaces, and have been identified as key regulators of peripheral tolerance to allografts. Toll-like receptor 2 (TLR2) is a PRR involved in bacterial responses and the regulation of intestinal inflammation. We evaluated the impact of mast cells, TLR2, immunoglobulin E (IgE)-mediated mast cell activation, TLR2 activation, and histamine receptor blockade in the development of oral tolerance in mice. Models of tolerance to ovalbumin, peanut butter, and cow’s milk were established. Oral tolerance was assessed in wild type, TLR2-deficient, or mast cell-deficient mice and was measured primarily by analysis of antigen-specific antibody levels after a systemic antigen challenge. The development of antigen-specific Tregs was also assessed. We observed that neither mast cells nor TLR2 were necessary for oral tolerance induction. Moreover, IgE-mediated mast cell activation and antihistamine treatment did not significantly alter oral tolerance induction. TLR2 activators, notably Pam3CSK4, were administered orally concurrent with food antigen and were found to impair oral tolerance to a later systemic antigen challenge. When Pam3CSK4 was administered as an oral adjuvant with ovalbumin, a profound selective enhancement of the IgA response to oral challenge was observed. These results highlight an important differential regulation of oral tolerance by TLR2. Oral TLR2 activation selectively promotes IgA responses to antigen upon repeated oral challenge but prevents the maintenance of oral tolerance upon a systemic challenge. Taken together these results suggest that mast cells are not essential regulators of oral tolerance, but TLR2 is involved in regulating IgA and IgE responses during oral and systemic challenges. These findings inform mechanisms of commensal tolerance and have implications for the potential therapeutic manipulation of oral tolerance to foods.

abstract: Despite the minor differences in the inclusiveness of the word, there is a general assumption among the scientific community that the 'pursuit of knowledge' is the most fundamental element in defining the word 'science'. However, a closer examination of how science is being conducted in modern-day South Korea reveals a value system starkly different from the value of knowledge. By analyzing the political discourse of the South Korean policymakers, mass media, and government documents, this study examines the definition of science in South Korea. The analysis revealed that the Korean science, informed by the cultural, historical, and societal contexts, is largely focused on the values of national economic prosperity, international competitiveness, and international reputation of the country, overshadowing other values like the pursuit of knowledge or even individual rights. The identification of the new value system in South Korean science deviating from the traditional definition of science implies that there must be other definitions of science that also deviates, and that even in the Western world, the definition of science may yield similar deviations upon closer examination. The compatibility of the South Korean brand of science to the international scientific community also implies that a categorical quality is encompassing these different contextual definitions of science. / Dissertation/Thesis / M.S. Biology 2011

No description available.

Lipopolissacarídeos (LPS), pode tanto proteger quanto exacerbar o desenvolvimento da asma. LPS inicia a ativação da resposta imune via ligação da molécula Toll-like receptor 4 (TLR4) que sinaliza por duas vias distintas, as moléculas adaptadoras MyD88 e TRIF. LPS é um adjuvante que induz resposta do tipo Th1, enquanto que o hidróxido de alumínio (Alum) desperta respostas Th2, porém, a mistura de ambos adjuvantes na indução da resposta alérgica pulmonar ainda não foi investigada. No presente estudo, nós determinamos o efeito de dois agonistas de TLR4, um natural (LPS) e outro sintético (ER-803022) adsorvidos ao Alum sobre o desenvolvimento de doença alérgica pulmonar. Os animais foram sensibilizados pela via subcutânea com os antígenos, Ovoalbumina (OVA) ou Toxóide Tetânico (TT) na presença ou ausência de agonistas de TLR4 co-adsorvidos ao Alum e desafiados com os respectivos antígenos pela via intranasal. Nossos resultados mostraram que a sensibilização com OVA ou TT e LPS coadsorvidos ao Alum, impede o estabelecimento da resposta alérgica mediada por linfócitos Th2, tais como, influxo de eosinófilos, produção de citocinas do tipo 2, hiperreatividade brônquica, secreção de muco, e produção de IgE ou IgG1 anafilática. Apesar dos níveis de IgG2a, isotipo associado com as respostas Th1 estarem aumentados, análise da histopatologia pulmonar não revelou um desvio para o padrão Th1 de inflamação. Verificamos que a presença das moléculas TLR4, MyD88, IL-12/IFN-g mas não TRIF foram necessários para LPS exercer seu efeito inibitório. O agonista sintético de TLR4, menos tóxico que LPS, também protegeu contra o desenvolvimento de inflamação alérgica pulmonar. Em conclusão, nosso trabalho esclarece o efeito da sinalização do TLR4 na sensibilização alérgica e indica que agonista sintético de TLR4 com baixa toxicidade, pode ser utilizado para modular a capacidade adjuvante do Alum e conseqüentemente diminuir a indução de alergias. / Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. LPS triggers immune responses through Toll-like receptor (TLR) 4 that in turn activates two major signaling pathways via either MyD88 or TRIF adaptor proteins. LPS is a pro-Th1 adjuvant while aluminum hydroxide (Alum) is a strong Th2 adjuvant, but the effect of mixing both adjuvants on development of lung allergy has not been investigated. We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways we used TLR4, MyD88, TRIF, or IL-12/IFN-g deficient mice. Mice were sensitized subcutaneously to allergens such as ovalbumin (OVA) or tetanus toxoid (TT) with or without TLR4 agonists coadsorbed onto Alum and challenged twice via intranasal route with the same allergens. The development of type 2 immunity was evaluated 24 h after last allergen challenge. We found that sensitization with OVA or TT plus LPS co-adsorbed onto Alum impaired allergeninduced Th2-mediated responses such as airway eosinophilia, type 2 cytokines secretion, airway hyperreactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, a Th1 affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. LPS impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules via the IL-12/IFN-g axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. TLR4 agonists co-adsorbed with allergen onto Alum down modulate Th2 immunity and prevent the development of polarized T cell-mediated airway inflammation. Thus, our work clarifies the effect of TLR4 signaling in allergic sensitization and indicates that TLR4 agonists with low toxicity might be useful for down regulating the pro-Th2 adjuvant activity of alum and consequently decrease the induction of allergy.

Lipopolissacarídeos (LPS), pode tanto proteger quanto exacerbar o desenvolvimento da asma. LPS inicia a ativação da resposta imune via ligação da molécula Toll-like receptor 4 (TLR4) que sinaliza por duas vias distintas, as moléculas adaptadoras MyD88 e TRIF. LPS é um adjuvante que induz resposta do tipo Th1, enquanto que o hidróxido de alumínio (Alum) desperta respostas Th2, porém, a mistura de ambos adjuvantes na indução da resposta alérgica pulmonar ainda não foi investigada. No presente estudo, nós determinamos o efeito de dois agonistas de TLR4, um natural (LPS) e outro sintético (ER-803022) adsorvidos ao Alum sobre o desenvolvimento de doença alérgica pulmonar. Os animais foram sensibilizados pela via subcutânea com os antígenos, Ovoalbumina (OVA) ou Toxóide Tetânico (TT) na presença ou ausência de agonistas de TLR4 co-adsorvidos ao Alum e desafiados com os respectivos antígenos pela via intranasal. Nossos resultados mostraram que a sensibilização com OVA ou TT e LPS coadsorvidos ao Alum, impede o estabelecimento da resposta alérgica mediada por linfócitos Th2, tais como, influxo de eosinófilos, produção de citocinas do tipo 2, hiperreatividade brônquica, secreção de muco, e produção de IgE ou IgG1 anafilática. Apesar dos níveis de IgG2a, isotipo associado com as respostas Th1 estarem aumentados, análise da histopatologia pulmonar não revelou um desvio para o padrão Th1 de inflamação. Verificamos que a presença das moléculas TLR4, MyD88, IL-12/IFN-g mas não TRIF foram necessários para LPS exercer seu efeito inibitório. O agonista sintético de TLR4, menos tóxico que LPS, também protegeu contra o desenvolvimento de inflamação alérgica pulmonar. Em conclusão, nosso trabalho esclarece o efeito da sinalização do TLR4 na sensibilização alérgica e indica que agonista sintético de TLR4 com baixa toxicidade, pode ser utilizado para modular a capacidade adjuvante do Alum e conseqüentemente diminuir a indução de alergias. / Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. LPS triggers immune responses through Toll-like receptor (TLR) 4 that in turn activates two major signaling pathways via either MyD88 or TRIF adaptor proteins. LPS is a pro-Th1 adjuvant while aluminum hydroxide (Alum) is a strong Th2 adjuvant, but the effect of mixing both adjuvants on development of lung allergy has not been investigated. We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways we used TLR4, MyD88, TRIF, or IL-12/IFN-g deficient mice. Mice were sensitized subcutaneously to allergens such as ovalbumin (OVA) or tetanus toxoid (TT) with or without TLR4 agonists coadsorbed onto Alum and challenged twice via intranasal route with the same allergens. The development of type 2 immunity was evaluated 24 h after last allergen challenge. We found that sensitization with OVA or TT plus LPS co-adsorbed onto Alum impaired allergeninduced Th2-mediated responses such as airway eosinophilia, type 2 cytokines secretion, airway hyperreactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, a Th1 affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. LPS impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules via the IL-12/IFN-g axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. TLR4 agonists co-adsorbed with allergen onto Alum down modulate Th2 immunity and prevent the development of polarized T cell-mediated airway inflammation. Thus, our work clarifies the effect of TLR4 signaling in allergic sensitization and indicates that TLR4 agonists with low toxicity might be useful for down regulating the pro-Th2 adjuvant activity of alum and consequently decrease the induction of allergy.

<p>U disertaciji je ostvarena sineza amida i oksazolina žučnih kiselina, kao i njihovih alkil i alkilidenskih derivata polazeći od holne kiseline. Ipitano je pona&scaron;anje različitih okso derivata žučnih kiselina u uslovima Grignard-ove i Wittig-ove reakcije. Ispitana je biolo&scaron;ka aktivnost odabranih sintetizovanih jedinjenja</p> / <p>Synhesis of bile acid amide and oxazoline derivatives, and their alkyl and alkylidene derivatives was accomplished starting from cholic acid. Also, chemical behavior of different bile acid oxo derivatives in Grignard and Wittig reaction was investigated. Biological activity&nbsp; of selected synthesized compounds was evaluated.</p>