[pt] O propósito deste trabalho é apresentar a teoria dos nós legendreanos, que diz respeito a nós tangentes a uma estrutura de contato, assim como demonstrar o Teorema do Número Máximo de Thurston- Bennequin para nós de 2-pontes em termos do polinômio de Kaumman. Iniciamos este trabalho com uma introdução aos nós topológicos. Apresentamos a teoria de nós legendreanos, dando ênfase aos nós legendreanos em R3 tangentes à estrutura de contato canônica neste espa»co. Apresentamos dois invariantes clássicos de nós legendreanos: os números de Thurston- Bennequin e Maslov. Finalmente, obtemos o número máximo de Thurston-Bennequin, motivo de estudos nos dias atuais, para todos os nós legendreanos topologicamente isotópicos aos nós de 2-pontes na estrutura de contato canônica em R3. / [en] The purpose of this work is to present the Theory of the Legendrian knots, which refers to knots tangent to a contact structure, and also to prove the Theorem of the Maximal Thurston-Bennequin number for 2- bridge knots in terms of the Kaumman polynomial.We begin this study with an introduction to topological knots. We present the theory of the Legendrian knots, we emphasize Legendrian knots in R3, knots tangent to the standard contact structure in this space. We present two classical invariants of Legendrian knots, the Thurston-Bennequin and Maslov numbers. Finally we show the maximal Thurston-Bennequin number for Legendrian two- bridge knots in standard contact structure on R3, an active area of current research.

In der vorliegenden Arbeit wurde die Bedeutung von intraepithelialen Lymphozyten (IEL), oxidativem Streß und endogenen Schutzmechanismen bei GvHR, Dünndarmtransplantation, Sepsis, Morbus Crohn sowie intestinalem Ischämie/Reperfusionsschaden (I/RS) analysiert. Die Bestimmung der phänotypischen und funktionellen Charaktistika der IEL im Rahmen der o. g. Erkrankungen wies auf eine Selektion bestimmter T-Zell Subpopulationen in der Darmschleimhaut hin. Zusätzlich konnte gezeigt werden, daß IEL nicht nur als Effektorzellen zur mukosalen Barrierefunktion beitragen, sondern auch regulierende Funktionen bei weiteren Abwehrmechanismen der Darmschleimhaut, wie z.B. der NOS-2 Expression besitzen. Die Untersuchungen zum intestinalen I/RS zeigten eine Gewebeschädigung nicht nur im Darm sondern auch der Leber nach selektiver intestinaler Ischämie. Dabei konnte in beiden Organen oxidativer Streß als ein Faktor der Gewebeschädigung nachgewiesen werden. Bei der Modulation des I/RS durch Gabe von Zytokinen konnte eine Zunahme des I/RS durch Gabe von IL-10 und eine Abnahme des I/RS durch IL-2 erreicht werden. Der positive Effekt der IL-2 Gabe war von einer verstärkten und verlängerten NOS-2 mRNA Expression sowie einer gesteigerten NO-Freisetzung begleitet. Im Gegensatz dazu fehlte nach IL-10 Gabe die Zunahme der NOS-2 Epxression ebenso wie ein Anstieg der NO-Metabolite im Serum. Die verminderte NO-Produktion könnte somit den negativen Effekt des anti-inflammatorischen IL-10 auf den I/RS erklären. / In this study, the role of intraepithelial lymphocytes (IEL) was analyzed in Graft-versus-Host disease, small bowel transplantation, sepsis and inflammatory bowel disease. Furthermore, the influence of oxidative stress and endogenous protective mechanisms on the development of intestinal ischemia/reperfusion injury was determined. The phenotypic and functional characteristics of IEL in these diseases indicated that only specific T-cell subsets selectively migrate and/or survive in the intestinal mucosa. In addition, it was demonstrated that IEL display several functions in the intestinal barrier system: they are cytolytic effector cells, but do also exert regulatory functions on the expression of mucosal host defense mechanisms such as NOS-2 expression. The investigations on intestinal ischemia / reperfusion injury revealed that selective intestinal ischemia induces tissue injury not only in the intestine, but in the liver as well. In both organs, oxidative stress plays a predominant role in the development of tissue destruction. Modulation of I/RS by administration of cytokines lead to increased tissue damage after IL-10 administration and reduced tissue injury after IL-2 administration. The beneficial effect of IL-2 may have been due to an increased NOS-2 mRNA expression and the subsequently increased NO production. In contrast, IL-10 administration failed to induce an increased NOS-2 mRNA expression or NO production in the intestine and liver.

Made available in DSpace on 2010-04-20T20:20:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-10-08T00:00:00Z / This paper discusses the innovation of Business Models in organizations. A Business Model is the way a company organizes its resources, abilities and relationships, creating value to its customers. In the current environment of increasing dynamism and competitiveness, companies must develop innovative Business Models in order to differentiate themselves from their competitors, and to create sustainable competitive advantages. Companies like Dell, Amazon, Walmart and Starbucks had developed unique Business Models, which explore their own abilities, and anticipate customer's needs. Many examples of innovative Business Models are described in this paper. The innovation process involves creativity and imagination. Innovative Business Models can be developed through a creativity process of generating ideas and transforming the ideas of best potential into new enterprises. This way companies can create conditions to explore the entrepreneurship potential of its employees. The paper analyses a Case Study in the Institute of Technological Research of São Paulo State (IPT). A new Business Model is suggested to develop the company' entrepreneurship capacity. / O trabalho discute a inovação de Modelo de Negócio nas organizações. Um Modelo de Negócio é a maneira como uma empresa organiza seus recursos, competências e relacionamentos, de forma a criar valor para seus clientes. No ambiente atual de dinamismo e competitividade crescentes, passa a ser fundamental que as empresas desenvolvam Modelos de Negócio inovadores, para poderem se diferenciar de seus concorrentes, e criarem vantagens competitivas duradouras. Empresas como Dell, Amazon, Walmart e Starbucks desenvolveram Modelos de Negócio únicos, baseados em suas próprias competências, e que conseguiram antecipar necessidades de seus clientes. Muitos outros exemplos de Modelos de Negócio inovadores são descritos neste trabalho. A inovação é fundamentalmente um processo que envolve criatividade e imaginação. Modelos de Negócio inovadores podem ser desenvolvidos através de processos criativos que envolvem a geração de idéias, e transformação das idéias de maior potencial em novos empreendimentos. Dessa forma, as empresas podem criar condições para explorar o potencial empreendedor de seus empregados. o final do trabalho retrata um Estudo de Caso no Instituto de Pesquisas Tecnológicas do Estado de São Paulo. Um novo Modelo de Negócio é sugerido para desenvolver a capacidade empreendedora do IPT.

Made available in DSpace on 2015-05-14T13:00:09Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1776418 bytes, checksum: 744ac3ac5030bc552fceb05b70d06ca5 (MD5) Previous issue date: 2015-03-02 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Leishmaniasis is one of the neglected diseases. High cost, systemic toxicity, and diminished efficacy due to development of resistance by the parasites has a negative impact on the current treatment options. Thus, the search for a new, effective and safer antileishmanial drug becomes of paramount importance. Compounds derived from natural products may be a better and cheaper source in this regard. This study evaluated the in vitro, in vivo and in silico antileishmanial activity of Spiranthera odoratíssima (Rutaceae) fractions and isolated compounds, using promastigote and amastigote forms of different Leishmania species. J774 A.1 macrophage was used as the parasite host cell for the in vitro assays. Evaluations of cytoxicity, nitric oxide (NO), interleukin-10, interleukin-12, IFN-γ were obtained in vitro and expression of p38 mitogen activated protein kinase (p38 MAPK), NF-κB (p50 and p65) was studied by western blotting.in vivo and in silico analysis were carried out. In vitro experiments showed that the fruit hexanic fraction (Fhf) and its alkaloid skimmianine (Skm) have a significant (P<0·001) effect against L. braziliensis. This anti-L. braziliensis activity of Fhf and Skm was due to increased production of NO and attenuation of IL-10 production in the macrophages in contrast of IL-12 and IFN-γ levels increased at concentrations ranging from 1·6 to 40·0 μg/ml. Fhf and Skm showed expression of p38 and NF-κB, pathways involved in the production of Th1 cytokines and nitric oxide. In vivo testing showed reduction in lesion size in mice infected with L. braziliensis, as well as reduction in parasite burden in linfonode and spleen. The in silico assay demonstrated significant interaction between Skm and amino acid residues of NOS2.Skm is thus a promising drug candidate for L. braziliensis due to its potent immunomodulatory activity. / A leishmaniose é uma doença negligenciada cujo tratamento disponibilizado está associado a uma série de efeitos tóxicos, alto custo e diminuição da eficácia terapêutica devido ao aumento da resistência pelos parasitas. Assim, a pesquisa de novas drogas mais eficazes e seguras torna-se de grande importância. Compostos derivados de produtos naturais pode ser uma fonte mais eficaz e econômica para o tratamento desta parasitose. Este estudo avaliou a atividade leishmanicida da espécie Spiranthera odoratíssima (Rutaceae) testando suas frações e isolados in vitro, in vivo e in silico utilizando formas promastigota e amastigota de diferentes espécies de Leishmania em macrófagos J774 A.1. Os ensaios in vitro avaliaram citotoxicidade, produção de óxido nítrico (NO), produção de citocinas interleucina 10, interleucina 12 e IFN-γ. A expressão da proteína quinase p38 ativada por mitógeno (p38 MAPK) e NF-κB (p50 e p65) foi avaliada in vitro por western blotting. Os resultados observados in vitro da fração hexânica do fruto (Fhf) e seu alcaloide isolado esquimianina (Skm) demostraram uma significante ação leishmanicida (P<0·001) contra L. braziliensis. Esta ação foi associada ao aumento da produção de óxido nítrico e diminuição de IL-10 em macrófagos assim como aumento da produção de citocinas Th1 como Il-12 e IFNγ para as concentrações estabelecidas entre 1.6 a 40 μg/ml. Fhf e Skm demostraram induzir a expressão de p38 e NFκB, vias estas envolvidas na produção de citocinas Th1 e na indução de óxido nítrico. Os ensaios in vivo demostraram reduzir lesão em camundongos Swiss infectados com L. braziliensis, assim como foi reduzido à carga parasitária em linfonodos e baço destes animais. O ensaio in silico demonstrou interação significativa entre Skm e resíduos de aminoácidos de NOS-II. Estes resultados em conjunto sugerem que o alcaloide esquimianina é um candidato promissor contra L. braziliensis devido sua potente atividade imunomoduladora.

L’effet anti-tumoral d'un lipide A, l’OM-174 (partie lipidique des lipopolysaccharides) a été étudié dans un modèle de cancer mammaire chez la souris. In vivo, l’OM-174 augmente la survie de la souris alors qu’in vitro il n'est pas toxique pour les cellules cancéreuses. L’OM-174 se lie au récepteur TLR4 des cellules immunitaires induisant la production de cytokines comme l’IFNγ. In vitro, l’association de cette cytokine au lipide A est cytotoxique. L’objectif de cette thèse est d’en analyser les mécanismes moléculaires. Nous avons montré, aussi bien in vitro qu’in vivo, que la cytotoxicité du lipide A/IFNγ est dépendante du TLR4, du récepteur à l’IFNγ et de l’expression de la NOS II. Nous avons également montré que les espèces radicalaires, NO et anion superoxyde formant le peroxynitrite jouent un rôle crucial dans cette cytotoxicité. L’origine de ces espèces radicalaires se trouve être la NOS II selon un processus de découplage enzymatique. Nous avons également cherché d’autres mécanismes associés pouvant expliquer la cytotoxicité du lipide A/IFNγ. Nous avons ensuite montré que le NO est capable de réagir avec les résidus cystéine de certaines protéines, un processus appelé S-nitrosylation. Une analyse protéomique nous a permis d’identifier au moins une dizaine de protéines qui sont S-nitrosylées dans les cellules cancéreuses mammaires en réponse au lipide A/IFNγ. Nous avons étudié l’impact de cette modification sur la fonction d’une des ces protéines, l’enzyme de conjugaison E2 de l’ubiquitine Ubc13, une protéine impliquée dans la prolifération et la survie cellulaire. Nous avons confirmé la nitrosylation d’Ubc13 et identifié la cystéine 87 comme cible du NO. L’expression d’une forme mutée d’Ubc13 (remplacement de la cystéine 87 par une alanine) inhibe l’auto-ubiquitination de l’enzyme et sa capacité à ubiquitiner une de ses cibles IkBα. Nous avons montré que la S-nitrosylation d’Ubc13 induit sa migration vers le noyau et rend les cellules plus sensibles à l’effet cytotoxique du lipide A/IFNγ. En résumé, nos résultats révèlent un rôle majeur et insoupçonné de la NOS II et du NO dans l’effet antitumoral du lipide A OM-174 dans un modèle de cancer mammaire chez la souris ouvrant la voie pour la conception de nouveaux traitements anticancéreux. / The anti -tumor effect of a lipid A, OM -174 (lipid portion of LPS) was studied in a model of breast cancer in mice. In vivo, OM- 174 increases the survival of mice whereas in vitro it is not toxic to cancer cells. OM -174 binds to TLR4 immune cells inducing the production of cytokines such as IFNγ. In vitro, the combination of IFNγ to lipid A is cytotoxic. The objective of this thesis is to analyze those molecular mechanisms. We have shown both in vitro and in vivo that the cytotoxicity of the lipid A / IFNγ is dependent of TLR4 and of the receptor for IFNγ, and the NOS II expression. We also showed that the radical species, NO and superoxide anion forming peroxynitrite play a crucial role in this cytotoxicity. The origin of these radical species is being NOS II enzyme in a process of decoupling. We also looked for other associated mechanisms that may explain the cytotoxicity of lipid A / IFNγ. We then showed that NO is able to react with the cysteine residues of certain proteins, a process called S- nitrosylation. A proteomic analysis allowed us to identify at least a dozen proteins that are S- nitrosylated in breast cancer cells in response to lipid A / IFNγ. We studied the impact of this change on the basis of one of these proteins, the E2 conjugating enzyme UBC13 ubiquitin, a protein involved in cell proliferation and survival. We confirmed the UBC13 nitrosylation on cysteine 87 and identified as a target of NO. The expression of a mutant of UBC13 (replacement of cysteine 87 with alanine) forms inhibits the auto-ubiquitination of the enzyme and its ability to ubiquitinylated one of its targets IkBα. We have shown that S- nitrosylation of UBC13 induced its translocation to the nucleus and greater sensitivity to the cytotoxic effect of lipid A / IFNγ in cells. In summary, our results reveal an important and unexpected role of NOS II and NO in the antitumor effect of lipid A OM- 174 in a model of breast cancer in mice opening the way for the development of new cancer treatments.

Syftet med studien var att generera en förståelse för hur polisens NOS-projekt kan verka brottsförebyggande. Vi undersökte även hundägare som är delaktiga i projektet och deras inställning till att uppmärksamma och förebygga brott. Studien grundar sig i teorin om neighborhood watch, med delar av teorin om social kontroll samt rutinaktivtetsteorin. Utifrån sex semistrukturerade intervjuer med deltagare från Nospatrullen fick vi en förståelse för hur NOS-projektet fungerar brottspreventivt genom hundägares förmåga att uppmärksamma avvikande aktiviteter i sitt lokalområde. Resultatet visade att samtliga intervjupersoner hade en positiv inställning till NOS-projektet vilket vi anser kan ha bidragit till projektets möjlighet till att förebygga brott. / The aim of this study was to form a understanding for how a project by the police, the Nos-project, may work to prevent crime. We also examined dog owners that are involved in the NOS-project and their attitude towards crime prevention. The study is based on the theory of neighborhood watch and features the theory of social control and the theory of routine activity. Through six semi structured interviews we learned how the NOS-project may prevent crime through dog owners’ observations of unusual activity in their district. The results also show how all our participants had a positive attitude towards the NOSproject which we regard likely contributes to the projects ability to prevent crime.

Nature of Science (NOS) har varit i utbildares och forskares blickfång länge. Elevers kunskaper är av intresse att analysera eftersom det kan bidra till en utveckling av lärares undervisning och förståelse av lärandeprocesser i no-ämnena. Syftet med studien var att analysera hur elever i årskurs 4 ser på vad som är en vetenskaplig undersökning och ett experiment. Den data som används i studien består av redan insamlade frågeformulär från 2019. Studiens data analyseras genom en innehållsanalys. Resultatet visar att elevers kunskaper om undersökningar och experiment är varierande. Eleverna ger exempel på att undersökningar kan innefatta att antingen titta först och sedan ställa en fråga eller tvärtom och att ett experiment kan innebära att blanda eller att prova sig fram. Lärare kan utveckla sin undervisning genom att exempelvis använda elevnära innehåll som eleven känner igen och kan relatera till eller använda modeller och metoder för att visa på systematik och underbyggda slutsatser för att bidra till en högre förståelse om naturvetenskaplig kunskap hos eleverna.

Die Inzidenz des Diabetes mellitus (DM) nimmt weltweit jährlich zu und erlangt somit große Bedeutung für die Entwicklung der globalen Gesundheit. Die WHO rechnet bis zum Jahr 2030 mit ungefähr 366 Millionen erwachsenen Diabetikern. Es ist bekannt, dass Männer mit Diabetes mellitus Typ 1 (DMI) und 2 (DMII) häufiger an Subfertilität leiden, wobei dies möglicherweise auf erhöhte Apoptoseraten und vermehrte DNA-Fragmentierungen auf zellulärer Ebene zurückzuführen ist. Die Bedeutung der ROS als Regulatoren von physiologischen und pathologischen Signaltransduktionswegen ist bekannt. Demzufolge könnte die Aktivität der Stickstoffmonoxid-Synthetase (NOS) in diesem Zusammenhang eine Bedeutung haben. Das Ziel der vorliegenden Untersuchungen war es, die Auswirkungen von Apoptose und DNA-Fragmentierungen sowie die Bedeutung der NOS im Zusammenhang mit der Fertilitätsfähigkeit von Spermienzellen von DMI und DMII Patienten zu erfassen und damit erste Erklärungsansätze zur Pathophysiologie der diabetesassoziierten Subfertilität zu liefern. Samenproben von Normalspendern und Diabetikern wurden durch Dichtegradientenzentrifugation in Subpopulationen separiert und mittels fluoreszenzbasierten Assays zur Analyse von apoptoseassoziierten Parametern wie dem Zusammenbruch des mitochondrialen Membranpotentials (MMP), Aktivierung von Caspase-3 (CP3), DNA-Fragmentierungen und reaktiven Sauerstoffspezies (ROS) im Flowzytometer (FACS) untersucht. Die Ergebnisse zeigen eine signifikante Erhöhung von Apoptosemarkern (gestörtes MMP, aktivierte CP3), ROS und DNA-Fragmentationsraten in Spermien von DMI und DMII Patienten im Vergleich zu gesunden Normalspendern. Der Effekt ist bei DMII Patienten verstärkt ausgeprägt. Alle gemessenen Parameter korrelieren umgekehrt mit dem Fertilitätspotential der Spermien, gemessen anhand etablierter Spermiogramm-Analysen, womit ein möglicher Erklärungsmechanismus für die Subfertilität bei Diabetikern geliefert werden kann.

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

Intimal hyperplasia (IH) is defined as the abnormal migration and proliferation of smooth muscle cells with associated deposition of extracellular matrix in the intimal layer. It is a natural response to endovascular injury induced by procedures such as angioplasty, stent implantation, or atherectomy. Research on the molecular pathways and mediators has led to the discovery of a variety of substances aimed to interrupt or attenuate IH. Heparin, low-molecular-weight heparin, aspirin, corticoids, angiotensin-converting enzyme inhibitors, cyclosporin, vascular endothelial growth factor (VEGF) and other agents have been investigated. However, none of these agents has been used with marked success at the clinical level. Therapeutic angiogenesis studies have demonstrated the potential of heparin binding angiogenic growth factors such as VEGF and basic fibroblast growth factor (bFGF/FGF-2) to treat ischemic heart diseases. Studies on endothelial nitric oxide synthase (eNOS) gene transfer in vivo showed attenuated IH caused by constitutive generation of nitric oxide (NO) via the NOS pathway. FGF-2 increased VEGF mRNA levels in single-cultures of rabbit smooth muscle cells (SMC) and also promoted NO production from endothelial cells (EC). Therefore, we hypothesize that FGF-2 mediates SMC inhibition through the NOS pathway. In order to elucidate the influence of these growth factors, we employed an appropriate SMC-EC co-culture system.Studies on SMC-EC interactions have been established in various in vitro co-culture systems. However, there exist only few co-culture systems in which the structure of a vessel wall is imitated. A direct co-culture model was used in this study to determine the effect of growth factors on the SMC and EC proliferation. In the following study we investigate the effects of VEGF, FGF-2 and FGF-2+VEGF on porcine aorta smooth muscle and endothelial cells. Addition of the higher concentrations (>10 ng/ml) of FGF-2 to the SMC-EC direct co-culture greatly reduced smooth muscle cell numbers and cell cycle S-phase, as judged by propidium iodide DNA analysis using flow cytometry. We also observed that coadministration of FGF-2 with VEGF did not show any difference on SMC proliferation compared to control. These data demonstrate the potent regulatory capabilities of FGF-2 on smooth muscle cell inhibition. Nitric oxide which is generated by the enzyme NOS is hindered by the addition of NOS inhibitor, NG-Methyl-L-arginine acetate (L-NMMA). Utilizing L-NMMA we found that FGF-2 mediated smooth muscle cell inhibition does not follow the NOS pathway. This study is intended to understand the interactions of combination of therapeutic growth factors on vascular cells. The current study is a first step towards an overall goal of setting up an in vivo porcine model for clinical treatment of IH using FGF-2.