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Diabetic embryopathy is a major complication of pregnant women with type I diabetes. Immune defects in the pathogenesis of diabetic embryopathy have been suggested. We hypothesized that activated immune system can counteract diabetic effect and result in prevention of diabetic embryopathy. Diabetes was induced in pregnant ICR mice by streptozocin injection. Three different techniques of maternal immune stimulation, complete Freund's adjuvant (CFA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFN-g), were used to stimulate the maternal immune system. Approximately 50% of fetuses from hyperglycemic (>27 mM/L) dams were malformed, with neural tube defects predominating. Maternal immune stimulation during the time of normoglycemia, i.e. prior to onset of hyperglycemia, was necessary for reducing teratogenic effects associated with hyperglycemia. The immune-stimulated diabetic mice then produced significantly lower numbers of malformed fetuses: CFA 20.9%, GM-CSF 23.3%, IFN-g 13.9%. A gene microarray was then used to examine a selected panel of placental and splenic genes. We hypothesized that a shared profile of placental or splenic gene expression changes may correlate to the reduced birth defect outcome induced by the different immune stimulation procedures. Diabetes did not cause significant changes in placenta or spleen gene expression profile. In placenta, CFA and GM-CSF changed placental gene expression relative to control or diabetes, but differentially affected such genes relative to each other; further, IFN-g did not affect gene expression relative to control or diabetes. Thus no common pattern of improved placental cytokine, cell-cycle, apoptotic, transcription factor, or other gene expression was identified in the immune-stimulated mice. In spleen, all 3 immune activators produced a common altered gene expression profile. The overall gene expression profile after all immune stimulation procedures suggested increased splenocyte activity and cytokine production. The cytokine GM-CSF, in particular, was up-regulated in splenic leukocytes. This cytokine has previously been associated with reduced cleft palate in urethane-exposed mice after immune stimulation, and with reduced limb malformations in cyclophosphamide-treated mice after intra-uterine administration. In contrast, the TGF-beta3 gene was down-regulated in immune-stimulated diabetic mice. This gene was up-regulated in urethane-exposed mice, an effect that may be associated with reduced cleft palate. Thus unlike urethane, TGF-beta3 gene expression did not show a relationship with reduced diabetes-induced birth defects. Taken together, these data prove our hypotheses and suggest that mechanistically diverse forms of immune activation result in protection against diabetes-related teratogenesis, but only if given prior to onset of hyperglycemia. Such immune stimulation in mice may act through systemic immune organs, i.e. spleen, over-riding adverse effects of diabetes on development. / Ph. D.

<p dir="ltr">Object tracking in cislunar space has become an area of interest within many communities where cislunar space domain awareness (SDA) is critical to operations. Due to the influence of both the Earth and Moon on objects in this domain, the classical two body problem does not accurately describe the dynamics of the state. Legacy tracking capabilities fall short in providing accurate state estimates due to the large volume of space and the highly non-linear dynamics involved. In order to advance SDA in cislunar space, tracking capabilities must be updated for this domain. </p><p dir="ltr">Both the Extended Kalman Filter (EKF) and Gaussian Mixture Extended Kalman Filter (GM-EKF) are used for orbit determination in this thesis along side the Circular Restricted Three Body Problem (CR3BP) to model the non-linear dynamics. The filters are utilized to determine the best estimate of the state as well as its covariance. The two filter's performances are compared to highlight areas in which the assumptions surrounding the EKF are violated resulting in failed tracking, as well as to highlight the power of the GM-EKF for non-linear systems using splitting and merging techniques. </p><p dir="ltr">This thesis presents single and multiple object tracking of objects in a multitude of cislunar orbits using a Moon ground-based sensor. Multiple object tracking is accomplished using a novel Lyapunov-based scheduler in order to reduce the total system uncertainty. The environment is modeled to include exclusion zones which preclude measurements. These zones consist of conjunction from the Earth and Sun, brightness constraints, and camera field of regard (FOR). When measurements are unavailable the uncertainty in the state estimation rises significantly.</p><p dir="ltr">An investigation of varied sensor placements and Sun-Earth-Moon geometries provides results to inform locations and trends which are able to confidently track both single and multiple objects in cislunar orbits. </p>

<p>Disertacija je posvećena re&scaron;avanju jednačina distributivnosti gde&nbsp;nepoznate funkcije pripadaju nekim poznatim klasama operacija agregacije&nbsp;i primeni dobijenih re&scaron;enja u teoriji korisnosti. Dobijeni rezultati se generalno mogu podeliti u tri grupe. Prvu grupu čine rezultati iz Glave 2 dobijeni re&scaron;avanjem jednačina distributivnosti između GM-operacija agregacije i&nbsp;oslabljenih uninormi, GM-operacija agregacije i oslabljenih nulanormi, kao i&nbsp;GM-operacija agregacije i operacija agregacije bez neutralnog i absorbujućeg&nbsp;elementa. Druga grupa rezultata, takođe iz Glave 2, je dobijena re&scaron;avanjem&nbsp;jednačina uslovne (oslabljene) distributivnosi neprekidne nulanorme u odnosu&nbsp;na neprekidnu t-konormu, i neprekidne nulanonorme u odnosu na uninorme iz&nbsp;<br />klasa U_min &cup;U_max. Treća grupa rezultata (Glava 3) je proistekla iz primene dobijenih rezultata o uslovoj distributivnosti nulanorme u odnosu na t-konormu&nbsp;u teoriji korisnosti.</p> / <p>This dissertation is devoted to solving distributivity equations involving some well-known classes of aggregation operators, and application&nbsp;the obtained results to utility theory. In general, the obtained results can&nbsp;be divided into three groups. The first group are results from Chapter 2 obtained by solving distributivity equations between GM-aggregation operators&nbsp;and relaxed nullnorm, GM-aggregation operators and relaxed uninorms, as&nbsp;well as GM-aggregation operators and aggregation operators without neutral&nbsp;and absorbing element. The second group are results, also from Chapter 2,&nbsp;obtained by solving conditional (relaxed) distributivity of continuous nullnorm with respect to &nbsp;continuous t-conorm, as well as continuous nullnorm&nbsp;with respect to uninorms from the classes U_min &cup; U_max. The third group are&nbsp;results (Chapter 3) arising from the application results on conditional distributivity of nullnorm with respect to t-conorm in utility theory.</p>

Les lésions spinales conduisent à des altérations majeures des fonctions sensorimotrices. Les récupérations fonctionnelles consécutives à ces atteintes sont très limitées, notamment en raison des capacités réduites de réparation des tissus endommagés dans le SNC. En outre, ces récupérations dépendent notamment de plusieurs processus cellulaires tels que l'activation astrogliale qui conduit à la formation de la cicatrice gliale, ou encore l'inflammation dont les cellules microgliales et les mastocytes sont les effecteurs les plus précoces. Cette inflammation est connue pour exacerber les dommages tissulaires et restreindre les possibilités de récupération. Cependant, des études récentes chez l'animal et chez l'Homme montrent que l'inflammation pourrait également avoir des effets favorisant les processus de récupération. Le but de cette thèse était de mieux comprendre les liens qui existent entre neuroinflammation, neuroplasticité et récupérations fonctionnelles après lésion spinale. L’objectif expérimental visait à examiner les réactivités microgliales, mastocytaires et astrocytaires post-lésionnelles, en parallèle avec des restaurations fonctionnelles. Dans ce contexte nous nous sommes plus particulièrement intéressés à l'influence d'une cytokine pro-inflammatoire, le Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) sur ces processus inflammatoires et la plasticité fonctionnelle après une hémisection C4-C5 chez le rat adulte. L’ensemble de nos travaux suggère que le GM-CSF pourrait agir par l’intermédiaire de plusieurs événements cellulaires et moléculaires, en favorisant des phénomènes de plasticité adaptatifs et la récupération partielle de fonctions altérées. / Spinal cord injuries are mostly of traumatic origin and result in major sensorimotor deficits. Postlesion functional recovery is limited, especially because of the reduced capacity of repairing damaged tissues. Moreover, this recovery depends specifically on several cellular processes such as astroglial activation conducting to glial scar formation, or inflammation for which microglial and mast cells are the earliest effectors. This inflammation is known to exacerbate tissue damages and restrain the capacity to recover. However, recent studies in animals and humans show that inflammation may also have beneficial aeffects on recovery processes. The studies conducted during my doctoral research were intended to better understand the links between neuroinflammation, neuroplasticity and functional recovery following spinal cord injury. We aimed at examining microglial, mast cells and astroglial reactivities after the injury, in relation with functional recovery of somatosensory and motor functions. In this context, we were particularly interested in the influence of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) on inflammatory and plasticity mechanisms after a C4-C5 hemisection in the adult rat. Our doctoral research suggests that GM-CSF could act through several cellular and molecular events promoting adaptive plasticity phenomena underlying partial recovery of impaired functions.

Made available in DSpace on 2014-07-29T15:25:12Z (GMT). No. of bitstreams: 1 Dissertacao defendida e aprovada Narliane.pdf: 743771 bytes, checksum: 94853db1dabcb5389c9b89d2c92f21ac (MD5) Previous issue date: 2012-02-27 / The current panorama experienced by society, from the perspective of genetic improvement, especially the vegetables, attracts the questioning about application of legal principle of precaution, this due to scientific uncertainty of possible damage that they may trigger on long term. Thus, due to changes in environmental conditions and effect of necessary human health by use of biotechnology has brought the principal object of this work is to analyze the precautionary principle and the process of releasing plants genetically altered and improved, in particular of cultivars and of transgenic crops under the legal perspective. Because two processes were analyzed for release of genetically modified organisms, which are the "rice LL62" Bayer and the bean "GM Embrapa 5.1" of Embrapa, being that the first is an application of experiment and the second a request for marketing. Noting that both the studies of genetic improvement and the protection of the environment are guarded by the Federal Constitution of 1988. Also, due the questions in the legal field study examined whether the Commission's release process Tecnic National de Biossegurança CTNBio follows the fulfilment of the minimum specifications required by the precautionary principle and whether they are sufficient to ensure food safety and to avoid possible irreversible degradation of the environment. Social and legal context, remaining evidenced differences polemics in relation to the said applications for the release and the precautionary principle, which encounters a single technological challenge to be respected. Thus, the Judiciary, under the Constitutional vision, the environment and administrative nature, should grant the scientific advancement with the fulfilment of minimum requirements for these releases or require the fulfilment of bureaucracy hailed by society? / O atual panorama vivenciado pela sociedade, sob a ótica do melhoramento genético, em especial a dos vegetais, atrai o questionamento sobre aplicação do Princípio Jurídico da Precaução, isto devido à incerteza científica dos possíveis danos que estes podem deflagrar em longo prazo. Assim, devido às alterações nas condições do meio ambiente e por efeito necessário na saúde do ser humano pelo uso da Biotecnologia trouxe o principal objeto do presente trabalho, que é analisar o Princípio da Precaução e o processo de liberação de vegetais melhorados e alterados geneticamente, em específico dos Cultivares e dos Transgênicos sob a ótica jurídica. Porquanto, foram analisados dois processos de liberação dos Organismos Geneticamente Modificados, que são o arroz LL62 da Bayer e o feijão GM Embrapa 5.1 da Embrapa, sendo que o primeiro um pedido de experimento e o segundo um pedido de comercialização. Observando que tanto os estudos do melhoramento genético quanto a proteção do meio ambiente são resguardados pela Constituição Federal de 1988. Igualmente, devidos os questionamentos no campo jurídico o estudo analisou se o processo de liberação utilizado pela Comissão Técnica Nacional de Biossegurança CTNBio segue o cumprimento dos requisitos mínimos exigidos pelo Princípio da Precaução e se são suficientes para garantir a segurança alimentar e para evitar possíveis degradação irreversíveis ao meio ambiente. Do contexto social e legal, restam evidenciadas, as divergências polêmicas em relação aos referidos pedidos de liberação e o Princípio da Precaução, que encontra um desafio tecnológico único para conseguir ser respeitado. Destarte, o Poder Judiciário, sob a visão Constitucional, do Meio Ambiente e Administrativo, deve conceder o avanço científico com o cumprimento dos requisitos mínimos estabelecidos para estas liberações ou exigir o cumprimento da burocracia aclamada pela sociedade?

Afin de réaliser un appareil innovant pour la mesure de gaz polluants, la société SVS@CAP s’est associée avec le laboratoire de physique corpusculaire en 2009 pour la création du projet EREBUS. Ce projet a pour but la réalisation d’un ensemble de dispositifs sans fil permettant d’effectuer une surveillance de la concentration de gaz polluants. L’autonomie et la compacité d’un tel dispositif étant essentielles, la problématique principale porte sur la réduction de la consommation. A partir d’une première étude menée sur les différentes technologies existantes, les capteurs électrochimiques ont été identifiés comme les moins consommateurs d’énergie. Pour chacun des gaz cibles, un modèle électrique du capteur associé a été déterminé. A partir de ces modèles, une architecture dédiée et épurée a pu être déduite. Pour atteindre et même dépasser les objectifs de consommation, les efforts ont aussi été portés sur un dimensionnement avec la méthode gm/id. La réalisation de cette électronique intégrée a permis d’atteindre une consommation de l’ordre du μW pour chaque voie de mesure. Enfin, pour compléter la chaîne de lecture, plusieurs architectures de convertisseurs ont été étudiées et réalisées pour fonctionner à des fréquences déchantillonnage proches du Hz. Les consommations obtenues pour les convertisseurs sont limitées avec comme ordre de grandeur la centaine de nW. / In order to realize an innovative product for pollutants in the atmosphere, SVS@CAP company started in 2009 the EUREBUS project in collaboration with the "Laboratoire de Physique Corpusculaire". The aim of this project is to design a wireless equipement to measure gas concentrations. The key issues of this project are concerning the autonomy as well as the small size of the product. In consequence an integrated and low power electronics remains essential. From a first study of the existing technologies to detect gaz concentrations, electrochemical sensors were selected because of their low power consumption. For each of the target gas, an electrical model was determined. From those models, a specific architecture was designed. A special effort was made on the energy consumption thanks to the use of the gm/id methodology which was necessary to achieve and exceed the specifications. The final order of the power consumption of the front-end developped and realized is around the μW. Finally, in order to complete the chain of acquisition, some architectures of analog to digital converter were studied, developped and realized with sample frequencies close to the Hz. The power consumptions of the converters developped are limited to the order of the hundreds of nW.

No description available.

Charakterisierung des Zytokinprofils in Erwachsenen mit einer latenten oder aktiven Tuberkulose in einem hoch endemischen Gebiet Die Tuberkulose (TB) stellt mit rund 2 Milliarden Infizierten weltweit ein globales gesundheitliches Problem dar. Während die große Mehrheit der infizierten Personen in der Lage sind die Krankheit zu kontrollieren, entwickelt sich bei ungefähr 10 % die aktive Form der TB aus. Der zugrunde liegende immunologische Prozess für diese Verteilung ist bis heute nicht bekannt und im Fokus dieser Arbeit. Das adaptive Immunsystem spielt eine entscheidende Rolle in der Immunabwehr gegen Mycobacterium tuberculosis (M. tuberculosis), dem Erreger der TB. Hierbei sind besonders CD4+ T-Zellen für die erfolgreiche Eingrenzung der Erkrankung verantwortlich. Im Vorfeld konnte bereits mehrmals eine Assoziation zwischen polyfunktionalen CD4+ T-Zellen und einem Schutz gegen verschiedenste Krankheitserreger gezeigt werden. Im Rahmen dieser Doktorarbeit wird versucht die Frage zu beantworten, ob eine erhöhte Frequenz von polyfunktionalen CD4+ T-Zellen auch gegen die Ausbildung einer aktiven TB schützen kann. Zur Bearbeitung dieser Fragestellung wurde das TH1 Zytokinprofil von Patienten mit aktiver TB untersucht und mit dem von gesunden latent infizierten Probanden (LTBI) verglichen. Desweiteren wurden die TB Patienten während der antimikrobiellen Therapie begleitet um Änderungen im Zytokinprofil von CD4+ T-Zellen beobachten zu können. Im Rahmen dieser Arbeit wurde zum ersten Mal die simultane Expression der vier TH1 Zytokine IFNg, TNFa, IL-2 und GM-CSF mit Hilfe der multifarben Durchflusszytometrie untersucht. Nach antigenspezifischer Stimulation konnten sowohl in unbehandelten und behandelten Patienten mit aktiver TB ein großer Anteil an multifunktionale Gedächtnis-T-Zellen nachgewiesen werden, die alle vier Zytokine gleichzeitig exprimierten. Bemerkenswerterweise konnte diese Population ebenfalls in LTBI gezeigt werden. Nach den ersten zwei Monaten der Therapie war der Anteil an multifunktionalen T-Zellen signifikant erhöht welches auf einen positiven Einfluss dieser Zellen auf die Behandlung hinweist. Um detaillierte Information über das Expressionspotential von CD4+ T-Zellen zu gewinnen wurden PBMCs mit einem Superantigen inkubiert. Hierbei unterschied sich das Zytokinprofil zwischen den beiden Studiengruppen signifikant und veränderte sich ebenfalls unter Therapie. Während die Expression von IFNg in TB Patienten niedriger war als in LTBI, war die Frequenz von TNFa, IL-2 und GM-CSF-positiver CD4+ T-Zellen signifikant höher in Patienten mit aktiver TB. Zusammenfassend ist zu sagen, dass sowohl in TB Patienten vor und nach Therapie, als auch in LTBI, multifunktionale CD4+ T-Zellen nachgewiesen werden können. Ein Unterschied in der Frequenz konnte dabei nicht festgestellt werden. Daher kann ein Zusammenhang zwischen der Existenz von multifunktionellen CD4+ T-Zellen und einem Schutz gegen eine mögliche Reaktivierung von der latenten zu der aktiven TB nicht beschrieben werden. / Characterization of the cytokine profile in adults with latent and active tuberculosis from a high endemic country Tuberculosis (TB) is a global health problem with ~2 billion infected people worldwide. The vast majority of infected individuals is able to control TB, while only ~10% develop active disease. The immunologic correlates determining the protection against reactivation of the latent form of active TB remain elusive. The adaptive immune system plays an important role in the response against Mycobacterium tuberculosis (M. tuberculosis), especially CD4+ T cells are crucial for efficient containment of the pathogen. Since polyfunctional CD4+ T cells have been associated with protection against various pathogens, the question was raised if higher frequencies of polyfunctional CD4+ T cells can be linked to protection against reactivation of active TB. To address this the TH1 T cell cytokine profile of active TB patients was analyzed and compared with healthy latently infected individuals (LTBI). Furthermore TB patients were followed up under anti-microbial therapy to monitor changes in the cytokine pattern expressed by CD4+ T cells. Hereby, for the first time, the simultaneous expression of four TH1 cytokines, IFNg, TNFa, IL-2 and GM-CSF, was investigated using multi color flow cytometry. After antigen-specific stimulation multifunctional memory T cells (CD45RO+) co-expressing IFNg, TNFa, IL-2 and GM-CSF were strongly represented in both treated and untreated TB patients. Interestingly, this proportion of polyfunctional memory T cells was also found in LTBI. After the first two months of drug treatment the proportion of antigen-specific polyfunctional T cells was significantly increased, indicating a positive impact of these cells during therapy. To gain detailed information about the potential of CD4+ T cells to produce cytokines we incubated PBMCs with a superantigen. In this case the profile was significantly different between these two groups and it changed during therapy. While the expression of IFNg was significantly lower in CD4+ T cell of TB patients in comparison to LTBI, the expression of TNFa, IL2 and GM-CSF showed significant higher frequencies in memory T cells of TB patients. To conclude, upon antigen stimulation, polyfunctional memory T cells are found in TB patients pre- and post therapy as well as in LTBI. A difference in the frequency between active TB patients and LTBI could not be detected and therefore a correlation with protection against reactivation from the latent to the active form of TB cannot be drawn.

Il a été montré que les fonctions et la prolongation de la survie cellulaire des neutrophiles humains par les médiateurs de l'inflammation tendent à diminuer avec le vieillissement. Les protéines tyrosines phosphatase (PTPs), comme SHP-1, sont un des mécanismes qui permettent de moduler à la baisse et de terminer ces fonctions inflammatoires qui sont modulées par l'action des cytokines. Nous avons étudié le rôle des PTPs dans l'altération due au vieillissement des fonctions des neutrophiles humains. L'utilisation d'un inhibiteur pharmacologique des PTPs a suggéré une dérégulation de l'activité phosphatasique avec le vieillissement. Cette dérégulation était confirmée aussi dans le cas de l'apoptose mesurée après 18 heures d'incubation. L'activité phosphatasique de SHP-1 purifiée par immunoprécipitation de neutrophiles de sujets jeunes ou âgés stimulés par le GM-CSF est altérée de façon significative après une minute de stimulation chez les sujets âgés. Dans les sujets jeunes SHP-1 est déplacée des radeaux lipidiques après 1 minute de stimulation par le GM-CSF alors que chez les sujets âgés, SHP-1 est présente à tous les temps de stimulation utilisés. Des immunoblots faits avec des anticorps anti-phosphotyrosine et anti-phosphosérine ont montré une augmentation de la phosphorylation en sérine dans les neutrophiles des sujets jeunes après une stimulation au GM-CSF alors que ce n'était pas le cas chez les sujets âgés. Nous avons aussi trouvé des altérations dans l'activation et le recrutement aux radeaux lipidiques de la Src kinase Lyn chez les neutrophiles des sujets âgés. De plus, nous avons démontré que SHP-1 est continuellement recrutée à Lyn chez les sujets âgés alors que cette interaction, qui est observée dans des cellules non stimulées chez les sujets jeunes, est défaite par la stimulation au GM-CSF. En conclusion, les altérations observées dans la modulation de l'activité de SHP-1 par le GM-CSF dans les radeaux lipidiques sont un des facteurs qui contribuent à la diminution des effets du GM-CSF sur les neutrophiles humains avec le vieillissement.