En physique de l’atmosphère, la reconstruction d’une source polluante à partir des mesures de capteurs est une question importante. Elle permet en effet d’affiner les paramètres des modèles de dispersion servant à prévoir la propagation d’un panache de polluant, et donne aussi des informations aux primo-intervenants chargés d’assurer la sécurité des populations. Plusieurs méthodes existent pour estimer les paramètres de la source, mais leur application est coûteuse à cause de la complexité des modèles de dispersion. Toutefois, cette complexité est souvent nécessaire, surtout lorsqu’il s’agit de traiter des cas urbains où la présence d’obstacles et la météorologie instationnaire imposent un niveau de précision important. Il est aussi vital de tenir compte des différents facteurs d’incertitude, sur les observations et les estimations. Les travaux menés dans le cadre de cette thèse ont pour objectif de développer une méthodologie basée sur l’inférence bayésienne adaptative couplée aux méthodes de Monte Carlo pour résoudre le problème d’estimation du terme source. Pour cela, nous exposons d’abord le contexte scientifique du problème et établissons un état de l’art. Nous détaillons ensuite les formulations utilisées dans le cadre bayésien, plus particulièrement pour les algorithmes d’échantillonnage d’importance adaptatifs. Le troisième chapitre présente une application de l’algorithme AMIS dans un cadre expérimental, afin d’exposer la chaîne de calcul utilisée pour l’estimation de la source. Enfin, le quatrième chapitre se concentre sur une amélioration du traitement des calculs de dispersion, entraînant un gain important de temps de calcul à la fois en milieu rural et urbain. / In atmospheric physics, reconstructing a pollution source is a challenging but important question : it provides better input parameters to dispersion models, and gives useful information to first-responder teams in case of an accidental toxic release.Various methods already exist, but using them requires an important amount of computational resources, especially as the accuracy of the dispersion model increases. A minimal degree of precision for these models remains necessary, particularly in urban scenarios where the presence of obstacles and the unstationary meteorology have to be taken into account. One has also to account for all factors of uncertainty, from the observations and for the estimation. The topic of this thesis is the construction of a source term estimation method based on adaptive Bayesian inference and Monte Carlo methods. First, we describe the context of the problem and the existing methods. Next, we go into more details on the Bayesian formulation, focusing on adaptive importance sampling methods, especially on the AMIS algorithm. The third chapter presents an application of the AMIS to an experimental case study, and illustrates the mechanisms behind the estimation process that provides the source parameters’ posterior density. Finally, the fourth chapter underlines an improvement of how the dispersion computations can be processed, thus allowing a considerable gain in computation time, and giving room for using a more complex dispersion model on both rural and urban use cases.

Cyclooxygenases (COXs) are of important therapeutic value as they are the target site of aspirin-like drugs. Here I report nine new COX-1 splice variants in chapter 1, which I characterized with regard to heme-binding and other properties. Inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) are co-inducible in many tissues following mitogenic and proinflammatory stimulation. In chapter 2, I investigate the physical and enzymatic properties of human COX-2 and iNOS and demonstrate that, despite reports to the contrary by another laboratory, they do not interact. The only reported COX-1 splice variant to exhibit cyclooxygenase activity has been isolated from dog brain and is termed COX-3. It contains an in-frame insertion of intron 1. However the existence of human COX-3 remains questionable since intron 1 is out of frame. Two putative in-frame human COX-3 isozymes, COX-1b2 and COX-1b3, (herein designated as COX-3-72 and COX-3-50) have been reported in the literature, but only one of them, COX-3-72, has been characterized. In chapter 3, COX-3-50 and COX-3-72 are reported to be over-expressed and determined to be active cyclooxygenases. COX-3-72 and, to a greater extent, COX-3-50, were stimulated by rofecoxib at physiological concentrations. A similar rofecoxib-stimulated COX activity is observed in quiescent A549 cells. Immunoblot and immunoprecipitation analysis suggest that human platelet and potentially A549 cells, contain a COX-3-50 like protein. Lonicera japonica is used as an anti-inflammatory treatment in traditional Chinese medicine. Its working mechanism is not well known. In chapter 4, I report that extracts from this herb inhibit COX-2 by three mechanisms: direct inhibition, transcriptional and post-transcriptional down regulation. COX-1 and COX-2 are similar to each other in their crystallographic structures. One of the most striking differences is that there are eight amino acids immediately following the signal peptide in COX-1 which are not found in COX-2. The function of this sequence is unknown. In chapter 5, I found that deletion of these amino acids decreased COX-1 Vmax by approximately 4-fold, but had little effect on other properties of the enzyme. Selecting bacteria transformed with recombinant plasmids is a laborious step in gene cloning experiments. This selection process is even more tedious when large numbers of clones need to be screened. In appendix I, I describe an ultra fast plasmid screening method. This new method was frequently used in the experiments performed in chapters 2-6.

Thesis (M Med (Family Medicine) -- University of Limpopo, 2011. / Introduction The burden of type 2 diabetes mellitus continues to rise and constitutes a real threat especially in the developing world. As for most non-communicable diseases, change of behavior and adoption of healthy lifestyle habits help to prevent and slow down the increase of type 2 diabetes mellitus. Aim of the Study To establish the knowledge, attitudes and practices regarding lifestyle modifications among type 2 diabetic patients attending the diabetic clinic at Mamelodi hospital. Methods: This cross sectional study describes the knowledge, attitudes and practices regarding lifestyle modifications (KAP) among 217 type 2 diabetes mellitus patients attending Mamelodi Hospital, Pretoria, Republic of South Africa. A face-to-face interview using a structured questionnaire was carried out for data collection. Socio-demographic characteristics of the participants and anthropometric measurements were obtained and the body mass index (8MI) of participants were determined. The Knowledge, attitude and practice of participants were assessed. 2 Results: Majority of participants were female 176(81.1 %), while male were 41 (18.9%). This amounted to a female to male ratio of 4:1. Most participants were in the age group 51-60 years 93(42.9%). Majority of them had low level of education 108(49.5%) and low income 206(94.9%). Majority of participants were obese 153(71 %) with more female diabetic patients being obese 120 (78.4%) than male 33 (21.6%). 15 participants (14 females and 1 male) were morbidly obese (BMI~40kg/m2). 108 participants (49.5%) did not have a formal education. No respondent had good knowledge and 92.6% of respondents had poor knowledge of the benefits of exercise, weight loss and healthy diet. Majority of respondents (97.7%) had bad practices in relation to lifestyle modifications. Nevertheless, majority of them (84.3%) had positive attitudes toward lifestyle modifications. Significant positive correlation (r= 0.170, p=0.012) was found between the global knowledge level and attitude level alone, whereas there was no significant correlation found between the global knowledge level and practice level as well as the attitude level and practice level. Conclusion: In conclusion, despite positive attitudes of participants toward healthy lifestyle habits, the knowledge and practices regarding lifestyle modifications among type 2 diabetes mellitus patients attending Mamelodi Hospital were generally low. Nevertheless the positive attitudes of participants should be encouraged and the implementation of a lifestyle intervention program will help improve the knowledge and practices of type 2 diabetes mellitus patients attending Mamelodi Hospital for the better management and control of this current pandemic of type 2 diabetes mellitus.

The Christian congregation in Corinth found Paul’s “weak” presentation of the gospel and his approach to ministry to be scandalous. Recently arrived “apostles” reinforced and accentuated attitudes the congregation had already imbibed from contemporary Corinthian culture. As a result many in the congregation were less than satisfied with Paul’s manner of speech, his apparent lack of “charismatic” qualities, his refusal to accept money from them, his lack of commendatory letters, and his lifestyle that was characterised by suffering, affliction, opposition and weakness. However, Paul’s criteria for evaluating ministry, and by implication God’s criteria, were significantly different from those of the Corinthian congregation. Key verses such as 2 Cor 1:9; 3:5; 4:7; 6:7; 12:9 and 13:4 indicate that Paul maintained that Christian life and ministry generally, and apostolic ministry in particular, must be carried out through divine power, not human power. His apostolic ministry was valid because it was exercised as God’s representative, in God’s presence (2:17), with God as judge (5:10) and as a result of God’s mercy (4:1), not as a result of his own power, authority, eloquence or charismatic presence. The theological underpinning for Paul’s approach to ministry is found in 13:4 where Christ who “was crucified as a result of weakness, but lives as a result of God’s power” is the model for Paul who “shares in his weakness”, but in ministry to the Corinthians, also “lives as a result of God’s power”. Paul’s model for ministry was one of dependence on God. This is most clearly demonstrated in the “affliction” he experienced in Asia where he despaired of life itself, but in the process learned to rely on “God who raises the dead”. Thus his suffering, weakness and affliction, far from being disqualifiers for ministry, were in fact, demonstrations of his authenticity as a minister whose competency came from God and not from himself (3:6).

Duisburg, Essen, Univ., Diss., 2006 / Dateien in unterschiedlichen Formaten

A significant number of long-term climate change simulations are to be carried out in the Integrated Framework of the MIT Global Change Joint Program. Since Global Circulation Models (GCMs) require an enormous amount of computer time, the two-dimensional statistical-dynamic model developed by Stone and Yao was chosen to be used for the initial stage of the Joint Program. At MIT, the model has been modified to make it more suitable for the purposes of the Joint Program, including developing a new scheme for a surface flux calculation. A number of simulations with the modified version of the model have been performed in which a few schemes for cloud and ocean heat transport calculation have been tested. Comparisons of the results of the present climate simulations with observational data show that the model reasonably reproduces main features of zonally averaged atmospheric circulation. A climate sensitivity produced by the model coupled with a mixed layer ocean model in response to the doubling of the atmospheric CO2 concentration lies in the range of the results obtained with GCMs. The results of the simulations with a gradual increase of the greenhouse gas concentrations in the atmosphere, in which diffusion of heat into the deep ocean was taken into account, are also similar to those obtained in the analogous simulations with GCMs. As a whole, presented results demonstrate that the modified version of the two-dimensional model can be successfully used for climate change predictions in the Integrated Framework of the Joint Program. / Includes bibliographical references (p. 13-14). / Abstract in HTML and technical report in HTML and PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).

IL-2 has multiple functions in T cell-mediated adaptive immunity. The stringent control of its expression is important for T cell activation, proliferation and the subsequent T cell clone contraction. Our lab has recently shown that the transcriptional repressor Blimp-1 is part of a negative feedback loop which controls IL-2 gene expression in mice. Understanding the molecular mechanisms of this signaling loop in T cells might help us to better understand the regulation as well as the role of IL-2 in T cell immunity. The human ortholog to murine Blimp-1 is termed PRDI-BF1 (each encoded by the respective Prdm1 gene). Both genes contain five zinc finger regions, whereby the first two zinc fingers are dispensable for DNA binding. In case of the human protein they are instead required to recruit the G9?Ñ methyltransferase to the gene promotor. We found that the human wild-type PRDI-BF1 protein suppressed IL-2 production in murine T cells, while deletion of the first two zinc fingers abolished this ability. Thus, a similar Blimp-1-mediated methylation mechanism might exist in IL-2 gene silencing. IL-2/IL-2R signaling is indispensable for Blimp-1 induction. PI-3Kinase and Stat5 are downstream of the IL-2 receptor complex and are known to contribute to IL-2 inhibition in T cells from C57BL/6 mice. However, activating only these two pathways are still not sufficient to induce Blimp-1 or suppress IL-2 expression in in IL-2R beta-/- mice. The Blimp-1-dependent IL-2 self regulatory loop is not functional in IL-2R beta-/-mice. In order to conveniently study this dysregulation we crossed these mice with a GFP transgenic strain in which the GFP transgene is under the control of IL-2 promoter sequence. In IL-2R beta-/-IL-2p-GFP mice about five times as many spleenic CD4+ T cells transcribe IL-2pGFP, compared to the littermate IL-2R beta+/-IL-2p-GFP control animals. And most of the GFP cells demonstrate activated phenotype (CD44HighCD62Llow). Blimp-1 is known as a master regulator of B cell terminal differentiation. Since a recent report indicated that IL-2 signaling via STAT5 constrains Th17 Cell differentiation, we speculated that Blimp-1 might play a similar role in effector T cell differentiation. In order to evaluate this possibility, activated CD4+ T cells from C57BL/6 mice were transduced with Blimp-1 and cultured under Th17 polarizing conditions. Blimp-1 overexpression in did not change the profile of IL-17 production.

Presented in this thesis are the results obtained from the project: Asymmetric synthesis of substituted 2-aminotetralins. The initial goal was to establish new or improved routes to enantiopure 2-aminotetralin (2-AT) derivatives. The motivation for this project was based on the diverse applications various 2-ATs represent as biologically active compounds. Despite the role of 2-aminotetralins as interesting target molecules, reflected by the massive research activity in the field, no general and cost efficient route has really been established. Chapter 1 in this thesis gives an introduction to 2-ATs as biologically active compounds, as well as a brief survey of the concepts of chirality and asymmetric synthesis. Aziridines are also presented, given their role as key intermediates in our developed strategies (chapters 2-4). In chapter 2, a total synthesis of substituted (S)-2-ATs is presented, starting from natural L-aspartic acid. Two 2-AT derivatives were successfully synthesised, but especially one step (ring-closing to tetralones) proved difficult, providing up to 41% yield only. Chapter 3 is directly based on the experiences we made in the former chapter, and presents an improved route from the same starting point (chiral pool strategy utilising L-aspartic acid). Again we struggled with one specific cyclisation reaction (up to 36% yield), but the remaining steps provided overall good yields. In Chapter 4, a different approach has been targeted, i.e. asymmetric aziridination of 1,2-dihydronaphthalenes. Here, various copper, rhodium and ruthenium catalytic systems were tested with alternative nitrogen sources. While we were able to achieve quite good results for non-substituted 1,2-dihydronaphthalene, substituted substrates provided only mediocre yields and enantioselectivity. Aziridines were selectively ring-opened by catalytic hydrogenation to their respective N-protected 2-ATs in good yields.

The process of ubiquitination plays an essential role in numerous cell functions, including apoptosis and the induction of immune responses. Ariadne 2 is a RING finger E3 ligase and is part of the highly conserved RBR (RING-B-Box-RING) superfamily, however, little is known of its function in mammalian systems. To further examine the physiological role, Ariadne 2 deficient mice were generated. In a mixed background, Ariadne 2 deficient (Arih2-/-) mice die prematurely after birth however lethality is not fully penetrant. Adult mice that escape lethality have lower body weight and reduced viability due to an apparent lymphoproliferative disorder. In a C57BL/6 background, Ariadne 2 deficiency leads to a fully penetrate embryonic lethality, occurring after embryonic day 16.5. Arih2-/- foetal liver have reduced cellularity and increased apoptosis, however haematopoietic cells are capable of differentiating into myeloid and granulocytic progenitors and can fully reconstitute lethally irradiated Rag1-/- recipient mice. These Rag1-/-Arih2-/- chimeras recapitulate the lymphoproliferative disorder observed in the mixed background Arih2-/- mice. Further analysis show Rag1-/-Arih2-/- chimeras display increased number of lymphocytes, granulocytes, macrophages and dendritic cells, increased serum immunoglobulin levels and pro-inflammatory cytokines, and dramatic heterogeneous cellular organ infiltration, consisting mainly of T cells. T cell homeostasis is also altered, as seen by increased activated and ‘memory-like’ T cells, elevated TH1 and TH2 cytokines, increased regulatory T cells (Treg), and increased T cell proliferation. This may be due to an observed premature maturation of Arih2-/- dendritic cells. Arih2-/- foetal liver derived dendritic cells (FLDC) express high levels of maturation markers CD80/B7.1, CD86/B7.2, CD83, CD40 and MHCII and are capable of activating T cells in the RIP-GP model of induced diabetes. This may be linked to modulation of the NFκB and ERK pathways, in particular increase in nuclear p65/RelA and phospho-p65/RelA leading to an increase in NFκB and AP-1 binding to DNA and sustained and hyperactive NFκB response in Arih2-/- dendritic cells. Overall, Ariadne 2 is shown to be a negative regulator in the activation of immune cells, in particular dendritic cells, and is a novel regulator in the maintenance of peripheral tolerance and the pathogenesis of autoimmunity.

The process of ubiquitination plays an essential role in numerous cell functions, including apoptosis and the induction of immune responses. Ariadne 2 is a RING finger E3 ligase and is part of the highly conserved RBR (RING-B-Box-RING) superfamily, however, little is known of its function in mammalian systems. To further examine the physiological role, Ariadne 2 deficient mice were generated. In a mixed background, Ariadne 2 deficient (Arih2-/-) mice die prematurely after birth however lethality is not fully penetrant. Adult mice that escape lethality have lower body weight and reduced viability due to an apparent lymphoproliferative disorder. In a C57BL/6 background, Ariadne 2 deficiency leads to a fully penetrate embryonic lethality, occurring after embryonic day 16.5. Arih2-/- foetal liver have reduced cellularity and increased apoptosis, however haematopoietic cells are capable of differentiating into myeloid and granulocytic progenitors and can fully reconstitute lethally irradiated Rag1-/- recipient mice. These Rag1-/-Arih2-/- chimeras recapitulate the lymphoproliferative disorder observed in the mixed background Arih2-/- mice. Further analysis show Rag1-/-Arih2-/- chimeras display increased number of lymphocytes, granulocytes, macrophages and dendritic cells, increased serum immunoglobulin levels and pro-inflammatory cytokines, and dramatic heterogeneous cellular organ infiltration, consisting mainly of T cells. T cell homeostasis is also altered, as seen by increased activated and ‘memory-like’ T cells, elevated TH1 and TH2 cytokines, increased regulatory T cells (Treg), and increased T cell proliferation. This may be due to an observed premature maturation of Arih2-/- dendritic cells. Arih2-/- foetal liver derived dendritic cells (FLDC) express high levels of maturation markers CD80/B7.1, CD86/B7.2, CD83, CD40 and MHCII and are capable of activating T cells in the RIP-GP model of induced diabetes. This may be linked to modulation of the NFκB and ERK pathways, in particular increase in nuclear p65/RelA and phospho-p65/RelA leading to an increase in NFκB and AP-1 binding to DNA and sustained and hyperactive NFκB response in Arih2-/- dendritic cells. Overall, Ariadne 2 is shown to be a negative regulator in the activation of immune cells, in particular dendritic cells, and is a novel regulator in the maintenance of peripheral tolerance and the pathogenesis of autoimmunity.