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Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 57-60).

Thesis (doctoral)--Universität Köln.

Thesis (MBus) -- AUT University, 2007. / Includes bibliographical references. Also held in print (74 leaves ; 30 cm.) in the Archive at the City Campus (T 343.93042 THA)

Thesis (Ph. D.)--New York University, 1995. / Includes bibliographical references (leaves 168-173).

Mycobacterium tuberculosis (Mtb) is the leading cause of death from an infectious disease. The success of the pathogen lies in its ability to subvert hostile intracellular macrophage environment. We performed genome-wide transcriptional deep sequencing on total RNA in murine bone marrow-derived macrophages (BMDM) infected with hypervirulent Beijing strain (HN878) in an extensive time kinetic manner using single molecule sequencer and cap analysis gene expression (CAGE) technique. CAGE analysis revealed nearly 36000 unique RNA transcripts with approximately 16000 are not unannotated to a specific gene. This thesis addressed global changes in RNA expression levels in macrophages infected with Mtb in a time kinetic manner to pinpoint novel host protection and immune evasion genes and elucidate the role of these genes in vitro macrophage assays and in vivo knockout mouse studies. The data in this thesis showed that basic leucine zipper transcription factor 2 (Batf2) was an important factor that regulates inflammatory responses in Mtb infection. Deletion of Batf2 led to the survival of mice with reduced lung inflammation and histopathology due to reduced recruitment of inflammatory macrophages. We also showed that Batf2 was highly expressed in peripheral blood from adolescents who progressed from infection to tuberculosis disease and a predictive human biomarker for tuberculosis disease. In contrast to Batf2, we showed that Protein Kinase C-delta (PKC-δ) deficient mice are highly susceptible to tuberculosis and human lung proteomics dataset revealed that PKC-δ was highly upregulated in the necrotic and cavitory regions of human granulomas in multi-drug resistant subjects. PKC-δ deficient mice had a significant reduction in alveolar macrophages and dendritic cells, reduced accumulation of lipid bodies and serum fatty acids. In vitro experiments showed that PKCδ was required for optimal killing effector functions which were independent of phagosome maturation and autophagy in primary murine macrophages. Our studies suggested that these novel genes play a role in the immune response to Mtb and should be studied more thoroughly to evaluate their potential in possible TB interventions.

Cette recherche a pour objet d’étudier les formes dont les différents concepts de justice fiscale ont été traduits en formes juridiques.Il convient de souligner que l’on trouve des développements importants sur le concept de Justice dans les écrits d’Aristote qui distinguait la justice générale et la justice particulière. Celle-ci est fractionnée en justice commutative et justice distributive. Cette dernière notion a souvent été reprise par les théoriciens de la fiscalité, elle est encore implicitement très active de nos jours. Cette vision unitaire de la justice légale et morale fut remise en question par celle du positivisme juridique qui a séparé droit et morale. Néanmoins si le concept de Justice est au cœur d’une réflexion générale sur le Droit, il est particulièrement présent au sein du Droit fiscal.Il faut souligner que la Déclaration des droits de l’homme et du citoyen de 1789 a posé les bases de ce droit avec les principes figurant aux articles 13 et 14. Et c’est sur ce socle qu’ont été progressivement organisés les éléments d’une justice fiscale distributive puis redistributive. Il en est résulté un droit reflétant les atermoiements de doctrines fiscales développant des représentations très diverses de la question. Aujourd’hui, bien que les débats soient toujours présents, le pragmatisme semble l’emporter en focalisant le sujet sur la lutte contre la fraude et l’évasion fiscales. / This research aims to study the forms which different tax justice concepts were translated into legal forms.It should be stressed that there are important developments on the concept of justice in the writings of Aristotle, who distinguished the general justice and particular justice. This is divided into commutative justice and distributive justice. This notion has often been taken up by the theorists of taxation, it is still implicitly active today. This unitary vision of the legal and moral justice was challenged by the legal positivism that separated law and morality. However if the concept of justice is at the heart of a general reflection on the Law, it is particularly present in the tax law. Note that the Bill of Rights of Man and Citizen of 1789 laid the foundation of this law with the principles contained in Articles 13 and 14. It is on this foundation that were gradually organized the elements a distributive and redistributive tax justice. This resulted in a law reflecting the procrastination of fiscal doctrines developing diverse representations of the question. Today, although discussions are still present, pragmatism seems to outweigh the subject by focusing on the fight against fraud and tax evasion.

No description available.

Evasion of an immune response mounted by a host is fundamental to the survival of a parasite. Immune evasion can be mediated in many ways from the production of molecules by the parasite which mimic cytokines produced by the human immune system to hiding from the immune system by locating within host cells. The production of immune cell mediating molecules in excretory secretory products is another means by which the parasite can tailor its surroundings to facilitate prolonged survival. The hypothesis of immunosuppression by parasite products, in particular members of the Venom Allergen Like (VAL) family, is key to this thesis. VAL proteins are members of the much larger SCP/TAPS family, which covers proteins from parasitic helminths such as Heligmosomoides polygyrus (H.polygyrus)to the free-living nematode Caenorhabditis elegans. These nematodes may have one or more genes encoding proteins that contain the SCP/TAPS domains often choosing to express these proteins at critical points within the helminths lifecycle. Phylogenetic analysis of a selection of these proteins revealed that their classification could be determined based upon the number of SCP/TAPS domains. Alternatively the presence or absence of the signal sequence combined with conserved cysteine residue data could be used. Further investigations into possible functions of the VAL proteins from H.polygyrus were carried out using recombinant protein produced in an insect cell expression system. To further examine the function of VAL genes a system that allows the heterologous expression of a gene in the well-documented Leishmania infection setting was employed. In vitro and in vivo studies were carried out which examined various infection parameters. Parasite infectivity in bone marrow derived macrophages in vitro along with cytokine production was observed. In vivo the development of lesions and subsequent parasite recovery from infected mice gave indications of changes in virulence that could be attributed to the presence and expression of the HpVAL genes. The ability of parasites to ameliorate symptoms of allergic and autoimmune diseases is now well documented with the most extreme use of this knowledge resulting in administration of an active parasitic infection as a treatment regime. We hope to identify individual molecules from a parasite that is known to reduce allergic symptoms in the allergic airway inflammation (AAI) model and produce these in a more structured and regulated fashion. It is plausible that VAL proteins from H.polygyrus may possess these regulatory properties, as has been shown for the excretory secretory products (HES) of the parasite; to that end HpVAL-1 and HpVAL-4 were tested in the allergic airway inflammation model and were shown to reduce both cell numbers in the bronchioalveolar lavage fluid and eosinophilia. Finally, the position of the parasite and products secreted by the parasite was examined. Directly labelled HES and recombinant VAL proteins were used to identify binding sites inside the parasite and within the parasites’ locality in the host i.e. the gut. Confocal microscopy revealed binding of HES to the parasites surface and internal structures and of both HES and HpVAL-4 to goblet cells and Paneth cells inside the gut. Paneth cells may affect parasite survival by influencing the gut microbiota and goblet cells have been shown to influence parasite persistence by production of mucus. Thus HES and more specifically HpVAL proteins may, through their interactions with these cells, interfere with mechanisms employed by the host to expel the parasite.

Tax authorities utilize a wide range of instruments to motivate honest taxpaying ranging from strict audits to fair procedures or personalized support, differing from country to country. However, little is known about how these different instruments and taxpayers' trust influence the generation of interaction climates between tax authorities and taxpayers, motivations to comply, and particularly, tax compliance. The present research examines the extended slippery slope framework (eSSF), which distinguishes tax authorities' instruments into different qualities of power of authority (coercive and legitimate) and trust in authorities (reasonbased and implicit), to shed light on the effect of differences between power and trust. We test eSSF assumptions with survey data from taxpayers from three culturally different countries (N = 700) who also vary concerning their perceptions of power, trust, interaction climates, and tax motivations. Results support assumptions of the eSSF. Across all countries, the relation of coercive power and tax compliance was mediated by implicit trust, which leads to an antagonistic climate and enforced motivation. The connection from legitimate power to tax compliance is partially mediated by reason-based trust. The relationship between implicit trust and tax compliance is mediated by a confidence climate and committed cooperation. Theoretical and practical implications are discussed.