Mechanisms of regulation in the interferon factor 3 (IRF- 3) pathway

Interferon regulatory factor 3 (IRF-3) plays a critical role in the host cell response to both bacterial and viral infection. IRF-3 is activated by Toll-like receptors (TLRs) and cytoplasmic nucleic acid sensors, and serves to upregulate interferon beta and interferon stimulated genes (ISGs), thereby providing a quick and effective response to infection. In this work, two novel mechanisms of regulation in the IRF-3 pathway are revealed. The first part of this thesis work shows that upon binding to lipopolysaccharide, TLR-4 signaling activates phospholipase C gamma 2 (PLCg2), which cleaves phosphatidylinositol (4,5)-bisphosphate (PIP₂) into Inositol 1,4,5-triphosphate (IP₃) and regulates IP₃R activity. Inositol 1,4,5-triphosphate receptors (IP₃Rs) mediate the release of calcium from the endoplasmic reticulum into the cytosol. The hypothesis presented here is that, upon calcium release, the calcium-dependent phosphatase calcineurin becomes activated and activates dynamin-dependent endocytosis of the LPS-TLR4 complex. Signaling occurs from the early endosomes via the TRAM- TRIF pathway, and induces the IRF3-dependent gene response. Our results suggest a novel means by which the IRF3 pathway is regulated. The second part of this thesis work describes the Schlafen (Slfn) gene family and its complex role in the immune response. The family is comprised of nine murine members, which are divided into short (Slfn 1 and 2), medium (Slfn 3 and 4) and long (Slfn 5, 8, 9, 10,14) subtypes. The short subtype member, Slfn2, is a cytoplasmic protein that binds to foreign nucleic acids and inhibits protein translation, putatively as a host defense strategy. However, short and medium subtypes, Slfn2 and Slfn3, appear to inhibit Interferon stimulated gene (ISG) production via the IRF3 pathway, thus indicating a role in attenuating the immune response. Moreover, Slfn8, a long subtype member, does not appear to have any effect on ISG induction, indicating divergent roles of different individual Slfn family members. We propose that the Slfn family is differentially regulated during a response to infection, thus initially mediating cellular defense and, later, downregulation of response through the varying participation of individual Slfn proteins within a comple

Spatial Mobility, Family Dynamics, and Housing Transitions

This paper summarizes theoretical approaches and empirical research on the links between partnership and family dynamics on the one hand and spatial mobility and housing transitions on the other. Spatial mobility includes residential relocations and commuting. We consider three types of partnerships—living apart together, unmarried and married co-residential unions—and the transitions between them. We also consider separations and the death of a partner. Moreover, we pay attention to childbirth and its consequences for relocation decisions and housing. We differentiate spatial mobility according to distance and direction; housing transitions are considered mainly with respect to changes in ownership status and housing quality (e.g. size of the accommodation). In line with the adjustment perspective on spatial mobility, this paper demonstrates that spatial mobility is a means for individuals and households to adjust their housing situation and their place of residence to requirements of a changing household size and composition as well as to demands of the labor market. At the same time, spatial mobility seems to be more than a mere adjustment process of individuals or households: it is also a determinant of life course changes