The homeodomain-interacting protein kinase (HIPK) family is comprised of four evolutionarily conserved and highly related serine/threonine kinases originally identified as co-repressors for homeodomain-containing transcription factors. While the HIPKs are most noted for regulation of apoptosis, proliferation and differentiation, I report a pleiotropic function of HIPK1 within the B cell lineage. Although lymphocyte development was normal within the thymus and bone marrow of HIPK1-deficient (HIPK1-/-) mice, the spleen exhibited a reduced number of transitional and follicular (FO) B cells, but with an increase in the marginal zone (MZ) B cell population. HIPK1-/- B cells exhibited impaired proliferation in response to B cell receptor (BCR) cross-linking in vitro; and immunization of HIPK1-/- mice with T-independent type 2 (TI-2) antigen resulted in a significantly impaired humoral response despite the expanded MZ B cell population. Immunization with T-dependent (TD) antigen resulted in a kinetically delayed response, with impaired affinity maturation. Identification of a kinase-substrate interaction between HIPK1 and the B cell adaptor 3BP2 suggests a potential context for HIPK1 function in BCR signaling. HIPK1-/- B cells were uniquely resistant to reactive oxygen species (ROS)-induced apoptosis, but equally susceptible to UV- and γ-irradiation compared to controls. In vitro class-switch recombination (CSR) assays revealed that HIPK1 is required for the negative regulation of CSR. HIPK1-/- B cell cultures harbored more viable cells, more switched cells, and elevated AID mRNA levels. The findings presented in this thesis demonstrate that HIPK1 is required for splenic B cell homeostasis and optimal BCR-responsiveness. In contrast, HIPK1 is also required for the negative regulation of CSR, possibly by mediating CSR-induced apoptosis.

B lymphopoiesis is regulated by cytokines, chemokines and cell surface proteins that initiate signal transduction pathways necessary for maturation to proceed. Many of these factors are expressed by cells in the surrounding bone marrow (BM) microenvironment, which also form the niches that support development. Interleukin-7 (IL-7) is an essential cytokine for progenitor B cells and is important in providing survival, proliferation and maturation signals. By growing BM B cells for extended periods of time in vitro with IL-7 it is possible to select for cells that possess the ability to grow indefinitely, and these cultures can be used to generate cell lines. Data presented herein describe the generation and characterization of IL-7-dependent B cell lines as well as their utility in investigating aspects of B cell development. As B cells mature they lose responsiveness to IL-7, yet retain IL-7 receptor expression. I demonstrate that a B cell’s ability to respond to IL-7 is controlled by the expression of suppressor of cytokine signaling (SOCS) proteins, which are regulated by a variety of signaling pathways including those initiated by IL-7. Development of progenitor B cells to mature immunoglobulin secreting B cells is mediated in part by surface proteins present on stromal cells as well as on B cells themselves. Heparan sulfate and CD19 play important roles in regulating this transition and I provide data that demonstrates how their ability to regulate Erk activation downstream of the pre-B cell receptor (pre-BCR) alters the proliferation and maturation of developing B cells.

B lymphopoiesis is regulated by cytokines, chemokines and cell surface proteins that initiate signal transduction pathways necessary for maturation to proceed. Many of these factors are expressed by cells in the surrounding bone marrow (BM) microenvironment, which also form the niches that support development. Interleukin-7 (IL-7) is an essential cytokine for progenitor B cells and is important in providing survival, proliferation and maturation signals. By growing BM B cells for extended periods of time in vitro with IL-7 it is possible to select for cells that possess the ability to grow indefinitely, and these cultures can be used to generate cell lines. Data presented herein describe the generation and characterization of IL-7-dependent B cell lines as well as their utility in investigating aspects of B cell development. As B cells mature they lose responsiveness to IL-7, yet retain IL-7 receptor expression. I demonstrate that a B cell’s ability to respond to IL-7 is controlled by the expression of suppressor of cytokine signaling (SOCS) proteins, which are regulated by a variety of signaling pathways including those initiated by IL-7. Development of progenitor B cells to mature immunoglobulin secreting B cells is mediated in part by surface proteins present on stromal cells as well as on B cells themselves. Heparan sulfate and CD19 play important roles in regulating this transition and I provide data that demonstrates how their ability to regulate Erk activation downstream of the pre-B cell receptor (pre-BCR) alters the proliferation and maturation of developing B cells.

Syftet med arbetet är att undersöka  distanselevers motivation till distanskurser ochom det finns några samband mellan elevernas motivation och deras prestationer. Detta görs för att förhoppningsvis kunna anpassa framtida utbildning efter de elever som läser. Tidigare forskning har visat att det finns ett problem inom distansundervisningen då det kommer till elever som hoppar av sina kurser. Forskning inom området har visat att det inte finns någon enkel förklaring till varför fler hoppar av vid distansundervisning än vid vanliga studier.Detta var även ett problem vid den undersökta skolan då det var en stor andel elever som antingen hoppade av sin kurs eller gick ut utan ett godkänt betyg. En enkätstudie användes för att få en bred bild av elevernas motivation och sedan användes intervjuer bland de elever som ej fullföljt vald kurs. Intervjuerna användas för att få en mer detaljerad bild av vad som motiverade eller inte motiverade de elever som ej fullföljde kursen med ett godkänt betyg. Resultatet från enkäten tyder på att de flesta som läser Matematik A och B på distans gör det för att de behöver kursen för att komma in på en utbildning. Man kunde även se att matematiken ej ansågs vara särskilt rolig även om den ansågs vara viktig. Från enkäten framkom även att de elever som ej fullföljt kursen med ett godkänt betyg har ett sämre förhållande till matematik de som fullföljt kursen med godkänt eller högre,  och att detta främst beror på deras tidigare möten med matematiken.  Från intervjustudien framkom det att yttre faktorer  som t.ex. hög arbetsbelastning på jobbet eller personliga bekymmer,  var en vanlig anledning till att elever hoppar av kursen. Resultaten från intervjuerna var även att de som fullföljt kursen utan ett godkänt betyg ofta tyckte att matematik var tråkigt och att när de fastnade på uppgifter så tappade de ofta motivationen.

A b-coloring of G is a proper vertex coloring such that there is a vertex in each color class, which is adjacent to at least one vertex in every other color class. Such a vertex is called a color-dominating vertex. The b-chromatic number of G is the largest k such that there is a b-coloring of G by k colors. Moreover, if for every integer k, between chromatic number and b-chromatic number, there exists a b-coloring of G by k colors, then G is b-continuous. Determining the b-chromatic number of a graph G and the decision whether the given graph G is b-continuous or not is NP-hard. Therefore, it is interesting to find new results on b-colorings and b-continuity for special graphs. In this thesis, for several graph classes some exact values as well as bounds of the b-chromatic number were ascertained. Among all we considered graphs whose independence number, clique number, or minimum degree is close to its order as well as bipartite graphs. The investigation of bipartite graphs was based on considering of the so-called bicomplement which is used to determine the b-chromatic number of special bipartite graphs, in particular those whose bicomplement has a simple structure. Then we studied some graphs whose b-chromatic number is close to its t-degree. At last, the b-continuity of some graphs is studied, for example, for graphs whose b-chromatic number was already established in this thesis. In particular, we could prove that Halin graphs are b-continuous.

The intramolecular nucleophile catalyzed aldol-lactonization (NCAL) process was optimized successfully. A variety of C9-acylated cinchona alkaloids were synthesized and used for NCAL reactions with non-activated aldehydes. New pyridinium salts, derivatives of Mukaiyama’s reagent, led to marked improvements in efficiency for the catalytic, asymmetric NCAL process while maintaining high enantioselectivity. Larger scale versions of the catalytic, asymmetric NCAL reaction were also developed allowing practical access to chiral bicyclic b-lactones. As an extension of the intramolecular NCAL process, pyrrolidine and piperidine fused blactones were synthesized. Simple g-lactam fused b-lactones were synthesized as a model study for omuralide, salinosporamide A, and derivative synthesis. Synthesis of asubstituted aldehyde acids was extensively studied but steric effects from both acid and amine moieties led to great difficulties in this approach.

Thèse Médecine Paris, 1811 numéro 129.

Reproduction de : Thèse de doctorat : Informatique et télécommunications : Toulouse, INPT : 2000. / Titre provenant de l'écran-titre. Bibliogr. 90 réf.

Reproductin de : Thèse de doctorat : Immunologie : Lyon 1 : 2006. / Titre provenant de l'écran titre. 410 réf. bibliogr.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 77-109). Also available in print.