Btk expression is controlled by Oct and BOB.1/OBF.1

BOB.1/OBF.1 is a lymphocyte-restricted transcriptional coactivator. It binds together with the Oct1 and Oct2 transcription factors to DNA and enhances their transactivation potential. Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in differentiation, function and signaling of B cells. In search of BOB.1/OBF.1 regulated genes we identified Btk—a cytoplasmic tyrosine kinase—as a direct target of BOB.1/OBF.1. Analyses of the human as well as murine Btk promoters revealed a non-consensus octamer site close to the start site of transcription. Here we show that Oct proteins together with BOB.1/OBF.1 are able to form ternary complexes on these sites in vitro and in vivo. This in turn leads to the induction of Btk promoter activity in synergism with the transcription factor PU.1. Btk, like BOB.1/OBF.1, plays a critical role in B cell development and B cell receptor signalling. Therefore the down-regulation of Btk expression in BOB.1/OBF.1-deficient B cells could be related to the functional and developmental defects observed in BOB.1/OBF.1-deficient mice

B Cell–specific Transgenic Expression of Bcl2 Rescues Early B Lymphopoiesis but Not B Cell Responses in BOB.1/OBF.1-deficient Mice

Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre–B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment

All-trans retinoic acid release from biodegradable polyester microcapsules

[Excerpt] Tissue engineering strategies frequently include a scaffold, living cells and bioactive substances to promote cell growth and guide cell differentiation. The encapsulation in carriers enables protects the bioactivity of those substances upon implantation, avoids being transported by the body fluids and also allows controlling the release rate. Encapsulation materials are preferably biodegradable polymers. In this work, all-trans retinoic acid (atRA) was used as a model bioactive agent; since it was shown that atRA enhances the expression of osteocalcin, a specific osteogenic marker. [...]info:eu-repo/semantics/publishedVersio

Nachhaltigkeit

Nach Definition der Brundtland-Kommission ist eine Entwicklung nachhaltig, wenn sie "den Bedürfnissen der heutigen Generation entspricht, ohne die Möglichkeiten künftiger Generationen zu gefährden, ihre eigenen Bedürfnisse zu befriedigen und ihren Lebensstil [frei] zu wählen". Diese Definition fordert, dass es künftigen Generationen nicht schlechter gehen soll als den heute lebenden Menschen. Gleichzeitig sagt sie aber auch aus, dass die Bedürfnisse der heutigen Armen berücksichtigt werden müssen, da diese Teil der gegenwärtigen Generation sind. Ökonomisch kann Nachhaltigkeit dann als eine im Zeitverlauf nicht abnehmende Wohlfahrt interpretiert werden. Diese liegt vor, sofern das Gesamtkapital pro Kopf - die Summe aus physischem, natürlichem und intangiblem Kapital - im Zeitverlauf nicht abnimmt. Die Betrachtung des Gesamtkapitals erzwingt die Analyse von Wasser, Land und anderen natürlichen Ressourcen wie der Tier- und Pflanzenwelt. Deren Einsatz ermöglicht die derzeitige Form des Wirtschaftens und ist damit essenziell für den heutigen Wohlstand und Lebensstandard. Folglich sind die Entwicklung des Verbrauchs dieser Ressourcen und die entsprechende Prognose von großem Interesse. Dabei müssen zwei unterschiedliche Aspekte betrachtet werden: Einerseits ist eine Analyse der Entwicklung von Gesamtverfügbarkeiten unerlässlich, andererseits sind Zugangs- und Verteilungsaspekte von großer Bedeutung. Konkret werden in der Studie die Bereiche Landwirtschaft und Nahrungsmittel, Fisch- und Waldbestände sowie Wasser und Biodiversität betrachtet

Characterization and differentiation of the tumor microenvironment (TME) of orthotopic and subcutaneously grown head and neck squamous cell carcinoma (HNSCC) in immunocompetent mice

For the development and evaluation of new head and neck squamous cell carcinoma (HNSCC) therapeutics, suitable, well-characterized animal models are needed. Thus, by analyzing orthotopic versus subcutaneous models of HNSCC in immunocompetent mice, we evaluated the existence of adenosine-related immunosuppressive B- and T lymphocyte populations within the tumor microenvironment (TME). Applying the SCC VII model for the induction of HNSCC in immunocompetent C3H/HeN mice, the cellular TME was characterized after tumor initiation over time by flow cytometry. The TME in orthotopic grown tumors revealed a larger population of tumor-infiltrating lymphocytes (TIL) with more B cells and CD4+ T cells than the subcutaneously grown tumors. Immune cell populations in the blood and bone marrow showed a rather distinct reaction toward tumor induction and tumor location compared to the spleen, lymph nodes, or thymus. In addition, large numbers of immunosuppressive B- and T cells were identified within the TME but also in secondary lymphoid organs, independently of the tumor initiation site. The altered immunogenic TME may influence the response to any treatment attempt. Moreover, when analyzing the TME and other lymphoid organs of tumor-bearing mice, we observed conditions reflecting largely those of patients suffering from HNSCC suggesting the C3H/HeN mouse model as a suitable tool for studies aiming to target immunosuppression to improve anti-cancer therapies

NF-κB and its role in checkpoint control

Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade

The Lagrangian Atmospheric Radionuclide Transport Model (ARTM) - development, description and sensitivity analysis

Atmospheric dispersion models are applied to describe and predict the dispersion of emitted plumes. Here, we describe the Lagrangian Atmospheric Radionuclide Transport Model (ARTM) 2.8.0 which was developed to simulate the atmospheric dispersion of the emissions of nuclear facilities under routine operation for regulatory purposes over annual time scales. ARTM includes a diagnostic wind field model and a particle dispersion model. It simulates size-dependent wet and dry deposition, plume rise and cloud shine of radioactive exhaust plumes in the simulation domain