Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody

Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents

Human and climatic impact on mires: a case study of Les Amburnex mire, Swiss Jura Mountains

Modern period long-term human and climatic impacts on a small mire in the Jura Mountains were assessed using testate amoebae, macrofossils and pollen. This multiproxy data analysis permitted detailed interpretations of local and regional environmental change and thus a partial disentanglement of the different variables that influence long-term mire development. From the Middle Ages until a.d. 1700 the mire vegetation was characterised by ferns, Caltha and Vaccinium, but then abruptly changed into the modern vegetation characterised by Cyperaceae, Potentilla and Sphagnum. The cause for this change was most probably deforestation, possibly enhanced by climatic cooling. A decrease in trampling intensity by domestic animals from a.d. 1950 onwards allowed Sphagnum growth and climatic warming in the a.d. 1980s and 1990s may have been responsible for considerable changes in the species composition. The mire investigated is an example of the rapid changes in mire vegetation and peat development that occurred throughout the central European mountain region during the past centuries as a result of changing climate and land-use practice. These processes are still active today and will determine the future development of high-altitude mires