Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice

Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971–990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971–990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk. By creating IAk/and IEk/SERCA2a 971–990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971–990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971–990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971–990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971–990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans

The DATUM project: a cost estimating environment for the support of aerospace design decision making

The results of a Rolls-Royce sponsored programme of design to cost research are outlined. The role of cost modelling within the design process for the development of a civil gas turbine engine is outlined. The novel application of a generic financial modelling tool to an engineering cost estimating problem is demonstrated. This use of this tool to capture and disseminate costing knowledge is described and the use of modular library elements to develop cost models is shown. A prototype systems for the creation of an elegant cost model structure to enable direct integration with a CAD representation of a part and the integration of the costing capability within an automated design search and optimization environment is describe

Challenges of triangular relations: The US, the EU, and Turkish accession

The US government became deeply involved in European Union (EU)-Turkey relations from the mid-1990s and has provided extensive diplomatic support for full Turkish membership in the EU since then. Washington's strategic considerations have been paramount in the US government's approach to Turkey's full integration into the EU. The US policy on this issue has played a constructive role in Turkish-US relations. However, it has also created strains in transatlantic ties, since the pressure the US has put on the EU has angered many European officials, who resent what they view as interference in the EU's internal affairs. The US has become more sensitive to the complaints voiced by European leaders and EU officials, and it has adopted a more subtle approach to the issue of Turkish membership. While Washington continues to support Turkey's European integration, it has also recognised that the accession process is likely to be lengthy