Small-Scale XMI Programming: A Revolution in UML Tool Use?

The main motivation for the development of the OMG's XML Metadata Interchange Format (XMI) was the need to have a standard way for UML tools to interchange UML models. However, the fact that UML models, saved as XML documents, are now accessible to standard XML tools, opens up new possibilities to which less attention has so far been paid. This paper discusses how XMI can be exploited for performing model analysis and housekeeping tasks and for the integration of third party or in-house tools. With the help of examples we focus on what can be achieved with small-scale XMI programming by a single developer in hours rather than days. We suggest that this new capability may have important and positive implications for the future of UML modelling using tools.     

Guest editors’ introduction: Advancements and extensions of verification techniques

This special section is devoted to a selection of journal versions of papers that appeared originally in the Proceedings of the 8th International Conference on Tools and Algorithms for the Construction and Analysis of Systems (TACAS), which took place in Grenoble, France in April 2002 as a constituent event of the European joint conferences on Theory and Practice of Software (ETAPS). All papers are relevant to the field of systems validation. The first three papers advance and extend model-checking techniques, the fourth presents algorithms for run-time verification, and the last paper is about animation and test generation for formal system specifications.     

Design and synthesis of conformationally constrained cyclophilin inhibitors showing a cyclosporin-A phenotype in C. elegans

Cyclophilin A (CypA) is a member of the immunophilin family of proteins and receptor for the immunosuppressant drug cyclosporin A (CsA). Here we describe the design and synthesis of a new class of small-molecule inhibitors for CypA that are based upon a dimedone template. Electrospray mass spectrometry is utilised as an initial screen to quantify the protein affinity of the ligands. Active inhibitors and fluorescently labelled derivatives are then used as chemical probes for investigating the biological role of cyclophilins in the nematode Caenorhabditis elegans.     

Molecular Insights into the Thermal Stability of mAbs with Variable‐Temperature Ion‐Mobility Mass Spectrometry

The aggregation of protein‐based therapeutics such as monoclonal antibodies (mAbs) can affect the efficacy of the treatment and can even induce effects that are adverse to the patient. Protein engineering is used to shift the mAb away from an aggregation‐prone state by increasing the thermodynamic stability of the native fold, which might in turn alter conformational flexibility. We have probed the thermal stability of three types of intact IgG molecules and two Fc‐hinge fragments by using variable‐temperature ion‐mobility mass spectrometry (VT‐IM‐MS). We observed changes in the conformations of isolated proteins as a function of temperature (300–550 K). The observed differences in thermal stability between IgG subclasses can be rationalized in terms of changes to higher‐order structural organization mitigated by the hinge region. VT‐IM‐MS provides insights into mAbs structural thermodynamics and is presented as a promising tool for thermal‐stability studies for proteins of therapeutic interest.     

Bidirectional model transformations in QVT: semantic issues and open questions

We consider the OMG’s queries, views and transformations standard as applied to the specification of bidirectional transformations between models. We discuss what is meant by bidirectional transformations, and the model-driven development scenarios in which they are needed. We analyse the fundamental requirements on tools which support such transformations, and discuss some semantic issues which arise. In particular, we show that any transformation language sufficient to the needs of model-driven development would have to be able to express non-bijective transformations. We argue that a considerable amount of basic research is needed before suitable tools will be fully realisable, and suggest directions for this future research.     

A simple game-theoretic approach to checkonly QVT Relations

The QVT Relations (QVT-R) transformation language allows the definition of bidirectional model transformations, which are required in cases where two (or more) models must be kept consistent in the face of changes to either or both. A QVT-R transformation can be used either in checkonly mode, to determine whether a target model is consistent with a given source model, or in enforce mode, to change the target model. A precise understanding of checkonly mode transformations is prerequisite to a precise understanding of enforce mode transformations, and this is the focus of this paper. In order to give semantics to checkonly QVT-R transformations, we need to consider the overall structure of the transformation as given by when and where clauses, and the role of trace classes. In the standard, the semantics of QVT-R are given both directly, and by means of a translation to QVT Core, a language which is intended to be simpler. In this paper, we argue that there are irreconcilable differences between the intended semantics of QVT-R and those of QVT Core, so that no translation from QVT-R to QVT Core can be semantics-preserving, and hence no such translation can be helpful in defining the semantics of QVT-R. Treating QVT-R directly, we propose a simple game-theoretic semantics. We demonstrate its behaviour on examples and show how it can be used to prove an example result comparing two QVT-R transformations. We demonstrate that consistent models may not possess a single trace model whose objects can be read as traceability links in either direction. We briefly discuss the effect of variations in the rules of the game, to elucidate some design choices available to the designers of the QVT-R language.     

The formation of a complex between calmodulin and neuronal nitric oxide synthase is determined by ESI-MS.

Calmodulin (CaM) is an acidic ubiquitous calcium binding protein, involved in many intracellular processes, which often involve the formation of complexes with a variety of protein and peptide targets. One such system, activated by Ca2+ loaded CaM, is regulation of the nitric oxide synthase (NOS) enzymes, which in turn control the production of the signalling molecule and cytotoxin NO. A recent crystallographic study mapped the interaction of CaM with endothelial NOS (eNOS) using a 20 residue peptide comprising the binding site within eNOS. Here the interaction of CaM to the FMN domain of neuronal nitric oxide synthase (nNOS) has been investigated using electrospray ionization mass spectrometry (ESI-MS). The 46 kDa complex formed by CaM-nNOS has been retained in the gas-phase, and is shown to be exclusively selective for CaM.4Ca2+. Further characterization of this important biological system has been afforded by examining a complex of CaM with a 22 residue synthetic peptide, which represents the linker region between the reductase and oxygenase domains of nNOS. This nNOS linker peptide, which is found to be random coil in aqueous solution by both circular dichroism and molecular modelling, also exhibits great discrimination for the form of CaM loaded with 4[Ca2+]. The peptide binding loop is presumed to be configured to an alpha-helix on binding to CaM as was found for the related eNOS binding peptide. Our postulate is supported by gas-phase molecular dynamics calculations performed on the isolated nNOS peptide. Collision induced dissociation was employed to probe the strength of binding of the nNOS binding peptide to CaM.4Ca2+. The methodology taken here is a new approach in understanding the CaM-nNOS binding site, which could be employed in future to inform the specificity of CaM binding to other NOS enzymes.