Abnormal ryanodine receptor channels in malignant hyperthermia.

Previous studies have demonstrated a defect associated with the calcium release mechanism of sarcoplasmic reticulum (SR) from individuals susceptible to malignant hyperthermia (MH). To examine whether SR calcium release channels were indeed altered in MH, SR vesicles were purified from normal and MH susceptible (MHS) porcine muscle. The Ca2+ dependence of calcium efflux rates from 45Ca2(+)-filled SR vesicles was then compared with the Ca2+ dependence of single-channel recordings of SR vesicles incorporated into planar lipid bilayers. The rate constants of 45Ca2+ efflux from MHS SR were two to threefold larger than from normal SR over a wide range of myoplasmic Ca2+. Normal and MHS single channels were progressively activated in a similar fashion by cis Ca2+ from pCa 7 to 4. However, below pCa 4, normal channels were inactivated by cis Ca2+, whereas MHS channels remained open for significantly longer times. The altered Ca2+ dependence of channel inactivation in MHS SR was also evident when Ca2+ was increased on the trans side while cis Ca2+ was held constant. We propose that a defect in a low-affinity Ca2+ binding site is responsible for the altered gating of MHS SR channels. Such a defect could logically result from a mutation in the gene encoding the calcium release channel, providing a testable hypothesis for the molecular basis of this inherited disorder

Towards Extending the Validation Possibilities of ADOxx with Alloy

While ADOxx is a popular platform for the creation and use of enterprise modeling languages, it provides only limited support for a well-formedness check of created enterprise models. In this paper, we propose to complement the meta modeling platform ADOxx with Alloy, which natively provides extensive model checking capabilities, so as to enable a well-formedness check of enterprise models created in ADOxx. Using the e3value modeling language as a point of departure, we particularly provide (a) a partial ADOxx implementation of e3value, (b) a proof-of-concept XML2Alloy parser, which allows for converting e3value models created in ADOxx into Alloy format, so that (c) e3value well-formedness constraints stated in Alloy can be used to check the valid- ity of an e3value model with the Alloy Evaluator. Beyond the specific proof-of-concept, we also discuss further possibilities of using ADOxx in conjunction with Alloy, particularly in checking the soundness of meta models underlying an enterprise modeling language