Functional modulation of the transient outward current Ito by KCNE beta-subunits and regional distribution in human non-failing and failing hearts

Objectives: The function of Kv4.3 (KCND3) channels, which underlie the transient outward current I,, in human heart, can be modulated by several accessory subunits such as KChIP2 and KCNE1-KCNE5. Here we aimed to determine the regional expression of Kv4.3, KChIP2, and KCNE mRNAs in non-failing and failing human hearts and to investigate the functional consequences of subunit coexpression in heterologous expression systems. Methods: We quantified mRNA levels for two Kv4.3 isoforms, Kv4.3-S and Kv4.3-L, and for KChIP2 as well as KCNE1-KCNE5 with real-time RT-PCR. We also studied the effects of KCNEs on Kv4.3 + KChIP2 current characteristics in CHO cells with the whole-cell voltage-clamp method. Results: In non-failing hearts, low expression was found for KCNE1, KCNE3, and KCNE5, three times higher expression for KCNE2, and 60 times higher for KCNE4. Transmural gradients were detected only for KChIP2 in left and right ventricles. Compared to non-failing tissue, failing hearts showed higher expression of Kv4.3-L and KCNE1 and lower of Kv4.3-S, KChIP2, KCNE4, and KCNE5. In CHO cells, Kv4.3 + KChIP2 currents were differentially modified by co-expressed KCNEs: time constants of inactivation were shorter with KCNE1 and KCNE3-5 while time-to-peak was decreased, and V-0.5 of steady-state inactivation was shifted to more negative potentials by all KCNE subunits. Importantly, KCNE2 induced a unique and prominent 'overshoot' of peak current during recovery from inactivation similar to that described for human I-to while other KCNE subunits induced little (KCNE4,5) or no overshoot. Conclusions: All KCNEs are expressed in the human heart at the transcript level. Compared to It. in native human myocytes, none of the combination of KChIP2 and KCNE produced an ideal congruency in current characteristics, suggesting that additional factors contribute to the regulation of the native I-to channel

Spontaneous emission of radiation by metallic electrons in the presence of electromagnetic fields of surface plasmon oscillations

The spontaneous emission of radiation of metallic electrons embedded in a high-intensity enhanced surface plasmon field is considered analytically. The electrons are described by exact dressed quantum states which contain the interaction with the plasmon field non-perturbatively. Considerable deviations from the pertubative behaviour have been found in the intensity dependence of the emitted fundamental and the second harmonic signals, even at moderate incoming laser intensities. The theoretical predictions deduced from the formalism are in good qualitative agreement with the experimental results.Comment: 23 pages, 6 figure

Non-functional properties in the model-driven development of service-oriented systems

Systems based on the service-oriented architecture (SOA) principles have become an important cornerstone of the development of enterprise-scale software applications. They are characterized by separating functions into distinct software units, called services, which can be published, requested and dynamically combined in the production of business applications. Service-oriented systems (SOSs) promise high flexibility, improved maintainability, and simple re-use of functionality. Achieving these properties requires an understanding not only of the individual artifacts of the system but also their integration. In this context, non-functional aspects play an important role and should be analyzed and modeled as early as possible in the development cycle. In this paper, we discuss modeling of non-functional aspects of service-oriented systems, and the use of these models for analysis and deployment. Our contribution in this paper is threefold. First, we show how services and service compositions may be modeled in UML by using a profile for SOA (UML4SOA) and how non-functional properties of service-oriented systems can be represented using the non-functional extension of UML4SOA (UML4SOA-NFP) and the MARTE profile. This enables modeling of performance, security and reliable messaging. Second, we discuss formal analysis of models which respect this design, in particular we consider performance estimates and reliability analysis using the stochastically timed process algebra PEPA as the underlying analytical engine. Last but not least, our models are the source for the application of deployment mechanisms which comprise model-to-model and model-to-text transformations implemented in the framework VIATRA. All techniques presented in this work are illustrated by a running example from an eUniversity case study

Entangled States and Entropy Remnants of a Photon-Electron System

In the present paper an example of entanglement between two different kinds of interacting particles, photons and electrons is analysed. The initial-value problem of the Schroedinger equation is solved non-perturbatively for the system of a free electron interacting with a quantized mode of the electromagnetic radiation. Wave packets of the dressed states so obtained are constructed in order to describe the spatio-temporal separation of the subsystems before and after the interaction. The joint probability amplitudes are calculated for the detection of the electron at some space-time location and the detection of a definite number of photons. The analytical study of the time evolution of entanglement between the initially separated electron wave packet and the radiation mode leads to the conclusion that in general there are non-vanishing entropy remnants in the subsystems after the interaction. On the basis of the simple model to be presented here, the calculated values of the entropy remnants crucially depend on the character of the switching-on and off of the interaction.Comment: 12 pages, 2 figure

Reverse engineering of model transformations for reusability

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-08789-4_14Proceedings of 7th International Conference, ICMT 2014, Held as Part of STAF 2014, York, UK, July 21-22, 2014Reuse techniques are key for the industrial adoption of Model-Driven Engineering (MDE). However, while reusability has been successfully applied to programming languages, its use is scarce in MDE and, in particular, in model transformations. In previous works, we developed an approach that enables the reuse of model transformations for different meta-models. This is achieved by defining reusable components that encapsulate a generic transformation template and expose an interface called concept declaring the structural requirements that any meta-model using the component should fulfil. Binding the concept to one of such meta-models induces an adaptation of the template, which becomes applicable to the meta-model. To facilitate reuse, concepts need to be concise, reflecting only the minimal set of requirements demanded by the transformation. In this paper, we automate the reverse engineering of existing transformations into reusable transformation components. To make a transformation reusable, we use the information obtained from its static analysis to derive a concept that is minimal with respect to the transformation and maximizes its reuse opportunities, and then evolve the transformation accordingly. The paper describes a prototype implementation and an evaluation using transformations from the ATL zoo.This work has been funded by the Spanish Ministry of Economy and Competitivity with project “Go Lite” (TIN2011-24139

Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

Background: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti- inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 mM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl 2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 mg/kg) significantly lengthened the QT c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT c . Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 mM) decreased the amplitude of rapid (I Kr ) and slow (I Ks ) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I Ca ) was slightly diminished, but the transient outward (I to ) and inward rectifier (I K1 ) potassium currents were not influenced. Conclusions: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve

Genome-Wide Identification of Expression Quantitative Trait Loci (eQTLs) in Human Heart.

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits

Graphical Encoding of a Spatial Logic for the pi-Calculus

This paper extends our graph-based approach to the verification of spatial properties of π-calculus specifications. The mechanism is based on an encoding for mobile calculi where each process is mapped into a graph (with interfaces) such that the denotation is fully abstract with respect to the usual structural congruence, i.e., two processes are equivalent exactly when the corresponding encodings yield isomorphic graphs. Behavioral and structural properties of π-calculus processes expressed in a spatial logic can then be verified on the graphical encoding of a process rather than on its textual representation. In this paper we introduce a modal logic for graphs and define a translation of spatial formulae such that a process verifies a spatial formula exactly when its graphical representation verifies the translated modal graph formula

Reusable model transformation components with bentō

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-21155-8_5Building high-quality transformations that can be used in real projects is complex and time-consuming. For this reason, the ability to reuse existing transformations in different, unforeseen scenarios is very valuable. However, there is scarce tool support for this task. This paper presents bentō, a tool which supports the development and execution of reusable transformation components. In bentō, a reusable transformation is written as a regular ATL transformation, but it uses concepts as meta-models. Reuse is achieved by binding such concepts to meta-models, which induces the transformation adaptation. Moreover, composite components enable chaining transformations, and it is possible to convert an existing transformation into a reusable component. Bentō is implemented as an Eclipse plug-in, available as free software.This work was supported by the Spanish Ministry of Economy and Competitivity with project Go-Lite (TIN2011-24139), the R&D programme of the Madrid Region with project (SICOMORO S2013/ICE-3006), and the EU commission with project MONDO (FP7-ICT 2013-10, #611125)