RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays.

Elevated cytoplasmic [Ca2+] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [3H]ryanodine binding to RyR1 at nanomolar Ca2+. Both compounds also decrease RyR1 Ca2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by > 50% but only slightly affected Ca2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance

The communication processor of TUMULT-64

Tumult (Twente University MULTi-processor system) is a modular extendible multi-processor system designed and implemented at the Twente University of Technology in co-operation with Oce Nederland B.V. and the Dr. Neher Laboratories (Dutch PTT). Characteristics of the hardware are: MIMD type, distributed memory, message passing, high performance, real-time and fault tolerant. A distributed real-time operating system has been realized, consisting of a multi-tasking kernel per node, inter process communication via typed messages and a distributed file system. In this paper first a brief description of the system is given, after that the architecture of the communication processor will be discussed. Reduction of the communication overhead due to message passing will be emphasized.\ud \u

Constraint rule-based programming of norms for electronic institutions

Peer reviewedPostprin

The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network

Orthogonal learning particle swarm optimization

Particle swarm optimization (PSO) relies on its learning strategy to guide its search direction. Traditionally, each particle utilizes its historical best experience and its neighborhood’s best experience through linear summation. Such a learning strategy is easy to use, but is inefficient when searching in complex problem spaces. Hence, designing learning strategies that can utilize previous search information (experience) more efficiently has become one of the most salient and active PSO research topics. In this paper, we proposes an orthogonal learning (OL) strategy for PSO to discover more useful information that lies in the above two experiences via orthogonal experimental design. We name this PSO as orthogonal learning particle swarm optimization (OLPSO). The OL strategy can guide particles to fly in better directions by constructing a much promising and efficient exemplar. The OL strategy can be applied to PSO with any topological structure. In this paper, it is applied to both global and local versions of PSO, yielding the OLPSO-G and OLPSOL algorithms, respectively. This new learning strategy and the new algorithms are tested on a set of 16 benchmark functions, and are compared with other PSO algorithms and some state of the art evolutionary algorithms. The experimental results illustrate the effectiveness and efficiency of the proposed learning strategy and algorithms. The comparisons show that OLPSO significantly improves the performance of PSO, offering faster global convergence, higher solution quality, and stronger robustness

Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism.

Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems