scholarly journals Three-Dimensional Heart Model-Based Screening of Proarrhythmic Potential by in silico Simulation of Action Potential and Electrocardiograms

2019 ◽  
Vol 10 ◽  
Author(s):  
Minki Hwang ◽  
Seunghoon Han ◽  
Min Cheol Park ◽  
Chae Hun Leem ◽  
Eun Bo Shim ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Three Dimensional ◽  
Heart Model ◽  
Model Based ◽  
In Silico Simulation

scholarly journals Characterization of a novel LQT3 variant with a selective efficacy of mexiletine treatment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyun-Ji Kim ◽  
Bok-Geon Kim ◽  
Jong Eun Park ◽  
Chang-Seok Ki ◽  
June Huh ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Action Potential ◽  
In Silico ◽  
Voltage Dependence ◽  
Underlying Mechanism ◽  
Sustained Ventricular Tachycardia ◽  
Inactivation Kinetics ◽  
Channel Blockers ◽  
Prolonged Action ◽  
In Silico Simulation

Abstract Pathogenic variants in the human SCN5A gene encoding the a-subunit of the principle Na+ channel (Nav1.5) are associated with long QT syndrome (LQTS) 3. LQT3 patients display variable responses to Na+ channel blockers demanding for the development of variant-specific therapeutic strategies. Here we performed a combined electrophysiological analysis with in silico simulation of variant channel to elucidate mechanisms of therapeutic responsiveness. We identified a novel SCN5A variant (A1656D) in a LQTS patient with a distinct response to mexiletine resulting in suppression of non-sustained ventricular tachycardia and manifestation of premature atrial contraction. Patch clamp analysis revealed that A1656D variant exerted gain-of-function effects including hyperpolarizing shift of the voltage-dependence of activation, depolarizing shift in the voltage-dependence of inactivation, and slowing of fast inactivation. Among ranolazine, flecainide, and mexiletine, only mexiletine restored inactivation kinetics of A1656D currents. In silico simulation to assess the effect of A1656D variant on ventricular cardiac cell excitation predicted a prolonged action potential which is consistent with the prolonged QT and non-sustained ventricular tachycardia of the patient. It also predicted that only mexiletine suppressed the prolonged action potential of human ventricular myocytes expressing A1656D. These data elucidate the underlying mechanism of the distinct response to mexiletine in this patient.

In Silico Identification and Molecular Characterization of Extracellular Cathepsin L Proteases from Giardia duodenalis

2020 ◽  
Vol 17 (4) ◽  
pp. 342-351
Author(s):  
Sergio A. Durán-Pérez ◽  
José G. Rendón-Maldonado ◽  
Lucio de Jesús Hernandez-Diaz ◽  
Annete I. Apodaca-Medina ◽  
Maribel Jiménez-Edeza ◽  
...  
Keyword(s):  
In Silico ◽  
Cathepsin L ◽  
Three Dimensional ◽  
Giardia Duodenalis ◽  
Evolutionary Genetics ◽  
Extracellular Proteins ◽  
In Silico Identification ◽  
Dimensional Models ◽  
Three Dimensional Models

Background: The protozoan Giardia duodenalis, which causes giardiasis, is an intestinal parasite that commonly affects humans, mainly pre-school children. Although there are asymptomatic cases, the main clinical features are chronic and acute diarrhea, nausea, abdominal pain, and malabsorption syndrome. Little is currently known about the virulence of the parasite, but some cases of chronic gastrointestinal alterations post-infection have been reported even when the infection was asymptomatic, suggesting that the cathepsin L proteases of the parasite may be involved in the damage at the level of the gastrointestinal mucosa. Objective: The aim of this study was the in silico identification and characterization of extracellular cathepsin L proteases in the proteome of G. duodenalis. Methods: The NP_001903 sequence of cathepsin L protease from Homo sapienswas searched against the Giardia duodenalisproteome. The subcellular localization of Giardia duodenaliscathepsin L proteases was performed in the DeepLoc-1.0 server. The construction of a phylogenetic tree of the extracellular proteins was carried out using the Molecular Evolutionary Genetics Analysis software (MEGA X). The Robetta server was used for the construction of the three-dimensional models. The search for possible inhibitors of the extracellular cathepsin L proteases of Giardia duodenaliswas performed by entering the three-dimensional structures in the FINDSITEcomb drug discovery tool. Results: Based on the amino acid sequence of cathepsin L from Homo sapiens, 8 protein sequences were identified that have in their modular structure the Pept_C1A domain characteristic of cathepsins and two of these proteins (XP_001704423 and XP_001704424) are located extracellularly. Threedimensional models were designed for both extracellular proteins and several inhibitory ligands with a score greater than 0.9 were identified. In vitrostudies are required to corroborate if these two extracellular proteins play a role in the virulence of Giardia duodenalisand to discover ligands that may be useful as therapeutic targets that interfere in the mechanism of pathogenesis generated by the parasite. Conclusion: In silicoanalysis identified two proteins in the Giardia duodenalisprotein repertoire whose characteristics allowed them to be classified as cathepsin L proteases, which may be secreted into the extracellular medium to act as virulence factors. Three-dimensional models of both proteins allowed the identification of inhibitory ligands with a high score. The results suggest that administration of those compounds might be used to block the endopeptidase activity of the extracellular cathepsin L proteases, interfering with the mechanisms of pathogenesis of the protozoan parasite Giardia duodenalis.

Design and Marker-Based Validation of a Biplane Fluoroscopy System for Studying the Foot and Ankle

2012 ◽  
Author(s):  
Joseph M. Iaquinto ◽  
Richard Tsai ◽  
Michael J. Fassbind ◽  
David R. Haynor ◽  
Bruce J. Sangeorzan ◽  
...  
Keyword(s):  
Precise Measurement ◽  
Three Dimensional ◽  
The Body ◽  
Initial Evaluation ◽  
Foot And Ankle ◽  
Research Groups ◽  
The Past ◽  
Model Based ◽  
Biplane Fluoroscopy ◽  
Model Based Analysis

The ability to accurately measure three dimensional (3D) bone kinematics is key to understanding the motion of the joints of the body, and how such motion is altered by injury, disease, and treatment. Precise measurement of such kinematics is technically challenging. Biplane fluoroscopy is ideally suited to measure bone motion. Such systems have been developed in the past for both radiographic stereo-photogrammetric analysis (RSA) [1] and the more challenging model-based analysis [2]. Research groups have studied the knee [3,4], shoulder [5] and ankle [6] motion with similar techniques. The work presented here is an initial evaluation of the performance of our system, i.e., a validation that this in-house system can detect magnitudes of motion on-par with other existing systems.

Model-Based Three-Dimensional Vision System

1989 ◽  
Author(s):  
Keiichi Kemmotsu ◽  
Yuichi Sasano ◽  
Katsumi Oshitani
Keyword(s):  
Vision System ◽  
Three Dimensional ◽  
Model Based ◽  
Three Dimensional Vision

scholarly journals Extracting Surface Activation Time from the Optically Recorded Action Potential in Three-Dimensional Myocardium

2012 ◽  
Vol 102 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Richard D. Walton ◽  
Rebecca M. Smith ◽  
Bogdan G. Mitrea ◽  
Edward White ◽  
Olivier Bernus ◽  
...  
Keyword(s):  
Action Potential ◽  
Three Dimensional ◽  
Surface Activation ◽  
Activation Time

An Approach to Generate Three Dimensional Machining Process Model According to Information from Design Model Based on Definition

2016 ◽  
Vol 693 ◽  
pp. 1684-1692 ◽  
Author(s):  
Hong Lei Zhang ◽  
Wen He Liao ◽  
Yu Guo ◽  
Wen An Yang
Keyword(s):  
Process Model ◽  
Three Dimensional ◽  
Design Model ◽  
Machining Process ◽  
Model Generation ◽  
Geometric Models ◽  
Model Based

Faced with the problem of generation for 3D machining process model, an approach to generate three dimensional machining process model according to information from design model based on definition is proposed. Compared with the existing methods, the approach utilizes multiple information of design model based on definition and takes many phases into consideration of 3D process model generation. The structure of 3D machining process model is defined and the course of 3D process model generation is researched, including multiple information acquirement, generation of procedure geometric models and annotation. Finally, the framework of system and application for 3D machining process model generation are presented for validation purposes.

Sign in / Sign up

Export Citation Format

Share Document