Simulation Methods and Validation Criteria for Modeling Cardiac Ventricular Electrophysiology

We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations.     

The Boundary Condition in the Gibbs Ensemble Simulation of a Stockmayer Fluid under an Applied Field

Abstract

We calculate the vapour-liquid coexistence properties of the Stockmayer fluid with reduced permanent dipole μ? = 2.0 under an applied electrostatic field E ₀? = 1.0 for various boundary conditions by the Gibbs ensemble simulation. In contrast to the system under no field, the phase behaviour of the Stockmayer fluid under the applied field calculated in simulation strongly depends on the dielectric constant of the surroundings used in the Hamiltonian. We propose that the value of the dielectric constant of the surroundings for the vapour and the liquid phase used in the simulation should be adjusted to that of the system in the corresponding phase, in order to best represent the thermodynamics of the bulk system under applied field.     

Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling

Aim

Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction.

Methods and Results

We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase^−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase^−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase^−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca²⁺) transient demonstrated profound Ca²⁺ handling abnormalities in 1α-OHase^−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D₃ analog, significantly attenuated defective Ca²⁺ handling in 1α-OHase^−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase^−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca²⁺ handling abnormalities and cardiac function compared to the vehicle treated animals.

Conclusions

Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca²⁺ handling and defective vitamin D signaling in 1α-OHase^−/− mice.     

一类竞争扩散方程组在Neumann边条件下解的渐近行为

本文主要采用比较方法讨论了一类竞争扩散方程组在Neumann边条件下解的渐近行为,得到了解的稳定性区域．     

High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors

[3H]Vardenafil (Levitra) or [3H]tadalafil (Cialis) binding was used to quantify PDE5 in rat lung and heart tissue. Each radioligand bound to purified recombinant phosphodiesterase-5 (PDE5) or to PDE5 in crude extracts with strong affinity, high specificity, slow dissociation, and good stoichiometry. PDE5, the only 3H inhibitor-binding protein detected in extracts, was 15 times higher in lung than in heart extracts, and the level measured by PDE5 catalytic activity agreed with that determined by 3H inhibitor binding. High level of PDE5 in lung approximated that in penile corpus cavernosum, the tissue targeted by PDE5 inhibitors. PDE5 was the predominant cGMP-PDE in lung, and on a molar basis was five times higher than cGMP-dependent protein kinase (PKG), which phosphorylates PDE5 in vivo. The PDE5 level was one-half that of PKG in heart. Thus, abundance of PDE5 in lung vascular smooth muscle provides a strong molecular basis for PDE5 inhibitor treatment of pulmonary hypertension.     

MHD Free Convective Boundary Layer Flow of a Nanofluid past a Flat Vertical Plate with Newtonian Heating Boundary Condition

Steady two dimensional MHD laminar free convective boundary layer flows of an electrically conducting Newtonian nanofluid over a solid stationary vertical plate in a quiescent fluid taking into account the Newtonian heating boundary condition is investigated numerically. A magnetic field can be used to control the motion of an electrically conducting fluid in micro/nano scale systems used for transportation of fluid. The transport equations along with the boundary conditions are first converted into dimensionless form and then using linear group of transformations, the similarity governing equations are developed. The transformed equations are solved numerically using the Runge-Kutta-Fehlberg fourth-fifth order method with shooting technique. The effects of different controlling parameters, namely, Lewis number, Prandtl number, buoyancy ratio, thermophoresis, Brownian motion, magnetic field and Newtonian heating on the flow and heat transfer are investigated. The numerical results for the dimensionless axial velocity, temperature and nanoparticle volume fraction as well as the reduced Nusselt and Sherwood number have been presented graphically and discussed. It is found that the rate of heat and mass transfer increase as Newtonian heating parameter increases. The dimensionless velocity and temperature distributions increase with the increase of Newtonian heating parameter. The results of the reduced heat transfer rate is compared for convective heating boundary condition and found an excellent agreement.     

DECA,A Comprehensive,Automatic Post-processing Program for HDX-MS Data*

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Highlights

• •Open source software for comprehensive HDX-MS data analysis.
• •Automatic back-exchange correction options.
• •Rigorous statistical analysis of the significance of uptake differences.
• •High quality visualization tools.

     

MixtureTree Annotator: A Program for Automatic Colorization and Visual Annotation of MixtureTree

The MixtureTree Annotator, written in JAVA, allows the user to automatically color any phylogenetic tree in Newick format generated from any phylogeny reconstruction program and output the Nexus file. By providing the ability to automatically color the tree by sequence name, the MixtureTree Annotator provides a unique advantage over any other programs which perform a similar function. In addition, the MixtureTree Annotator is the only package that can efficiently annotate the output produced by MixtureTree with mutation information and coalescent time information. In order to visualize the resulting output file, a modified version of FigTree is used. Certain popular methods, which lack good built-in visualization tools, for example, MEGA, Mesquite, PHY-FI, TreeView, treeGraph and Geneious, may give results with human errors due to either manually adding colors to each node or with other limitations, for example only using color based on a number, such as branch length, or by taxonomy. In addition to allowing the user to automatically color any given Newick tree by sequence name, the MixtureTree Annotator is the only method that allows the user to automatically annotate the resulting tree created by the MixtureTree program. The MixtureTree Annotator is fast and easy-to-use, while still allowing the user full control over the coloring and annotating process.     

对于未知来源个体进行族群推断的自动分析系统

建立一种基于概率算法、聚类分析和主成分分析的DNA族群推断系统(DNA Ancestry Analyzer Version1.0,简称DAA v1.0),用于对未知来源个体进行族群推断。DAA v1.0基础部分用Python语言、R语言、C语言编写;前端部分用node.js语言、HTML语言、css语言编写。DAA v1.0可对未知来源个体的族群进行推断,与已有分析方法相比,结果的一致性为100%,运算效率提升了600%。该系统可界面化、自动化地计算DNA来源人的群体匹配概率和似然比值、群体成分,绘制群体归类图,在人类遗传学、法医遗传学等领域有重要的应用价值。     

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.     

微波真空干燥大蒜片数学模型边界条件

本文通过确定大蒜片微波真空干燥的临界水分含量,修正Cu i等提出的胡萝卜片微波真空干燥动力学模型,使其适用于大蒜片,并对大蒜片与胡萝卜片微波真空干燥的临界水分含量不同的机理进行了探讨。采用质构仪和扫描电子显微镜分别对新鲜大蒜片、新鲜胡萝卜片以及干燥至边界条件下的大蒜片、胡萝卜片的质构和超微结构进行了测定。确定了大蒜片微波真空干燥的临界水分含量为Xw=1,在干燥后期对此模型进行了修正,修正系数为k=10.924e-3.2394Xw(0相似文献   

MatriX Generator （MG）：一个基于DNA片段的0／1矩阵生成程序

分子群体遗传学研究的特点是取样量人——存在于群体样本中的遗传变异必须要充分代表该群体和该物种的遗传变异量及分析的位点数多——位点样本必须恰当代表基因组。大样本的群体取样和位点取样产生大量的原始数据,使原始数据人工处理非常困难甚至不可能,从而迫切需要原始数据处理的自动化。目前一些大公司提供的凝胶图像收集仪器和配套的软件已经使原始数据的获取基本上自动化或半自动化。获得DNA片段分子量数据后,必须把这些分子量数据转变成可反映操作单位(样本)之间关系的数据矩阵,原来用于计算分子量的那些软件已不实用或派不上用场。目前,除了用于fAFLP的Binthere弥补了部分不足外,还没有此类软件。Binthere存在固定栏宽(Bin)的缺陷,也就是将分子量最大值与最小值之间等分的方法来归纳不同操作单位(OUT)之间的异同,使得分子量绝对值差很小的数据可能被归入不同的栏,导致结果不正确。为了解决这类问题,我们设计编写了一个新的软件,取名为Matrix Generator (MG)。与同类软件相比,MG具有两个主要优点：(1)采用动态栏宽和智能归并算法,克服了固定栏宽可能造成的错误：(2)可用于非荧光标记的分子标记技术。MG的基本思路是：分子量差异越小的片段,越可能是同缘片段,越应该处于相同的栏内。为此,我们采用绝对对应的动态过程。也就是说,从最小分子量到最大分子量之间的栏目数不是事先确定,而是由所分析的所有样品的特点和所使用的凝胶的分辨率(用户根据凝胶的特点给出数值)决定的。当两片段的差异小于凝胶所能达到的分辨率时,两片段被认为是同缘片段而归入相同的栏内。归并的过程从差异最小值开始,直至任意两片段的差异都大于凝胶的分辨率为止。这样就排除了同缘片段被隔离或者非同缘片段被合并的错误,从而使最可能同缘的片段归结在同一位点。MG第一版(v1．0,DOS版)集中体现了实用和易用的优点而没有包含同类软件所具有的一些功能,所以MG必须与其他软件结合使用。对于非荧光标记的分子标记技术,如RAPD、RFLP、AFLP等,可用Quantity One等软件得到分子量,用Excel生成样品与(分子量数据代表的)DNA片段矩阵,然后用MG处理。对于荧光标记的分子标记技术,如fAFIP、fSSR等,除可以用Excel牛成矩阵外,可直接用Binthere和Genotyper等生成分子量矩阵,然后用MG处理。MG输出的矩阵经过适当编辑后,就可用后续的软件如Paup、Ntsys、Philip等运算。为了检验MG的有效性,我们用六道木属(Abelia)的AFIJP分析数据进行检验,14个样品的DNA片段分别用Binthere和MG进行处理。前者得到295个含信息的位点,后者得到210个含信息的位点。用Nei and Li (1979)的算法分别计算距离矩阵并对两距离矩阵作Mantel检验。结果,两矩阵之间存在一定的差别,但相似性系数高达0．941 63,说明两种方法总体上会得到相似的结果,但局部会有所不同。用Paup对两矩阵作进一步分析,生成两个Neighbor-joining (NJ)树。结果表明,MG生成的数据更符合实际情况,而且分辨率高。     

Matrix Generator(MG):一个基于DNA片段的0/1矩阵生成程序

分子群体遗传学研究的特点是取样量大--存在于群体样本中的遗传变异必须要充分代表该群体和该物种的遗传变异量及分析的位点数多--位点样本必须恰当代表基因组.大样本的群体取样和位点取样产生大量的原始数据,使原始数据人工处理非常困难甚至不可能,从而迫切需要原始数据处理的自动化.目前一些大公司提供的凝胶图像收集仪器和配套的软件已经使原始数据的获取基本上自动化或半自动化.获得DNA片段分子量数据后,必须把这些分子量数据转变成可反映操作单位(样本)之间关系的数据矩阵,原来用于计算分子量的那些软件已不实用或派不上用场.目前,除了用于fAFLP的Binthere弥补了部分不足外,还没有此类软件.Binthere存在固定栏宽(Bin)的缺陷,也就是将分子量最大值与最小值之间等分的方法来归纳不同操作单位(OUT)之间的异同,使得分子量绝对值差很小的数据可能被归入不同的栏,导致结果不正确.为了解决这类问题,我们设计编写了一个新的软件,取名为Matrix Generator(MG).与同类软件相比,MG具有两个主要优点:(1)采用动态栏宽和智能归并算法,克服了固定栏宽可能造成的错误;(2)可用于非荧光标记的分子标记技术.MG的基本思路是:分子量差异越小的片段,越可能是同缘片段,越应该处于相同的栏内.为此,我们采用绝对对应的动态过程.也就是说,从最小分子量到最大分子量之间的栏目数不是事先确定,而是由所分析的所有样品的特点和所使用的凝胶的分辨率(用户根据凝胶的特点给出数值)决定的.当两片段的差异小于凝胶所能达到的分辨率时,两片段被认为是同缘片段而归入相同的栏内.归并的过程从差异最小值开始,直至任意两片段的差异都大于凝胶的分辨率为止.这样就排除了同缘片段被隔离或者非同缘片段被合并的错误,从而使最可能同缘的片段归结在同一位点.MG第一版(V1.0,DOS版)集中体现了实用和易用的优点而没有包含同类软件所具有的一些功能,所以MG必须与其他软件结合使用.对于非荧光标记的分子标记技术,如RAPD、RFLP、AFLP等,可用Quantity One等软件得到分子量,用Excel生成样品与(分子量数据代表的)DNA片段矩阵,然后用MG处理.对于荧光标记的分子标记技术,如fAFLP、fSSR等,除可以用Excel生成矩阵外,可直接用Binthere和Genotyper等生成分子量矩阵,然后用MG处理.MG输出的矩阵经过适当编辑后,就可用后续的软件如Paup、Ntsys、Philip等运算.为了检验MG的有效性,我们用六道木属(Abelia)的AFLP分析数据进行检验,14个样品的DNA片段分别用Binthere和MG进行处理.前者得到295个含信息的位点,后者得到210个含信息的位点.用Nei and Li(1979)的算法分别计算距离矩阵并对两距离矩阵作Mantel检验.结果,两矩阵之间存在一定的差别,但相似性系数高达0.941 63,说明两种方法总体上会得到相似的结果,但局部会有所不同.用Paup对两矩阵作进一步分析,生成两个Neighbor-joining(NJ)树.结果表明,MG生成的数据更符合实际情况,而且分辨率高.     

Identifying Regulators for EAG1 Channels with a Novel Electrophysiology and Tryptophan Fluorescence Based Screen

Background

Ether-à-go-go (EAG) channels are expressed throughout the central nervous system and are also crucial regulators of cell cycle and tumor progression. The large intracellular amino- and carboxy- terminal domains of EAG1 each share similarity with known ligand binding motifs in other proteins, yet EAG1 channels have no known regulatory ligands.

Methodology/Principal Findings

Here we screened a library of small biologically relevant molecules against EAG1 channels with a novel two-pronged screen to identify channel regulators. In one arm of the screen we used electrophysiology to assess the functional effects of the library compounds on full-length EAG1 channels. In an orthogonal arm, we used tryptophan fluorescence to screen for binding of the library compounds to the isolated C-terminal region.

Conclusions/Significance

Several compounds from the flavonoid, indole and benzofuran chemical families emerged as binding partners and/or regulators of EAG1 channels. The two-prong screen can aid ligand and drug discovery for ligand-binding domains of other ion channels.     

Automatic 4D Reconstruction of Patient-Specific Cardiac Mesh with 1-to-1 Vertex Correspondence from Segmented Contours Lines

We propose an automatic algorithm for the reconstruction of patient-specific cardiac mesh models with 1-to-1 vertex correspondence. In this framework, a series of 3D meshes depicting the endocardial surface of the heart at each time step is constructed, based on a set of border delineated magnetic resonance imaging (MRI) data of the whole cardiac cycle. The key contribution in this work involves a novel reconstruction technique to generate a 4D (i.e., spatial–temporal) model of the heart with 1-to-1 vertex mapping throughout the time frames. The reconstructed 3D model from the first time step is used as a base template model and then deformed to fit the segmented contours from the subsequent time steps. A method to determine a tree-based connectivity relationship is proposed to ensure robust mapping during mesh deformation. The novel feature is the ability to handle intra- and inter-frame 2D topology changes of the contours, which manifests as a series of merging and splitting of contours when the images are viewed either in a spatial or temporal sequence. Our algorithm has been tested on five acquisitions of cardiac MRI and can successfully reconstruct the full 4D heart model in around 30 minutes per subject. The generated 4D heart model conforms very well with the input segmented contours and the mesh element shape is of reasonably good quality. The work is important in the support of downstream computational simulation activities.     

A Computer Simulation of an Intracellular Mechanism for the Generation and Suppression of Cardiac Arrhythmias

Biophysics - Abstract—This paper reports an analysis of a stochastic model of ion dynamics in the cardiac pacemaker cell within the framework of the generalized two-oscillator...     

Double Diffusive Magnetohydrodynamic (MHD) Mixed Convective Slip Flow along a Radiating Moving Vertical Flat Plate with Convective Boundary Condition

In this study combined heat and mass transfer by mixed convective flow along a moving vertical flat plate with hydrodynamic slip and thermal convective boundary condition is investigated. Using similarity variables, the governing nonlinear partial differential equations are converted into a system of coupled nonlinear ordinary differential equations. The transformed equations are then solved using a semi-numerical/analytical method called the differential transform method and results are compared with numerical results. Close agreement is found between the present method and the numerical method. Effects of the controlling parameters, including convective heat transfer, magnetic field, buoyancy ratio, hydrodynamic slip, mixed convective, Prandtl number and Schmidt number are investigated on the dimensionless velocity, temperature and concentration profiles. In addition effects of different parameters on the skin friction factor, , local Nusselt number, , and local Sherwood number are shown and explained through tables.     

Surfactant Therapy for Patients with ARDS After Cardiac Surgery

This multicenter study investigated the possibility of reducing mortality rate by administering natural lung surfactant additional to standard therapy to treat patients after cardiac surgery who developed an acute respiratory failure (ARDS/ALI).

A total of 78 patients (1998–2002) diagnosed with ALI or ARDS were enrolled in the study; patients were considered for study entry only if they developed ALI/ARDS within 72h after cardiac surgery. A total of 36 patients (2000–2002) received Surfactant-BL via bronchoscope at a dose of 3 mg/kg twice a day, and 42 patients (1998–2000) served as the historical control.

Within 24h after the first Surfactant-BL administration the PaO₂/FiO₂ ratio increased from (mean ± SEM) 129.7 ± 9.9 mm Hg to 187.6 ± 17.6 mm Hg (p < 0.01), FiO₂ decreased from (mean ± SEM) 0.71 ± 0.03 to 0.56 ± 0.03 (p < 0.01), and 69.4% of the patients treated with surfactant were weaned from the ventilator compared with 50% of the control group during a 28-day period. The mortality rate among patients treated with Surfactant-BL was 30.6% compared with 50% in the control group.

In conclusion, early administration of Surfactant-BL leads to the reduction of mortality in cardiac patients who develop postoperatively an ALI or ARDS.