Multiscale Modeling of Dyadic Structure-Function Relation in Ventricular Cardiac Myocytes.

Cardiovascular disease is often related to defects of subcellular components in cardiac myocytes, specifically in the dyadic cleft, which include changes in cleft geometry and channel placement. Modeling of these pathological changes requires both spatially resolved cleft as well as whole cell level descriptions. We use a multiscale model to create dyadic structure-function relationships to explore the impact of molecular changes on whole cell electrophysiology and calcium cycling.

A multiscale computational model of spatially resolved calcium cycling in cardiac myocytes: from detailed cleft dynamics to the whole cell concentration profiles.

Mathematical modeling of excitation-contraction coupling (ECC) in ventricular cardiac myocytes is a multiscale problem, and it is therefore difficult to develop spatially detailed simulation tools. ECC involves gradients on the length scale of 100 nm in dyadic spaces and concentration profiles along the 100 μm of the whole cell, as well as the sub-millisecond time scale of local concentration changes and the change of lumenal Ca(2+) content within tens of seconds. Our concept for a multiscale mathematical model of Ca(2+) -induced Ca(2+) release (CICR) and whole cardiomyocyte electrophysiology incorporates stochastic simulation of individual LC- and RyR-channels, spatially detailed concentration dynamics in dyadic clefts, rabbit membrane potential dynamics, and a system of partial differential equations for myoplasmic and lumenal free Ca(2+) and Ca(2+)-binding molecules in the bulk of the cell.

Attenuated and protease-profile modified sendai virus vectors as a new tool for virotherapy of solid tumors.

Multiple types of oncolytic viruses are currently under investigation in clinical trials. To optimize therapeutic outcomes it is believed that the plethora of different tumor types will require a diversity of different virus types. Sendai virus (SeV), a murine parainfluenza virus, displays a broad host range, enters cells within minutes and already has been applied safely as a gene transfer vector in gene therapy patients.

Evaluation of a novel immunogenic vaccine platform based on a genome replication-deficient Sendai vector.

We developed a novel vaccine platform based on a paramyxoviral, genome replication-deficient Sendai virus vector that can express heterologous genes inserted into the genome. To validate the novel approach in vivo, we generated a combined vaccine candidate against human respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (PIV3). The present study compares two different methods of displaying heterologous antigens: (i) the RSV fusion (F) protein, encoded as a secretable version in an additional transcription unit, serves as an antigen only after being expressed in infected cells; (ii) PIV3 fusion (F) and hemagglutinin-neuraminidase (HN) genes, replacing Sendai counterparts in the vector genome, are also expressed as structural components on the surface of vaccine particles.