Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.

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Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Signaling Recognition Events with Fluorescent Sensors and Switches.

A main bottleneck in proteomics is the downstream biological analysis of highly multivariate quantitative protein abundance data generated using mass-spectrometry-based analysis. We developed the Perseus software platform (http://www.perseus-framework.org) to support biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiple-hypothesis testing. A machine learning module supports the classification and validation of patient groups for diagnosis and prognosis, and it also detects predictive protein signatures. Central to Perseus is a user-friendly, interactive workflow environment that provides complete documentation of computational methods used in a publication. All activities in Perseus are realized as plugins, and users can extend the software by programming their own, which can be shared through a plugin store. We anticipate that Perseus's arsenal of algorithms and its intuitive usability will empower interdisciplinary analysis of complex large data sets.

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The Perseus computational platform for comprehensive analysis of (prote)omics data.

This review compiles positively and negatively solvatochromic compounds which have been used to establish empirical scales of solvent polarity by means of UV/vis/near-IR spectroscopic measurements in solution-with particular emphasis on the E ~ ( 3 0 ) scale derived from negatively solvatochromic pyridinium N-phenolate betaine dyes. This requires a short discussion of the concept of solvent polarity and how empirical parameters of solvent polarity can be derived and understood in the framework of linear free-energy relationships. The preconditions for the occurrence of solvatochromism, and further requirements of solvatochromic compounds for them to be useful as solvent polarity indicators will be discussed. In addition to spectroscopically based single parameters of solvent polarity, multiparameter treatments of solvent effects by means of solvatochromic parameters will also be mentioned. The mutual interrelation between some of the more important W/vis/near-IR spectroscopically derived solvent scales, and their correlations with solvatochromic multiparameter equations will be exemplarily given.

Solvatochromic Dyes as Solvent Polarity Indicators

Fluorescence intensity in a spectrofluorometer is proportional to the concentration of analyte over a wide dynamic range and is, therefore, an excellent quantitative analytical tool. In this paper we use the techniques of deconvolution and convolution to extend the utility of quantitative fluorescence to the measurement of analyte concentrations inside cells and their organelles. This permits us to assess the physiological state of living cells in situ. To successfully turn a voxel within a 3D image into a microcuvette, 2 conditions must be met. First, to be sure the voxel is associated with only one fluorescent structure, the object that is being measured must be fully resolved from neighboring objects in all three dimensions. For structures separated by distances larger than about 300nm in the xy plane or 600nm in z (where z is the optical axis), this can be achieved with either digital deconvolution of 3D widefield images or by confocal microscopy.

Convolution and Deconvolution For 3D Imaging Of Cell Physiology

T-tubules (TT) are invaginations of the surface sarcolemma (SS) that mediate the rapid propagation of the action potential (AP) to the cardiomyocyte core. We employed the advantages of an ultrafast random access multi-photon (RAMP) microscope (Sacconi et al., PNAS 2012) with a double staining approach to optically record t-tubular AP and, simultaneously, the corresponding local Ca2+-release in different positions across the cardiomyocytes. Despite a uniform AP between SS and TT at steady-state stimulation, in control cardiomyocytes we observed a non-negligible be variability of local Ca2+-transient amplitude and kinetics. This variability was significantly reduced by applying 0.1μM Isoproterenol, which increases the opening probability of Ca2+-release units. In the rat heart failure model (HF), we previously demonstrated that some tubular elements fail to propagate AP. We found that the tubules unable to propagate AP, displayed a reduced correspondent Ca2+-transient amplitude as well as a slower Ca2+ rise compared to electrically coupled tubules. Moreover variability of Ca2+-transient kinetics were increased in HF. Finally, TT that did not show AP, occasionally exhibited spontaneous depolarizations that were never accompanied by local Ca2+-release in the absence of any pro-arrhythmogenic stimulation. Simultaneous recording of AP and Ca2+-transient allows us to probe the spatio-temporal variability of Ca2+-release, whereas the investigation of Ca2+-transient in HF discloses an unexpected uncoupling between t-tubular depolarization and Ca2+-release in remodeled tubules. This work was funded by the European Union 7th Framework Program (FP7/2007- 2013) under grant agreement n° 284464, 241526, by the Italian Ministry of University and Research (NANOMAX), and by Telethon-Italy (GGP13162).

Simultaneous recording of t-tubular electrical activity and Ca2+-release in heart failure

Introduction: Mechanisms underlying cardiac arrhythmias are typically driven by abnormalities in cardiac conduction and/or heterogeneities in repolarization time (RT) across the heart. While conduction slowing can be caused by either electrophysiological defects or physical blockade in cardiac tissue, RT heterogeneities are mainly related to action potential (AP) prolongation or abbreviation in specific areas of the heart. Importantly, the size of the area with altered RT and the difference between the short RT and long RT (RT gradient) have been identified as critical determinators of arrhythmogenicity. However, current experimental methods for manipulating RT gradient rely on the use of ion channel inhibitors, which lack spatial and temporal specificity and are commonly only partially reversible. Therefore, the conditions facilitating sustained arrhythmia upon the presence of RT heterogeneities and/or defects in cardiac conduction remain to be elucidated. Methods: We here employ an approach based on optogenetic stimulation in a low-intensity fashion (sub-threshold illumination), to selectively manipulate cardiac electrical activity in defined areas of the heart. Results: As previously described, subthreshold illumination is a robust tool able to prolong action potentials (AP), decrease upstroke velocity as well as slow cardiac conduction, in a fully reversible manner. By applying a patterned sub-threshold illumination in intact mouse hearts constitutively expressing the light-gated ion channel channelrhodopsin-2 (ChR2), we optically manipulate RT gradients and cardiac conduction across the heart in a spatially selective manner. Moreover, in a proof-of-concept assessment we found that in the presence of patterned sub-threshold illumination, mouse hearts were more susceptible to arrhythmias. Hence, this optogenetic-based approach may be able to mimic conduction slowing and RT heterogeneities present in pathophysiological conditions.

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Optogenetic manipulation of cardiac repolarization gradients using sub-threshold illumination

Physiological cytosolic Ca2+transients evokeconcurrent mitochondrial depolarizations (membrane potential/fluorescence/bioenergetics/image

The Virtual Cell is a simulation package created by the National Resource for Cell Analysis and Modeling (NRCAM). It enables users to model cell biological processes [J.C. Schaff et al. (2001)]. The core of the Virtual Cell is solving a system of PDEs. Sequential runs of the Virtual Cell can take large amounts of time and hence parallelization is needed. In this paper we present a parallel implementation of a model that is inspired by the one-dimensional version of the Virtual Cell. Our experimental results show that this parallelization is quite effective. In particular, the speedups we obtain are good implying that the parallel techniques employed could improve the performance of the Virtual Cell.

Leslie M. Loew

Papers

Convolution and Deconvolution For 3D Imaging Of Cell Physiology

Simultaneous recording of t-tubular electrical activity and Ca2+-release in heart failure

Optogenetic manipulation of cardiac repolarization gradients using sub-threshold illumination

Physiological cytosolic Ca2+transients evokeconcurrent mitochondrial depolarizations (membrane potential/fluorescence/bioenergetics/image

Parallel techniques for Virtual Cell