After endocytic uptake, influenza viruses transit early endosomal compartments and eventually reach late endosomes. There, the viral glycoprotein hemagglutinin (HA) triggers fusion between endosomal and viral membrane, a critical step that leads to release of the viral segmented genome destined to reach the cell nucleus. Endosomal maturation is a complex process involving acidification of the endosomal lumen as well as endosome motility along microtubules. While the pH drop is clearly critical for the conformational change and membrane fusion activity of HA, the effect of intracellular transport dynamics on the progress of infection remains largely unclear. In this study, we developed a comprehensive mathematical model accounting for the first steps of influenza virus infection. We calibrated our model with experimental data and challenged its predictions using recombinant viruses with altered pH sensitivity of HA. We identified the time point of virus-endosome fusion and thereby the diffusion distance of the released viral genome to the nucleus as a critical bottleneck for efficient virus infection. Further, we concluded and supported experimentally that the viral RNA is subjected to cytosolic degradation strongly limiting the probability of a successful genome import into the nucleus.

SUMMARY: SensA is a web-based application for sensitivity analysis of mathematical models. The sensitivity analysis is based on metabolic control analysis, computing the local, global and time-dependent properties of model components. Interactive visualization facilitates interpretation of usually complex results. SensA can contribute to the analysis, adjustment and understanding of mathematical models for dynamic systems. AVAILABILITY AND IMPLEMENTATION: SensA is available at http://gofid.biologie.hu-berlin.de/ and can be used with any modern browser. The source code can be found at https://bitbucket.org/floettma/sensa/ (MIT license)

MOTIVATION: The rapid accumulation of knowledge in the field of Systems Biology during the past years requires advanced, but simple-to-use, methods for the visualization of information in a structured and easily comprehensible manner. RESULTS: We have developed biographer, a web-based renderer and editor for reaction networks, which can be integrated as a library into tools dealing with network-related information. Our software enables visualizations based on the emerging standard Systems Biology Graphical Notation. It is able to import networks encoded in various formats such as SBML, SBGN-ML and jSBGN, a custom lightweight exchange format. The core package is implemented in HTML5, CSS and JavaScript and can be used within any kind of web-based project. It features interactive graph-editing tools and automatic graph layout algorithms. In addition, we provide a standalone graph editor and a web server, which contains enhanced features like web services for the import and export of models and visualizations in different formats. AVAILABILITY: The biographer tool can be used at and downloaded from the web page http://biographer.biologie.hu-berlin.de/. The different software packages, including a server-independent version as well as a web server for Windows and Linux based systems, are available at http://code.google.com/p/biographer/ under the open-source license LGPL