Multiscale Modeling of Influenza A Virus Infection Supports the Development of Direct-Acting Antivirals

Influenza A viruses are respiratory pathogens that cause seasonal epidemics with up to 500,000 deaths each year. Yet there are currently only two classes of antivirals licensed for treatment and drug-resistant strains are on the rise. A major challenge for the discovery of new anti-influenza agents is the identification of drug targets that efficiently interfere with viral replication. To support this step, we developed a multiscale model of influenza A virus infection which comprises both the intracellular level where the virus synthesizes its proteins, replicates its genome, and assembles new virions and the extracellular level where it spreads to new host cells. This integrated modeling approach recapitulates a wide range of experimental data across both scales including the time course of all three viral RNA species inside an infected cell and the infection dynamics in a cell population. It also allowed us to systematically study how interfering with specific steps of the viral life cycle affects virus production. We find that inhibitors of viral transcription, replication, protein synthesis, nuclear export, and assembly/release are most effective in decreasing virus titers whereas targeting virus entry primarily delays infection. In addition, our results suggest that for some antivirals therapy success strongly depends on the lifespan of infected cells and, thus, on the dynamics of virus-induced apoptosis or the host's immune response. Hence, the proposed model provides a systems-level understanding of influenza A virus infection and therapy as well as an ideal platform to include further levels of complexity toward a comprehensive description of infectious diseases

A Molecular and Co-Evolutionary Context for Grazer Induced Toxin Production in Alexandrium tamarense

Marine dinoflagellates of the genus Alexandrium are the proximal source of neurotoxins associated with Paralytic Shellfish Poisoning. The production of these toxins, the toxin biosynthesis and, thus, the cellular toxicity can be influenced by abiotic and biotic factors. There is, however, a lack of substantial evidence concerning the toxins' ecological function such as grazing defense. Waterborne cues from copepods have been previously found to induce a species-specific increase in toxin content in Alexandrium minutum. However, it remains speculative in which context these species-specific responses evolved and if it occurs in other Alexandrium species as well. In this study we exposed Alexandrium tamarense to three copepod species (Calanus helgolandicus, Acartia clausii, and Oithona similis) and their corresponding cues. We show that the species-specific response towards copepod-cues is not restricted to one Alexandrium species and that co-evolutionary processes might be involved in these responses, thus giving additional evidence for the defensive role of phycotoxins. Through a functional genomic approach we gained insights into the underlying molecular processes which could trigger the different outcomes of these species-specific responses and consequently lead to increased toxin content in Alexandrium tamarense. We propose that the regulation of serine/threonine kinase signaling pathways has a major influence in directing the external stimuli i.e. copepod-cues, into different intracellular cascades and networks in A. tamarense. Our results show that A. tamarense can sense potential predating copepods and respond to the received information by increasing its toxin production. Furthermore, we demonstrate how a functional genomic approach can be used to investigate species interactions within the plankton community

A multi-scale model of influenza virus infection elucidates the performance of antivirals

This contribution deals with the analysis of the renovation layer quality of continuous casting steel rolls, developed through the submerged arc surfacing method (SAW). The continuous casting roll was analysed via the degradation phenomena which act during the operation. Four kinds of filler materials were used for the renovation of the worn roll. Surfacing was carried out as a three-layer in order to eliminate the need for intermediate layer formation. The quality of weld deposits was evaluated in terms of the structure, hardness and wear resistance of weld deposits at 23°C and 400 °C using pin-on-disc wear test. The best properties showed newly developed filler material W8-WLDC8 from the point of view of the hardness, together with wear resistance of the deposited layers in room and elevated temperatures