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.
We design, analyze and numerically validate a novel discontinuous Galerkin method for solving the coagulation-fragmentation equations. The DG discretization is applied to the conservative form of the model, with flux terms evaluated by Gaussian quadrature with Q = k+1 quadrature points for polynomials of degree k. The positivity of the numerical solution is enforced through a simple scaling limiter based on positive cell averages. The positivity of cell averages is propagated by the time discretization provided a proper time step restriction is imposed.
In this article we prove the existence of solutions to the coagulation equation with singular kernels. We use weighted L 1 -spaces to deal with the singularities in order to obtain regular solutions. The Smoluchowski kernel is covered by our proof. The weak L 1 compactness methods are applied to suitably chosen approximating equations as a base of our proof. A more restrictive uniqueness result is also mentioned.
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