Respiratory viruses present major public health challenges, as evidenced by the 1918 Spanish Flu, the 1957 H2N2, 1968 H3N2, and 2009 H1N1 influenza pandemics, and the ongoing severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) pandemic. Severe RNA virus respiratory infections often correlate with high viral load and excessive inflammation. Understanding the dynamics of the innate immune response and its manifestations at the cell and tissue levels is vital to understanding the mechanisms of immunopathology and to developing strain-independent treatments. Here, we present a novel spatialized multicellular computational model of RNA virus infection and the type-I interferon-mediated antiviral response that it induces within lung epithelial cells. The model is built using the CompuCell3D multicellular simulation environment and is parameterized using data from influenza virus-infected cell cultures. Consistent with experimental observations, it exhibits either linear radial growth of viral plaques or arrested plaque growth depending on the local concentration of type I interferons. The model suggests that modifying the activity of signaling molecules in the JAK/STAT pathway or altering the ratio of the diffusion lengths of interferon and virus in the cell culture could lead to plaque growth arrest. The dependence of plaque growth arrest on diffusion lengths highlights the importance of developing validated spatial models of cytokine signaling and the need for in vitro measurement of these diffusion coefficients. Sensitivity analyses under conditions leading to continuous or arrested plaque growth found that plaque growth is more sensitive to variations of most parameters and more likely to have identifiable model parameters when conditions lead to plaque arrest. This result suggests that cytokine assay measurements may be most informative under conditions leading to arrested plaque growth. The model is easy to extend to include SARS-CoV-2-specific mechanisms or to use as a component in models linking epithelial cell signaling to systemic immune models.
Simulations of tissue-specific effects of primary acute viral infections like COVID-19 are essential for understanding disease outcomes and optimizing therapies. Such simulations need to support ...continuous updating in response to rapid advances in understanding of infection mechanisms, and parallel development of components by multiple groups. We present an open-source platform for multiscale spatiotemporal simulation of an epithelial tissue, viral infection, cellular immune response and tissue damage, specifically designed to be modular and extensible to support continuous updating and parallel development. The base simulation of a simplified patch of epithelial tissue and immune response exhibits distinct patterns of infection dynamics from widespread infection, to recurrence, to clearance. Slower viral internalization and faster immune-cell recruitment slow infection and promote containment. Because antiviral drugs can have side effects and show reduced clinical effectiveness when given later during infection, we studied the effects on progression of treatment potency and time-of-first treatment after infection. In simulations, even a low potency therapy with a drug which reduces the replication rate of viral RNA greatly decreases the total tissue damage and virus burden when given near the beginning of infection. Many combinations of dosage and treatment time lead to stochastic outcomes, with some simulation replicas showing clearance or control (treatment success), while others show rapid infection of all epithelial cells (treatment failure). Thus, while a high potency therapy usually is less effective when given later, treatments at late times are occasionally effective. We illustrate how to extend the platform to model specific virus types (e.g., hepatitis C) and add additional cellular mechanisms (tissue recovery and variable cell susceptibility to infection), using our software modules and publicly-available software repository.
The biophysics of an organism span multiple scales from subcellular to organismal and include processes characterized by spatial properties, such as the diffusion of molecules, cell migration, and ...flow of intravenous fluids. Mathematical biology seeks to explain biophysical processes in mathematical terms at, and across, all relevant spatial and temporal scales, through the generation of representative models. While non-spatial, ordinary differential equation (ODE) models are often used and readily calibrated to experimental data, they do not explicitly represent the spatial and stochastic features of a biological system, limiting their insights and applications. However, spatial models describing biological systems with spatial information are mathematically complex and computationally expensive, which limits the ability to calibrate and deploy them and highlights the need for simpler methods able to model the spatial features of biological systems.
In this work, we develop a formal method for deriving cell-based, spatial, multicellular models from ODE models of population dynamics in biological systems, and vice versa. We provide examples of generating spatiotemporal, multicellular models from ODE models of viral infection and immune response. In these models, the determinants of agreement of spatial and non-spatial models are the degree of spatial heterogeneity in viral production and rates of extracellular viral diffusion and decay. We show how ODE model parameters can implicitly represent spatial parameters, and cell-based spatial models can generate uncertain predictions through sensitivity to stochastic cellular events, which is not a feature of ODE models. Using our method, we can test ODE models in a multicellular, spatial context and translate information to and from non-spatial and spatial models, which help to employ spatiotemporal multicellular models using calibrated ODE model parameters. We additionally investigate objects and processes implicitly represented by ODE model terms and parameters and improve the reproducibility of spatial, stochastic models.
We developed and demonstrate a method for generating spatiotemporal, multicellular models from non-spatial population dynamics models of multicellular systems. We envision employing our method to generate new ODE model terms from spatiotemporal and multicellular models, recast popular ODE models on a cellular basis, and generate better models for critical applications where spatial and stochastic features affect outcomes.
La filosofía tiene aún vigencia. Sin embargo, esa vigencia, su rol particular respecto de las condiciones sociales en las que nos encontramos, dista de ser clara y evidente. Por eso es necesaria una ...reconceptualización de la filosofía que capture su verdadera esencia transformadora. De la mano de diferentes autores, pertenecientes a diferentes escuelas de pensamiento filosófico, se produce aquí una reflexión en torno a los problemas pertinentes para la filosofía, vista desde su capacidad de incidir decisivamente en transformar el contexto social actual. En primer lugar, se contraponen dos visiones de la práctica, como objetos de reflexión filosófica tal cual fueran formulados por Carlos Marx: la poiesis y la praxis. Luego de rescatar para la praxis el carácter moral, se especifican las condiciones originarias de la praxis moral, analizada desde la perspectiva de Emmanuel Levinas, Zygmunt Bauman y Enrique Dussel. Finalmente, se propone una visión de la filosofía que la inserta en el proceso de transformación política y moral de la sociedad: la filosofía debe propiciar un cambio en la mirada hacia el rostro de los otros. Palabras clave: Bauman, cara-a-cara, Dussel, Levinas, moral, otro Philosophy is still relevant. However, this validity, its particular role in the social conditions we found ourselves, is far from clear and evident. For that reason is necessary to rethink philosophy in a way that captures its transforming role. Accompanied by different authors, pertaining different philosophical school of thoughts, it is produced here a reflection on the relevant issues of Philosophy, considering it capable to influence decisively and to change the actual social context. First, two visions of the practice, as formulated by Karl Marx, are opposed: poiesis and praxis. After reclaiming for the praxis the moral dimensión, the original conditions of the moral practice as concieved by Emmanuel Levinas, Zygmunt Bauman and Enrique Dussel, are exposed. Finally, a conception of philosophy as capable of partake in the process of transformation of our moral and political context is proposed: the philosophy must propitate a change in the gaze toward the face of the others. Key-words: Bauman, Dussel, face-to-face, Levinas, moral, the other
La filosofía tiene aún vigencia. Sin embargo, esa vigencia, su rol particu-lar respecto de las condiciones sociales en las que nos encontramos, dis-ta de ser clara y evidente. Por eso es necesaria ...una reconceptualización de la filosofía que capture su verdadera esencia transformadora. De la mano de diferentes autores, pertenecientes a diferentes escuelas de pensamiento filosófico, se produce aquí una reflexión en torno a los problemas pertinentes para la filosofía, vista desde su capacidad de inci-dir decisivamente en transformar el contexto social actual. En primer lugar, se contraponen dos visiones de la práctica, como objetos de refle-xión filosófica tal cual fueran formulados por Carlos Marx: la poiesis y la praxis. Luego de rescatar para la praxis el carácter moral, se especifican las condiciones originarias de la praxis moral, analizada desde la pers-pectiva de Emmanuel Levinas, Zygmunt Bauman y Enrique Dussel. Fi-nalmente, se propone una visión de la filosofía que la inserta en el pro-ceso de transformación política y moral de la sociedad: la filosofía debe propiciar un cambio en la mirada hacia el rostro de los otros.
Philosophy is still relevant. However, this validity, its particular role in the social conditions we found ourselves, is far from clear and evident. For that reason is necessary to rethink philosophy in a way that captures its transforming role. Accompanied by different authors, pertaining dif-ferent philosophical school of thoughts, it is produced here a reflection on the relevant issues of Philosophy, considering it capable to influence decisively and to change the actual social context. First, two visions of the practice, as formulated by Karl Marx, are opposed: poiesis and prax-is. After reclaiming for the praxis the moral dimensión, the original con-ditions of the moral practice as concieved by Emmanuel Levinas, Zyg-munt Bauman and Enrique Dussel, are exposed. Finally, a conception of philosophy as capable of partake in the process of transformation of our moral and political context is proposed: the philosophy must propitate a change in the gaze toward the face of the others.
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