MBI Publications

MBI Publications for Judy Day (8)

  • J. Day, J. Rubin, Y. Vodovotz, C. Chow and G. Clermont
    Using nonlinear model predictive control to optimize inflammation-modulating therapy.
    (2008) (In Preparation)

    Abstract

  • J. Day, A. Friedman and L. Schlesinger
    Modeling the immune rheostat of macrophages in the lung in response to infection
    Proc. Natl Acad Sci USAVol. 106 No. 27 (2009) pp. 11246-11251

    Abstract

    In the lung, alternatively activated macrophages (AAM) form the first line of defense against microbial infection. Due to the highly regulated nature of AAM, the lung can be considered as an immunosuppressive organ for respiratory pathogens. However, as infection progresses in the lung, another population of macrophages, known as classically activated macrophages (CAM) enters; these cells are typically activated by IFN-. CAM are far more
    effective than AAM in clearing the microbial load, producing proinflammatory cytokines and antimicrobial defense mechanisms necessary to mount an adequate immune response. Here, we are concerned with determining the first time when the population of CAM becomes more dominant than the population of AAM. This proposed €˜€˜switching time€™€™ is explored in the context of Mycobacterium tuberculosis (MTb) infection. We have developed a mathematical model that describes the interactions among cells, bacteria, and cytokines involved in the activation of both AAM and CAM. The model, based on a system of differential equations, represents a useful tool to analyze strategies for reducing the switching time, and to generate hypotheses for experimental testing.
  • J. Day, J. Rubin and C. Chow
    Competition between transients in the rate of approach to a fixed point
    SIAM J. Appl. Dyn. Syst.Vol. 8 No. 4 (2009) pp. 1523-1563

    Abstract

    The goal of this paper is to provide and apply tools for analyzing a specific aspect of transient dynamics not covered by previous theory. The question we address is whether one component of a perturbed solution to a system of differential equations can overtake the corresponding component of a reference solution as both converge to a stable node at the origin, given that the perturbed solution was initially farther away and that both solutions are nonnegative for all time. We call this phenomenon tolerance, for its relation to a biological effect. We show using geometric arguments that tolerance will exist in generic linear systems with a complete set of eigenvectors and in excitable nonlinear systems. We also define a notion of inhibition that may constrain the regions in phase space where the possibility of tolerance arises in general systems. However, these general existence theorems do not not yield an assessment of tolerance for specific initial conditions. To address that issue, we develop some analytical tools for determining if particular perturbed and reference solution initial conditions will exhibit tolerance.
  • J. Day, L. Schlesinger and A. Friedman
    Tuberculosis research: Going forward with a powerful "Translation Systems Biology" approach
    Tuberculosis (Edinb)Vol. 90 No. 1 (2010) pp. 7-8

    Abstract

    Due to the complexity of the immune response to a Mycobacterium tuberculosis infection, identifying new, effective therapies and vaccines to combat it has been a problematic issue. Although many advances have been made in understanding particular mechanisms involved, they have, to date, proved insufficient to provide real breakthroughs in this area of tuberculosis research. The term €œTranslational Systems Biology€? has been formally proposed to describe the use of experimental findings combined with mathematical modeling and/or engineering principles to understand complex biological processes in an integrative fashion for the purpose of enhancing clinical practice. This opinion piece discusses the importance of using a translational systems biology approach for tuberculosis research as a means by which to go forward with the potential for significant breakthroughs to occur.
  • J. Day, J. Rubin and G. Clermont
    Using nonlinear model predictive control to find optimal therapeutic strategies to modulate inflammation
    Math. Biosci. Eng.Vol. 7 No. 4 (2010) pp. 739-763

    Abstract

    Modulation of the inflammatory response has become a key focal point in the treatment of critically ill patients. Much of the computational work in this emerging field has been carried out with the goal of unraveling the primary drivers, interconnections, and dynamics of systemic inflammation. To translate these theoretical efforts into clinical approaches, the proper biological targets and specific manipulations must be identified. In this work, we pursue this goal by implementing a nonlinear model predictive control (NMPC) algorithm in the context of a reduced computational model of the acute inflammatory response to severe infection. In our simulations, NMPC successfully identifies patient-specific therapeutic strategies, based on simulated observations of clinically accessible inflammatory mediators, which outperform standardized therapies, even when the latter are derived using a general optimization routine. These results imply that a combination of computational modeling and NMPC may be of practical use in suggesting novel immuno-modulatory strategies for the treatment of intensive care patients.
  • J. Day, A. Friedman and L. Schlesinger
    Modeling the host response to inhalation anthrax
    J Theor BiolVol. 276 No. 1 (2011) pp. 199-208

    Abstract

    Inhalation anthrax, an often fatal infection, is initiated by endospores of the bacterium Bacillus anthracis, which are introduced into the lung. To better understand the pathogenesis of an inhalation anthrax infection, we propose a two-compartment mathematical model that takes into account the documented early events of such an infection. Anthrax spores, once inhaled, are readily taken up by alveolar phagocytes, which then migrate rather quickly out of the lung and into the thoracic/mediastinal lymph nodes. En route, these spores germinate to become vegetative bacteria. In the lymph nodes, the bacteria kill the host cells and are released into the extracellular environment where they can be disseminated into the blood stream and grow to a very high level, often resulting in the death of the infected person. Using this framework as the basis of our model, we explore the probability of survival of an infected individual. This is dependent on several factors, such as the rate of migration and germination events and treatment with antibiotics.
  • J. Day, A. Friedman and L. Schlesinger
    Modeling the immune rheostat of macrophages in the lung in response to infection.
    Proc. Natl Acad Sci USAVol. 106 No. 27 (2012) pp. 11246-11251

    Abstract

  • J. Day, J. Rubin and C. Chow
    Competition between transients in the rate of approach to a fixed point.
    SIAM J. Appl. Dyn. Syst.Vol. 8 No. 4 (2012) pp. 1523-1563

    Abstract

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