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- All Subjects: Time Delay
- Creators: Kostelich, Eric J.
- Resource Type: Text
Description
Autonomic closure is a recently-proposed subgrid closure methodology for large eddy simulation (LES) that replaces the prescribed subgrid models used in traditional LES closure with highly generalized representations of subgrid terms and solution of a local system identification problem that allows the simulation itself to determine the local relation between each subgrid term and the resolved variables at every point and time. The present study demonstrates, for the first time, practical LES based on fully dynamic implementation of autonomic closure for the subgrid stress and the subgrid scalar flux. It leverages the inherent computational efficiency of tensorally-correct generalized representations in terms of parametric quantities, and uses the fundamental representation theory of Smith (1971) to develop complete and minimal tensorally-correct representations for the subgrid stress and scalar flux. It then assesses the accuracy of these representations via a priori tests, and compares with the corresponding accuracy from nonparametric representations and from traditional prescribed subgrid models. It then assesses the computational stability of autonomic closure with these tensorally-correct parametric representations, via forward simulations with a high-order pseudo-spectral code, including the extent to which any added stabilization is needed to ensure computational stability, and compares with the added stabilization needed in traditional closure with prescribed subgrid models. Further, it conducts a posteriori tests based on forward simulations of turbulent conserved scalar mixing with the same pseudo-spectral code, in which velocity and scalar statistics from autonomic closure with these representations are compared with corresponding statistics from traditional closure using prescribed models, and with corresponding statistics of filtered fields from direct numerical simulation (DNS). These comparisons show substantially greater accuracy from autonomic closure than from traditional closure. This study demonstrates that fully dynamic autonomic closure is a practical approach for LES that requires accuracy even at the smallest resolved scales.
ContributorsStallcup, Eric Warren (Author) / Dahm, Werner J.A. (Thesis advisor) / Herrmann, Marcus (Committee member) / Calhoun, Ronald (Committee member) / Kim, Jeonglae (Committee member) / Kostelich, Eric J. (Committee member) / Arizona State University (Publisher)
Created2020
Description
Cancer is a worldwide burden in every aspect: physically, emotionally, and financially. A need for innovation in cancer research has led to a vast interdisciplinary effort to search for the next breakthrough. Mathematical modeling allows for a unique look into the underlying cellular dynamics and allows for testing treatment strategies without the need for clinical trials. This dissertation explores several iterations of a dendritic cell (DC) therapy model and correspondingly investigates what each iteration teaches about response to treatment.
In Chapter 2, motivated by the work of de Pillis et al. (2013), a mathematical model employing six ordinary differential (ODEs) and delay differential equations (DDEs) is formulated to understand the effectiveness of DC vaccines, accounting for cell trafficking with a blood and tumor compartment. A preliminary analysis is performed, with numerical simulations used to show the existence of oscillatory behavior. The model is then reduced to a system of four ODEs. Both models are validated using experimental data from melanoma-induced mice. Conditions under which the model admits rich dynamics observed in a clinical setting, such as periodic solutions and bistability, are established. Mathematical analysis proves the existence of a backward bifurcation and establishes thresholds for R0 that ensure tumor elimination or existence. A sensitivity analysis determines which parameters most significantly impact the reproduction number R0. Identifiability analysis reveals parameters of interest for estimation. Results are framed in terms of treatment implications, including effective combination and monotherapy strategies.
In Chapter 3, a study of whether the observed complexity can be represented with a simplified model is conducted. The DC model of Chapter 2 is reduced to a non-dimensional system of two DDEs. Mathematical and numerical analysis explore the impact of immune response time on the stability and eradication of the tumor, including an analytical proof of conditions necessary for the existence of a Hopf bifurcation. In a limiting case, conditions for global stability of the tumor-free equilibrium are outlined.
Lastly, Chapter 4 discusses future directions to explore. There still remain open questions to investigate and much work to be done, particularly involving uncertainty analysis. An outline of these steps is provided for future undertakings.
In Chapter 2, motivated by the work of de Pillis et al. (2013), a mathematical model employing six ordinary differential (ODEs) and delay differential equations (DDEs) is formulated to understand the effectiveness of DC vaccines, accounting for cell trafficking with a blood and tumor compartment. A preliminary analysis is performed, with numerical simulations used to show the existence of oscillatory behavior. The model is then reduced to a system of four ODEs. Both models are validated using experimental data from melanoma-induced mice. Conditions under which the model admits rich dynamics observed in a clinical setting, such as periodic solutions and bistability, are established. Mathematical analysis proves the existence of a backward bifurcation and establishes thresholds for R0 that ensure tumor elimination or existence. A sensitivity analysis determines which parameters most significantly impact the reproduction number R0. Identifiability analysis reveals parameters of interest for estimation. Results are framed in terms of treatment implications, including effective combination and monotherapy strategies.
In Chapter 3, a study of whether the observed complexity can be represented with a simplified model is conducted. The DC model of Chapter 2 is reduced to a non-dimensional system of two DDEs. Mathematical and numerical analysis explore the impact of immune response time on the stability and eradication of the tumor, including an analytical proof of conditions necessary for the existence of a Hopf bifurcation. In a limiting case, conditions for global stability of the tumor-free equilibrium are outlined.
Lastly, Chapter 4 discusses future directions to explore. There still remain open questions to investigate and much work to be done, particularly involving uncertainty analysis. An outline of these steps is provided for future undertakings.
ContributorsDickman, Lauren (Author) / Kuang, Yang (Thesis advisor) / Baer, Steven M. (Committee member) / Gardner, Carl (Committee member) / Gumel, Abba B. (Committee member) / Kostelich, Eric J. (Committee member) / Arizona State University (Publisher)
Created2020