Browsing by Author "Conrad, Emery David"

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    Bifurcation Analysis and Qualitative Optimization of Models in Molecular Cell Biology with Applications to the Circadian Clock
    Conrad, Emery David (Virginia Tech, 2006-04-14)
    Circadian rhythms are the endogenous, roughly 24-hour rhythms that coordinate an organism's interaction with its cycling environment. The molecular mechanism underlying this physiological process is a cell-autonomous oscillator comprised of a complex regulatory network of interacting DNA, RNA and proteins that is surprisingly conserved across many different species. It is not a trivial task to understand how the positive and negative feedback loops interact to generate an oscillator capable of a) maintaining a 24-hour rhythm in constant conditions; b) entraining to external light and temperature signals; c) responding to pulses of light in a rather particular, predictable manner; and d) compensating itself so that the period is relatively constant over a large range of temperatures, even for mutations that affect the basal period of oscillation. Mathematical modeling is a useful tool for dealing with such complexity, because it gives us an object that can be quickly probed and tested in lieu of the experiment or actual biological system. If we do a good job designing the model, it will help us to understand the biology better by predicting the outcome of future experiments. The difficulty lies in properly designing a model, a task that is made even more difficult by an acute lack of quantitative data. Thankfully, our qualitative understanding of a particular phenomenon, i.e. the observed physiology of the cell, can often be directly related to certain mathematical structures. Bifurcation analysis gives us a glimpse of these structures, and we can use these glimpses to build our models with greater confidence. In this dissertation, I will discuss the particular problem of the circadian clock and describe a number of new methods and tools related to bifurcation analysis. These tools can effectively be applied during the modeling process to build detailed models of biological regulatory with greater ease.
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    Mathematical Models of Biochemical Oscillations
    Conrad, Emery David (Virginia Tech, 1999-04-21)
    The goal of this paper is to explain the mathematics involved in modeling biochemical oscillations. We first discuss several important biochemical concepts fundamental to the construction of descriptive mathematical models. We review the basic theory of differential equations and stability analysis as it relates to two-variable models exhibiting oscillatory behavior. The importance of the Hopf Bifurcation will be discussed in detail for the central role it plays in limit cycle behavior and instability. Once we have exposed the necessary mathematical framework, we consider several specific models of biochemical oscillators in three or more variables. This will include a detailed analysis of Goodwin's equations and their modification first studied by Painter. Additionally, we consider the consequences of introducing both distributed and discrete time delay into Goodwin's model. We will show that the presence of distributed time lag modifies Goodwin's model in no significant way. The final section of the paper will discuss discrete time lag in the context of a minimal model of the circadian rhythm. In the main, this paper will address mathematical, as opposed to biochemical, issues. Nevertheless, the significance of the mathematics to the biochemistry will be considered throughout.