Browsing by Author "Hong, Christian I."

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    Mathematical Modeling of Circadian Rhythms in Drosophila melanogaster
    Hong, Christian I. (Virginia Tech, 1999-04-13)
    Circadian rhythms are periodic physiological cycles that recur about every 24 hours, by means of which organisms integrate their physiology and behavior to the daily cycle of light and temperature imposed by the rotation of the earth. Circadian derives from the Latin word circa "about" and dies "day". Circadian rhythms have three noteworthy properties. They are endogenous, that is, they persist in the absence of external cues (in an environment of constant light intensity, temperature, etc.). Secondly, they are temperature compensated, that is, the nearly 24 hour period of the endogenous oscillator is remarkably independent of ambient temperature. Finally, they are phase shifted by light. The circadian rhythm can be either advanced or delayed by applying a pulse of light in constant darkness. Consequently, the circadian rhythm will synchronize to a periodic light-dark cycle, provided the period of the driving stimulus is not too far from the period of the endogenous rhythm. A window on the molecular mechanism of 24-hour rhythms was opened by the identification of circadian rhythm mutants and their cognate genes in Drosophila, Neurospora, and now in other organisms. Since Konopka and Benzer first discovered the period mutant in Drosophila in 1971 (Konopka and Benzer, 1971), there have been remarkable developments. Currently, the consensus opinion of molecular geneticists is that the 24-hour period arises from a negative feedback loop controlling the transcription of clock genes. However, a better understanding of this mechanism requires an approach that integrates both mathematical and molecular biology. From the recent discoveries in molecular biology and through a mathematical approach, we propose that the mechanism of circadian rhythm is based upon the combination of both negative and positive feedback.
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    Modeling of Circadian Rhythms: Robust Temperature Compensation in Drosophila melanogaster and Testable Hypotheses in Neurospora crassa
    Hong, Christian I. (Virginia Tech, 2003-12-03)
    Circadian rhythms are periodic physiological events that recur about every 24 hours. The word circadian derives from the Latin words circa "about" and dies "day". The importance of circadian rhythms is well recognized in many different organisms' survival as well as in human physiology. It was in the 1950's that scientists demonstrated the existence of an endogenous biological clock, and that the clock is temperature compensated. However, the molecular mechanism of circadian rhythms began to come clear only after the discovery of the period (per) gene in Drosophila melanogaster in 1971, and the frequency (frq) gene in Neurospora crassa in 1973. Since the breakthrough discoveries of the per and frq genes and their mutants (short period mutants, perS or frq1, frq2; and long period mutants perL or frq3, frq7), molecular biologists have discovered other crucial components of the mechanism of circadian rhythms. Currently, there are about a dozen identified circadian genes in Drosophila melanogaster. The consensus idea of the mechanism is that it involves two-interlocked feedback loops largely based on transcription-translation controls. However, based on our mathematical models and analysis, we propose that there is also an autocatalytic effect based on proteolysis and stabilization of PER proteins. Based on the dynamics of multiple steady states and limit cycle oscillation, we propose an alternative mechanism for robust temperature compensation. We start with a simple model in order to understand the core dynamics of the clock mechanism, and move to a more comprehensive model. In both cases, we use bifurcation analysis as a tool to understand the dynamics of the system. With our model, we propose hypotheses to be tested in Neurospora crassa.
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    A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM
    Tyson, John J.; Hong, Christian I.; Thron, C. Dennis; Novak, Bela (CELL PRESS, 1999-11)
    Many organisms display rhythms of physiology and behavior that are entrained to the 24-h cycle of light and darkness prevailing on Earth. Under constant conditions of illumination and temperature, these internal biological rhythms persist with a period close to 1 day("circadian"), but it is usually not exactly 24 h. Recent discoveries have uncovered stunning similarities among the molecular circuitries of circadian clocks in mice, fruit flies, and bread molds. A consensus picture is coming into focus around two proteins (called PER and TIM in fruit flies), which dimerize and then inhibit transcription of their own genes. Although this picture seems to confirm a venerable model of circadian rhythms based on time-delayed negative feedback, we suggest that just as crucial to the circadian oscillator is a positive feedback loop based on stabilization of PER upon dimerization. These ideas can be expressed in simple mathematical form(phase plane portraits), and the model accounts naturally for several hallmarks of circadian rhythms, including temperature compensation and the per(L) mutant phenotype. In addition, the model suggests how an endogenous circadian oscillator could have evolved from a more primitive, light-activated switch.