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The internal circadian rhythms of cells and organisms coordinate their physiological properties …

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- A proposal for robust temperature compensation of circadian rhythms

mcith_F1-medium.gif Figure 1 One-parameter bifurcation diagrams for the differential equations (B1) and (B2), described in Appendix. (A) Parameter values: v m = 2, k m = 0.2, k p1 = 53.36, k p2 = 0.06, k p3 = 0.2, K eq = 1, P crit = 0.6, J p = 0.05. (B) All rate constants increased 2-fold. For each value of the bifurcation parameter, v p, we plot the value of [PER] on recurrent solutions of the differential equations (steady states and limit cycle oscillations). Solid curve, stable steady state; dashed curve, unstable steady state. Curves labeled [PER]max and [PER]min indicate the range of an oscillatory solution at fixed value of v p. At the Hopf bifurcation, the steady state changes stability and small amplitude, stable limit cycle oscillations arise. At the SNIC bifurcation, two steady states (a stable node and an unstable saddle) annihilate each other and are replaced by a large amplitude limit cycle. (A Inset) The period of oscillation at the SNIC bifurcation is infinite, but drops quickly to a value of ≈15 h. Superimposed on the bifurcation diagrams are the trajectories (dashed/dotted line) generated by the resetting hypothesis (see text). Although the locations of the bifurcation points depend strongly on parameter values, as do the shapes of the resetting trajectories (dashed/dotted line), the period of the two trajectories is precisely 24 h.

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mcith_F2-medium.gif Figure 2 Time courses of per mRNA and protein, and the resetting parameter, v p, for the mechanism described in the text. (A) Parameter values as in Fig. 1A, plus P thresh = 2, μ = 0.0288, σ = 0.5. (B) Parameter values as in Fig. 1B, plus P thresh = 2, μ = 0.0576, σ = 0.25. 

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mcith_F3-medium.gif Figure 3 Robustness of compensated oscillator period as a function of perturbation strength (σp) for the models LG, TH and RS. (A) The CV of the period is plotted vs. σp, indicating each model's response to test A. RS is virtually unaffected (extremely robust), whereas LG and TH fail to compensate the period to different degrees. (B) ΔT is averaged over all possible single reaction mutants (Test B) for a given perturbation strength, σp. We see that RS is robustly temperature compensated for such mutations (very low ΔT), whereas both LG and TH fail to compensate over the given temperature range. 

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mcith_F4-medium.gif Figure 4 Sensitivity of oscillation (% of samples that lose oscillation) as a function of perturbation strength (σp) in test A. At σp = 0.2, LG loses oscillation ≈47% of the time, TH ≈59% of the time, and RS ≈40% of the time. Oscillations are most robust to small perturbations for LG, whereas RS is considerably more robust than either LG or TH for large perturbations.

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