PubMed · 5206181
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C E Rhodes. 1971. Circadian rhythms.. https://pubmed.ncbi.nlm.nih.gov/5206181/
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Interlocked feedback loops may represent a common feature among the regulatory systems controlling circadian rhythms. The Neurospora circadian feedback loops involve white collar-1 (wc-1), wc-2, and frequency (frq) genes. We show that WC-1 and WC-2 proteins activate the transcription of frq gene, whereas FRQ protein plays dual roles: repressing its own transcription, probably by interacting with the WC-1/WC-2 complex, and activating the expression of both WC proteins. Thus, they form two interlocked feedback loops: one negative and one positive. We establish the physiological significance of the interlocked positive feedback loops by showing that the levels of WC-1 and WC-2 determine the robustness and stability of the clock. Our data demonstrate that with WC-1 being the limiting factor in the WC-1/WC-2 complex, the greater the levels of WC-1 and WC-2, the higher the level of the FRQ oscillation and the more robust the overt rhythms. Our data also show that, despite considerable changes in the levels of WC-1, WC-2, and FRQ, the period of the clock has been limited to a small range, suggesting that the interlocked circadian feedback loops are also important for determining the circadian period length of the clock.
OBJECTIVES: The study was designed to comprehensively evaluate the circadian effects of aldosterone blockade on autonomic tone and QT dispersion in chronic heart failure (CHF). BACKGROUND: Spironolactone therapy given in addition to angiotensin-converting enzyme inhibitors improved survival in CHF, but the mechanism of its benefit is uncertain. Experimental evidence suggests that aldosterone may have detrimental effects on the autonomic nervous system, especially during the morning hours. METHODS: Twenty-eight patients with New York Heart Association class II to IV CHF received spironolactone 50 mg daily and placebo for four weeks each in a double-blind crossover fashion. After each treatment phase, a full circadian assessment was undertaken of spironolactone's autonomic effects. The assessment included monitoring heart rate, QT dispersion, continuous Holter recordings, heart rate variability (HRV) and norepinephrine kinetics. RESULTS: Spironolactone significantly reduced all indices of QT dispersion. The reductions in QTcmax, QTd and QTcd were greatest at 6 AM. In addition, spironolactone had favorable autonomic effects, which were limited to the morning (6-10 AM), including heart rate reduction and an improvement in HRV. CONCLUSIONS: Spironolactone reduced heart rate and improved HRV and QT dispersion in CHF. Its effects were particularly prominent during the morning hours.
The Goodwin oscillator is a minimal model that describes the oscillatory negative feedback regulation of a translated protein which inhibits its own transcription. Now, over 30 years later this scheme provides a basic description of the central components in the circadian oscillators of Neurospora, Drosophila, and mammals. We showed previously that Neurospora's resetting behavior by pulses of temperature, cycloheximide or heat shock can be simulated by this model, in which degradation processes play an important role for determining the clock's period and its temperature-compensation. Another important environmental factor for the synchronization is light. In this work, we show that on the basis of a light-induced transcription of the frequency (frq) gene phase response curves of light pulses as well as the influence of the light pulse length on phase shifts can be described by the Goodwin oscillator. A relaxation variant of the model predicts that directly after a light pulse inhibition in frq -transcription occurs, even when the inhibiting factor Z (FRQ) has not reached inhibitory concentrations. This has so far not been experimentally investigated for frq transcription, but it complies with a current model of light-induced transcription of other genes by a phosphorylated white-collar complex. During long light pulses, the relaxational model predicts that the sporulation rhythm is arrested in a steady state of high frq -mRNA levels. However, experimental results indicate the possibility of oscillations around this steady state and more in favor of the results by the original Goodwin model. In order to explain the resetting behavior by two light pulses, a biphasic first-order kinetics recovery period of the blue light receptor or of the light signal transduction pathway has to be assumed.