The 2017 Nobel Prize in Physiology or Medicine was awarded to three scientists (Jeffrey Hall, Michael Rosbash, and Michael Young) who identified the working principles of circadian clocks 26. The core clock genes in mammals ( Per1, Per2, Per3, Cry1, Cry2, Clock, Bmal1, Rev-erbα, and Rorα) cause the rhythmic gene expression and govern the physiological features of circadian rhythms 24, 25. Genetic studies in the fruit fly Drosophila melanogaster 6 and the model filamentous fungus, Neurospora crassa 22, which were later extended to mammals 23, revealed that circadian oscillations are formed at the molecular level. provided the first solid evidence for circadian rhythms in prokaryotes 21. An examination of the nitrogen-fixation property of a cyanobacterium Synechococcus sp. Even in the presence of metabolic fluctuations, the circadian clock functions as a precise biological timekeeper 20. Nearly all living organisms maintain an internal clock with a free-running period close to 24 h 19. 18, nonlinear reaction kinetics, and opposing chemical processes with correct balanced timeframes are also required to create oscillations.Īmong different types of biological oscillations, circadian oscillation is widely spread, as the internal clock of most organisms gets synchronized to the environmental day/night cycle changes. In all of these systems the emergence of oscillations results from a delayed negative feedback loop (NFB) 17. Essential biological processes such as cell cycles 1, pacemaker cell’s response 2– 4, circadian rhythms 5– 7, calcium oscillations 8, transcription factor responses 9– 13, hormone secretion 14, fertility cycles 15 are only a few examples of biological oscillations 16. Oscillations are everywhere, both in the physical and biological domains. We also show that a positive feedback loop can reduce extrinsic noise in periods of circadian oscillators, while intrinsic noise is reduced by negative feedback loops. We discovered that the negative feedback loop system performs the best in compensating temperature changes. We investigated four basic circadian oscillators with negative, positive, and combinations of positive and negative feedback loops to explore network features necessary for circadian clock resilience. What makes a circadian oscillatory network robust to extrinsic noise is unclear. Positive feedback loops with substrate depletion can also generate oscillations, inspiring other circadian clock models. In comparison, the circadian clock of cyanobacteria is controlled by a strong positive feedback loop. The presence of a time-delayed negative feedback loop in the regulatory network generates autonomous circadian oscillations in eukaryotic systems. These features allow the circadian pacemaker to maintain a steady oscillation in a wide range of environmental conditions. Temperature compensation and robustness to biological noise are two key characteristics of the circadian clock.
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