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Phosphorylation was first discovered to be of major importance in vertebrate circadian clock regulation in the tau mutation in Syrian hamsters, where a lowered rate of CKI-dependent phosphorylation of Per2 occurred, resulting in shortened period of free running rhythms (Lowrey et al., 2000)

In addition, real-world use is frequently confounded by co-administration of multiple agents and inconsistent sourcing, limiting external validity and complicating attribution of benefit or harm

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