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Objectives: To investigate the emergence of biological rhythms in the first months of life in human infants, by measuring age-related changes in core body temperature during night-time sleep, hormones (cortisol and 6-sulfatoxymelatonin) and the expression of a clock-controlled gene H3f3b in oral epithelial cells., Design: Observational longitudinal study., Setting: We measured overnight core body temperature, actigraphy, day-night urinary cortisol and 6-sulfatoxymelatonin, as well as circadian gene expression, in infants at home from March 2007 to July 2008 in Leicester., Participants: We recruited 35 healthy Caucasian infants who were born at term. They were monitored from 6 to 18 weeks of age., Results: At 8 weeks of age the day-night rhythm of cortisol secretion was the first to appear followed by 6-sulfatoxymelatonin 1 week later; at the same time that night-time sleep was established. At 10 weeks, the maximum fall in deep body temperature occurred with the onset of night-time sleep, followed at 11 weeks by the rhythmical expression of the H3f3b gene., Conclusions: In human infants, there is a clear sequential pattern for the emergence of diurnal biological rhythms between 6 and 18 weeks of postnatal age, led by the secretion of cortisol and linked with the establishment of consolidated night-time sleep. It is likely that this represents part of a maturation and adaption process as infants gain equilibrium with their external environment after birth., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Circadian (approximately 24 h) control impinges on an array of diverse physiological processes in many organisms, ranging from plants to human. Disruption of the mammalian circadian clockwork can lead to severe chronic illnesses such as cardiovascular disease, cancer progression and metabolic disorders. Transcriptional regulation of plasminogen activator inhibitor 1 (PAI-1) is of particular importance because of its crucial role in these pathological conditions. Pai-1 expression is partly regulated by the circadian clock, although direct mechanisms on Pai-1 rhythmicity are unknown. In the present study, we have identified a conserved functional E-box cis-element in the distal part of the mouse Pai-1 gene that is necessary and sufficient to drive circadian expression in Pai-1 activity after dexamethasone synchronisation in vitro. Mutagenesis and in vitro transfection analysis indicated this E-box provides a cognate binding site for cross-talk between clock and hypoxia factors, thus providing a potential cooperation mechanism between circadian and stress pathways, which is conserved in the human Pai-1 gene. Together, these results suggest that the canonical E-box is a target for glucocorticoid action, thus providing the molecular interface between gene transcription and drug action. The mechanism described has global impact on diverse dynamic biological processes governed by the neuroendocrine axis and the circadian clockwork to control complex coordination of gene cascades and biology.

The molecular core of the vertebrate circadian clock is a set of clock genes, whose products interact to control circadian changes in physiology. These clock genes are expressed in all tissues known to possess an endogenous self-sustaining clock, and many are also found in peripheral tissues. In the present study, the expression patterns of two clock genes, cBmal1 and cMOP4, were examined in the chicken, a useful model for analysis of the avian circadian system. In two tissues which contain endogenous clocks--the pineal gland and retina--circadian fluctuations of both cBmal1 and cMOP4 mRNAs were observed to be synchronous; highest levels occurred at Zeitgeber time 12. Expression of these genes is also rhythmic in several peripheral tissues; however, the phases of these rhythms differ from those in the pineal gland and retina: in the liver the peaks of cMOP4 and cBmal1 mRNAs are delayed 4-8 h and in the heart they are advanced by 4 h, relative to those in the pineal gland and retina. These results provide the first temporal characterization of cBmal1 and cMOP4 mRNAs in avian tissues: their presence in avian peripheral tissues indicates they may influence temporal features of daily rhythms in biochemical, physiological, and behavioral functions at these sites.