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PubMed1996

A temperature-compensated ultradian clock of Tetrahymena: oscillations in respiratory activity and cell division.

Both a circadian clock and an ultradian clock (period 4-5 h) have previously been described for the ciliated protozoon Tetrahymena. The present communication demonstrates the existence of yet another cellular clock: an ultradian rhythm with a period of about 30 min. The period was found to be well temperature-compensated over the range studied, i.e., between 19 degrees C and 33 degrees C. Ultradian rhythmicity was initiated by dilution of stationary-phase cultures, which were kept previously in a light-dark cycle, into fresh medium. LD treatment during stationary phase was an absolute requirement, since cultures kept in either LL or DD did not produce the ultradian rhythmicity after refeeding. The clock exerts control over respiration; the observed oscillation in oxygen uptake is just a hand of the clock: after a limitation of oxygen supply had ended, the rhythm resumed with the same phase and period as that in control cultures. The clock exerts temporal control also over cell division; in the refed culture cell division resumed with an oscillation in the number of dividing organisms. The period of this oscillation corresponded to that of the rhythm in respiratory activity, indicating that the same ultradian clock may exert control over different cellular functions. Analysis of a second Tetrahymena strain indicates that period length of the ultradian clock is a strain-specific characteristic.

Activity Cycles↗
PubMed2003

Circadian clock-controlled regulation of cGMP-protein kinase G in the nocturnal domain.

The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mammalian SCN. Signaling via the cGMP-PKG pathway is required for light- or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMP-PKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by approximately 3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide (alphaODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GC-PKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMP-PKG. Inhibition of the cGMP-PKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMP-PKG-necessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GC-cGMP-PKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by light-GLU-activated GC-cGMP-PKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.

Alkaloids↗
PubMedDate not supplied

[New assessment variables in the Clock Drawing Test (CDT) allow an early and easy diagnosis of degrees of cognitive impairment].

OBJECTIVE: We developed new subroutines and scoring procedures of the CDT to detect markers of early cognitive impairment. SUBJECTS AND METHODS: We compared the performance of 41 mild Alzheimer's patients (AD) (MMSE 22.7+/-3.2); and 18 mild cognitive impairment patients (MCI) (MMSE 28.3+/-1.4), with 33 age and education matched normal controls (NC) regarding their ability in drawing a clock on command, copying a printed clock, setting hands and reading the time. We search for differences in the placement of the hands using a colloquial hour code ("a quarter to ten") and a formal numeric code ("10:45"). We focused our attention on placement and clock hands size. The drawing of hands pointing at 2:50 hs and 8:40 hs were of particular interest. RESULTS: Planning strategies, placement of clock hands using a formal numeric code, clock hands size and hands drawing pointing at 2:50 hs. and 8:40 hs. were the variables that best discriminated AD, MCI and NC ( p<0.01). A stepwise regression analysis using as dependent variables (AD - NC ) and (MCI - NC) showed in both cases that the best predictor model was that formed by: planning strategies, clock hands pointing to 8:40, clock hands size, reading hours and set up clock hands following a formal numeric code (p<.001). CONCLUSIONS: Our proposed modifications in this test convert it in an appropriate tool for cognitive impairment screening because they do not only detect visuoconstructional abilities but also frontal planning, contents and processing of the hour memory code and transcodification of semantic memory processes.

Aged↗
PubMed1995

Temperature compensation and temperature entrainment of the chick pineal cell circadian clock.

We have used an in vitro model system of the circadian clock, dispersed chick pineal cells, to examine the effects of temperature on the circadian clock of a homeotherm. This preparation enabled us to isolate a circadian clock from in vivo homeostatic temperature regulation and expose cells to both constant temperatures and abrupt temperature changes. By manipulating the temperature of the pineal cells, we have demonstrated that (1) the circadian clock compensates its period for temperature changes over the range of 34-40 degrees C; Q10 = 0.83, a value within the range of Q10 values measured for poikilothermic circadian clocks; (2) temperature pulses (42 degrees C, 6 hr duration) shift the phase (advance and delay) of the circadian rhythm in a phase-dependent manner; and (3) a temperature cycle (18 hr at 37 degrees C, 6 hr at 42 degrees C) will entrain the circadian clock in vitro. This is the first demonstration of temperature entrainment of the circadian clock of a homeotherm in vitro. In addition we have found that temperature directly influences the synthesis and release of melatonin, the primary hormonal product of the pineal gland. The biosynthesis of melatonin is strongly temperature dependent with a Q10 > 11 when melatonin release is measured at ambient temperatures between 31 degrees C and 40 degrees C. In contrast, 6 hr 42 degrees C temperatures pulses acutely inhibit melatonin release in a manner similar to that seen previously with light pulses. These results demonstrate that a circadian clock from a homeothermic vertebrate is temperature compensated, yet temperature cycles can entrain the circadian melatonin rhythm. Thus, the chick pineal circadian oscillator has retained all the fundamental properties of circadian rhythms.

Acclimatization↗
PubMed1997

The Clock Drawing Test for dementia of the Alzheimer's type: A comparison of three scoring methods in a memory disorders clinic.

OBJECTIVES: To examine the reliability and validity of the Clock Drawing Test when used as a cognitive screening instrument for mild to moderate dementia, and to compare different scoring mechanisms. DESIGN: Retrospective analysis of clock drawing performance using three published scoring methods (Shulman, Sunderland and Wolf-Klein). SETTING: Hospital-based memory disorders clinic. PARTICIPANTS: A sample of 28 consecutive patients attending the memory clinic for assessment who were given a diagnosis of Alzheimer's disease (mild or moderate) and 28 age- and sex-matched control subjects comprising 17 memory clinic attenders found to be normal and 11 community volunteers. MEASUREMENTS: Sensitivity and specificity of the three clock rating scales against memory clinic diagnoses of dementia using DSM-III-R; their respective interrater reliabilities; and comparisons of each with measures of cognitive impairment (the Mini-Mental State Examination and the Blessed Orientation-Information-Memory-Concentration Test), daily performance of basic and instrumental activities (the Blessed Dementia Scale) and depression (the Hamilton Rating Scale for Depression). RESULTS: All methods of scoring the Clock Drawing Test correlated well with measures of cognitive impairment (r = 0.57-0.73) and daily performance (r = 0.38-0.48), were independent of mild depression and demonstrated high sensitivity, specificity and interrater reliability. While all clock scales identified mild to moderate dementia reasonably well, the Shulman method performed best. In screening for dementia, clock drawing proved superior to the MMSE: 24/28 vs 20/28 cases identified. When compared with the MMSE, clock drawing provided additional diagnostic discrimination, identifying 7/8 AD patients with MMSE scores = 24. CONCLUSIONS: In a clinic population, clock drawing, especially if scored according to the Shulman scale and combined with the MMSE, is an extremely efficient test screening measure for mild to moderate dementia of the Alzheimer's type with low false negative and false positive rates. This may have implications for screening elderly populations.

Aged↗
PubMed1998

Vibroacoustic Stimulation of the Fetus Using a Conventional Mechanical Alarm Clock.

> Objective: For more than 20 years, vibroacoustic stimulation testing (VAST) using an artificial larynx has been used worldwide when fetal heart rate monitoring produced patterns with absent or very low variability. In addition to the artificial larynx many other appliances have been used to stimulate a seemingly dormant fetus, but these have rarely been evaluated properly. In this study we tried to evaluate the use of standard mechanical wind-up alarm clocks for VAST. Methods: VAST with an alarm clock was performed successfully in 80 women with normal pregnancies from 36 weeks to term. It was tested by placing the alarm clock on the maternal abdomen just above the fetal head or on the controlateral side of the maternal abdomen to see whether position made any difference and whether coupling with ultrasound gel applied between the alarm clock and the maternal abdomen would affect the degree of fetal reaction to VAST as expressed in heart rate acceleration. Similarly, the effect of the alarm clock VAST on subjective and objective fetal movement patterns as registered by kineto-cardiotocotraphy (K-CTG) in addition to heart rate patterns was investigated. Results: All fetuses showed heart rate acceleration, an increase in heart variability, and increase in movement patterns in the 6 min after the application of alarm clock VAST. No statistically significant difference was found which would favor a particular placement of the alarm clock on the maternal abdomen or the use of ultrasound coupling gel. When K-CTG was performed, patient-perceived fetal movements as expressed with an event marker showed agreement with the machine-registered movements only when patients could see the tracing during registration and no accordance when the K-CTG was turned toward the wall during registation. Conclusion: In keeping with the ALARA principle a conventional wind-up alarm clock appears to be an inexpensive and effective alternative to the electrolarynx.

Journal Article↗
PubMed2007

Cryptochromes impair phosphorylation of transcriptional activators in the clock: a general mechanism for circadian repression.

CLOCK and BMAL1 [brain and muscle ARNT (arylhydrocarbon receptor nuclear translocator)-like protein 1] are central components of the molecular clock in mammals and belong to the bHLH (basic helix-loop-helix)/PAS [PER (Period)/ARNT/SIM (single-minded)] family. Features of their dimerization have never been investigated. Here, we demonstrate that PAS domain function requires regions extending over the short PAS core repeats. Strikingly, while deleting PAS core repeats does not overtly affect dimerization, it abolishes the transcriptional activity of the heterodimer. Interestingly, these deletions also abolish co-dependent phosphorylation of CLOCK and BMAL1, suggesting a link between the phosphorylation status of the heterodimer and its transactivation potential. We demonstrate that NPAS2 (neuronal PAS domain protein 2) and BMAL2 also undergo similar posttranslational modifications, thereby establishing the mechanism proposed for CLOCK-BMAL1 as a common feature of transcriptional activators in the circadian clock. The discovery of two novel splice variants of BMAL2 confirms the crucial role of the PAS domain and further strengthens the view that co-dependent phosphorylation is of functional significance. In agreement with this, we demonstrate that CRY1-2 (cryptochromes 1-2) affect transactivation and phosphorylation of transcriptional activators of the clock. Furthermore, CRY proteins stabilize the unphosphorylated forms of BMAL1(BMAL2) thereby shifting the phosphorylated/unphosphorylated ratio towards a predominantly unphosphorylated (transcriptionally inactive) form. In contrast, PER proteins, which are weak repressors, are without effect. From these results, we propose a general mechanism for the inhibition of CLOCK(NPAS2)-BMAL1(BMAL2) circadian transcriptional activation by CRY1-2.

ARNTL Transcription Factors↗
PubMed2002

Temporal expression of seven clock genes in the suprachiasmatic nucleus and the pars tuberalis of the sheep: evidence for an internal coincidence timer.

The 24-h expression of seven clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2, and CK1 epsilon ) was assayed by in situ hybridization in the suprachiasmatic nucleus (SCN) and the pars tuberalis (PT) of the pituitary gland, collected every 4 h throughout 24 h, from female Soay sheep kept under long (16-h light/8-h dark) or short (8-h light/16-h dark) photoperiods. Locomotor activity was diurnal, inversely related to melatonin secretion, and prolactin levels were increased under long days. All clock genes were expressed in the ovine SCN and PT. In the SCN, there was a 24-h rhythm in Clock expression, in parallel with Bmal1, in antiphase with cycles in Per1 and Per2; there was low-amplitude oscillation of Cry1 and Cry2. The waveform of only Per1 and Per2 expression was affected by photoperiod, with extended elevated expression under long days. In the PT, the high-amplitude 24-h cycles in the expression of Bmal1, Clock, Per1, Per2, Cry1, and Cry2, but not CK1 epsilon, were influenced by photoperiod. Per1 and Per2 peaked during the day, whereas Cry1 and Cry2 peaked early in the night. Hence, photoperiod via melatonin had a marked effect on the phase relationship between Per/Cry genes in the PT. This supports the conclusion that an "external coincidence model" best explains the way photoperiod affects the waveform of clock gene expression in the SCN, the central pacemaker, whereas an "internal coincidence model" best explains the way melatonin affects the phasing of clock gene expression in the PT to mediate the photoperiodic control of a summer or winter physiology.

ARNTL Transcription Factors↗
PubMed2005

Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder.

In recent years, circadian rhythm sleep disorders in humans have been increasing. Clinical features characteristic of this disorder are well known, but the specific causes remain unknown. However, various derangements of circadian expression of the clock gene are a probable cause of this disease. We have attempted to elucidate the relationship between the expression of the clock genes in whole blood cells and the clinical features characteristic of this disorder. In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects. The peak phase of Per1, Per2, and Per3 appeared in the early morning, whereas that of Bmal1 and Clock appeared in the midnight hours. Furthermore, in one patient case with circadian rhythm sleep disorder, we observed variations of the peak phase in clock genes by treatments such as light therapy, exercise therapy, and medicinal therapy. This study suggested that the monitoring of human clock genes in whole blood cells, which may be functionally important for the molecular control of the circadian pacemaker as well as in suprachiasmatic nucleus, might be useful to evaluate internal synchronization.

ARNTL Transcription Factors↗
PubMed2005

Clock gene expression in the submandibular glands.

Clock genes, which mediate molecular circadian rhythms, are expressed in a circadian fashion in the suprachiasmatic nucleus and in various peripheral tissues. To establish a molecular basis for circadian regulation in the salivary glands, we examined expression profiles of clock-related genes and salivary gland-characteristic genes. Clock-related genes-including Per1, Per2, Cry1, Bmal1, Dec1, Dec2, Dbp, and Reverbalpha-showed robust circadian expression rhythms in the submandibular glands in 12:12-hour light-dark conditions. In addition, a robust circadian rhythm was observed in amylase 1 mRNA levels, whereas the expression of other salivary-gland-characteristic genes examined was not rhythmic. The Clock mutation resulted in increased or decreased mRNA levels of Per2, Bmal1, Dec1, Dec2, and Dbp, and in Cry1-/- background, Cry2 disruption also increased or decreased mRNA levels of these clock-related genes and the amylase 1 gene. These findings indicate that the Clock- and Cry-dependent molecular clock system is active in the salivary glands.

ARNTL Transcription Factors↗
PubMed2003

Molecular cogs of the insect circadian clock.

During the last five years, enormous progress has been made in understanding the molecular basis of circadian systems, mainly by molecular genetic studies using the mouse and fly. Extensive evidence has revealed that the core clock machinery involves "clock genes" and "clock proteins" functioning as molecular cogs. These participate in transcriptional/translational feedback loops and many homologous clock-components in the fruit fly Drosophila are also expressed in mammalian clock tissues with circadian rhythms. Thus, the mechanisms of the central clock seem to be conserved across animal kingdom. However, some recent studies imply that the present widely accepted molecular models of circadian clocks may not always be supported by the experimental evidence.

Animals↗
PubMed2000

[Molecular mechanism of biological clock: for chronobiological approach to stress].

Recent progress in molecular chronobiology revealed that the clock genes control intracellular feedback loops. CLOCK protein and BMAL1 protein, first discovered as components of the circadian clock in mammals, are known to function as transcriptional activators in the circadian feedback loop of drosophila. PERIOD and TIMELESS proteins work as inhibitors for these activators in drosophila and possibly in mammals. The clock genes described above are also expressed in peripheral tissues with circadian rhythmicity. Cultured rat-1 fibroblast shows circadian expression of clock genes after serum shock or forskolin stimulation. These results indicate that the clock genes function not only as components of the endogenous clock, but also as a coordinator of the circadian activity of peripheral tissues. It will be important to study stress from the aspect of circadian rhythm.

ARNTL Transcription Factors↗
PubMed2000

The clocks controlling the tide-associated rhythms of intertidal animals.

The living clock that governs tide-associated organismic rhythms has previously been assumed to have a fundamental period of approximately 12.4 h, an interval that reflects the average period of the ebb and flow of the tide. But, in 1986, marine chronobiologists began to accumulate laboratory results that could not be explained by the action of such a clock. Prime among these findings was the discovery that, occasionally, one of the two daily peaks in an organism's rhythm assumed a different period from its partner. Similar results have since been observed in a host of different organisms. These data led to the circalunidian-clock hypothesis that envisions two basic 24.8 h clocks, coupled together in antiphase, as the driving force for these rhythms. There is, however, only a slight difference (50 minutes) in running times between a solar-day clock with a period of approximately 24 h and a lunar-day clock with a period of approximately 24.8 h, both of which display "circa" periods that overlap. Here, I postulate that the two clocks are fundamentally one and the same. BioEssays 22:32-37, 2000.

Adaptation, Physiological↗
PubMed2004

The circadian clock in the brain: a structural and functional comparison between mammals and insects.

The circadian master clocks in the brains of mammals and insects are compared in respect to location, organization and function. They show astonishing similarities. Both clocks are anatomically and functionally connected to the optic system and possess multiple output pathways allowing synchronization with the environmental light-dark cycles as well as the control of diverse endocrine, autonomic and behavioral functions. Both circadian master clocks are composed of multiple neurons, which are organized in populations with different morphology, physiology and neurotransmitter content and appear to subserve different functions. In the hamster and in the cockroach, the master clock consists of a core region that gets input from the eyes, and a shell region from which the majority of output projections originate. Communication between core and shell, between all other populations of clock neurons as well as between the master clocks of both brain hemispheres is a prerequisite of normal rhythmic function. Phenomena like rhythm splitting and internal desynchronization can be observed under constant light conditions and are caused by the "uncoupling" of the master clocks of both brain hemispheres.

Animals↗
PubMed2002

Clock mechanisms in Drosophila.

Mechanisms underlying circadian clock function in Drosophila melanogaster have been revealed by genetic and molecular approaches. Two interlocked transcriptional feedback loops involving at least the period, timeless, Clock,and cycle genes generate molecular oscillations that are believed to control behavioral rhythmicity and other clock outputs. These oscillations are further enhanced and fine-tuned to match the duration of the solar day by post-transcriptional and post-translational mechanisms depending on the PERIOD and TIMELESS proteins and on the protein kinases DOUBLE-TIME and SHAGGY. Light is the principal zeitgeber for synchronizing molecular and behavioral rhythmicity via the blue-light photoreceptor CRYPTOCHROME and the TIMELESS protein. In addition, light seems required for maintaining robust molecular oscillations at least in peripheral clock-gene-expressing tissues like the eyes, antennae, or Malpighian tubules. Relaying temporal information to cells and tissues expressing overt biological rhythms involves regulation of "output genes" at multiple levels. Although their regulation depends on the major clock genes, the majority of the clock-controlled genes are not direct targets of clock factors.

Animals↗
PubMed2006

Acute systemic inflammation transiently synchronizes clock gene expression in equine peripheral blood.

Peripheral clocks receive timing signals from the master mammalian pacemaker in the suprachiasmatic nucleus (SCN) and function to adaptively anticipate daily changes that influence local physiology. Evidence suggests that peripheral immune activation may act as a resetting signal for circadian clocks in peripheral tissues. We wished to investigate whether acute systemic inflammation could synchronize clock gene expression in equine peripheral blood, a tissue that does not normally oscillate in this species. We report that in vivo administration of lipopolysaccharide (LPS) results in significant upregulation of the core clock genes Per2 and Bmal1 in equine blood, in association with an acute rise in tumor necrosis factor (TNF) alpha and core body temperature compared to vehicle-treated control animals. Furthermore, co-administration of LPS and phenylbutazone, a non-steroidal anti-inflammatory drug (NSAID) known to inhibit prostaglandin (PG) E(2) synthesis in the horse, prevents both the febrile response and the synchronized increase in clock gene expression. However, the rise in Per2 and Bmal1 expression cannot be replicated in equine peripheral blood mononuclear cells (PBMCs) ex vivo by treatment with PGE(2), LPS or a heat shock mimicking the in vivo febrile response. These results may suggest an indirect communication pathway between immune modulators and the molecular machinery of cell clocks in peripheral blood. This potential immune feedback regulation of an equine peripheral clock implies a role for the circadian system in contributing to innate immune reactions and maintaining homeostasis in a tissue that acts as the first line of defense during an infectious challenge.

ARNTL Transcription Factors↗
PubMed2006

The circadian protein Clock localizes to the sarcomeric Z-disk and is a sensor of myofilament cross-bridge activity in cardiac myocytes.

In the mammalian heart, the circadian protein Clock regulates glucose and fatty acid metabolism. In this study, we determined some of the factors that regulate Clock expression and subcellular distribution in myocytes. Using immunochemistry and biochemical subcellular fractionation, we have shown that Clock localizes to the Z-disk of the myofilaments. Increasing calcium and cross-bridge cycling with 10 microM phenylephrine for 48 h resulted in a threefold increase in Clock and a translocation of the protein to the nucleus. When myofilament cross-bridge cycling was inhibited with 10 microM verapamil or 7.5mM butanedione monoxime for 48 h, both significantly reduced the presence of Clock in the nucleus and cytoskeleton. These results suggest that the expression and subcellular distribution of Clock can be altered by changes in cross-bridge cycling, a major source of energy expenditure in myocytes. We suggest that the circadian Clock protein may help coordinate the sensing of energy expenditure with energy supply.

Actin Cytoskeleton↗
PubMed2006

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1.

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions.

ARNTL Transcription Factors↗