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PubMed2006

Starting the zebrafish pineal circadian clock with a single photic transition.

The issue of what starts the circadian clock ticking was addressed by studying the developmental appearance of the daily rhythm in the expression of two genes in the zebrafish pineal gland that are part of the circadian clock system. One encodes the photopigment exorhodopsin and the other the melatonin synthesizing enzyme arylalkylamine N-acetyltransferase (AANAT2). Significant daily rhythms in AANAT2 mRNA abundance were detectable for several days after fertilization in animals maintained in a normal or reversed lighting cycle providing 12 h of light and 12 h of dark. In contrast, these rhythms do not develop if animals are maintained in constant lighting or constant darkness from fertilization. In contrast to exorhodopsin, rhythmicity of AANAT2 can be initiated by a pulse of light against a background of constant darkness, by a pulse of darkness against a background of constant lighting, or by single light-to-dark or dark-to-light transitions. Accordingly, these studies indicate that circadian clock function in the zebrafish pineal gland can be initiated by minimal photic cues, and that single photic transitions can be used as an experimental tool to dissect the mechanism that starts the circadian clock in the pineal gland.

Animals↗
PubMed1980

Maturation of the clock-timed gonadotropin release mechanism in hamsters: a key event in the pubertal process?

Gonadotropin secretion patterns were monitored in 10, 14 to 21-, and 35-day-old prepubertal female hamsters by RIA. Blood samples were obtained between 1500-1900 h to coincide with the time when the adult female hamster experiences a clock-timed surge in gonadotropin release. Before 16 days of age, the female hamster appears to exhibit a tonic pattern of gonadotropin release. On day 16 and thereafter, the female hamster exhibits a daily surge of gonadotropin release. Around the clock sampling (every 3 h) has shown that this cyclic pattern of gonadotropin release is not present at any time studied in female hamsters younger than 16 days of age, appears to be clock timed, and occurs at the same time of day as the proestrus surge in cyclic adults. The maturation of the clock timed gonadotropin release mechanism may indicate maturation of the reproductive control system, a key event in the pubertal process.

Animals↗
PubMed2006

Heterogeneous genomic molecular clocks in primates.

Using data from primates, we show that molecular clocks in sites that have been part of a CpG dinucleotide in recent past (CpG sites) and non-CpG sites are of markedly different nature, reflecting differences in their molecular origins. Notably, single nucleotide substitutions at non-CpG sites show clear generation-time dependency, indicating that most of these substitutions occur by errors during DNA replication. On the other hand, substitutions at CpG sites occur relatively constantly over time, as expected from their primary origin due to methylation. Therefore, molecular clocks are heterogeneous even within a genome. Furthermore, we propose that varying frequencies of CpG dinucleotides in different genomic regions may have contributed significantly to conflicting earlier results on rate constancy of mammalian molecular clock. Our conclusion that different regions of genomes follow different molecular clocks should be considered when inferring divergence times using molecular data and in phylogenetic analysis.

Animals↗
PubMed1969

Periodic shock with added clock.

Rats were shocked every 6 min while responding was maintained on a variable-interval schedule of reinforcement. With some rats, shocks were interspersed with a sequence of three different stimulus conditions (S3-->S2-->S1), or clock cues, each lasting 2 min. For other rats, a single stimulus condition prevailed between shocks at the beginning of the experiment and clock cues were introduced later. Response rate decreased from S3 to S1. Response rate in S3, S2, and S1 was inversely related to shock intensity. When clock cues were added, response rate increased in all 2-min intershock periods. During clock cues, an index of curvature, indicating the degree of negative acceleration of response rate, was greatest for S1 and least for S3, and was directly related to shock intensity. The response-facilitating effect of shock and its relation to a possible discriminative function of shock and to behavioral contrast is discussed.

Journal Article↗
PubMed1998

Clock tests in depression, Alzheimer's disease, and elderly controls.

OBJECTIVE: While clock-drawing tests are commonly used to screen for cognitive impairment in the elderly, little is known about the performance of elderly depressives. METHODS: We compared thirty-three patients with major depression to forty-two Alzheimer's disease and thirty age-matched controls on clock-drawing, copying, and reading. RESULTS: Patients with Alzheimer's disease had significantly lower scores on clock-drawing, copying, and reading than patients with depression or the controls (p < 0.05). Patients with depression did not differ significantly from controls on quantitative scores or qualitative errors. CONCLUSIONS: Clock tests may be useful for identifying depressed patients with underlying dementia.

Aged↗
PubMed2005

Use of the ten-point clock test to compare executive functioning across 24 months in patients with subcortical vascular dementia.

The Ten-point Clock Test can be used to identify early forms of Alzheimer's disease because it is reliable, well accepted, and easily administered at the bedside. Nevertheless, its clinical role in the detection of early dementia and its correlations with other cognitive processes is still under investigation. Vascular dementia is an uncertain nosological entity, in which unevenly distributed patterns of cognitive deficits comprising slowing of cognitive processing and impairment of executive function occur. The present study assessed how the Clock Test scores correlated with a number of other neuropsychological and functional tests in a sample of 144 patients with vascular dementia, who were followed for a period of 24 mo. At baseline, at 12 mo. and at 24 mo. subjects were administered a battery of tests, including the Mini-Mental State Examination, word fluency, visuospatial skills, an evaluation of hetero- and autotopognosia (knowledge of self), the Proverbs Test, and the Ten-point Clock Test. For these patients scores on the Clock Test correlated significantly with semantic abilities, with abstract reasoning capacities, visuospatial perception, and with right and left recognition.

Aged↗
PubMed1996

Stop-reaction time and the internal clock.

In a stop-reaction-time (stop-RT) task, a subject is presented with a regular, isochronous sequence of brief signals separated by a constant time interval, or stimulus onset asynchrony (SOA). His/her task is to press a response key as fast as possible when the sequence stops. As the sequence unfolds, an internal representation of the SOA duration builds up. Stop-RT is assumed to be triggered when an internal clock, operating as an "alarm clock," reaches a time criterion. Criterion setting is contingent upon variability in the SOA's internal representation. In Experiment 1A, stop-RT was measured for isochronous sequences of brief tones, light flashes, and also sequences of tones and flashes presented in regular alternation (tone-light-tone ...). Stop-RT was a linear function of SOA duration (ranging from 250 to 1,000 msec), regardless of modality, supporting a "central-clock" hypothesis. On the other and, taken together, the results of Experiments 1A, 1B, 2, and 3 suggest that no internal representation of the bimodal (tone-light) SOA of alternating sequences builds up. Indeed, an alternating sequence is physically equivalent to two interlaced isochronous subsequences, one auditory and one visual. So, two internal representations, one for the auditory (tone-tone) and one for the visual (light-light) SOA, could build up, and two time criteria running "in parallel" could thus support stop-RT. To provide a critical test of parallel timing, stop-RT was measured for bimodal 5:3 polyrhythms formed by the superposition of auditory and visual isochronous sequences that had different SOA durations (Experiment 4). Parallel timing accounted for a large proportion of variance in polyrhythmic stop-RT data. Overall findings can be accounted for by assuming a functional architecture of an internal clock in which pulses emitted by a central pacemaker are available in parallel with two modality-specific switch-accumulator "timing modules."

Acoustic Stimulation↗
PubMed2000

Validity of clinical use of the clock-drawing test in Thai elderly patients with memory problems.

Forty eight elderly Thai patients, 12 demented, 36 non-demented who consecutively attended a geriatric clinic, at Chulalongkorn University Hospital, with a memory problem were recruited in the study which aimed to determine the validity of the clock-drawing test (CDT) and Chula mental test (CMT). Subjects took the Chula Mental Test (CMT) and were asked to draw a clock on a preprinted 12 centimeters circle showing the time of 11:10. Clocks were scored using the Chula Clock-drawing Scoring System (CCSS). Ten subjects voluntarily participated and completed the WAIS test. The best cutoff score of the CMT and the CDT using diagnosis of dementia as a gold standard were 15 and 7 respectively. Sensitivity and specificity for detecting dementia by the CDT were 100 per cent and 94.1 per cent respectively. Sensitivity and specificity for detecting dementia by the CMT were 83.3 per cent 91.7 per cent. The likelihood ratio (95% confidence interval) of the CMT and the CDT were 10 (3.3-30.4) and 17 (4.4-65.2) respectively. There was a good correlation of the CDT score and the CMT score with the WAIS score. Although the CDT was better than the CMT in literate patients, the CDT had limitation of use among illiterate patients but not the CMT. The benefits of simultaneously application on dementia screening was shown. This study showed that the CDT was a valuable, brief method of dementia screening in elderly Thai patients with memory problems.

Aged↗
PubMed2000

Hormonal and pharmacological manipulation of the circadian clock: recent developments and future strategies.

The mammalian circadian oscillator, located in the suprachiasmatic nuclei of the anterior hypothalamus, serves as the principal source of rhythmic temporal information for virtually all physiologic processes in the organism, including the alternating expression of sleep and wakefulness. Recent studies, in both animal models and human subjects, have demonstrated the important modulation of sleep and wakefulness mediated by the circadian clock. Independent of other factors, notably prior sleep-wake history, the circadian clock potentiates wakefulness (and alertness) at one phase of the diurnal cycle, while facilitating sleep and its attendant processes at the opposite phase. The adaptive advantage of synchronizing sleep-wake behaviors with the daily changes in the external environment is clear. But in a modern world where the constraints of environmental time are less and less important, the circadian clock still imposes rigid boundaries on the timing of sleep and alert wakefulness that are increasingly perceived as limitations on human performance. This conflict underlies the sleep "disorders" of jet lag and shiftwork sleep disruption, problems that are not really diseases at all, but instead reflect normal function of circadian timing in the context of extraordinary demands on sleep-wake scheduling. Whatever their proper classification, both jet lag and shiftwork insomnia represent important societal problems deserving of public health and medical attention. Barring a worldwide rejection of air-travel, jet lag will continue to afflict tens of thousands of people annually. The effects of jet lag on human performance, while typically transient, can nonetheless be significant, affecting commerce, government, and even the outcome of professional sports contests. More important, only a global regression to an agrarian economy will eliminate the problem of tens of millions of workers in this country who regularly attempt to work at night and sleep during the day. In contrast to jet lag, shiftwork produces chronic sleep disruption lasting for the duration of shiftwork exposure. For while individual differences in the ability to adjust to a nocturnal work schedule clearly exist, recent studies suggest that few if any night workers regularly experience restful and restorative day sleep equivalent to that considered normal at night. This chronic sleep limitation is associated with significant increases in a number of consequent problems including sleepiness-related accidents, social disruption, and psychiatric disturbances. In addition, chronic exposure to shiftwork has now been shown to be an independent risk factor for the development of both cardiovascular and gastrointestinal diseases. While these epidemiological studies have not identified the specific aspect of shiftwork that is associated with increased risk of these disorders, the chronic limitation and disruption is foremost among plausible factors. The most important aspect of human circadian physiology that limits adaptation to the extreme schedules inherent in shiftwork and jet travel is the primacy of light among entraining signals, or zeitgebers. Exposure to sunlight for night shiftworkers, or for jet travelers at their destination, results in maintenance (or resetting) of the clock to environmental time. This response can be prevented or overridden with extraordinary avoidance of sunlight or with provision of artificial light of sufficient duration and intensity to negate the sunlight signal, an approach shown to be effective in the treatment of shiftwork sleep disruption. Practical issues sharply limit the application of artificial lighting to all shiftwork settings, however, and the role for a pharmacological chronobiotic agent capable of accomplishing the same end is potentially very large (Copinschi et al., 1995; Jamieson et al., 1998). For example, the effects of zolpidem vs. placebo on sleep, daytime alertness, and fatigue in travelers who complain of jet lag was co

Antidepressive Agents, Tricyclic↗
PubMed2002

The value of clock drawing in identifying executive cognitive dysfunction in people with a normal Mini-Mental State Examination score.

BACKGROUND: Executive cognitive dysfunction can precede the memory disturbances of dementia. People with executive cognitive dysfunction can have a normal Mini-Mental State Examination (MMSE) score but still have severe functional limitations. We evaluated the usefulness of clock drawing in identifying people with executive dysfunction who have a normal MMSE score. METHODS: We reviewed the charts of consecutive patients referred between July 1999 and June 2000 to a multidisciplinary geriatric assessment clinic because of concerns about functional inabilities. The patients had all undergone the Executive Interview for the diagnosis of executive cognitive dysfunction as well as an MMSE and clock-drawing test (scored by 2 methods: one described by Watson and colleagues [the Watson method] and one described by Sunderland and colleagues [the Sunderland method]). RESULTS: We reviewed the charts of 68 patients (40 women, 28 men); their mean age was 79 years (range 55-94). Thirty-six patients had an MMSE score of less than 24, and 32 had a "normal" MMSE score (24-30). Among those with a normal MMSE score, 22 had an abnormal Executive Interview score. Using the Executive Interview as the gold standard, the sensitivity and specificity of the Watson method of scoring clock drawings to predict an abnormal Executive Interview score were 59% and 70% respectively; the corresponding values were 18% and 100% for the Sunderland method. INTERPRETATION: The presence of an abnormal MMSE score alerts clinicians to the possibility of cognitive impairment. For patients referred for geriatric assessment who have a normal MMSE score, a clock-drawing test, scored by either the Watson or the Sunderland method, is a moderately sensitive and specific adjunct for detecting executive cognitive dysfunction.

Aged↗
PubMed1992

Resetting of the mammalian circadian clock through lowering of the amplitude: rat pineal N-acetyltransferase rhythm as a model.

During resetting of the mammalian circadian clock, not only phase of the clock is shifted, but amplitude of overt rhythms driven by the clock may be temporarily reduced or even abolished. The present paper is aimed to elucidate the mechanism of amplitude reduction of the overt circadian rhythm in the rat pineal N-acetyltransferase (NAT). The rhythm has two phase markers, namely the time of the evening NAT rise and that of the morning decline. When the phase relationship between both markers is compressed drastically, the NAT rise may occur just close to or at the time of the decline and consequently the NAT rhythm with a full amplitude cannot be expressed. Such a compression may occur in two ways: either animals are subjected to a considerable advance in the light onset which phase advances the morning NAT decline and at the same time phase delays the evening NAT rise, or they are subjected to a considerable delay in the light offset, which primarily phase delays more the NAT rise than the decline. While in the former case the phase markers move in opposite directions, in the latter case they move in the same direction, but to a different extent. The data suggest a complex structure of the underlying clock.

Animals↗
PubMed1988

[The Black Forest arched clock in the x-ray picture].

The typical painted wooden Black Forest clock of the late eighteenth and early nineteenth century was the original famous Black Forest clock. The clocks changed from a useful article to an object in great demand by collectors; however, among them there are many fakes. Because of the use of colors containing lead and zinc at that time, the paint on these clocks can be evaluated radiologically and restaurations made later or even fakes can be detected easily. Important information can even be obtained about the wood used: its condition, the wooden axles, and abrasion of the gears.

Art↗
PubMed1979

On the 'clock' mechanism determining the time of tissue-specific enzyme development during ascidian embryogenesis. I. Acetylcholinesterase development in cleavage-arrested embryos.

During ascidian embryogenesis a tissue-specific enzyme, muscle acetylcholinesterase (AChE) may first be detected histochemically in the presumptive muscle cells of the neurula. In order to investigate the 'clock' or counting mechanism that is determining the time when AChE first appears, Whittaker's experiment (1973) has been repeated using eggs of the ascidian, Halocynthia roretzi. Embryos that had been permanently cleavage-arrested with cytochalasin B were able to differentiate AChE in their muscle lineage blastomeres. The time of first AChE occurrence in embryos that had been cleavage-arrested in the 32-cell stage with cytochalasin B was about the same as in normal embryos. This result indicates that the clock is not apparently regulated by the events of cytokinesis. The early gastrulae which had been arrested with colchicine or with colcemid could develop AChE activity, although no histochemically detectable AChE activity was observed in the cleavage-stage embryos that had been arrested with either drug. Therefore the clock does not seem to be controlled by the mitotic cycle of the nucleus. It is suggested that the cycle of DNA replication may be related to the regulation of the clock that is determining the time of development of histospecific protein.

Acetylcholinesterase↗
PubMed1997

Resetting the biological clock: mediation of nocturnal CREB phosphorylation via light, glutamate, and nitric oxide.

Synchronization between the environmental lighting cycle and the biological clock in the suprachiasmatic nucleus (SCN) is correlated with phosphorylation of the Ca2+/cAMP response element binding protein (CREB) at the transcriptional activating site Ser133. Mechanisms mediating the formation of phospho-CREB (P-CREB) and their relation to clock resetting are unknown. To address these issues, we probed the signaling pathway between light and P-CREB. Nocturnal light rapidly and transiently induced P-CREB-like immunoreactivity (P-CREB-lir) in the rat SCN. Glutamate (Glu) or nitric oxide (NO) donor administration in vitro also induced P-CREB-lir in SCN neurons only during subjective night. Clock-controlled sensitivity to phase resetting by light. Glu, and NO is similarly restricted to subjective night. The effects of NMDA and nitric oxide synthase (NOS) antagonists on Glu-mediated induction of P-CREB-lir paralleled their inhibition of phase shifting. Significantly, among neurons in which P-CREB-lir was induced by light were NADPH-diaphorase-positive neurons of the SCN's retinorecipient area. Glu treatment increased the intensity of a 43 kDa band recognized by anti-P-CREB antibodies in subjective night but not day, whereas anti-alpha CREB-lir of this band remained constant between night and day. Inhibition of NOS during Glu stimulation diminished the anti-P-CREB-lir of this 43 kDa band. Together, these data couple nocturnal light, Glu, NMDA receptor activation and NO signaling to CREB phosphorylation in the transduction of brief environmental light stimulation of the retina into molecular changes in the SCN resulting in phase resetting of the biological clock.

2-Amino-5-phosphonovalerate↗
PubMed2025

Circadian clock control of ribosome composition promotes rhythmic translation and termination fidelity.

Ribosome composition is dynamic, shifting with cell state and stress, but whether it varies with circadian time is unknown. Here, we uncover circadian clock-driven changes in ribosome composition in Neurospora crassa. Mass spectrometry of ribosomes across circadian time identified six ribosomal proteins and one associated factor under clock control. Rhythms in eL31 abundance were validated in purified ribosomes, and deletion of el31 disrupted translation rhythms in nearly half of rhythmically translated mRNAs. N. crassa eL31 promotes circadian control of translation termination and impacts elongation fidelity while maintaining Mg homeostasis, a key determinant of translational accuracy. These findings reveal that the circadian clock reprograms ribosome composition to orchestrate rhythmic translation and fidelity, temporally expanding the proteome beyond the static genome to align cellular function with time of day.

Neurospora crassa↗
PubMed1999

Cycling vrille expression is required for a functional Drosophila clock.

We identified a novel regulatory loop within Drosophila's circadian clock. A screen for clock-controlled genes recovered vrille (vri), a transcription factor essential for embryonic development. vri is expressed in circadian pacemaker cells in larval and adult brains. vri RNA levels oscillate with a circadian rhythm. Cycling is directly regulated by the transcription factors dCLOCK and CYCLE, which are also required for oscillations of period and timeless RNA. Eliminating the normal vri cycle suppresses period and timeless expression and causes long-period behavioral rhythms and arrhythmicity, indicating that cycling vri is required for a functional Drosophila clock. We also show that dCLOCK and VRI independently regulate levels of a neuropeptide, pigment dispersing factor, which appears to regulate overt behavior.

ARNTL Transcription Factors↗
PubMed2003

Circadian clocks: self-assembling oscillators?

Circadian clocks are auto-regulatory loops in which 'clock' gene products feedback to regulate their own expression. This explains how they keep oscillating, but how do they first get going? It appears that the transcription factor dClock not only drives the oscillation within the fruit fly's clock, but also plays a pivotal role in pre-assembling the clockwork.

Animals↗
PubMed2005

Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin-proteasome pathway.

Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) promotes its degradation through the ubiquitin-proteasome pathway. Ubiquitination of FRQ requires FWD-1 (F-box/WD-40 repeat-containing protein-1), which is the substrate-recruiting subunit of an SCF (SKP/Cullin/F-box)-type ubiquitin ligase. In the fwd-1 mutant strains, FRQ degradation is defective, resulting in the accumulation of hyperphosphorylated FRQ and the loss of the circadian rhythmicities. The CSN (COP9 signalosome) promotes the function of SCF complexes in vivo. But in vitro, deneddylation of cullins by CSN inhibits SCF activity. In Neurospora, the disruption of the csn-2 subunit impairs FRQ degradation and compromises the normal circadian functions. These defects are due to the dramatically reduced levels of FWD-1 in the csn-2 mutant, a result of its rapid degradation. Other components of the SCF(FWD-1) complex, SKP-1 and CUL-1 are also unstable in the mutant. These results establish important roles for SCF(FWD-1) and CSN in the circadian clock of Neurospora and suggest that they are conserved components of the eukaryotic circadian clocks. In addition, these findings resolve the CSN paradox and suggest that the major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.

Biological Clocks↗