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PubMed1978

Comparisons of mental clocks.

Subjects in three experiments were presented with pairs of clock times and were required to choose the one in which the hour and minute hand formed the smaller angle. In Experiments 1 and 2, the times were presented digitally, necessitating a transformation into symbolic representations from which the angular size difference could be inferred. The results revealed orderly symbolic distance effects so that comparison reaction time increased as the angular size difference decreased. Moreover, subjects generally reported using imagery to make the judgment, and subjects scoring high on test of imagery ability were faster than those scoring low on such tests. Experiment 3 added a direct perceptual condition in which subjects compared angles between pairs of hands on two drawn (analog) clocks, as well as a mixed condition involving one digital and one analog clock time. The results showed comparable distance effects for all conditions. In addition, reaction time increased from the perceptual, to the mixed, to the pure-digital condition. These results are consistent with predictions from an image-based dual-coding theory.

Female↗
PubMed1988

Creatine accelerates the circadian clock in a unicellular alga.

The circadian clock is considered to be a universal feature of eucaryotic organisms, controlling the occurrence and rates of many different aspects of life, ranging from single enzymatic reactions and metabolism to complex behaviours such as activity and rest. Although the nature of the underlying cellular/biochemical oscillator is still unknown, many substances are known to influence either phase or period of circadian rhythms in different organisms. These include D2O, electrolytes and ion channel inhibitors, small organic molecules such as alcohols and aldehydes, inhibitors of protein synthesis and amino-acid analogues. Certain transmitter and neurochemical drugs also influence the circadian clock in higher animals. We report here that the period of free-running circadian rhythms in the unicellular marine alga Gonyaulax polyedra is shortened by extracts from mammalian cells. The effect is dose-dependent, accelerating the circadian clock by as much as 4 hours per day. The substance responsible for this effect has been isolated from bovine muscle and identified as creatine. Authentic creatine has identical biological effects at micromolar concentrations and is known in animal systems for its involvement in cellular energy metabolism. A period shortening substance with similar chemical properties is also present in extracts of Gonyaulax itself.

Animals↗
PubMed2001

Time zones: a comparative genetics of circadian clocks.

The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals. Intense genetic analysis during recent years has uncovered many of the components and molecular mechanisms comprising these clocks. Although autoregulatory genetic networks are a consistent feature in the design of all clocks, the weight of evidence favours their independent evolutionary origins in different kingdoms.

Animals↗
PubMed1996

A light-entrainment mechanism for the Drosophila circadian clock.

Biochemical studies indicate that the Drosophila timeless protein (Tim) is a stoichiometric partner of the period protein (Per) in fly head extracts. A Per-Tim heterodimeric complex explains the reciprocal autoregulation of the proteins on transcription. The complex is under clock control, and many circadian features of the Tim cycle resemble those of the Per cycle. However, Tim is rapidly degraded in the early morning or in response to light, releasing Per from the complex. The Per-Tim complex is a functional unit of the Drosophila circadian clock, and Tim degradation may be the initial response of the clock to light.

Animals↗
PubMed1989

Silicone oil in the aphakic eye: the influence of a six o'clock peripheral iridectomy.

Complications after six months, in a series of 44 aphakic eyes treated by vitrectomy and fluid/silicone-oil exchange with six o'clock (Ando) peripheral iridectomy, are reported. Comparisons are made with the complications after six months in a similar series treated prior to the introduction of the six o'clock iridectomy. It is concluded that a patent six o'clock iridectomy is effective in reducing the complications of intraocular silicone oil in the aphakic eye.

Adolescent↗
PubMed2005

Molecular clocks: four decades of evolution.

During the past four decades, the molecular-clock hypothesis has provided an invaluable tool for building evolutionary timescales, and has served as a null model for testing evolutionary and mutation rates in different species. Molecular clocks have also influenced the development of theories of molecular evolution. As DNA-sequencing technologies have progressed, the use of molecular clocks has increased, with a profound effect on our understanding of the temporal diversification of species and genomes.

Animals↗
PubMed2004

Crystal structure of the C-terminal clock-oscillator domain of the cyanobacterial KaiA protein.

KaiA, KaiB and KaiC constitute the circadian clock machinery in cyanobacteria, and KaiA activates kaiBC expression whereas KaiC represses it. Here we show that KaiA is composed of three functional domains, the N-terminal amplitude-amplifier domain, the central period-adjuster domain and the C-terminal clock-oscillator domain. The C-terminal domain is responsible for dimer formation, binding to KaiC, enhancing KaiC phosphorylation and generating the circadian oscillations. The X-ray crystal structure at a resolution of 1.8 A of the C-terminal clock-oscillator domain of KaiA from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1 shows that residue His270, located at the center of a KaiA dimer concavity, is essential to KaiA function. KaiA binding to KaiC probably occurs via the concave surface. On the basis of the structure, we predict the structural roles of the residues that affect circadian oscillations.

Amino Acid Sequence↗
PubMed1991

The use of the sugar clock in dental health education.

An important factor in the prevention of dental caries is limiting the number of times in a day that sugar enters the mouth. This can be simply illustrated by using the sugar clock. The effectiveness of this as a technique for teaching 9-11-year-old children the importance of limiting frequency of sugar intakes was tested in a controlled study. Four weeks and 4 months after sugar clocks were used with a study group of children, they showed a significant increase over baseline in the number of correct answers given to a questionnaire. A control group showed no significant increase. It was concluded that the sugar clock is an effective method of teaching the importance of limiting frequency of sugar intake to this age group.

Child↗
PubMed2001

Qualitative analyses of clock drawings in Alzheimer's disease and vascular dementia.

Although quantitative analyses of clock drawings (CD) have achieved widespread clinical use as a cognitive screening, little is known about the qualitative profiles of CD in Alzheimer's disease (AD) and vascular dementia (VD). To address this issue, the present study examined the significance of qualitative analyses of CD in AD and VD. Sixty-seven AD patients, 44 VD patients and eight controls underwent a clock drawing test and took the Mini-Mental State Examinations (MMSE). In the dementia groups, quantitative scores significantly decreased compared with controls and were significantly correlated with MMSE scores. Qualitative analysis demonstrated that in AD patients qualitative error patterns were stable and independent of severity. In contrast, in VD patients the frequency of graphic difficulties and conceptual deficit increased, while the frequency of spatial and/or planning deficit decreased, as severity worsened. In mild dementia groups the frequency of spatial and/or planning deficit was significantly higher in VD. In moderate dementia groups, the frequency of graphic difficulties was significantly higher in VD and the difference in the frequency of spatial and/or planning deficit seen in mild dementia disappeared. The present study suggests that qualitative analyses of clock drawings could demonstrate the neuropsychological profiles of AD and VD and their differences between these dementias.

Aged↗
PubMed1998

Stimuli which entrain the circadian clock of the neonatal Syrian hamster in vivo regulate the phosphorylation of the transcription factor CREB in the suprachiasmatic nucleus in vitro.

Photic resetting of the adult mammalian circadian clock in vivo is associated with phosphorylation of the Ser133 residue of the calcium/cyclic AMP response-element binding-protein (CREB) in the retinorecipient region of the suprachiasmatic nucleus (SCN). Western blotting and immunocytochemistry were used to investigate whether agonists known to reset the clock of neonatal hamsters in vivo are also able to influence the phosphorylation of CREB in the suprachiasmatic hypothalamus in vitro. Antisera raised against synthetic CREB peptide sequences were used to differentiate between total CREB and the Ser133 phosphorylated form of CREB (pCREB). Western blot analysis of proteins isolated from suprachiasmatic tissue of 1-day-old Syrian hamsters revealed bands at approximately 45 kDa corresponding to total CREB and pCREB. Treatment of the tissue with a mixture of glutamatergic agonists [N-methyl-D-aspartate (NMDA), amino-methyl proprionic acid (AMPA) and kainate, all at 1 microM], or native glutamate (1 microM) had no effect on the total CREB signal, but increased the pCREB signal, indicative of agonist-stimulated phosphorylation of CREB on Ser133. A similar effect was seen following treatment of the suprachiasmatic blocks with either dopamine (1 microM) or forskolin (1 microM). Simultaneous treatment with melatonin (1 microM) significantly attenuated stimulation by forskolin. The effect of the agonists on nuclear pCREB-immunoreactivity (-ir) was investigated in primary cultures which contained a mixture of cell types characteristic of the suprachiasmatic nuclei in vivo. Basal expression of nuclear total CREB-ir was high, whereas expression of pCREB-ir was low. Treatment with glutamate (1 microM) or dopamine (1 microM) had no effect on total CREB-ir, but increased pCREB-ir in approximately 50 and 30% of cells, respectively, whereas forskolin (1 microM) increased pCREB-ir in almost all cells (> 90%). The effects of all three agonists were rapid (< 15 min), and dose and time dependent. Melatonin reversed the effects of forskolin in mixed cultures, but not in pure astrocyte cultures. Dual-immunocytochemistry (ICC) revealed that glutamate (1 microM) increased nuclear pCREB-ir in cells immunoreactive for microtubule-associated protein II (MAP II-ir), but not other cells, indicating an effect predominantly on neurons. This occurred equally in gamma-amino butyric acid (GABA)-ir and non-GABA-ir neurons. Dopamine (1 microM) was more selective, increasing pCREB-ir only in GABA-ir neurons, whereas forskolin increased pCREB-ir in all cells. The specific stimulation of pCREB-ir in GABA-ir neurons by dopamine was reversed by melatonin, but melatonin had no effect on the increase in pCREB-ir induced in GABA-ir neurons by glutamate. These results demonstrate that agonists known to entrain the circadian clock in vivo modulate phosphorylation of CREB in GABA-ir neurons derived from the neonatal suprachiasmatic nuclei.

Animals↗
PubMed2003

Expression of the circadian clock gene Period 1 in neuroendocrine cells: an investigation using mice with a Per1::GFP transgene.

The circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily temporal organization in behaviour and neuroendocrine function. The molecular basis for circadian rhythm generation is an interacting transcriptional/translational feedback loop comprised of several 'clock genes' and their respective protein products. Clock genes are expressed not only in the SCN but also in numerous other locations throughout the brain, including regions rich in neuroendocrine cells. In order to investigate whether neuroendocrine cells function as autonomous oscillators, we used female transgenic mice in which an unstable, degradable jellyfish green fluorescent protein (GFP) gene is driven by a mouse Period 1 (Per1) gene promoter. Mice were injected (s.c.) with fluorogold (FG) in order to label neuroendocrine cells and brain sections were double-labelled for either FG and Per1 mRNA (labelled by GFP immunostaining) or FG and PER1 protein using fluorescence immunocytochemistry. Mice were killed during either the day or night. Neuroendocrine cells contained Per1 mRNA and PER1 protein in several brain regions with the greatest proportion of double-labelled cells occurring in the arcuate nucleus (Arc). The number of neuroendocrine cells labelled was not affected by the stage of the estrous cycle. Fewer FG-labelled cells expressed Per1 message and protein during the night compared to the day. In the Arc, staining for tyrosine hydroxylase revealed that neuroendocrine cells expressing Per1 message and protein were dopaminergic. Together, these findings suggest that neuroendocrine cells contain the molecular machinery necessary to oscillate independently. It remains to be determined whether these cells actually function as autonomous oscillators or whether these rhythms are driven by signals from the SCN. These findings also indicate that the endocrine system represents an opportunity to study the interactions between central (SCN and neuroendocrine cells) and peripheral circadian (endocrine gland) oscillators.

Animals↗
PubMed2003

Periodic absence of nursing mothers phase-shifts circadian rhythms of clock genes in the suprachiasmatic nucleus of rat pups.

Effects of absence of nursing mothers on the circadian pacemaker of their offspring were examined by measuring clock genes, the rat Per1 (rPer1) and rPer2 expression rhythms in the pup suprachiasmatic nuclei (SCN). Neonate rats born to mothers kept under a 12-h light : 12-h dark cycle (LD) were blinded immediately after birth and exposed to periodic maternal deprivation where pups were deprived of their mothers during the light phase of 12-h for the first week of life. At postnatal day 6, the periodic maternal deprivation completely phase-reversed the circadian rhythms in expression of the clock genes in the pup SCN and in spontaneous locomotor activity after the pups were weaned at postnatal day 21. The periodic maternal absence also altered the patterns of stress-related gene expressions such as corticotropine-releasing hormone, arginine vasopressin, and glucocorticoid receptor in particular brain areas of the mother-deprived pups at P6. These findings indicate that periodic absence of the nursing mother in the first week of life produces a resetting effect on the neonatal circadian clock and induces stress responses in the hypothalamus-pituitary-adrenal axis.

Animals↗
PubMed2002

A comparison of scoring protocols on the Clock Drawing Test in relation to ease of use, diagnostic group, and correlations with Mini-Mental State Examination.

OBJECTIVES: To compare five scoring protocols for the Clock Drawing Test (CDT). DESIGN: A retrospective study in which four formal and one informal scoring methods were used to rate clock drawings. Correlations between CDT scores and the abbreviated version of the Mini-Mental State Examination (MMSE-brief) total and memory scores were compared for the total sample and for three diagnostic groups. Protocols were also compared for content and ease of use. SETTING: A comprehensive, community mental health service for older adults. PARTICIPANTS: Sixty-three patients with dementia of the Alzheimer's type, multi-infarct dementia, or a mixed diagnosis. MEASUREMENTS: The CDT, scored under five different scoring protocols, and the MMSE-brief. RESULTS: For the total sample, significant correlations were obtained between all five scoring methods and MMSE scores. Two scoring methods stood out. By diagnostic group, all correlations except one between scoring methods were significant, whereas relationships between the MMSE and the CDT varied. CONCLUSIONS: Deterioration in clock drawing scored under five different scoring protocols correlates with severity of global cognitive impairment, as assessed by the MMSE-brief. Although two scoring methods were easier to use, the type of dementia may dictate which scoring protocol is most suitable. Because clinicians now also use the CDT to screen for executive functioning, future scoring methods may need to be selected in terms of what the CDT is screening.

Aged↗
PubMed1990

The internal clock: evidence for a temporal oscillator underlying time perception with some estimates of its characteristic frequency.

Evidence for the proposition that human time perception is determined by an internal clock is largely indirect. It would strengthen the case for this hypothesis if a model for the internal clock were available from which predictions could be derived and tested, and if the basic parameter of such a model, the frequency at which the clock runs, could be estimated. A model for an internal temporal pacemaker is briefly described and its properties are explored by computer simulation. Results are obtained that provide a basis for predicting that, under appropriate conditions, interference between an imposed rhythm and the frequency of a temporal oscillator may cause perturbations in temporal judgment which are related to the characteristic frequency of that oscillator. Experimental data are reported which appear to demonstrate such an interference pattern. These results allow some estimates of the characteristic frequency of the temporal oscillator to be obtained.

Adult↗
PubMed2004

A clock gene, period, plays a key role in long-term memory formation in Drosophila.

The cAMP-responsive transcription factor, CREB, is required for formation of long-term memory (LTM) in Drosophila melanogaster and regulates transcription of a circadian clock gene, period (per). Involvement of CREB both in LTM and circadian rhythm raises the possibility that per also plays a role in LTM. Assaying the experience-dependent courtship inhibition in male flies as a measure for LTM, we show here that per mutants are defective in LTM formation. This defect was rescued by induction of a wild-type per transgene in a per-null mutant, and overexpression of per enhanced LTM formation in the wild-type background. Furthermore, we found that synaptic transmission through per-expressing cells is most likely to be required during retrieval of LTM. In contrast, mutations in other clock genes (timeless, dClock, and cycle) did not affect LTM formation. Thus, independent of the core oscillator of circadian clock, per plays a key role in LTM formation.

Animals↗
PubMed2004

The timing of eukaryotic evolution: does a relaxed molecular clock reconcile proteins and fossils?

The use of nucleotide and amino acid sequences allows improved understanding of the timing of evolutionary events of life on earth. Molecular estimates of divergence times are, however, controversial and are generally much more ancient than suggested by the fossil record. The limited number of genes and species explored and pervasive variations in evolutionary rates are the most likely sources of such discrepancies. Here we compared concatenated amino acid sequences of 129 proteins from 36 eukaryotes to determine the divergence times of several major clades, including animals, fungi, plants, and various protists. Due to significant variations in their evolutionary rates, and to handle the uncertainty of the fossil record, we used a Bayesian relaxed molecular clock simultaneously calibrated by six paleontological constraints. We show that, according to 95% credibility intervals, the eukaryotic kingdoms diversified 950-1,259 million years ago (Mya), animals diverged from choanoflagellates 761-957 Mya, and the debated age of the split between protostomes and deuterostomes occurred 642-761 Mya. The divergence times appeared to be robust with respect to prior assumptions and paleontological calibrations. Interestingly, these relaxed clock time estimates are much more recent than those obtained under the assumption of a global molecular clock, yet bilaterian diversification appears to be approximately 100 million years more ancient than the Cambrian boundary.

Animals↗
PubMed2004

The rate of DNA evolution: effects of body size and temperature on the molecular clock.

Observations that rates of molecular evolution vary widely within and among lineages have cast doubts on the existence of a single "molecular clock." Differences in the timing of evolutionary events estimated from genetic and fossil evidence have raised further questions about the accuracy of molecular clocks. Here, we present a model of nucleotide substitution that combines theory on metabolic rate with the now-classic neutral theory of molecular evolution. The model quantitatively predicts rate heterogeneity and may reconcile differences in molecular- and fossil-estimated dates of evolutionary events. Model predictions are supported by extensive data from mitochondrial and nuclear genomes. By accounting for the effects of body size and temperature on metabolic rate, this model explains heterogeneity in rates of nucleotide substitution in different genes, taxa, and thermal environments. This model also suggests that there is indeed a single molecular clock, as originally proposed by Zuckerkandl and Pauling [Zuckerkandl, E. & Pauling, L. (1965) in Evolving Genes and Proteins, eds. Bryson, V. & Vogel, H. J. (Academic, New York), pp. 97-166], but that it "ticks" at a constant substitution rate per unit of mass-specific metabolic energy rather than per unit of time. This model therefore links energy flux and genetic change. More generally, the model suggests that body size and temperature combine to control the overall rate of evolution through their effects on metabolism.

Animals↗
PubMed2005

Winter disruption of the circadian clock in chestnut.

Circadian clock performance during winter dormancy has been investigated in chestnut by using as marker genes CsTOC1 and CsLHY, which are homologous to essential components of the central circadian oscillator in Arabidopsis. During vegetative growth, mRNA levels of these two genes in chestnut seedlings and adult plants cycled daily, as expected. However, during winter dormancy, CsTOC1 and CsLHY mRNA levels were high and did not oscillate, indicating that the circadian clock was altered. A similar disruption was induced by chilling chestnut seedlings (to 4 degrees C). Normal cycling resumed when endodormant or cold-treated plants were returned to 22 degrees C. The behavior of CsTOC1 and CsLHY during a cold response reveals a relevant aspect of clock regulation not yet encountered in Arabidopsis.

Amino Acid Sequence↗