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PubMed2005

Transcriptional feedback of Neurospora circadian clock gene by phosphorylation-dependent inactivation of its transcription factor.

The circadian clock protein Frequency (FRQ) feedback-regulates its own expression by inhibiting its transcriptional activator, White Collar Complex (WCC). We present evidence that FRQ regulates the bulk of WCC through modulation of its phosphorylation status rather than via direct complex formation. In the absence of FRQ, WCC is hypophosphorylated and transcriptionally active, while WCC is hyperphosphorylated and transcriptionally inactive when FRQ is expressed. The phosphorylation status of WCC changes rhythmically over a circadian cycle. Dephosphorylation and activation of WCC depend on protein phosphatase 2A (PP2A), and WCC is a substrate of PP2A in vitro. Hypophosphorylated WCC binds to the clock box of the frq promoter even in the presence of FRQ, while binding of hyperphosphorylated WCC is compromised even when FRQ is depleted. We propose that negative feedback in the circadian clock of Neurospora is mediated by FRQ, which rhythmically promotes phosphorylation of WCC, functionally equivalent to a cyclin recruiting cyclin-dependent kinase to its targets.

Circadian Rhythm↗
PubMed2005

Impairment in clock-time estimation following right hemisphere ischemic damage.

In order to assess clock-time estimation (CTE), we asked "what time is it in your opinion?" to 48 recent stroke in-patients, 21 with right (RH), 27 with left hemispheric (LH) lesions, and to 20 control in-patients without brain lesions (C). Errors were measured in terms of the number of minutes by which the estimated clock-time was later (advance errors) or earlier (delay errors) than the real clock-time. CTE was considered pathological when exceeding the mean advance or delay errors observed in control patients plus 2.5 standard deviations. The estimation of the duration of a short psychological interview was also assessed. CTE, and not duration estimation, was disturbed in patients. RH patients made significantly more pathological advance errors than LH patients (43% vs. 12%). This study points out the RH dominance for CTE in stroke patients.

Adult↗
PubMed2004

Daily injection of insulin attenuated impairment of liver circadian clock oscillation in the streptozotocin-treated diabetic mouse.

Recent studies have shown a dampened amplitude of clock gene rhythm in the heart and liver of streptozotocin (STZ)-treated rats and mice, however it is unknown whether impairment is due to dysfunction of the suprachiasmatic nucleus (SCN) or not. Rhythmic expression of mPER2 was dampened in the STZ-treated mouse liver but not SCN and cerebral cortex. Injection of insulin could normalize an impairment of mPer2 and mPER2 expression rhythm in the liver, when it was injected at nighttime, but not at daytime. In the present study, we demonstrated that insulin-dependent diabetes impaired oscillation of the peripheral clock gene and its product. Insulin injection can recover dampened oscillation of the peripheral clock depending on its injection time.

Animals↗
PubMed2006

Sensitivity and specificity of the Clock Drawing Test, incorporating Rouleau scoring system, as a screening instrument for questionable and mild dementia: scale development.

OBJECTIVE: The objective of this study was to validate the Rouleau scoring system for the Clock Drawing Test (CDT) in northern Taiwan, a non-English speaking area, to increase its generalization by detecting subjects with questionable dementia (QD) from normal controls (NC) and subjects with mild dementia (AD). The system consists of two parts: a 10-point scoring and error types. A cross-sectional design was used. One hundred and sixteen subjects were recruited from a memory disorder clinic (n=40 NC; n=34 QD; n=42 AD). Reliability and validity were estimated, the predictive accuracy was calculated using the receiver operating characteristic (ROC) curve analysis, and the error types were counted. RESULTS: The results indicated that most of the error types committed were conceptual deficiencies and graphic difficulties; more errors were found in the command condition (CDT-command) than in the copy condition (CDT-copy); 15% of the subjects drew smaller clock circles in CDT-command, which did not relate to any other errors. No small clock was found in CDT-copy because a pre-dawn circle was provided. The inter-rater reliability of the Rouleau scoring system was .87 and .83 for the CDT-command and -copy, respectively, while the discriminate accuracy of the scoring system was relatively low in detecting QD vs. NC, QD vs. AD, but somewhat better in distinguishing AD vs. NC groups for the areas under the ROC curves was equal to .72 for the CDT-command, and .73 for the CDT-copy. Visuospatial construction and executive functioning explained the largest score variance of the CDT in both conditions, while depressive symptoms were not significantly associated with the CDT performance. CONCLUSION: The CDT using the Rouleau scoring system has been validated in mild AD subjects in Taiwan; however, to screen for QD sufferers, alternative scoring systems emphasizing hands or combining CDT with different neuropsychological tests such as the Clinical Abilities Screening Instrument are recommended.

Aged↗
PubMed2005

PER/TIM-mediated amplification, gene dosage effects and temperature compensation in an interlocking-feedback loop model of the Drosophila circadian clock.

We have analysed a first-order kinetic representation of a interlocking-feedback loop model for the Drosophila circadian clock. In this model, the transcription factor Drosophila CLOCK (dCLK) which activates the clock genes period (per) and timeless (tim) is subjected to positive and negative regulations by the proteins 'PAR Domain Protein 1' (PDP1) and VRILLE (VRI), whose transcription is activated by dCLK. The PER/TIM complex binds to dCLK and in this way reduces the activity of dCLK. The results of our simulations suggest that the positive and negative feedback loops of Pdp1 and vri are essential for the overall oscillations. Although self sustained oscillations can be obtained without per/tim, the model shows that the PER/TIM complex plays an important role in amplification and stabilization of the oscillations generated by the Pdp1/vri positive/negative feedback loops. We further show that in contrast to a single (per/tim) negative feedback loop oscillator, the interlocking-feedback loop model can readily account for the effect of gene dosages of per, vri, and Pdp1 on the period length. Calculations of phase resetting on a temperature compensated version of the model shows good agreement with experimental phase response curves for high and low temperature pulses. Also, the partial losses of temperature compensation in perS and perL mutants can be described, which are related to decreased stabilities of the PER/TIM complex in perS and the stronger/more stable inhibitory complex between dCLK and PER/TIM in perL, respectively. The model shows (somewhat surprisingly) poor entrainment properties, especially under extended light/dark (L/D) cycles, which suggests that parts of the L/D tracking or sensing system are not well represented.

Animals↗
PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗
PubMed2003

Effects of uncoupling of mitochondrial energy conservation on the ultradian clock-driven oscillations in Saccharomyces cerevisiae continuous culture.

Protonophores have several different perturbative effects on dissolved O2 concentrations in continuous cultures of Saccharomyces cerevisiae. As well as uncoupling energy conservation from mitochondrial electron transport in vivo, they reset ultradian clock-driven respiratory oscillations and produce cell cycle effects. Thus, additions at low concentration (1.25 microM) of either m-chlorocarbonyl-cyanide phenylhydrazone (CCCP) or 5-chloro-3-t-butyl-2-chloro-4(1)-nitrosalicylanilide (S13) led to phase resetting of the 48 min ultradian clock-driven respiratory oscillations. At 2.5 microM CCCP or 4 microM S13, transient inhibition of oscillatory respiration (for 5 h) preceded synchronisation of the cell division cycle seen as a slow (9 h period) wave that enveloped the 48 min oscillation. At still higher concentrations of CCCP (5 microM), the cell division cycle was prolonged by about 7 h, and during this phase, the respiratory oscillation became undetectable. The significance of these observations with respect to the time-keeping functions of the ultradian clock is discussed.

Journal Article↗
PubMed2005

Crystal structure and interactions of the PAS repeat region of the Drosophila clock protein PERIOD.

PERIOD proteins are central components of the Drosophila and mammalian circadian clock. Their function is controlled by daily changes in synthesis, cellular localization, phosphorylation, degradation, as well as specific interactions with other clock components. Here we present the crystal structure of a Drosophila PERIOD (dPER) fragment comprising two tandemly organized PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B) and two additional C-terminal alpha helices (alphaE and alphaF). Our analysis reveals a noncrystallographic dPER dimer mediated by intermolecular interactions of PAS-A with PAS-B and helix alphaF. We show that alphaF is essential for dPER homodimerization and that the PAS-A-alphaF interaction plays a crucial role in dPER clock function, as it is affected by the 29 hr long-period perL mutation.

Amino Acid Sequence↗
PubMed2005

Circadian clocks: neural and peripheral pacemakers that impact upon the cell division cycle.

Circadian clocks are pervasive entities that allow organisms to maintain rhythms of approximately 24h, independently of external cues, thereby adapting them to the solar cycle. Recent studies have shown that molecular circadian clocks are important for the proper orchestration of the cell division cycle. For the first time, this provides a framework to understand the interactions between these two evolutionarily linked timers. Here we review the current model of the circadian clock and the molecular methods that can be used to investigate its function. We then map out links to the cell cycle at the cellular level. Furthermore, we review recent progress that has linked dysfunction of the clockwork with the pathogenesis of cancer. Disruption of circadian timing (as occurs in jet-lag, shift work and dementia) thus has far reaching consequences for normal regulation of cell division. The implications of this for the health of a "24-h society" are apparent.

Animals↗
PubMed2004

Clock Drawing Test in patients with schizophrenia.

Investigations of the usefulness of the Clock Drawing Test (CDT) in schizophrenia have focused primarily on institutionalized or elderly patients. The purpose of the present study was to compare CDT performance of patients with schizophrenia living in the community with that of normal controls. Fifty-three patients with schizophrenia were compared with 66 age- and gender-matched normal controls. The CDT ('free-drawn', 'pre-drawn' and three 'examiner' conditions) and the Mini-Mental State Examination (MMSE) were administered to all participants. In patients with schizophrenia, symptom severity was assessed with the Positive and Negative Syndrome Scale (PANSS). Patients with schizophrenia had significantly lower scores on the MMSE and the five CDT conditions than the control group. When MMSE scores and level of education were included in the comparisons as covariates, the differences between the two groups remained significant. MMSE scores of the patients with schizophrenia correlated significantly with four clock conditions: 'free-drawn' 'pre-drawn' and two of the 'examiner' conditions (11:10 and 8:20). Poorer performance on the CDT correlated with higher scores on the PANSS positive symptoms subscale. Qualitative analysis of the clocks that were drawn revealed specific errors in the schizophrenia group relating to frontal processes: difficulty placing numbers in the correct position, failure to indicate the minute targets, displacement of the minute hand from the minute number, and failure to draw a longer minute hand. The fact that the CDT is sensitive enough to detect the cognitive impairment inherent in schizophrenia, as well as being correlated with symptom severity, makes this test useful in roughly assessing cognitive state in schizophrenia.

Activities of Daily Living↗
PubMed2005

Relaxed molecular clocks for dating historical plant dispersal events.

Age estimation from molecular sequences has emerged as a powerful tool for inferring when a plant lineage arrived in a particular area. Knowing the tenure of lineages within a region is key to understanding the evolution of traits, the evolution of biotic interactions, and the evolution of floras. New analytical methods model change in substitution rates along individual branches of a phylogenetic tree by combining molecular data with time constraints, usually from fossils. These "relaxed clock" approaches can be applied to several gene regions that need not all have the same substitution rates, and they can also incorporate multiple simultaneous fossil calibrations. Since 1995, at least 100 plant biogeographic studies have used molecular-clock dating, and about a fifth has used relaxed clocks. Many of these report evidence of long-distance dispersal. Meta-analyses of studies from the same geographic region can identify directional biases because of prevailing wind or water currents and the relative position and size of landmasses.

Geography↗
PubMed2003

Serotonin phase-shifts the mouse suprachiasmatic circadian clock in vitro.

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) receives multiple afferent signals that could potentially modulate its phase. One input, the serotonin (5-HT) projection from the raphe nuclei, has been extensively investigated in rats and hamsters, yet its role(s) in modulating circadian clock phase remains controversial. To expand our investigation of 5-HT modulation of the SCN clock, we investigated the phase-shifting effects of 5-HT and its agonist, (+)8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), when applied to mouse SCN brain slices. 5-HT induced 2-3 h phase advances when applied during subjective day, while non-significant phase shifts were seen after 5-HT application at other times. These phase shifts were completely blocked by the 5-HT antagonist, metergoline. DPAT also induced phase shifts when applied during mid-subjective day, and this effect appeared dose-dependent. Together, these results demonstrate that the mouse SCN, like that of the rat, is directly sensitive to in vitro phase-resetting by 5-HT.

Animals↗
PubMed2004

Judging the angles formed by visible and imaginary clock hands: a study of hemispatial effects in healthy volunteers.

Healthy, right-handed volunteers (six male, six female) either saw or imagined the hands of a clock set a particular time. In both conditions, they then judged whether the angle between the clock hands was greater than or less than 90 degrees. Subjects pressed one of two response keys to indicate their decision, and hand of response (left/right) was counterbalanced within and between subjects. The subjects had significantly longer reaction times and made significantly more errors when the imaginary angles formed by the clock hands were located in left hemispace (e.g. 8:30) than right hemispace (e.g. 4:30). With visible hands, there was no reaction time difference between visual hemifields, although significantly more errors were made when the angle formed by the hands fell within the left visual field. In the perceptual task (visible hands), reaction times and error rates increased monotonically as the distance between the hands approximated more closely to 90 degrees. This psychophysical relationship was not found in the representational task (imaginary hands). Rather, there was a significant positive correlation between reaction times/error rates and the magnitude of the number indicative of the position of the minute hand. The latter finding is consistent with the hypothesis that the lateral asymmetry in the representational task (reaction times and error rates are higher in left hemispace) is due to the time taken to mentally rotate the imaginary minute hand in a clockwise direction. No such operation is required in the perceptual condition where the hands are clearly visible.

Adolescent↗
PubMed2001

Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2.

Casein kinase Iepsilon (CKIepsilon), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) [Keesler, G.A. et al. (2000) NeuroReport 5, 951-955]. A mutation in CKIepsilon causes a shortened circadian period in Syrian Golden hamster. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). Immunohistochemical staining of rat brains demonstrates that CKIdelta protein is localized in the suprachiasmatic nuclei, the central location of the master clock. These results indicate that CKIdelta may play a role similar to CKIepsilon, suggesting that it may also be involved in regulating circadian rhythmicity by post-translation modification of mammalian clock proteins hPER1 and 2.

Animals↗
PubMed2001

Malfunction of circadian clock in the non-photoperiodic-diapause mutants of the drosophilid fly, Chymomyza costata.

The diel rhythmicity of adult eclosion was recorded in reciprocal F1 hybrids between the wild-type (Sapporo) and mutant (NPD) strains of Chymomyza costata and the functionality of central circadian clocks was checked in both strains by assessing diel and circadian patterns of the per gene mRNA abundance oscillations in fly heads using competitive polymerase chain reaction methodology. The previously detected mutations in the per coding region of the NPD strain (Shimada, Entomol. Sci. 2 (1999) 575) were found to be primarily neither responsible for the loss of the eclosion rhythm nor for the malfunction of the circadian clocks. While distinct diel and circadian rhythms in per mRNA abundance were found in the wild-type flies, the npd-mutants showed constant (arrhythmic) and low abundance of the per mRNA transcripts. Because the non-photoperiodism, arrhythmicity of adult eclosion and the malfunction of central circadian clocks all seem to result from a mutation in the autosomal npd locus, we hypothesize, that a product coded by this locus may represent a 'point of contact' between the circadian and photoperiodic time measurement systems in C. costata.

Journal Article↗
PubMed2001

Photoperiodic clock of diapause induction in Pseudopidorus fasciata (Lepidoptera: Zygaenidae).

Pseudopidorus fasciata enters diapause as fourth instar larvae at short day lengths. Using 24-h light-dark cycles, the photoperiodic response curves in this species appeared to be similar with a critical night length of 10.5h at temperatures below 30 degrees C. At an average temperature of 30.5 degrees C, the critical night length had shifted to between 15 and 17h. In experiments using non-24-h light-dark cycles, it was clearly demonstrated that the dark period (scotophase) was the decisive phase for a diapause determination. In night interruption experiments using 24-h light-dark cycles, a 1-h light pulse at LD12:12 completely reversed the long night effect and averted diapause in all treatments. At LD 9:15 light pulses of 1-h, 30- or 15-min also averted diapause effectively when both the pre-interruption (D(1)) or the post-interruption scotophases (D(2)) did not exceed the critical night length. If D(1) or D(2) exceeded the critical night length diapause was induced. The most crucial event for the photoperiodic time measurement in this species is the length of the scotophase. A 10-min light pulse placed in the most photosensitive phase reversed diapause in over 50% of the individuals. Night interruption experiments under non-24-h light-dark cycles indicated that the photoperiodic clock measured only D(1) regardless of the length of D(2), suggesting that the most inductive cycles are often those in which L+D are close to 24h. In resonance experiments, this species showed a circadian periodicity at temperatures of 24.5 or 26 degrees C, but not at 30.5 and 23.3 degrees C. On the other hand, Bünsow and skeleton photoperiod experiments failed to reveal the involvement of a circadian system in this photoperiodic clock. These results suggest the photoperiodic clock in this species is a long-night measuring hourglass and the circadian effect found in the final expression of the photoperiodic response in the resonance experiments may be caused by a disturbing effect of the circadian system in unnatural regimes.

Journal Article↗
PubMed2000

Phasic response of the photoperiodic clock to wavelength and intensity of light in the redheaded bunting, Emberiza bruniceps.

We have investigated phasic response of the photoperiodic clock to wavelength (color) and intensity of light in the male redheaded bunting (Emberiza bruniceps). Two experiments were performed. Experiment I examined whether varying the wavelength and intensity of first (entraining, E) and/or second (inducing, I) light pulse will alter the effects of a skeleton photoperiod. Birds were subjected for a period of 6 weeks to skeleton photoschedules (6L:5D:1L:12D; 6 h E-light pulse, 1 h I-light pulse) containing either an E-pulse at 5 or 20 lx coupled with I-pulse at 100 lx, or an E-pulse at 100 lx, coupled with I-pulse at 5- or 20-lx intensity. Additional two groups that received both E- and I-pulses at 100 lx served as controls. All photoschedules were employed in two colors-white and red (654 nm). There was the wavelength- and intensity-dependent stimulation of the testis growth and development. Long wavelengths of light (red light) induced faster and greater gonadal response, but the effects were also intensity dependent. Experiment II tested whether in the photostimulated birds held on long photoperiods the change in wavelength and intensity of light hours in the morning (entraining period) or the evening (inducing period) will influence the maintenance of the photoperiodic sensitivity. Birds were subjected initially to a long photoperiod of 14L:10D (L = approximately 500 lx; D = 0 lx) and then after 3 weeks, a 4-h light period in the morning (zeitgeber time, zt, 0-4) or in the evening (zt 10-14) of 14 L was substituted with white, green (528 nm), or red (654 nm) light at approximately 20-lx intensity. One group maintained on 14L:10D and other exposed to 10L:14D served as controls. After another 7 weeks, all birds were subjected to 16L:8D for a further 4 weeks to test for their responsivity to long-day photostimulation as a consequence of exposure to different experimental photoperiods. Testes regrew under 16L:8D only in birds that were exposed to 10L:14D or to 14L:10D with a green light pulse. However, there was no effect of the timing (morning, evening) of the light pulse. Taken together, the results from both the experiments indicate that in the redheaded bunting (1) the photoperiodic clock responds differentially to different wavelengths (colors, spectra) and intensities of light, and (2) the effects of wavelength and intensity of light on the clock are phase dependent, and such phasic effects can be seen in skeleton photoperiods in which light is applied discretely at different circadian phases.

Animals↗
PubMed1998

Circadian and ultradian clock-controlled rhythms in unicellular microorganisms.

The time structure of a biological system is at least as intricate as its spatial structure. Whereas we have detailed information about the latter, our understanding of the former is still rudimentary. As techniques for monitoring intracellular processes continuously in single cells become more refined, it becomes increasingly evident that periodic behaviour abounds in all time domains. Circadian timekeeping dominates in natural environments. Here the free-running period is about 24 h. Circadian rhythms in eukaryotes and prokaryotes allow predictive matching of intracellular states with environmental changes during the daily cycles. Unicellular organisms provide excellent systems for the study of these phenomena, which pervade all higher life forms. Intracellular timekeeping is essential. The presence of a temperature-compensated oscillator provides such a timer. The coupled outputs (epigenetic oscillations) of this ultradian clock constitute a special class of ultradian rhythm. These are undamped and endogenously driven by a device which shows biochemical properties characteristic of transcriptional and translational elements. Energy-yielding processes, protein turnover, motility and the timing of the cell-division cycle processes are all controlled by the ultradian clock. Different periods characterize different species, and this indicates a genetic determinant. Periods range from 30 min to 4 h. Mechanisms of clock control are being elucidated; it is becoming evident that many different control circuits can provide these functions.

Activity Cycles↗