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PubMed2006

Constitutive activation of ras in neurons: implications for the regulation of the mammalian circadian clock.

Almost all organisms living on earth exhibit rhythms under the control of autonomous timekeeping mechanisms referred to as circadian clocks. In mammals, peripheral clocks are synchronized (entrained) with high precision in a 24 h periodicity by the master circadian clock located in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus. Light is the strongest phase-adjusting stimulus of the circadian clock. Circadian oscillations are driven by transcription/translation-based feedback/feedforward loops, comprising a set of clock genes and their protein products. The signalling pathways that couple light input to transcriptional, translational, and post-translational changes to ensure precise entrainment of the clock are not yet well characterized. A candidate pathway for transmission of photic information in the SCN is represented by the extracellular signal-regulated kinases ERK1/ERK2. In neurons, the ERK pathway is activated by a large array of stimuli, including trophic factors, neurotransmitters, and modulatory peptides. An upstream element of the ERK signalling route is the small intracellular membrane-anchored G-protein, Ras. In order to study its possible role in the entrainment of the circadian clock we are using transgenic gain-of-function mice expressing constitutively activated Val-12 Ha-Ras selectively in neurons (synRas mice). The Ha-Ras transgene protein is expressed in the SCN of synRas mice neurons serving as a model for interfering with the normal rhythmic changes in Ras activities in the SCN. This will allow us to investigate whether the associated modulation of the downstream targets such as ERK activities will interfere with the mechanisms of entrainment.

Animals↗
PubMed2006

Dating dispersal and radiation in the gymnosperm Gnetum (Gnetales)--clock calibration when outgroup relationships are uncertain.

Most implementations of molecular clocks require resolved topologies. However, one of the Bayesian relaxed clock approaches accepts input topologies that include polytomies. We explored the effects of resolved and polytomous input topologies in a rate-heterogeneous sequence data set for Gnetum, a member of the seed plant lineage Gnetales. Gnetum has 10 species in South America, 1 in tropical West Africa, and 20 to 25 in tropical Asia, and explanations for the ages of these disjunctions involve long-distance dispersal and/or the breakup of Gondwana. To resolve relationships within Gnetum, we sequenced most of its species for six loci from the chloroplast (rbcL, matK, and the trnT-trnF region), the nucleus (rITS/5.8S and the LEAFY gene second intron), and the mitochondrion (nad1 gene second intron). Because Gnetum has no fossil record, we relied on fossils from other Gnetales and from the seed plant lineages conifers, Ginkgo, cycads, and angiosperms to constrain a molecular clock and obtain absolute times for within-Gnetum divergence events. Relationships among Gnetales and the other seed plant lineages are still unresolved, and we therefore used differently resolved topologies, including one that contained a basal polytomy among gymnosperms. For a small set of Gnetales exemplars (n = 13) in which rbcL and matK satisfied the clock assumption, we also obtained time estimates from a strict clock, calibrated with one outgroup fossil. The changing hierarchical relationships among seed plants (and accordingly changing placements of distant fossils) resulted in small changes of within-Gnetum estimates because topologically closest constraints overrode more distant constraints. Regardless of the seed plant topology assumed, relaxed clock estimates suggest that the extant clades of Gnetum began diverging from each other during the Upper Oligocene. Strict clock estimates imply a mid-Miocene divergence. These estimates, together with the phylogeny for Gnetum from the six combined data sets, imply that the single African species of Gnetum is not a remnant of a once Gondwanan distribution. Miocene and Pliocene range expansions are inferred for the Asian subclades of Gnetum, which stem from an ancestor that arrived from Africa. These findings fit with seed dispersal by water in several species of Gnetum, morphological similarities among apparently young species, and incomplete concerted evolution in the nuclear ITS region.

Base Sequence↗
PubMed2005

Caenorhabditis elegans opens up new insights into circadian clock mechanisms.

The roundworm, Caenorhabditis elegans, is known to carry homologues of clock genes such as per (=period) and tim (=timeless), which constitute the core of the circadian clock in Drosophila and mammals: lin-42 and tim-1. Analyses using WormBase (C. elegans gene database) have identified with relatively high identity analogous of the clock genes recognized in Drosophila and mammals, with the notable exception of cry (=cryptochrome), which is lacking in C. elegans. All of these C. elegans cognates of the clock genes appear to belong to members of the PAS-superfamily and to participate in development or responsiveness to the environment but apparently are not involved in the C. elegans circadian clock. Nevertheless, C. elegans exhibits convincing circadian rhythms in locomotor behavior in the adult stage and in resistance to hyperosmotic stress in starved larvae (L1) after hatching, indicating that it has a circadian clock with a core design entirely different from that of Drosophila and mammals. Here two possibilities are considered. First, the core of the C. elegans circadian clock includes transcriptional/translational feedback loops between genes and their protein products that are entirely different from those of Drosophila and mammals. Second, a more basic principle such as homeostasis governs the circadian cellular physiology, and was established primarily to minimize the accumulation of DNA damage in response to an environment cycling at 24 h intervals.

Animals↗
PubMed1998

Clock-face drawing, reading and setting tests in the screening of dementia in Chinese elderly adults.

Comprehensive neuropsychological batteries focus on the subtle cognitive deficits in dementia, but a brief screening instrument is also of immense practical value. As the clock-drawing test encompasses a number of cognitive domains frequently disturbed by the dementing process, it is considered to be a suitable screening instrument for the disorder. We documented the usefulness of a new scoring method of the clock-drawing test for screening of dementia in the elderly Chinese in Hong Kong. Fifty-three demented individuals and 53 healthy elderly controls were assessed. At a cutoff score of 3/4, the sensitivity and specificity of the clock-drawing test in screening of dementia was 83% and 79%. With a composite test of clock reading and clock setting, the positive predictive value of the clock face test was 98%. This new scoring method of clock-drawing proved to be a valid measure for screening of dementia. It is applicable in non-English speaking populations and should be a useful adjunct for quick screening assessment of dementia.

Aged↗
PubMed2000

Orientation of the first polar body of the oocyte at 6 or 12 o'clock during ICSI does not affect clinical outcome.

This study was designed to clarify whether orientation of the first polar body (PB) of the oocyte at 6 o'clock rather than 12 o'clock, during intracytoplasmic sperm injection (ICSI), significantly affects a number of clinically important outcome measures including fertilization, zygote cleavage, embryonic morphology, and clinical pregnancy and implantation rates. In all, 114 patients were allocated to one of two groups on the basis of strict alternation, both groups being treated by the same ICSI practitioner. In one group, all oocytes were injected with their first PB at 6 o'clock, whereas in the other, the orientation of the PB was reversed (12 o'clock). In all cases, a normally bevelled injection pipette was inserted into the oocyte in the 3 towards 9 o'clock direction. The orientation of the PB did not significantly affect the proportion of oocytes that failed to survive injection or the proportion scored as having either zero, one, two or three pronuclei. The proportion of normally fertilized zygotes that cleaved was not significantly different between the two groups, nor was the proportion of embryos classified as either grade 1, 2 or 3. However, the proportion of grade 4 embryos (the poorest grade) was significantly lower in the 12 o'clock, compared to the 6 o'clock group. Most importantly, there was no significant difference between the two groups in the proportion of patients having a positive clinical pregnancy test, nor in either the implantation rate or the mean number of fetal hearts detected per patient presenting with a clinical pregnancy.

Adult↗
PubMed2002

Signs of the time: environmental input to the circadian clock.

The circadian clock forms one of the most fascinating adaptations to life on earth. Organisms can not only anticipate the day/night cycle but can make use of an internal clock to measure daylength as an indicator of the changing of the seasons. The innate period of the clock is not exactly equal to 24 h, but is reset each day by environmental signals at dawn and dusk, most notably by changes in light and temperature. This ability to re-entrain also ensures that the clock is synchronized with the day/night cycle which in turn is crucial for anticipation of dawn and dusk. Recent advances in the field have identified the photoreceptors involved in resetting the clock in several systems. This has revealed surprising similarities, but also key differences in the circadian systems of plants, fungi, insects, and mammals. One recurring feature emerging from this research is that the photoreceptors themselves are under the control of the clock with transcript abundance being tightly regulated. Furthermore, elements of a feedback pathway whereby the clock modulates the activity of the light input pathway are now being identified.

Animals↗
PubMed2005

The Arabidopsis pseudo-response regulators, PRR5 and PRR7, coordinately play essential roles for circadian clock function.

In Arabidopsis thaliana, a number of clock-associated protein factors have been identified. Among them, TOC1 (TIMING OF CAB EXPRESSION 1) is believed to be a component of the central oscillator. TOC1 is a member of a small family of proteins, designated as ARABIDOPSIS PSEUDO-RESPONSE REGULATOR, including PRR1/TOC1, PRR3, PRR5, PRR7 and PRR9. It has not been certain whether or not other PRR family members are also implicated in clock function per se. To clarify this problem, here we constructed a double mutant line, which is assumed to have severe lesions in both the PRR5 and PRR7 genes. Resulting homozygous prr5-11 prr7-11 young seedlings showed a marked phenotype of hyposensitivity to red light during de-etiolation. In addition, they displayed a phenotype of extremely late flowering under long-day photoperiod conditions, but not short-day conditions. The rhythms at the level of transcription of certain clock-controlled genes were severely perturbed in the double mutant plants when they were released into continuous light (LL) and darkness (DD). The observed phenotype was best interpreted as 'arrhythmic in both LL and DD' and/or 'very short period with markedly reduced amplitude'. Even under the light entrainment (LD) conditions, the mutant plants showed anomalous diurnal oscillation profiles with altered amplitude and/or phase with regard to certain clock-controlled genes, including the clock component CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1) gene. Such events were observed even under temperature entrainment conditions, suggesting that the prr5-11 prr7-11 lesions cannot simply be attributed to a defect in the light signal input pathway. These pleiotropic circadian-associated phenotypes of the double mutant were very remarkable, as compared with those observed previously for each single mutant. Taking these results together, we propose for the first time that PRR5 and PRR7 coordinately (or synergistically) play essential clock-associated roles close to the central oscillator.

Arabidopsis↗
PubMed2003

Discrimination of dementia with lewy bodies from Alzheimer disease and Parkinson disease using the clock drawing test.

OBJECTIVE: The authors' objective was to examine the ability of the Clock Drawing Test to discriminate Dementia with Lewy bodies from Alzheimer disease and Parkinson disease. BACKGROUND: Recent advances in medical treatments for dementia underscore the importance of differentiating among dementia subtypes. Clinically, Dementia with Lewy bodies can often be difficult to discriminate from Alzheimer disease and Parkinson disease because of similar and overlapping cognitive and motor features. While the Clock Drawing Test has been shown to discriminate dementia from normal aging fairly accurately, less is known about its ability to discriminate between various dementia groups. METHODS: Patients with Alzheimer disease (n = 22), patients with cognitively impaired Parkinson disease (n = 17), and patients with Dementia with Lewy bodies (n = 20), matched for age, education, and dementia severity, were compared on the Clock Drawing Test, scored for overall accuracy as well as the presence of specific error types. RESULTS: There were no significant group differences on a global quantitative measure of Clock Drawing Test performance. With regard to differences on the error types evaluated, the patients with Dementia with Lewy bodies were more likely to make conceptual errors than the patients with Alzheimer disease and Parkinson disease, and the patients with Parkinson disease and Dementia with Lewy bodies made more planning errors than the patients with Alzheimer disease. Classification accuracy was fair, with 69% overall classification for Alzheimer disease versus Dementia with Lewy bodies, and 68% overall classification for Parkinson disease versus Dementia with Lewy bodies. CONCLUSIONS: Although some differences may exist in the qualitative features of clock drawing performance between these patient groups, overall clock drawing performance is relatively similar, and as a single instrument, the Clock Drawing Test provides limited discrimination of Dementia with Lewy bodies from Alzheimer disease and Parkinson disease.

Aged↗
PubMed2001

Peripheral clocks and their role in circadian timing: insights from insects.

Impressive advances have been made recently in our understanding of the molecular basis of the cell-autonomous circadian feedback loop; however, much less is known about the overall organization of the circadian systems. How many clocks tick in a multicellular animal, such as an insect, and what are their roles and the relationships between them? Most attempts to locate clock-containing tissues were based on the analysis of behavioural rhythms and identified brain-located timing centres in a variety of animals. Characterization of several essential clock genes and analysis of their expression patterns revealed that molecular components of the clock are active not only in the brain, but also in many peripheral organs of Drosophila and other insects as well as in vertebrates. Subsequent experiments have shown that isolated peripheral organs can maintain self-sustained and light sensitive cycling of clock genes in vitro. This, together with earlier demonstrations that physiological output rhythms persist in isolated organs and tissues, provide strong evidence for the existence of functionally autonomous local circadian clocks in insects and other animals. Circadian systems in complex animals may include many peripheral clocks with tissue-specific functions and a varying degree of autonomy, which seems to be correlated with their sensitivity to external entraining signals.

Animals↗
PubMed2001

Flies, clocks and evolution.

The negative feedback model for gene regulation of the circadian mechanism is described for the fruitfly, Drosophila melanogaster. The conservation of function of clock molecules is illustrated by comparison with the mammalian circadian system, and the apparent swapping of roles between various canonical clock gene components is highlighted. The role of clock gene duplications and divergence of function is introduced via the timeless gene. The impressive similarities in clock gene regulation between flies and mammals could suggest that variation between more closely related species within insects might be minimal. However, this is not borne out because the expression of clock molecules in the brain of the giant silk moth, Antheraea pernyi, is not easy to reconcile with the negative feedback roles of the period and timeless genes. Variation in clock gene sequences between and within fly species is examined and the role of co-evolution between and within clock molecules is described, particularly with reference to adaptive functions of the circadian phenotype.

Adaptation, Physiological↗
PubMed2005

Pineal circadian clocks gate arylalkylamine N-acetyltransferase gene expression in the mouse pineal gland.

In mammals it has been thought that the circadian clock localizes only in the suprachiasmatic nucleus of the hypothalamus. Recent studies have revealed that certain brain regions and peripheral tissues may also have intrinsic circadian clocks. However, the roles played by 'peripheral circadian clocks' have not been fully elucidated. In this study, we investigated their function using mouse pineal glands, and found that expression of the arylalkylamine N-acetyltransferase (Aa-Nat, EC 2.3.1.87, the rate-limiting enzyme of melatonin synthesis) gene after adrenergic receptor stimulation depended on the time of day even in vitro (gating). Phase-dependent Aa-Nat responses were observed in both melatonin-proficient and melatonin-deficient mouse pineal glands. Phosphodiesterases are unlikely to suppress Aa-Nat induction because a phosphodiesterase inhibitor itself had no effect on the mRNA levels. Puromycin was ineffective in inducing Aa-Nat mRNA levels in either the presence or absence of isoproterenol, suggesting that newly synthesized proteins may not be necessary to gate the Aa-Nat responses. We also discovered circadian dependence of the expression of Period1-luminescence in Period1-luciferase transgenic mouse pineal glands: circadian clocks may be functional in culture. Aa-Nat mRNA levels showed no significant circadian rhythms in the absence of isoproterenol, thus suggesting that Aa-Nat mRNA levels are induced by adrenergic mechanisms, not by a pineal circadian clock. Our results suggest that the pineal circadian clock may determine timing when Aa-Nat gene expression can respond to inputs from the master circadian clock in the suprachiasmatic nucleus, e.g. adrenergic stimulation.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Clock completion: an objective screening test for dementia.

OBJECTIVE: To develop a simple, readily administered and scored screening test for dementia utilizing the clock-drawing task. DESIGN: Retrospective analysis of clock-drawing errors and prospective validations. SETTING: Hospital-based outpatient geriatric assessment clinic, rehabilitation service, apartment building for older adults, and long-term care facility. PARTICIPANTS: Convenience sample of patients attending the geriatric assessment clinic, patients on the rehabilitation service, or residents of the above sites. MEASUREMENTS: Sensitivity and specificity of a clock-scoring system in identifying patients with dementia and the comparison of this system with the Short Blessed Test (SBT) in the diagnosis of dementia and in the prospective validation of the test. RESULTS: Of the 10 clock-drawing errors evaluated, placement of digits in a pre-drawn circle had the greatest sensitivity and specificity in distinguishing patients with irreversible dementia from patients with other disorders who did not meet NINCDS-ADRDA criteria for probable dementia. The derived scoring system had a sensitivity of 87% and a specificity of 82%, compared with a sensitivity of 82% and a specificity of 88% for the SBT in identifying dementia. Test-retest reliability for the distinction between demented and non-demented was 82%, with a Kappa of 0.63 for the clock completion, and 82%, with a Kappa of 0.62 for the SBT. Inter-rater reliability for clock completion was 0.90 to 0.93. CONCLUSION: A simple, completely objective scoring system for a clock completion test has been developed which involves only the number of digits placed in the fourth quadrant of a pre-drawn circle. This readily administered test is as effective in screening for dementia as the longer six-item SBT.

Aged↗
PubMed2002

Neurospora clock-controlled gene 9 (ccg-9) encodes trehalose synthase: circadian regulation of stress responses and development.

The circadian clock of Neurospora crassa regulates the rhythmic expression of a number of genes encoding diverse functions which, as an ensemble, are adaptive to life in a rhythmic environment of alternating levels of light and dark, warmth and coolness, and dryness and humidity. Previous differential screens have identified a number of such genes based solely on their cycling expression, including clock-controlled gene 9 (ccg-9). Sequence analysis now shows the predicted CCG-9 polypeptide to be homologous to a novel form of trehalose synthase; as such it would catalyze the synthesis of the disaccharide trehalose, which plays an important role in protecting many cells from environmental stresses. Consistent with this, heat, glucose starvation, and osmotic stress induce ccg-9 transcript accumulation. Surprisingly, however, a parallel role in development is suggested by the finding that inactivation of ccg-9 results in altered conidiophore morphology and abolishes the normal circadian rhythm of asexual macroconidial development. Examination of a clock component, FRQ, in the ccg-9-null strain revealed normal cycling, phosphorylation, and light induction, indicating that loss of the conidiation rhythm is not due to changes in either the circadian oscillator or light input into the clock but pointing instead to a defect in circadian output. These data imply an interplay between a role of trehalose in stress protection and an apparent requirement for trehalose in clock regulation of conidiation under constant environmental conditions. This requirement can be bypassed by a daily light signal which drives a light-entrained rhythm in conidiation in the ccg-9-null strain; this bypass suggests that the trehalose requirement is related to clock control of development and not to the developmental process itself. Circadian control of trehalose synthase suggests a link between clock control of stress responses and that of development.

Circadian Rhythm↗
PubMed2002

Distinct signaling pathways from the circadian clock participate in regulation of rhythmic conidiospore development in Neurospora crassa.

Several different environmental signals can induce asexual spore development (conidiation) and expression of developmentally regulated genes in Neurospora crassa. However, under constant conditions, where no environmental cues for conidiation are present, the endogenous circadian clock in N. crassa promotes daily rhythms in expression of known developmental genes and of conidiation. We anticipated that the same pathway of gene regulation would be followed during clock-controlled conidiation and environmental induction of conidiation and that the circadian clock would need only to control the initial developmental switch. Previous experiments showed that high-level developmental induction of the clock-controlled genes eas (ccg-2) and ccg-1 requires the developmental regulatory proteins FL and ACON-2, respectively, and normal developmental induction of fl mRNA expression requires ACON-2. We demonstrate that the circadian clock regulates rhythmic fl gene expression and that fl rhythmicity requires ACON-2. However, we find that clock regulation of eas (ccg-2) is normal in an fl mutant strain and ccg-1 expression is rhythmic in an acon-2 mutant strain. Together, these data point to the endogenous clock and the environment following separate pathways to regulate conidiation-specific gene expression.

Aerobiosis↗
PubMed2005

Persisting reversed clock syndrome.

BACKGROUND: The reversed clock phenomenon results in the transposition of objects from one side to another. Its major manifestation consists in the reversal of clock numbers in clock-drawing test. It could be due to a stroke disrupting attentional cerebral network. This phenomenon usually regresses in a few days. OBJECTIVE: To report a case of reversed clock phenomenon with disorders of space representation that did not regress spontaneously. DESIGN: Case report. PATIENT: A 67 year-old woman was referred due to headaches associated with gait disorder, visual field deficit and disturbance of space representation. RESULTS: Magnetic resonance imaging demonstrates two right cerebral infarcts mainly localized in the parieto-occipital region. A week after her stoke, clinical testing confirms a reversed clock phenomenon. The patient placed the hands of a clock in the opposite direction of what was specified. She got lost at home locating rooms in directions opposite to their real ones. Rehabilitation sessions partially improved these manifestations. CONCLUSION: Although it usually improves in a few days, reversed clock phenomenon can persist longer. Rehabilitation sessions based on localization exercises may be helpful in such situations.

Aged↗
PubMed1999

Correlation between the Folstein Mini-Mental State Examination and three methods of clock drawing scoring.

The objective of this study was to assess the correlation between (1) the Folstein Mini-Mental State Examination (MMSE) score and three methods of clock drawing scoring and (2) three methods of clock drawing scoring themselves. A convenience sample of consecutive community-dwelling seniors and attendees at a referral seniors clinic in a tertiary care hospital was used. One hundred fifty participants (72 women, 78 men) were seen with an average age of 76 years. There was a significant correlation (P = .01) between MMSE scores and all three methods of clock drawing (R = .67, .618, -.498, respectively), as well as among the three methods of clock drawing scoring. The clock drawing scores showed good correlation with the MMSE score. The clock drawing is well accepted (by the patient) and easily administered (by the health care provider). Clock drawings are recommended as the minimum requirement for cognitive assessment of elderly patients in busy primary care practices and can be used to highlight those patients requiring additional cognitive testing.

Aged↗
PubMed2002

Circadian clock system in the pineal gland.

The pineal gland is a neuroendocrine organ that functions as a central circadian oscillator in a variety of nonmammalian vertebrates. In many cases, the pineal gland retains photic input and endocrinal-output pathways both linked tightly to the oscillator. This contrasts well with the mammalian pineal gland equipped only with the output of melatonin production that is subject to neuronal regulation by central circadian oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Molecular studies on animal clock genes were performed first in Drosophila and later developed in rodents. More recently, clock genes such as Per, Cry, Clock, and Bmal have been found in a variety of vertebrate clock structures including the avian pineal gland. The profiles of the temporal change of the clock gene expression in the avian pineal gland are more similar to those in the mammalian SCN rather than to those in the mammalian pineal gland. Avian pineal gland and mammalian SCN seem to share a fundamental molecular framework of the clock oscillator composed of a transcription/translation-based autoregulatory feedback loop. The circadian time-keeping mechanism also requires several post-translational events, such as protein translocation and degradation processes, in which protein phosphorylation plays a very important role for the stable 24-h cycling of the oscillator and/or the photic-input pathway for entrainment of the clock.

Animals↗
PubMed1972

Some effects of response-dependent clock stimuli in a fixed-interval schedule.

Two experiments studied the effects of brief response-dependent clock stimuli in fixed-interval schedules of reinforcement. In the first experiment, two pigeons were exposed to a fixed-interval schedule. Two conditions were compared. In both conditions each peck on the key produced a brief stimulus. In one condition, pecks produced a different stimulus in successive sixths of the interval. This was the clock condition. In the other condition, the same stimulus was produced throughout the interval. Response rates were lower and the pause after reinforcement was longer in the clock condition. In the second experiment, a two-key optional clock procedure was used. Responding on the clock key produced one of three stimuli correlated with the three successive minutes of a fixed-interval schedule. A response on the other key produced grain at the end of the 3 min. When the final stimulus was removed from the situation and pecking produced nothing during the third minute, responding to the clock key declined to a very low rate. When the first two stimuli were removed and the third one replaced, responding to the clock key was resumed.

Journal Article↗