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PubMed1989

Molecular cloning of genes under control of the circadian clock in Neurospora.

To investigate the regulation of messenger RNA abundance by circadian clocks, genomic and complementary DNA libraries were screened with complementary DNA probes enriched, by means of sequential rounds of subtractive hybridization, for sequences complementary to transcripts specific to either early morning or early evening cultures of Neurospora. Only two morning-specific genes were identified through this protocol. RNA blot analysis verified that the abundance of the transcripts arising from these genes oscillates with a period of 21.5 hours in a clock wild-type strain and 29 hours in the long-period clock mutant strain frq7. Genetic mapping through the use of restriction fragment length polymorphisms shows the two genes, ccg-1 and ccg-2, to be unlinked. These data provide a view of the extent of clock control of gene expression.

Chromosome Mapping↗
PubMed2000

An inherited functional circadian clock in zebrafish embryos.

Circadian clocks are time-keeping systems found in most organisms. In zebrafish, expression of the clock gene Period3 (Per3) oscillates throughout embryogenesis in the central nervous system and the retina. Per3 rhythmic expression was free-running and was reset by light but not by the developmental delays caused by low temperature. The time of fertilization had no effect on Per3 expression. Per3 messenger RNA accumulates rhythmically in oocytes and persists in embryos. Our results establish that the circadian clock functions during early embryogenesis in zebrafish. Inheritance of maternal clock gene products suggests a mechanism of phase inheritance through ovogenesis.

Amino Acid Sequence↗
PubMed1994

Phase shifting of the circadian clock by induction of the Drosophila period protein.

Virtually all organisms manifest circadian (24-hour) rhythms, governed by an ill-defined endogenous pacemaker or clock. Several lines of evidence suggest that the Drosophila melanogaster period gene product PER is a clock component. If PER were central to the time-keeping mechanism, a transient increase in its concentration would cause a stable shift in the phase of the clock. Therefore, transgenic flies bearing a heat-inducible copy of PER were subjected to temperature pulses. This treatment caused long-lasting phase shifts in the locomotor activity circadian rhythm, a result that supports the contention that PER is a bona fide clock component.

Animals↗
PubMed2006

The circadian clock Period 2 gene regulates gamma interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock.

The Period 2 (Per2) gene is a key molecular component in controlling mammalian circadian rhythms at the levels of gene expression, physiology, and pathogenesis. Although many immune parameters, such as the number of different subtypes of circulating immune cells and the level of cytokine production in response to infection with bacteria and viruses, have been well documented to display a circadian pattern in mammals, the basic features of molecular clock components in the immune system and the role of clock genes in regulating host immune defenses remain uncharacterized. Previously, we have reported that circadian clock genes oscillate in human mononuclear cells. Here we report that Per2-deficient mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. We further demonstrate that the levels of the proinflammatory cytokines gamma interferon (IFN-gamma) and interleukin-1beta (IL-1beta) in the serum were dramatically decreased in Per2-/- mice following LPS challenge, while production of tumor necrosis factor alpha, IL-6, and IL-10 was approximately normal, compared to that in control wild-type mice. Flow cytometric analyses confirmed that the cellularity of most of the immune cell subsets in the spleens of LPS-challenged mice was normal and that the impaired IFN-gamma production in Per2-/- mice was attributable to defective NK and NKT cell function. Our data suggest that Per2 is an important regulator of NK cell function, therefore providing the first direct link between the circadian clock system and innate immune responses.

Animals↗
PubMed1998

A period-extender gene, pex, that extends the period of the circadian clock in the cyanobacterium Synechococcus sp. strain PCC 7942.

We cloned the pS1K1 plasmid in the process of apparently "complementing" a circadian clock mutant of cyanobacterium Synechococcus sp. strain PCC 7942, SP22, which has a 22-h period (T. Kondo, N. F. Tsinoremas, S. S. Golden, C. H. Johnson, S. Kutsuna, and M. Ishiura, Science 266:1233-1236, 1994). Sequence analysis revealed that SP22 did not have a mutation in the genomic DNA segment carried on pS1K1, and the sp22 mutation was later found in a recently cloned new clock gene, kaiC. Therefore, the period-extender gene pex that was carried on pS1K1 was a suppressor gene for the sp22 mutation. The pex gene encoded a protein of 148 amino acid residues. No meaningful homologs were found in DNA or protein databases including the Synechocystis genome database. The pex gene was transcribed from 129 and 164 bp upstream of the translation initiation codon as 0.6-kb transcripts. The Pex protein was detected as a fusion protein with a molecular mass of 15 kDa by the epitope tag fusion method using a c-Myc epitope tag. Disruption of the pex gene in wild-type cells shortened the period of the rhythms by 1 h, although it did not affect other properties of the rhythms, whereas its overexpression extended the period by 3 h with a concomitant reduction in the amplitude of the rhythms. In various clock mutants examined, overexpression caused arrhythmicity. Thus, Pex is likely to function as a modifier of the circadian clock in Synechococcus.

Amino Acid Sequence↗
PubMed1991

Neurospora crassa clock-controlled genes are regulated at the level of transcription.

Although an extensive number of biological processes are under the daily control of the circadian biological clock, little is known about how the clock maintains its regulatory networks within a cell. An important aspect of this temporal control is the daily control of gene expression. Previously we identified two morning-specific genes that are regulated by the clock through daily control of gene expression (J. Loros, S. Denome, and J.C. Dunlap, Science 243:385-388, 1989). We have now introduced a method for transcriptional analysis in Neurospora crassa and used this nuclear run-on procedure to show that regulation of mRNA abundance for these two morning-specific genes occurs at the level of transcription. This transcriptional regulation by the circadian clock provides a basis for isolating circadian rhythm mutants.

Amanitins↗
PubMed2005

Role of cyclic mPer2 expression in the mammalian cellular clock.

To explore the role of mPer2 in the circadian oscillation in the mammalian cellular clock, we established fibroblast cell lines in which expression of mPer2 is controlled through a tetracycline-regulatable promoter. We revealed that constitutive expression and overexpression of mPer2 mRNA severely impair serum shock-induced cyclic circadian clock gene expression. Moreover, under conditions of lower mPer2 mRNA expression, mPER2 protein accumulation in these cells showed clear circadian oscillation even in constitutive mPer2 mRNA expression, suggesting that the protein cycling of mPER2 was required for oscillation of the circadian feedback loop. Since the rhythms of gene expression driven by the intrinsic clock oscillation system dampen rapidly in the absence of cyclic expression of mPer2, the transcriptional rhythm helps to sustain the clock oscillation.

Animals↗
PubMed1993

Comparison of clock drawing with Mini Mental State Examination as a screening test in elderly acute hospital admissions.

Clock drawing is a quick, easy to remember test that is well received by patients. It is a good screening test for Alzheimer's disease in the outpatient setting. We evaluated its usefulness compared with the standard Mini Mental State Examination (MMSE) in elderly acute medical and surgical hospital admissions. Within 48 hours of admission, 117 patients over 70 years old were administered the MMSE and asked to draw a clock. Using the MMSE as the standard, clock drawing had a sensitivity of 77% and a specificity of 87%. Patients with discrepant scores were then further evaluated. The findings suggest that normal clock drawing ability reasonably excludes cognitive impairment or other causes of an abnormal MMSE in elderly acute medical and surgical hospital admissions, where cognitive impairment is common and frequently missed.

Aged↗
PubMed1998

Effect of the shift of the sleep-wake cycle on three robust endocrine markers of the circadian clock.

To determine the effect of a phase shift in sleep on the circadian clock, thyroid-stimulating hormone (TSH), cortisol, and melatonin, three robust markers of the circadian clock, were analyzed using a 10-min blood sampling procedure. In an initial experiment eight subjects were studied during two experimental sessions: once under baseline conditions with normal nighttime sleep from 2300 to 0700 (baseline) and once after a night of sleep deprivation followed by daytime sleep from 0700 to 1500 (day 1). In a second experiment, carried out on seven subjects, the 24-h hormone profiles of the first day (day 1) were compared with those of the second day (day 2) of the sleep shift. During the night of sleep deprivation (day 1) the TSH surge was higher than during baseline conditions, whereas melatonin and cortisol rhythms remained unaffected. On day 2 the amplitude of the nocturnal TSH surge was reduced in comparison to day 1, whereas the amplitudes of melatonin and cortisol rhythms were unchanged. There was a clear phase shift in the three endocrine rhythms. Triiodothyronine levels were slightly higher in the morning after the first night of sleep deprivation. These results demonstrate that 2 consecutive days of sleep shift are sufficient to affect the timing of the commonly accepted circadian markers, suggesting the existence of a rapid resetting effect on the circadian clock. TSH reacts in a distinctive manner to the sleep-wake cycle manipulation by modulating the amplitude of the nocturnal surge. This amplitude modulation is probably an integral part of the phase-shifting mechanisms controlled by the circadian clock.

Adult↗
PubMed2006

Preliminary assessment of cognitive function in older adults by clock drawing, box copying and narrative writing.

OBJECTIVE: To examine 3 cognitive screening tasks in older adults and determine which demographic, medical and lifestyle variables obtained 13-17 years previously predicted cognitive performance. DESIGN: Population-based longitudinal cohort study begun in 1981. SETTING: Leisure World Laguna Hills, a California retirement community. PARTICIPANTS: The cohort is predominantly white, well educated, upper-middle class; two thirds are women. Data from 1,744 participants (mean age 83 years, range 57-103) were analyzed. MEASUREMENTS: The baseline postal survey (1981-1985) asked demographic information, medical history, selected drug use and personal habits. The 1998 follow-up included 3 tasks to assess cognitive function: (1) clock drawing, (2) copying a box drawing and (3) narrative writing to describe a pictured scene. RESULTS: Within age groups, women tended to have lower scores than men on box copying, similar scores on clock drawing, but higher informational and complexity scores on narrative writing. Performance decreased with increasing age and was poorest in individuals > or = 90 years old. In addition to age, sex and education, significant predictors of performance were: exercise, body mass index and cataract surgery (clock); vitamin E supplements, daily aspirin use and gallbladder surgery (box); vitamin A supplements (narrative writing). Mean scores on all tasks were lower in those later identified as demented compared with nondemented but significantly different only for clock and box drawings. CONCLUSION: Performance on 3 cognitive tests showed significant effects of age, sex and education and was related to later dementia. Better performance by users of antioxidant supplements and aspirin suggests that these drugs may maintain cognitive function in later life.

Aged↗
PubMedDate not supplied

Relationship between clock-drawing and neuropsychological and functional status in elderly institutionalized patients with schizophrenia.

OBJECTIVE: The authors sought to examine the usefulness of the clock-drawing test (CDT) as a measure of general cognitive and adaptive functioning in elderly patients with schizophrenia. METHODS: CDT performance of elderly institutionalized patients with schizophrenia were contrasted with a comparison group, similar in age. Cognitive and functional status was examined using an expanded battery from the Consortium to Establish a Registry for Alzheimer's disease and the Psychogeriatric Dependency Rating Scale. RESULTS: Patients (N=21) performed more poorly overall on the CDT than the comparison group (N=21), with greater clock number and hand errors. Production of the clock's gestalt did not differ between groups. In patients, overall CDT performance and clock hand placement were significantly correlated with general cognitive functioning, memory, visuoconstruction, and word-list generation. CDT global and hand placement performances corresponded to patients' general orientation. CONCLUSIONS: Impaired CDT performance in elderly patients with schizophrenia is not attributable to normal aging. Also, the CDT uniquely relates to an array of cognitive abilities in this population, validating its multicognitive character and implicating multiple brain regions. The CDT's tolerability and brevity make it attractive for use in geriatric schizophrenia.

Adaptation, Psychological↗
PubMed2001

Insect photoperiodism and circadian clocks: models and mechanisms.

Photoperiodic clocks allow organisms to predict the coming season. In insects, the seasonal adaptive response mainly takes the form of diapause. The extensively studied photoperiodic clock in insects was primarily characterized by a "black-box" approach, resulting in numerous cybernetic models. This is in contrast with the circadian clock, which has been dissected pragmatically at the molecular level, particularly in Drosophila. Unfortunately, Drosophila melanogaster, the favorite model organism for circadian studies, does not demonstrate a pronounced seasonal response, and consequently molecular analysis has not progressed in this area. In the current article, the authors explore different ways in which identified molecular components of the circadian pacemaker may play a role in photoperiodism. Future progress in understanding the Drosophila circadian pacemaker, particularly as further output components are identified, may provide a direct link between the clock and photoperiodism. In addition, with improved molecular tools, it is now possible to turn to other insects that have a more dramatic photoperiodic response.

Animals↗
PubMed1999

Photoperiodic time measurement in insects: a review of clock models.

Based on analyses of responses of insects and mites to a wide range of diel and nondiel experimental light-dark schedules, a variety of models have been developed for the photoperiodic clocks in these species by nearly as many investigators. According to some of these models, the photoperiodic clock is based on a mechanism separate from the circadian system, that is, a so-called "hourglass." According to other models, the clock is based on one or more circadian oscillators that may be coupled to each other and that may or may not show a certain degree of damping. In this context, a rapidly damping oscillator could be regarded as an hourglass. The present article gives an overview of the many different clock models and their philosophies, and it makes comparisons among them to provide a better understanding about how these models are related, if at all, and why the double circadian oscillator model is the most favored model at present.

Animals↗
PubMed2006

ACE clock scoring: a comparison with eight standard correction methods in a population of low educational level.

The authors compared the accuracy of Addenbrooke's Cognitive Examination Clock Drawing Test scoring method with 8 standard Clock Drawing Test scoring methods in a Spanish speaking population of low educational level. A clinical group composed of 70 patients affected by dementia and 25 patients with memory complaints without dementia was compared with 72 controls matched for gender, age, and educational level. The clinical group was studied with standard neuropsychological instruments and neuroimaging. Clock Drawing Tests extracted from Addenbrooke's Cognitive Examination were randomly distributed and scored by 2 independent raters. There were statistically significant differences between the different scoring methods. Addenbrooke's Cognitive Examination Clock Drawing Test scoring method obtained and optimal areas under the curve and interrater reliability, showing no statistical differences with previously standardized systems. In our population, Addenbrooke's Cognitive Examination and the methods of Cahn, Mendez, Rouleau, Shulman, and Sunderland were of optimal and equivalent usefulness regarding dementia detection.

Aged↗
PubMed1994

Qualitative Features of Clock Drawings in Normal Aging and Alzheimer's Disease

Two investigations examined qualitative features of clock drawings in normal aging and Alzheimer's disease (AD), using standard 3-point and 10-point scales and an expanded 16-point scoring system. In the first study, clock drawings by healthy adults aged 50-70 were found to be significantly better than those of adults aged 70-95 using all three scoring systems. Results based on the 16-point system were strongly associated with those of other scoring systems, but correlations with two other visuospatial measures were low. Older adults demonstrated more difficulty in terms of numerical position, time-setting, and addition of irrelevant details. In Study II, using the same scoring systems, AD patients were significantly impaired on clock drawings compared to matched controls. AD patients showed particular deficits in the following domains: numerical position, time setting, proportions, spatial accuracy, and omission of details. The 16-point clock scoring system was equivalent to other scoring procedures in differentiating groups and showed modest reliability coefficients. Results suggest that alterations in visuospatial relations in aging and dementia share some features with conceptual declines in the two groups, although there are qualitative differences that may be of utility in understanding the underlying processes involved in aging and dementia.

Journal Article↗
PubMed2003

Circadian clock genes oscillate in human peripheral blood mononuclear cells.

In mammals, it is well documented that observable circadian rhythms are controlled by a central oscillator that is organized in transcriptional and translational feedback loops involving several clock genes. Although recent studies have demonstrated that clock genes oscillate in many peripheral tissues, their characteristics in the human immune system remain unknown. The present study investigates whether circadian clock genes function in human peripheral blood mononuclear cells. On the basis of studies derived from 3 human subjects under controlled conditions, circadian clock genes hPer1, hPer2, hPer3, and hDec1 are expressed in a circadian manner in human peripheral blood mononuclear cells (PBMCs), with the peak level occurring during the habitual time of activity. The demonstration of functional circadian machinery in human PBMCs suggests that peripheral blood cells may be useful for the investigation of human circadian rhythms and their associated disorders.

Activities of Daily Living↗
PubMed2004

Molecular clock in neutral protein evolution.

BACKGROUND: A frequent observation in molecular evolution is that amino-acid substitution rates show an index of dispersion (that is, ratio of variance to mean) substantially larger than one. This observation has been termed the overdispersed molecular clock. On the basis of in silico protein-evolution experiments, Bastolla and coworkers recently proposed an explanation for this observation: Proteins drift in neutral space, and can temporarily get trapped in regions of substantially reduced neutrality. In these regions, substitution rates are suppressed, which results in an overall substitution process that is not Poissonian. However, the simulation method of Bastolla et al. is representative only for cases in which the product of mutation rate micro and population size Ne is small. How the substitution process behaves when micro Ne is large is not known. RESULTS: Here, I study the behavior of the molecular clock in in silico protein evolution as a function of mutation rate and population size. I find that the index of dispersion decays with increasing micro Ne, and approaches 1 for large micro Ne. This observation can be explained with the selective pressure for mutational robustness, which is effective when micro Ne is large. This pressure keeps the population out of low-neutrality traps, and thus steadies the ticking of the molecular clock. CONCLUSIONS: The molecular clock in neutral protein evolution can fall into two distinct regimes, a strongly overdispersed one for small micro Ne, and a mostly Poissonian one for large micro Ne. The former is relevant for the majority of organisms in the plant and animal kingdom, and the latter may be relevant for RNA viruses.

Amino Acid Substitution↗
PubMed2002

A comparative study of Mini-Mental Test, Clock Drawing task and Cognitive-FIM in evaluating functional outcome of elderly hip fracture patients.

OBJECTIVE: To compare the clock drawing task with other cognitive tests used for the prediction of discharge functional outcome, in elderly hip fracture patients. DESIGN: Cohort study. SETTING: A department of geriatric-orthopaedic rehabilitation of a tertiary hospital. PATIENTS: One hundred and forty-three consecutive patients undergoing inpatient comprehensive rehabilitation following hip fracture. MEASUREMENTS: Cognitive status was assessed by the Clock Drawing Task, Mini-Mental State Examination (MMSE) and the Cognitive-FIM (cognFIM). Functional status outcome was evaluated by the Functional Independence Measure (FIM), using absolute and relative parameters of efficacy and efficiency. RESULTS: Correlation coefficients (Pearson correlation) between the three cognitive tests resulted in values ranging from 0.607 to 0.732 (p < 0.001). Similar correlation coefficients were observed for all cognitive tests when correlated with relative efficacy and efficiency outcome parameters (p < 0.001), but not with absolute outcome parameters. CONCLUSIONS: Clock Drawing Test is similar to Mini-Mental and Cognitive-FIM with respect to the evaluation of functional status outcome following rehabilitation of hip fractures. The similar correlations with functional outcome parameters as well as the simplicity of administration favour the use of either Clock Drawing Task or MMSE in the initial assessment of elderly patients with hip fractures.

Aged↗