Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “CLOCK”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2003

The circadian Clock mutation increases exploratory activity and escape-seeking behavior.

Disturbances of circadian rhythms are associated with many types of mood disorders; however, it is unknown whether a dysfunctional circadian pacemaker can be the primary cause of altered emotional behavior. To test this hypothesis, male and female mice carrying a mutation of the circadian gene, Clock, were compared to wild-type mice in an array of behavioral tests used to measure exploratory activity, anxiety, and behavioral despair. Female Clock mutant mice exhibited significantly greater activity and rearing in an open field and a greater number of total arm entries in the elevated plus maze. In addition, female Clock mutant mice spent significantly more time swimming in the forced swim test than wild-type mice on both days of a 2-day test. Male Clock mutant mice also exhibited increased exploration of the open field and increased swimming in the forced swim test; however, behavioral changes were less robust in Clock mutant males compared to Clock mutant females. These changes in behavior were not dependent on the expression of a lengthened free-running period but were more or less striking depending on the testing conditions. These data indicate that the Clock mutation leads to increased exploratory behavior and increased escape-seeking behavior, and, conversely, does not result in increased anxiety or depressive-like behavior. These results suggest that the Clock gene is involved in regulating behavioral arousal, and that Clock may interact with sex hormones to produce these behavioral changes.

Animals↗
PubMed1977

Heavy water as a tool for study of the forces that control length of period of the 24-hour clock of the hamster.

In alternating 12-hr periods of light and darkness, start of the dark period entrains the hamster's 24-hr clock. Blinding or constant darkness frees the clock of entrainment by allowing it to run faster or slower than 24 hr. Constant light frees the clock from entrainment and permits it to run slower than 24 hr--that is, lengthening its period. Heavy water given in drinking water linearly lengthens the period of the 24-hr clock of blinded hamsters or of hamsters kept in constant darkness in direct proportion to concentration of heavy water (1--50%). Heavy water (1-35%) has very different effects on length of the periods of the 24-hr clock when given under conditions of alternating 12-hr periods of light and darkness. Under these conditions, length of the period is controlled by three factors: (i) heavy water which slows the 24-hr clock; (ii) constant light which also slows the 24-hr clock; (iii) the counteracting effects of entrainment. It is thus possible to observe the effects of all three forces simultaneously in the same animal. The clock slowed by heavy water (1--20%) showed a strong tendency to return to a 24-hr entrainment whenever possible. On a 50% concentration of heavy water, the length of period of the clock became markedly lengthened but very constant and apparently independent of all external and internal disturbances.

Animals↗
PubMed1997

The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit.

Clock is a semidominant mutation identified from an N-ethyl-N-nitrosourea mutagenesis screen in mice. Mice carrying the Clock mutation exhibit abnormalities of circadian behavior, including lengthening of endogenous period and loss of rhythmicity. To identify the gene affected by this mutation, we have generated a high-resolution genetic map (> 1800 meioses) of the Clock locus. We report that Clock is 0.7 cM distal of Kit on mouse chromosome 5. Mapping shows that Clock lies within the W19H deletion. Complementation analysis of different Clock and W19H compound genotypes indicates that the Clock mutation behaves as an antimorph. This antimorphic behavior of Clock strongly argues that Clock defines a gene centrally involved in the mammalian circadian system.

Animals↗
PubMed2006

Postnatal ontogenesis of the circadian clock within the rat liver.

In mammals, the circadian oscillator within the suprachiasmatic nuclei (SCN) entrains circadian clocks in numerous peripheral tissues. Central and peripheral clocks share a molecular core clock mechanism governing daily time measurement. In the rat SCN, the molecular clockwork develops gradually during postnatal ontogenesis. The aim of the present work was to elucidate when during ontogenesis the expression of clock genes in the rat liver starts to be rhythmic. Daily profiles of mRNA expression of clock genes Per1, Per2, Cry1, Clock, Rev-Erbalpha, and Bmal1 were analyzed in the liver of fetuses at embryonic day 20 (E20) or pups at postnatal age 2 (P2), P10, P20, P30, and in adults by real-time RT-PCR. At E20, only a high-amplitude rhythm in Rev-Erbalpha and a low-amplitude variation in Cry1 but no clear circadian rhythms in expression of other clock genes were detectable. At P2, a high-amplitude rhythm in Rev-Erbalpha and a low-amplitude variation in Bmal1 but no rhythms in expression of other genes were detected. At P10, significant rhythms only in Per1 and Rev-Erbalpha expression were present. At P20, clear circadian rhythms in the expression of Per1, Per2, Rev-Erbalpha, and Bmal1, but not yet of Cry1 and Clock, were detected. At P30, all clock genes were expressed rhythmically. The phase of the rhythms shifted between all studied developmental periods until the adult stage was achieved. The data indicate that the development of the molecular clockwork in the rat liver proceeds gradually and is roughly completed by 30 days after birth.

Animals↗
PubMed2006

Hypothermia modulates circadian clock gene expression in lizard peripheral tissues.

The molecular mechanisms whereby the circadian clock responds to temperature changes are poorly understood. The ruin lizard Podarcis sicula has historically proven to be a valuable vertebrate model for exploring the influence of temperature on circadian physiology. It is an ectotherm that naturally experiences an impressive range of temperatures during the course of the year. However, no tools have been available to dissect the molecular basis of the clock in this organism. Here, we report the cloning of three lizard clock gene homologs (Period2, Cryptochrome1, and Clock) that have a close phylogenetic relationship with avian clock genes. These genes are expressed in many tissues and show a rhythmic expression profile at 29 degrees C in light-dark and constant darkness lighting conditions, with phases comparable to their mammalian and avian counterparts. Interestingly, we show that at low temperatures (6 degrees C), cycling clock gene expression is attenuated in peripheral clocks with a characteristic increase in basal expression levels. We speculate that this represents a conserved vertebrate clock gene response to low temperatures. Furthermore, these results bring new insight into the issue of whether circadian clock function is compatible with hypothermia.

Animals↗
PubMed2003

No circadian rhythms in testis: Period1 expression is clock independent and developmentally regulated in the mouse.

Spermatogenesis is a process whereby haploid spermatozoa differentiate through meiosis from precursor stem cells. We examined the expression of circadian clock genes in the testis, to assess clock control over the timing of different developmental events. Clock genes are known to oscillate with circadian rhythmicity in the central clock structure, the suprachiasmatic nucleus of the hypothalamus, but also in peripheral tissues. Here we show that Per1 gene expression in the testis is constant over a 24-h period and that the Per1 transcript is expressed at a level higher than the peak values of the Per1 oscillations observed for other tissues. Bmal1, another clock gene whose expression oscillates in other tissues, also shows constant expression levels in the testis. In addition, the levels and phosphorylation state of the PER1 protein are not oscillating at all times of day. Strikingly, Per1 is restricted primarily to step 7 to 10 spermatids and thus appears to be developmentally regulated. The expression of the Clock transcript is also developmentally regulated, but it is found principally in spermatogonia and spermatocytes up until the time of the first meiotic division. Per1 expression is not altered in testes from Clock mutant mice, suggesting that CLOCK does not activate Per1 in male germ cells, in contrast to what it does in other mouse tissues. Taken together, our observations suggest that the testis, in contrast to all other peripheral tissues, lacks a functioning circadian clock.

ARNTL Transcription Factors↗
PubMed2004

Seasonal molecular timekeeping within the rat circadian clock.

In temperate zones duration of daylight, i.e. photoperiod, changes with the seasons. The changing photoperiod affects animal as well as human physiology. All mammals exhibit circadian rhythms and a circadian clock controlling the rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of two parts differing morphologically and functionally, namely of the ventrolateral (VL) and the dorsomedial (DM). Many aspects of SCN-driven rhythmicity are affected by the photoperiod. The aim of the present overview is to summarize data about the effect of the photoperiod on the molecular timekeeping mechanism in the rat SCN, especially the effect on core clock genes, clock-controlled genes and clock-related genes expression. The summarized data indicate that the photoperiod affects i) clock-driven rhythm in photoinduction of c-fos gene and its protein product within the VL SCN, ii) clock-driven spontaneous rhythms in clock-controlled, i.e. arginine-vasopressin, and in clock-related, i.e. c-fos, gene expression within the DM SCN, and iii) the core clockwork mechanism within the rat SCN. Hence, the whole central timekeeping mechanism within the rat circadian clock measures not only the daytime but also the time of the year, i.e. the actual season.

Animals↗
PubMed2006

Circadian clockwork machinery in neural retina: evidence for the presence of functional clock components in photoreceptor-enriched chick retinal cell cultures.

PURPOSE: Circadian clocks in retinas regulate a variety of biochemical and physiological processes. Retinal neurons, particularly photoreceptor cells, are thought to contain autonomous circadian clocks that control iodopsin expression, cFos expression, cAMP levels, and melatonin synthesis. Photoreceptor-enriched cell cultures prepared from chick embryo retina and entrained to a daily light-dark (LD) cycle exhibit circadian rhythms of cAMP levels and the activity of arylalkylamine N-acetyltransferase (AANAT), a key regulatory enzyme in melatonin synthesis. The present study was conducted to investigate the expression of circadian clockwork machinery comprised of clock genes; a clock-controlled gene, Aanat; and a clock output, melatonin, in the photoreceptor-enriched cultured retinal cells. METHODS: Photoreceptor-enriched cell cultures were prepared from E6 neural retinas and incubated under 14 h:10 h light-dark cycle (LD) of illumination for 8 days and then transferred to constant (24 h/day) darkness (DD). Cells were collected every 4 h in LD and DD, and RNA was isolated. cDNA was prepared from each sample and transcripts of clock genes and Aanat were measured using real-time polymerase chain reaction (PCR). Melatonin release into the culture medium was assayed by HPLC with fluorescence detection at intervals of 3 h in LD and DD. RESULTS: Cultured neural retina cells exposed to a light-dark cycle showed rhythmic expression of clock genes. Bmal1 and Npas2 (also known as Mop4) peaked late in the day in LD and in DD. Clock mRNA was high at night in LD, but arrhythmic in DD. Cry1 and Per2 transcripts increased rapidly in the early morning and were low at night. The rhythm of Per2 was reduced in amplitude in constant darkness (DD). Levels of Cry1 and Per2 transcripts were stimulated by light exposure at night. Melatonin release and Aanat mRNA were low during the day and high at night. Rhythmic expression of clock genes and Aanat was not observed in cultures not exposed to a LD cycle but treated otherwise identically to cultures described above. CONCLUSIONS: Photoreceptor-enriched cell cultures derived from chick embryo neural retina contain a complete circadian clockwork system that is entrained by the light-dark cycle, and has a core timekeeping mechanism and circadian output in the form of melatonin synthesis.

ARNTL Transcription Factors↗
PubMed2026

Understanding and making sense of epigenetic age misalignment across different aging clocks.

The output of an epigenetic aging clock can vary depending on the training method utilized, cell type composition, the nature of the training dataset, the technology used to generate the methylomic data, acute stressors, and other factors. On an individual level, epigenetic age can fluctuate across different clocks purely due to differences in model training. Among aging clock researchers, it is well-known that the epigenetic age of a single sample can vary across different models. Based on our observations and conversations with longevity scientists and stakeholders, however, this fact is often unappreciated among non-aging clock experts. To help bring more awareness to this important topic, we highlight key literature and, as an illustrative example, use eight blood-trained clocks to show that epigenetic age is frequently misaligned in a publicly available whole blood dataset. Our simple analysis revealed that the average sample difference between the youngest and oldest predicted ages across these clocks was 17 years. The smallest and largest individual-level differences observed were 4 and 45 years, respectively. Clock misalignment has implications for choosing which clock to utilize, interpreting the impact of an intervention on epigenetic age, personalized tracking, and relating epigenetic age to the abstract concept of biological age.

Humans↗
PubMed2000

Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissues.

BMAL1 is a putative clock gene which encodes a basic helix-loop-helix (bHLH)-PAS transcription factor. To examine whether the CLOCK protein is required for the circadian expression of BMAL1 mRNA, in situ hybridization and Northern blot analysis were performed in the suprachiasmatic nucleus (SCN) and peripheral tissues of homozygous Clock mutant mice. In the SCN of Clock mutants, BMAL1 mRNA did not oscillate significantly but apparently expressed with low levels, while in wild-type mice the mRNA was robustly oscillated in a circadian manner. The peak-trough amplitudes of BMAL1 mRNA levels were 6.5-, 8.6-, and 6.7-fold in liver, heart, and kidney of wild-type mice, respectively. In Clock mutants, the amplitudes were extremely damped to 1.2-, 2.1-, and 1.4-fold, respectively. Furthermore, expressions of BMAL1 mRNA in the peripheral of Clock mutant mice were close to the peak level in wild-type mice, whereas mPer2 mRNA levels were severely blunted at trough values. Daily expression of albumin site D-binding protein (DBP), a clock controlled output gene (CCG), was also abolished at trough values by the Clock mutation in all tissues examined. These observations suggest that the circadian expression of BMAL1 mRNA is affected by the CLOCK-induced transcriptional feedback loop in the SCN and peripheral tissues in a different way and that the regulation mechanism appeared to be different from those in mPer2 and DBP expressions in vivo.

ARNTL Transcription Factors↗
PubMed2005

Casein kinase 2, circadian clocks, and the flight from mutagenic light.

Circadian clocks play a fundamental role in biology and disease. Much has been learned about the molecular underpinnings of these biological clocks from genetic studies in model organisms, such as the fruit fly, Drosophila melanogaster. Here we review the literature from our lab and others that establish a role for the protein kinase CK2 in Drosophila clock timing. Among the clock genes described thus far, CK2 is unique in its involvement in plant, fungal, as well as animal circadian clocks. We propose that this reflects an ancient, conserved function for CK2 in circadian clocks. CK2 and other clock genes have been implicated in cellular responses to DNA damage, particularly those induced by ultraviolet (UV) light. The finding of a dual function of CK2 in clocks and in UV responses supports the notion that clocks evolved to assist organisms in avoiding the mutagenic effects of daily sunlight.

Animals↗
PubMed2000

Transplanted Drosophila excretory tubules maintain circadian clock cycling out of phase with the host.

Circadian rhythms in behaviors and physiological processes are driven by conserved molecular mechanisms involving the rhythmic expression of clock genes in the brains of animals [1]. The persistence of similar molecular rhythms in peripheral tissues in vitro [2] [3] suggests that these tissues contain self-sustained circadian clocks that may be linked to rhythmic physiological functions. It is not known how brain and peripheral clocks are organized into a synchronized timing system; however, it has been assumed that peripheral clocks submit to a master clock in the brain. To address this matter we examined the expression of two clock genes, period (per) and timeless (tim), in host and transplanted abdominal organs of Drosophila. We found that excretory organs in tissue culture display free-running, light-sensitive oscillations in per and tim gene activity indicating that they house self-sustained circadian clocks. To test for humoral factors, we monitored cycling of the TIM protein in excretory tubules transplanted into host flies entrained to an opposite light-dark cycle. We show that the clock protein in the donor tubules cycled out of phase with that in the host tubules, indicating that different organs may cycle independently, despite sharing the same hormonal milieu. We suggest that one way to achieve circadian coordination of physiological sub-systems in higher animals may be through the direct entrainment of light-sensitive clocks by environmental signals.

Animals↗
PubMed1971

Hour-glass behavior of the circadian clock controlling eclosion of the silkmoth Antheraea pernyi.

The emergence of the Pernyi silkmoth from the pupal exuviae is dictated by a brain-centered, photosensitive clock. In continuous darkness the clock displays a persistent free-running rhythm. In photoperiod regimens the interaction of the clock with the daily lightdark cycle produces a characteristic time of eclosion. But, in the majority of regimens (from 23L:1D to 4L:20D), the eclosion clock undergoes a discontinuous "hourglass" behavior. Thus, during each daily cycle, the onset of darkness initiates a free-running cycle of the clock. The next "lights-on" interrupts this cycle and the clock comes to a stop late in the photophase. The moment when the Pernyi clock stops signals the release of an eclosion-stimulating hormone and is demonstrated to be a function of the time when the free-running cycle is interrupted by lights-on. Moreover, the width (duration) of the eclosion peak in a photoperiod is shown to be dependent upon the length of the dark phase, and, consequently, upon the amount of the free-running cycle that is completed. This relationship demonstrates that the free-running cycle may be divided into two parts. The attainment of maximal accuracy (and thus the narrowest eclosion peak) is dependent upon the completion of only the first 2 hr of the free-running cycle. The completion of succeeding portions of the cycle, while having an effect upon the time of eclosion, no longer affects the accuracy of the clock. A mechanistic model of the eclosion clock is presented.

Animals↗
PubMed2006

GIGANTEA acts in blue light signaling and has biochemically separable roles in circadian clock and flowering time regulation.

Circadian clocks are widespread in nature. In higher plants, they confer a selective advantage, providing information regarding not only time of day but also time of year. Forward genetic screens in Arabidopsis (Arabidopsis thaliana) have led to the identification of many clock components, but the functions of most of these genes remain obscure. To identify both new constituents of the circadian clock and new alleles of known clock-associated genes, we performed a mutant screen. Using a clock-regulated luciferase reporter, we isolated new alleles of ZEITLUPE, LATE ELONGATED HYPOCOTYL, and GIGANTEA (GI). GI has previously been reported to function in red light signaling, central clock function, and flowering time regulation. Characterization of this and other GI alleles has helped us to further define GI function in the circadian system. We found that GI acts in photomorphogenic and circadian blue light signaling pathways and is differentially required for clock function in constant red versus blue light. Gene expression and epistasis analyses show that TIMING OF CHLOROPHYLL A/B BINDING PROTEIN1 (TOC1) expression is not solely dependent upon GI and that GI expression is only indirectly affected by TOC1, suggesting that GI acts both in series with and in parallel to TOC1 within the central circadian oscillator. Finally, we found that the GI-dependent promotion of CONSTANS expression and flowering is intact in a gi mutant with altered circadian regulation. Thus GI function in the regulation of a clock output can be biochemically separated from its role within the circadian clock.

Alleles↗
PubMed1993

Effect of education on the clock-drawing dementia screen in non-demented elderly persons.

OBJECTIVE: To examine the effect of education on clock-drawing ability in non-demented elderly persons. DESIGN, SETTING, PARTICIPANTS: Descriptive study of 187 elderly persons, 77 demented, 110 non-demented, 54 with 9+ years of education, 133 with 8 or fewer years of education, from three university medical center geriatric divisions. MEASUREMENTS: Subjects took the Folstein Mini-Mental State Exam and were asked to draw a clock showing a time of 3 o'clock. Clocks were scored using three previously described scoring scales (Shulman, Sunderland, and Wolf-Klein). Mean scores and proportions of normal and abnormal clocks were compared for well and poorly educated non-demented subjects. Sensitivities and specificities for detecting dementia were calculated. RESULTS: Mean scores of the well educated non-demented subjects were significantly better than mean scores of the poorly educated non-demented subjects on all three scales. However, proportions of abnormal clocks were not significantly different between well and poorly educated on the Wolf-Klein scale. For the poorly educated subgroup, sensitivity and specificity for detecting dementia by clock drawing were 90% and 42% by the Shulman scale, 74% and 44% by the Sunderland scale, and 48% and 90% by the Wolf-Klein scale. CONCLUSIONS: Clock-drawing ability is affected by education in non-demented elderly persons. The scoring method of Wolf-Klein is least educationally affected and maximizes specificity for detecting dementia but has low sensitivity. Educational effects make clock drawing a poor single screening test for dementia in a poorly educated population.

Aged↗
PubMed1996

The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women.

OBJECTIVES: To assess the associations of a clock drawing task with hormone replacement therapy and other factors in older women. DESIGN: Group comparisons. SETTING: Leisure World Laguna Hills, retirement community in southern California. PARTICIPANTS: Two hundred ninety-two postmenopausal women who were analyzed for lipoprotein levels in 1987-88 were contacted by postal survey, which included a clock drawing task, in 1992; 168 women who drew normal clocks were compared with 46 who drew abnormal or blank clocks. MEASUREMENTS: Clock drawings; lipoprotein cholesterol levels; serum progesterone, estrone, estradiol, and steroid hormone binding globin levels; self-reported data on smoking, alcohol intake, prior medical diagnoses, and use of certain medications including hormone replacement therapy and analgesics. RESULTS: Women with normal clocks had significantly lower total cholesterol (P = .01), LDL cholesterol (P = .03), and serum progesterone levels (P = .03). They weighed, on average, 5 more pounds at the time of last menstrual period (P = .05), were more likely to use combined hormonal replacement therapy (P = .06), and were less likely to use acetaminophen daily (P = .02) than women with abnormal clocks. Serum estrone and estradiol levels did not differ significantly between women with normal and abnormal clocks. CONCLUSION: The associations found here suggest that high serum cholesterol and progesterone levels might have a negative effect on clock drawing performance. Acetaminophen may also be related to worse performance on this task.

Acetaminophen↗
PubMedDate not supplied

The low anterior five-o'clock portal during arthroscopic shoulder surgery performed in the beach-chair position.

We evaluated the difficulty, accuracy, and safety of establishing a low anterior 5-o'clock portal for anterior capsulolabral repair in patients positioned in the beach-chair position during shoulder arthroscopy. An initial 5-o'clock portal was created using an inside-out technique as described by Davidson and Tibone. During establishment of the portal, significant force was required to lever the humeral head laterally, and chondral indentations were noted in several specimens. Because of the difficulty noted establishing the 5-o'clock portal using an inside-out technique, we attempted to establish a 5-o'clock anterior portal using an outside-in technique. Seven fresh-frozen cadaveric shoulders underwent shoulder arthroscopy in the beach-chair position. After the establishment of a 3-o'clock portal, a specially constructed guide was used to place a pin at the 5-o'clock position. The distances of the pins from the cephalic vein and the musculocutaneous and axillary nerves were recorded. The bottom (5-o'clock position) and top (3-o'clock position) pins varied from 12 to 20 mm from the musculocutaneous and axillary nerves. The bottom pin was located within 2 mm of the cephalic vein and varied from medial to lateral in different specimens. We do not recommend the use of a 5-o'clock portal using an inside-out or outside-in technique for patients positioned in the beach-chair position during shoulder arthroscopy because of the potential for cephalic vein or articular cartilage injury.

Arm↗
PubMed2006

Clock mutation affects circadian regulation of circulating blood cells.

BACKGROUND: Although the number of circulating immune cells is subject to high-amplitude circadian rhythms, the underlying mechanisms are not fully understood. METHODS: To determine whether intact CLOCK protein is required for the circadian changes in peripheral blood cells, we examined circulating white (WBC) and red (RBC) blood cells in homozygous Clock mutant mice. RESULTS: Daytime increases in total WBC and lymphocytes were suppressed and slightly phase-delayed along with plasma corticosterone levels in Clock mutant mice. The peak RBC rhythm was significantly reduced and phase-advanced in the Clock mutants. Anatomical examination revealed hemoglobin-rich, swollen red spleens in Clock mutant mice, suggesting RBC accumulation. CONCLUSION: Our results suggest that endogenous clock-regulated circadian corticosterone secretion from the adrenal gland is involved in the effect of a Clock mutation on daily profiles of circulating WBC. However, intact CLOCK seems unnecessary for generating the rhythm of corticosterone secretion in mice. Our results also suggest that CLOCK is involved in discharge of RBC from the spleen.

Journal Article↗