Altered expression pattern of clock genes in a rat model of depression

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Christiansen, Sofie; Bouzinova, Elena; Fahrenkrug, Jan

2016-01-01

BACKGROUND: Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation...... of clock gene expression in depressive patients many studies have reported single-nucleotide polymorphisms in clock genes in these patients. METHODS: In the present study we investigated whether a depression-like state in rats associates with alternations of the diurnal expression of clock genes....... The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes; Per1, Per2 and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at 4 h sampling interval within 24 h. We...

Glucocorticoids affect 24 h clock genes expression in human adipose tissue explant cultures.

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Purificación Gómez-Abellán

Full Text Available to examine firstly whether CLOCK exhibits a circadian expression in human visceral (V and subcutaneous (S adipose tissue (AT in vitro as compared with BMAL1 and PER2, and secondly to investigate the possible effect of the glucocorticoid analogue dexamethasone (DEX on positive and negative clock genes expression.VAT and SAT biopsies were obtained from morbid obese women (body mass index ≥ 40 kg/m(2 (n = 6. In order to investigate rhythmic expression pattern of clock genes and the effect of DEX on CLOCK, PER2 and BMAL1 expression, control AT (without DEX and AT explants treated with DEX (2 hours were cultured during 24 h and gene expression was analyzed at the following times: 10:00 h, 14:00 h, 18:00 h, 22:00 h, 02:00 h and 06:00 h, using qRT-PCR.CLOCK, BMAL1 and PER2 expression exhibited circadian patterns in both VAT and SAT explants that were adjusted to a typical 24 h sinusoidal curve. PER2 expression (negative element was in antiphase with respect to CLOCK and in phase with BMAL1 expression (both positive elements in the SAT (situation not present in VAT. A marked effect of DEX exposure on both positive and negative clock genes expression patterns was observed. Indeed, DEX treatment modified the rhythmicity pattern towards altered patterns with a period lower than 24 hours in all genes and in both tissues.24 h patterns in CLOCK and BMAL1 (positive clock elements and PER2 (negative element mRNA levels were observed in human adipose explants. These patterns were altered by dexamethasone exposure.

Clock genes × stress × reward interactions in alcohol and substance use disorders.

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Perreau-Lenz, Stéphanie; Spanagel, Rainer

2015-06-01

Adverse life events and highly stressful environments have deleterious consequences for mental health. Those environmental factors can potentiate alcohol and drug abuse in vulnerable individuals carrying specific genetic risk factors, hence producing the final risk for alcohol- and substance-use disorders development. The nature of these genes remains to be fully determined, but studies indicate their direct or indirect relation to the stress hypothalamo-pituitary-adrenal (HPA) axis and/or reward systems. Over the past decade, clock genes have been revealed to be key-players in influencing acute and chronic alcohol/drug effects. In parallel, the influence of chronic stress and stressful life events in promoting alcohol and substance use and abuse has been demonstrated. Furthermore, the reciprocal interaction of clock genes with various HPA-axis components, as well as the evidence for an implication of clock genes in stress-induced alcohol abuse, have led to the idea that clock genes, and Period genes in particular, may represent key genetic factors to consider when examining gene × environment interaction in the etiology of addiction. The aim of the present review is to summarize findings linking clock genes, stress, and alcohol and substance abuse, and to propose potential underlying neurobiological mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

Expression conservation within the circadian clock of a monocot: natural variation at barley Ppd-H1 affects circadian expression of flowering time genes, but not clock orthologs.

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Campoli, Chiara; Shtaya, Munqez; Davis, Seth J; von Korff, Maria

2012-06-21

The circadian clock is an endogenous mechanism that coordinates biological processes with daily changes in the environment. In plants, circadian rhythms contribute to both agricultural productivity and evolutionary fitness. In barley, the photoperiod response regulator and flowering-time gene Ppd-H1 is orthologous to the Arabidopsis core-clock gene PRR7. However, relatively little is known about the role of Ppd-H1 and other components of the circadian clock in temperate crop species. In this study, we identified barley clock orthologs and tested the effects of natural genetic variation at Ppd-H1 on diurnal and circadian expression of clock and output genes from the photoperiod-response pathway. Barley clock orthologs HvCCA1, HvGI, HvPRR1, HvPRR37 (Ppd-H1), HvPRR73, HvPRR59 and HvPRR95 showed a high level of sequence similarity and conservation of diurnal and circadian expression patterns, when compared to Arabidopsis. The natural mutation at Ppd-H1 did not affect diurnal or circadian cycling of barley clock genes. However, the Ppd-H1 mutant was found to be arrhythmic under free-running conditions for the photoperiod-response genes HvCO1, HvCO2, and the MADS-box transcription factor and vernalization responsive gene Vrn-H1. We suggest that the described eudicot clock is largely conserved in the monocot barley. However, genetic differentiation within gene families and differences in the function of Ppd-H1 suggest evolutionary modification in the angiosperm clock. Our data indicates that natural variation at Ppd-H1 does not affect the expression level of clock genes, but controls photoperiodic output genes. Circadian control of Vrn-H1 in barley suggests that this vernalization responsive gene is also controlled by the photoperiod-response pathway. Structural and functional characterization of the barley circadian clock will set the basis for future studies of the adaptive significance of the circadian clock in Triticeae species.

Direct Repression of Evening Genes by CIRCADIAN CLOCK-ASSOCIATED1 in the Arabidopsis Circadian Clock.

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Kamioka, Mari; Takao, Saori; Suzuki, Takamasa; Taki, Kyomi; Higashiyama, Tetsuya; Kinoshita, Toshinori; Nakamichi, Norihito

2016-03-01

The circadian clock is a biological timekeeping system that provides organisms with the ability to adapt to day-night cycles. Timing of the expression of four members of the Arabidopsis thaliana PSEUDO-RESPONSE REGULATOR(PRR) family is crucial for proper clock function, and transcriptional control of PRRs remains incompletely defined. Here, we demonstrate that direct regulation of PRR5 by CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) determines the repression state of PRR5 in the morning. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) analyses indicated that CCA1 associates with three separate regions upstream of PRR5 CCA1 and its homolog LATE ELONGATED HYPOCOTYL (LHY) suppressed PRR5 promoter activity in a transient assay. The regions bound by CCA1 in the PRR5 promoter gave rhythmic patterns with troughs in the morning, when CCA1 and LHY are at high levels. Furthermore,ChIP-seq revealed that CCA1 associates with at least 449 loci with 863 adjacent genes. Importantly, this gene set contains genes that are repressed but upregulated incca1 lhy double mutants in the morning. This study shows that direct binding by CCA1 in the morning provides strong repression of PRR5, and repression by CCA1 also temporally regulates an evening-expressed gene set that includes PRR5. © 2016 American Society of Plant Biologists. All rights reserved.

Trojan Horse Strategy for Non-invasive Interference of Clock Gene in the Oyster Crassostrea gigas.

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Payton, Laura; Perrigault, Mickael; Bourdineaud, Jean-Paul; Marcel, Anjara; Massabuau, Jean-Charles; Tran, Damien

2017-08-01

RNA interference is a powerful method to inhibit specific gene expression. Recently, silencing target genes by feeding has been successfully carried out in nematodes, insects, and small aquatic organisms. A non-invasive feeding-based RNA interference is reported here for the first time in a mollusk bivalve, the pacific oyster Crassostrea gigas. In this Trojan horse strategy, the unicellular alga Heterocapsa triquetra is the food supply used as a vector to feed oysters with Escherichia coli strain HT115 engineered to express the double-stranded RNA targeting gene. To test the efficacy of the method, the Clock gene, a central gene of the circadian clock, was targeted for knockout. Results demonstrated specific and systemic efficiency of the Trojan horse strategy in reducing Clock mRNA abundance. Consequences of Clock disruption were observed in Clock-related genes (Bmal, Tim1, Per, Cry1, Cry2, Rev.-erb, and Ror) and triploid oysters were more sensitive than diploid to the interference. This non-invasive approach shows an involvement of the circadian clock in oyster bioaccumulation of toxins produced by the harmful alga Alexandrium minutum.

Association between genetic variants of the clock gene and obesity and sleep duration.

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Valladares, Macarena; Obregón, Ana María; Chaput, Jean-Philippe

2015-12-01

Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.

A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.

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Michael J McCarthy

Full Text Available Circadian rhythm abnormalities in bipolar disorder (BD have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS. At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity. Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.

Regulation of circadian clock transcriptional output by CLOCK:BMAL1

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Trott, Alexandra J.

2018-01-01

The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of 15% of the transcriptome and control the daily regulation of biological functions. The recent characterization of CLOCK:BMAL1 cistrome revealed that although CLOCK:BMAL1 binds synchronously to all of its target genes, its transcriptional output is highly heterogeneous. By performing a meta-analysis of several independent genome-wide datasets, we found that the binding of other transcription factors at CLOCK:BMAL1 enhancers likely contribute to the heterogeneity of CLOCK:BMAL1 transcriptional output. While CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal, it is not sufficient to generate transcriptionally active enhancers as assessed by H3K27ac signal, RNA Polymerase II recruitment, and eRNA expression. Instead, the transcriptional activity of CLOCK:BMAL1 enhancers appears to rely on the activity of ubiquitously expressed transcription factors, and not tissue-specific transcription factors, recruited at nearby binding sites. The contribution of other transcription factors is exemplified by how fasting, which effects several transcription factors but not CLOCK:BMAL1, either decreases or increases the amplitude of many rhythmically expressed CLOCK:BMAL1 target genes. Together, our analysis suggests that CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape that primes its target genes for transcription activation rather than directly activating transcription, and provides a new framework to explain how environmental or pathological conditions can reprogram the rhythmic expression of clock-controlled genes. PMID:29300726

Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

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Zhu Zhu

2016-01-01

Full Text Available Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice by altering exposure to light. C57 BL/6J mice (C57 mice and ApoE-KO mice (ApoE-KO mice exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1 levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

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Polona Lavtar

Full Text Available Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02 distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001 and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002. The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

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Bluhm, A.P.C.; Obeid, N.N.; Castrucci, A.M.L.; Visconti, M.A. [Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil)

2012-05-25

Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression.

The expression of melanopsin and clock genes in Xenopus laevis melanophores and their modulation by melatonin

International Nuclear Information System (INIS)

Bluhm, A.P.C.; Obeid, N.N.; Castrucci, A.M.L.; Visconti, M.A.

2012-01-01

Vertebrates have a central clock and also several peripheral clocks. Light responses might result from the integration of light signals by these clocks. The dermal melanophores of Xenopus laevis have a photoreceptor molecule denominated melanopsin (OPN4x). The mechanisms of the circadian clock involve positive and negative feedback. We hypothesize that these dermal melanophores also present peripheral clock characteristics. Using quantitative PCR, we analyzed the pattern of temporal expression of Opn4x and the clock genes Per1, Per2, Bmal1, and Clock in these cells subjected to a 14-h light:10-h dark (14L:10D) regime or constant darkness (DD). Also, in view of the physiological role of melatonin in the dermal melanophores of X. laevis, we determined whether melatonin modulates the expression of these clock genes. These genes show a time-dependent expression pattern when these cells are exposed to 14L:10D, which differs from the pattern observed under DD. Cells kept in DD for 5 days exhibited overall increased mRNA expression for Opn4x and Clock, and a lower expression for Per1, Per2, and Bmal1. When the cells were kept in DD for 5 days and treated with melatonin for 1 h, 24 h before extraction, the mRNA levels tended to decrease for Opn4x and Clock, did not change for Bmal1, and increased for Per1 and Per2 at different Zeitgeber times (ZT). Although these data are limited to one-day data collection, and therefore preliminary, we suggest that the dermal melanophores of X. laevis might have some characteristics of a peripheral clock, and that melatonin modulates, to a certain extent, melanopsin and clock gene expression

Clock gene evolution: seasonal timing, phylogenetic signal, or functional constraint?

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Krabbenhoft, Trevor J; Turner, Thomas F

2014-01-01

Genetic determinants of seasonal reproduction are not fully understood but may be important predictors of organism responses to climate change. We used a comparative approach to study the evolution of seasonal timing within a fish community in a natural common garden setting. We tested the hypothesis that allelic length variation in the PolyQ domain of a circadian rhythm gene, Clock1a, corresponded to interspecific differences in seasonal reproductive timing across 5 native and 1 introduced cyprinid fishes (n = 425 individuals) that co-occur in the Rio Grande, NM, USA. Most common allele lengths were longer in native species that initiated reproduction earlier (Spearman's r = -0.70, P = 0.23). Clock1a allele length exhibited strong phylogenetic signal and earlier spawners were evolutionarily derived. Aside from length variation in Clock1a, all other amino acids were identical across native species, suggesting functional constraint over evolutionary time. Interestingly, the endangered Rio Grande silvery minnow (Hybognathus amarus) exhibited less allelic variation in Clock1a and observed heterozygosity was 2- to 6-fold lower than the 5 other (nonimperiled) species. Reduced genetic variation in this functionally important gene may impede this species' capacity to respond to ongoing environmental change.

Discrete gene replication events drive coupling between the cell cycle and circadian clocks.

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Paijmans, Joris; Bosman, Mark; Ten Wolde, Pieter Rein; Lubensky, David K

2016-04-12

Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push-pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.

Clock Synchronization, Dirac Observables and Gauge Variables in Canonical Gravity and the Objectivity of Spacetime

International Nuclear Information System (INIS)

Lusanna, Luca

2006-01-01

This is a review of the chrono-geometrical structure of special and general relativity with a special emphasis on the role of non-inertial frames and of the conventions for the synchronization of distant clocks. ADM canonical metric and tetrad gravity are analyzed in a class of space-times suitable to incorporate particle physics by using Dirac theory of constraints, which allows to arrive at a separation of the genuine degrees of freedom of the gravitational field, the Dirac observables describing generalized tidal effects, from its gauge variables, describing generalized inertial effects. A background-independent formulation (the rest-frame instant form of tetrad gravity) emerges, since the chosen boundary conditions at spatial infinity imply the existence of an asymptotic flat metric. By switching off the Newton constant in presence of matter this description deparametrizes to the rest-frame instant form for such matter in the framework of parametrized Minkowski theories. The problem of the objectivity of the spacetime point-events, implied by Einstein's Hole Argument, is analyzed

Clock gene polymorphism, migratory behaviour and geographic distribution: a comparative study of trans-Saharan migratory birds.

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Bazzi, Gaia; Cecere, Jacopo G; Caprioli, Manuela; Gatti, Emanuele; Gianfranceschi, Luca; Podofillini, Stefano; Possenti, Cristina D; Ambrosini, Roberto; Saino, Nicola; Spina, Fernando; Rubolini, Diego

2016-12-01

Migratory behaviour is controlled by endogenous circannual rhythms that are synchronized by external cues, such as photoperiod. Investigations on the genetic basis of circannual rhythmicity in vertebrates have highlighted that variation at candidate 'circadian clock' genes may play a major role in regulating photoperiodic responses and timing of life cycle events, such as reproduction and migration. In this comparative study of 23 trans-Saharan migratory bird species, we investigated the relationships between species-level genetic variation at two candidate genes, Clock and Adcyap1, and species' traits related to migration and geographic distribution, including timing of spring migration across the Mediterranean Sea, migration distance and breeding latitude. Consistently with previous evidence showing latitudinal clines in 'circadian clock' genotype frequencies, Clock allele size increased with breeding latitude across species. However, early- and late-migrating species had similar Clock allele size. Species migrating over longer distances, showing delayed spring migration and smaller phenotypic variance in spring migration timing, had significantly reduced Clock (but not Adcyap1) gene diversity. Phylogenetic confirmatory path analysis suggested that migration date and distance were the most important variables directly affecting Clock gene diversity. Hence, our study supports the hypothesis that Clock allele size increases poleward as a consequence of adaptation to the photoperiodic regime of the breeding areas. Moreover, we show that long-distance migration is associated with lower Clock diversity, coherently with strong stabilizing selection acting on timing of life cycle events in long-distance migratory species, likely resulting from the time constraints imposed by late spring migration. © 2016 John Wiley & Sons Ltd.

Crystal Structure of the CLOCK Transactivation Domain Exon19 in Complex with a Repressor

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Hou, Zhiqiang; Su, Lijing; Pei, Jimin; Grishin, Nick V.; Zhang, Hong (UTSMC)

2017-08-01

In the canonical clock model, CLOCK:BMAL1-mediated transcriptional activation is feedback regulated by its repressors CRY and PER and, in association with other coregulators, ultimately generates oscillatory gene expression patterns. How CLOCK:BMAL1 interacts with coregulator(s) is not well understood. Here we report the crystal structures of the mouse CLOCK transactivating domain Exon19 in complex with CIPC, a potent circadian repressor that functions independently of CRY and PER. The Exon19:CIPC complex adopts a three-helical coiled-coil bundle conformation containing two Exon19 helices and one CIPC. Unique to Exon19:CIPC, three highly conserved polar residues, Asn341 of CIPC and Gln544 of the two Exon19 helices, are located at the mid-section of the coiled-coil bundle interior and form hydrogen bonds with each other. Combining results from protein database search, sequence analysis, and mutagenesis studies, we discovered for the first time that CLOCK Exon19:CIPC interaction is a conserved transcription regulatory mechanism among mammals, fish, flies, and other invertebrates.

Effects of circadian clock genes and environmental factors on cognitive aging in old adults in a Taiwanese population.

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Lin, Eugene; Kuo, Po-Hsiu; Liu, Yu-Li; Yang, Albert C; Kao, Chung-Feng; Tsai, Shih-Jen

2017-04-11

Previous animal studies have indicated associations between circadian clock genes and cognitive impairment . In this study, we assessed whether 11 circadian clockgenes are associated with cognitive aging independently and/or through complex interactions in an old Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to evaluate cognitive function. Our data showed associations between cognitive aging and single nucleotide polymorphisms (SNPs) in 4 key circadian clock genes, CLOCK rs3749473 (p = 0.0017), NPAS2 rs17655330 (p = 0.0013), RORA rs13329238 (p = 0.0009), and RORB rs10781247 (p = 7.9 x 10-5). We also found that interactions between CLOCK rs3749473, NPAS2 rs17655330, RORA rs13329238, and RORB rs10781247 affected cognitive aging (p = 0.007). Finally, we investigated the influence of interactions between CLOCK rs3749473, RORA rs13329238, and RORB rs10781247 with environmental factors such as alcohol consumption, smoking status, physical activity, and social support on cognitive aging (p = 0.002 ~ 0.01). Our study indicates that circadian clock genes such as the CLOCK, NPAS2, RORA, and RORB genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-environment interactions.

Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men.

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Cedernaes, Jonathan; Osler, Megan E; Voisin, Sarah; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Zierath, Juleen R; Schiöth, Helgi B; Benedict, Christian

2015-09-01

Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230-0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P = .026) and in two promoter-interacting enhancer regions of PER1 (+15%; P = .036; +9%; P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (-18%; P = .033) and CRY1 (-22%; P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L; P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L; P = .011). Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.

Does exercise training impact clock genes in patients with coronary artery disease and type 2 diabetes mellitus?

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Steidle-Kloc, Eva; Schönfelder, Martin; Müller, Edith; Sixt, Sebastian; Schuler, Gerhard; Patsch, Wolfgang; Niebauer, Josef

2016-09-01

Recent findings revealed negative effects of deregulated molecular circadian rhythm in coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). Physical exercise training (ET) has been shown to promote anti-diabetic and anti-atherogenic responses in skeletal muscle of these patients, but the role of the circadian clock-machinery remains unknown. This study investigated whether mRNA expression of clock genes in skeletal muscle of CAD and T2DM patients is influenced by physical ET intervention. Nineteen patients with CAD and T2DM (age 64 ± 5 years) were randomised to either six months of ET (four weeks of in-hospital ET followed by a five-month ambulatory programme) or usual care. At the beginning of the study, after four weeks and after six months parameters of metabolic and cardiovascular risk factors, and physical exercise capacity were assessed. Gene expression was measured in skeletal muscle biopsies by quantitative real-time polymerase chain reaction (PCR). A selection of clock genes and associated components (circadian locomoter output cycle kaput protein (CLOCK), period (PER) 1, cryptochrome (CRY) 2 and aminolevulinate-deltA-synthase-1 (ALAS1)) was reliably measured and used for further analysis. A time-dependent effect in gene expression was observed in CLOCK (p = 0.013) and a significant interaction between time and intervention was observed for ALAS1 (p = 0.032; p = 0.014) as a result of ET. This is the first study to analyse clock gene expression in skeletal muscles of patients with CAD and T2DM participating in a long-lasting exercise intervention. ET, as one of the cornerstones in prevention and rehabilitation of CAD and T2DM, exerts no effects on CLOCK genes but meaningful effects on the clock-associated gene ALAS1. © The European Society of Cardiology 2016.

Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells

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Shimizu, Takashi; Hirai, Yuko; Murayama, Chiaki; Miyamoto, Akio; Miyazaki, Hitoshi; Miyazaki, Koyomi

2011-01-01

Highlights: → Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression. →Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom. → Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. →Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. → The expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. -- Abstract: Circadian Clock genes are associated with the estrous cycle in female animals. Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression in follicle-stimulating hormone FSH-treated granulosa cells. Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom, whereas Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. Similarly, expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. Our data provide a new insight that Per2 and Clock have different action on ovarian granulosa cell functions.

Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells

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Shimizu, Takashi, E-mail: shimizut@obihiro.ac.jp [Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Hirai, Yuko; Murayama, Chiaki; Miyamoto, Akio [Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Miyazaki, Hitoshi [Gene Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8572 (Japan); Miyazaki, Koyomi [Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) Central 6, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8566 (Japan)

2011-08-19

Highlights: {yields} Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression. {yields}Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom. {yields} Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. {yields}Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. {yields} The expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. -- Abstract: Circadian Clock genes are associated with the estrous cycle in female animals. Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression in follicle-stimulating hormone FSH-treated granulosa cells. Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom, whereas Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. Similarly, expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. Our data provide a new insight that Per2 and Clock have different action on ovarian granulosa cell functions.

Effect of monochromatic light on circadian rhythmic expression of clock genes in the hypothalamus of chick.

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Jiang, Nan; Wang, Zixu; Cao, Jing; Dong, Yulan; Chen, Yaoxing

2017-08-01

To clarify the effect of monochromatic light on circadian clock gene expression in chick hypothalamus, a total 240 newly hatched chickens were reared under blue light (BL), green light (GL), red light (RL) and white light (WL), respectively. On the post-hatched day 14, 24-h profiles of seven core clock genes (cClock, cBmal1, cBmal2, cCry1, cCry2, cPer2 and cPer3) were measured at six time points (CT 0, CT 4, CT 8, CT 12, CT 16, CT 20, circadian time). We found all these clock genes expressed with a significant rhythmicity in different light wavelength groups. Meanwhile, cClock and cBmal1 showed a high level under GL, and followed a corresponding high expression of cCry1. However, RL decreased the expression levels of these genes. Be consistent with the mRNA level, CLOCK and BMAL1 proteins also showed a high level under GL. The CLOCK-like immunoreactive neurons were observed not only in the SCN, but also in the non-SCN brain region such as the nucleus anterior medialis hypothalami, the periventricularis nucleus, the paraventricular nucleus and the median eminence. All these results are consistent with the auto-regulatory circadian feedback loop, and indicate that GL may play an important role on the circadian time generation and development in the chick hypothalamus. Our results also suggest that the circadian clock in the chick hypothalamus such as non-SCN brain region were involved in the regulation of photo information. Copyright © 2017 Elsevier B.V. All rights reserved.

Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

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Astha Malik

Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte

Core clock, SUB1, and ABAR genes mediate flooding and drought responses via alternative splicing in soybean.

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Syed, Naeem H; Prince, Silvas J; Mutava, Raymond N; Patil, Gunvant; Li, Song; Chen, Wei; Babu, Valliyodan; Joshi, Trupti; Khan, Saad; Nguyen, Henry T

2015-12-01

Circadian clocks are a great evolutionary innovation and provide competitive advantage during the day/night cycle and under changing environmental conditions. The circadian clock mediates expression of a large proportion of genes in plants, achieving a harmonious relationship between energy metabolism, photosynthesis, and biotic and abiotic stress responses. Here it is shown that multiple paralogues of clock genes are present in soybean (Glycine max) and mediate flooding and drought responses. Differential expression of many clock and SUB1 genes was found under flooding and drought conditions. Furthermore, natural variation in the amplitude and phase shifts in PRR7 and TOC1 genes was also discovered under drought and flooding conditions, respectively. PRR3 exhibited flooding- and drought-specific splicing patterns and may work in concert with PRR7 and TOC1 to achieve energy homeostasis under flooding and drought conditions. Higher expression of TOC1 also coincides with elevated levels of abscisic acid (ABA) and variation in glucose levels in the morning and afternoon, indicating that this response to abiotic stress is mediated by ABA, endogenous sugar levels, and the circadian clock to fine-tune photosynthesis and energy utilization under stress conditions. It is proposed that the presence of multiple clock gene paralogues with variation in DNA sequence, phase, and period could be used to screen exotic germplasm to find sources for drought and flooding tolerance. Furthermore, fine tuning of multiple clock gene paralogues (via a genetic engineering approach) should also facilitate the development of flooding- and drought-tolerant soybean varieties. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Food-Anticipatory Behavior in Neonatal Rabbits and Rodents: An Update on the Role of Clock Genes

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Mario Caba

2018-05-01

Full Text Available In mammals, the suprachiasmatic nucleus (SCN, the master circadian clock, is mainly synchronized to the environmental light/dark cycle. SCN oscillations are maintained by a molecular clockwork in which certain genes, Period 1–2, Cry1–2, Bmal1, and Clock, are rhythmically expressed. Disruption of these genes leads to a malfunctioning clockwork and behavioral and physiological rhythms are altered. In addition to synchronization of circadian rhythms by light, when subjects are exposed to food for a few hours daily, behavioral and physiological rhythms are entrained to anticipate mealtime, even in the absence of the SCN. The presence of anticipatory rhythms synchronized by food suggests the existence of an SCN-independent circadian pacemaker that might be dependent on clock genes. Interestingly, rabbit pups, unable to perceive light, suckle milk once a day, which entrains behavioral rhythms to anticipate nursing time. Mutations of clock genes, singly or in combination, affect diverse rhythms in brain activity and physiological processes, but anticipatory behavior and physiology to feeding time remains attenuated or unaffected. It had been suggested that compensatory upregulation of paralogs or subtypes genes, or even non-transcriptional mechanisms, are able to maintain circadian oscillations entrained to mealtime. In the present mini-review, we evaluate the current state of the role played by clock genes in meal anticipation and provide evidence for rabbit pups as a natural model of food-anticipatory circadian behavior.

Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders.

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Charrier, Annaëlle; Olliac, Bertrand; Roubertoux, Pierre; Tordjman, Sylvie

2017-04-29

In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

Clock Genes and Altered Sleep–Wake Rhythms: Their Role in the Development of Psychiatric Disorders

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Annaëlle Charrier

2017-04-01

Full Text Available In mammals, the circadian clocks network (central and peripheral oscillators controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder. However, the underlying mechanisms of these associations remain to be ascertained and the cause–effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep–wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders. First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep–wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

Deleting the Arntl clock gene in the granular layer of the mouse cerebellum

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Bering, Tenna; Carstensen, Mikkel Bloss; Rath, Martin Fredensborg

2017-01-01

nucleus. It has been suggested that the cerebellar circadian oscillator is involved in food anticipation, but direct molecular evidence of the role of the circadian oscillator of the cerebellar cortex is currently unavailable. To investigate the hypothesis that the circadian oscillator of the cerebellum...... is involved in circadian physiology and food anticipation, we therefore by use of Cre-LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located...

Genetic variation of clock genes and cancer risk: a field synopsis and meta-analysis.

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Benna, Clara; Helfrich-Förster, Charlotte; Rajendran, Senthilkumar; Monticelli, Halenya; Pilati, Pierluigi; Nitti, Donato; Mocellin, Simone

2017-04-04

The number of studies on the association between clock genes' polymorphisms and cancer susceptibility has increased over the last years but the results are often conflicting and no comprehensive overview and quantitative summary of the evidence in this field is available. Literature search identified 27 eligible studies comprising 96756 subjects (cases: 38231) and investigating 687 polymorphisms involving 14 clock genes. Overall, 1025 primary and subgroup meta-analyses on 366 gene variants were performed. Study distribution by tumor was as follows: breast cancer (n=15), prostate cancer (n=3), pancreatic cancer (n=2), non-Hodgkin's lymphoma (n=2), glioma (n=1), chronic lymphocytic leukemia (n=1), colorectal cancer (n=1), non-small cell lung cancer (n=1) and ovarian cancer (n=1).We identified 10 single nucleotide polymorphisms (SNPs) significantly associated with cancer risk: NPAS2 rs10165970 (mixed and breast cancer shiftworkers), rs895520 (mixed), rs17024869 (breast) and rs7581886 (breast); CLOCK rs3749474 (breast) and rs11943456 (breast); RORA rs7164773 (breast and breast cancer postmenopausal), rs10519097 (breast); RORB rs7867494 (breast cancer postmenopausal), PER3 rs1012477 (breast cancer subgroups) and assessed the level of quality evidence to be intermediate. We also identified polymorphisms with lower quality statistically significant associations (n=30). Our work supports the hypothesis that genetic variation of clock genes might affect cancer risk. These findings also highlight the need for more efforts in this research field in order to fully establish the contribution of clock gene variants to the risk of developing cancer. We conducted a systematic review and meta-analysis of the evidence on the association between clock genes' germline variants and the risk of developing cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate

A role for clock genes in sleep homeostasis.

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Franken, Paul

2013-10-01

The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dissecting Daily and Circadian Expression Rhythms of Clock-Controlled Genes in Human Blood.

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Lech, Karolina; Ackermann, Katrin; Revell, Victoria L; Lao, Oscar; Skene, Debra J; Kayser, Manfred

2016-02-01

The identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human peripheral blood during a sleep/sleep deprivation (S/SD) study and a constant routine (CR) study. Blood expression levels of 9 candidate CCGs (SREBF1, TRIB1, USF1, THRA1, SIRT1, STAT3, CAPRIN1, MKNK2, and ROCK2), were measured across 48 h in 12 participants in the S/SD study and across 33 h in 12 participants in the CR study. Statistically significant rhythms in expression were observed for STAT3, SREBF1, TRIB1, and THRA1 in samples from both the S/SD and the CR studies, indicating that their rhythmicity is driven by the endogenous clock. The MKNK2 gene was significantly rhythmic in the S/SD but not the CR study, which implies its exogenously driven rhythmic expression. In addition, we confirmed the circadian expression of PER1, PER3, and REV-ERBα in the CR study samples, while BMAL1 and HSPA1B were not significantly rhythmic in the CR samples; all 5 genes previously showed significant expression in the S/SD study samples. Overall, our results demonstrate that rhythmic expression patterns of clock and selected clock-controlled genes in human blood cells are in part determined by exogenous factors (sleep and fasting state) and in part by the endogenous circadian timing system. Knowledge of the exogenous and endogenous regulation of gene expression rhythms is needed prior to the selection of potential candidate marker genes for future applications in medical and forensic settings. © 2015 The Author(s).

Sparse canonical correlation analysis for identifying, connecting and completing gene-expression networks

NARCIS (Netherlands)

Waaijenborg, S.; Zwinderman, A.H.

2009-01-01

ABSTRACT: BACKGROUND: We generalized penalized canonical correlation analysis for analyzing microarray gene-expression measurements for checking completeness of known metabolic pathways and identifying candidate genes for incorporation in the pathway. We used Wold's method for calculation of the

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver.

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Su, Yan; Cailotto, Cathy; Foppen, Ewout; Jansen, Remi; Zhang, Zhi; Buijs, Ruud; Fliers, Eric; Kalsbeek, Andries

2016-02-15

The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH.

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Bruce, Kimberley D; Szczepankiewicz, Dawid; Sihota, Kiran K; Ravindraanandan, Manoj; Thomas, Hugh; Lillycrop, Karen A; Burdge, Graham C; Hanson, Mark A; Byrne, Christopher D; Cagampang, Felino R

2016-07-01

We have previously shown that high fat (HF) feeding during pregnancy primes the development of non-alcoholic steatohepatits (NASH) in the adult offspring. However, the underlying mechanisms are unclear. Since the endogenous molecular clock can regulate hepatic lipid metabolism, we investigated whether exposure to a HF diet during development could alter hepatic clock gene expression and contribute to NASH onset in later life. Female mice were fed either a control (C, 7%kcal fat) or HF (45%kcal fat) diet. Offspring were fed either a C or HF diet resulting in four offspring groups: C/C, C/HF, HF/C and HF/HF. NAFLD progression, cellular redox status, sirtuin expression (Sirt1, Sirt3), and the expression of core clock genes (Clock, Bmal1, Per2, Cry2) and clock-controlled genes involved in lipid metabolism (Rev-Erbα, Rev-Erbβ, RORα, and Srebp1c) were measured in offspring livers. Offspring fed a HF diet developed NAFLD. However HF fed offspring of mothers fed a HF diet developed NASH, coupled with significantly reduced NAD(+)/NADH (pNASH in adulthood, involving altered cellular redox status, reduced sirtuin abundance, and desynchronized clock gene expression. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Clock gene variation in Tachycineta swallows.

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Dor, Roi; Cooper, Caren B; Lovette, Irby J; Massoni, Viviana; Bulit, Flor; Liljesthrom, Marcela; Winkler, David W

2012-01-01

Many animals use photoperiod cues to synchronize reproduction with environmental conditions and thereby improve their reproductive success. The circadian clock, which creates endogenous behavioral and physiological rhythms typically entrained to photoperiod, is well characterized at the molecular level. Recent work provided evidence for an association between Clock poly-Q length polymorphism and latitude and, within a population, an association with the date of laying and the length of the incubation period. Despite relatively high overall breeding synchrony, the timing of clutch initiation has a large impact on the fitness of swallows in the genus Tachycineta. We compared length polymorphism in the Clock poly-Q region among five populations from five different Tachycineta species that breed across a hemisphere-wide latitudinal gradient (Fig. 1). Clock poly-Q variation was not associated with latitude; however, there was an association between Clock poly-Q allele diversity and the degree of clutch size decline within breeding seasons. We did not find evidence for an association between Clock poly-Q variation and date of clutch initiation in for any of the five Tachycineta species, nor did we found a relationship between incubation duration and Clock genotype. Thus, there is no general association between latitude, breeding phenology, and Clock polymorphism in this clade of closely related birds.Figure 1Photos of Tachycineta swallows that were used in this study: A) T. bicolor from Ithaca, New York, B) T. leucorrhoa from Chascomús, Argentina, C) T. albilinea from Hill Bank, Belize, D) T. meyeni from Puerto Varas, Chile, and E) T. thalassina from Mono Lake, California, Photographers: B: Valentina Ferretti; A, C-E: David Winkler.

Nucleotide sequences of immunoglobulin eta genes of chimpanzee and orangutan: DNA molecular clock and hominoid evolution

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Sakoyama, Y.; Hong, K.J.; Byun, S.M.; Hisajima, H.; Ueda, S.; Yaoita, Y.; Hayashida, H.; Miyata, T.; Honjo, T.

1987-02-01

To determine the phylogenetic relationships among hominoids and the dates of their divergence, the complete nucleotide sequences of the constant region of the immunoglobulin eta-chain (C/sub eta1/) genes from chimpanzee and orangutan have been determined. These sequences were compared with the human eta-chain constant-region sequence. A molecular clock (silent molecular clock), measured by the degree of sequence divergence at the synonymous (silent) positions of protein-encoding regions, was introduced for the present study. From the comparison of nucleotide sequences of ..cap alpha../sub 1/-antitrypsin and ..beta..- and delta-globulin genes between humans and Old World monkeys, the silent molecular clock was calibrated: the mean evolutionary rate of silent substitution was determined to be 1.56 x 10/sup -9/ substitutions per site per year. Using the silent molecular clock, the mean divergence dates of chimpanzee and orangutan from the human lineage were estimated as 6.4 +/- 2.6 million years and 17.3 +/- 4.5 million years, respectively. It was also shown that the evolutionary rate of primate genes is considerably slower than those of other mammalian genes.

Altered Rhythm of Adrenal Clock Genes, StAR and Serum Corticosterone in VIP Receptor 2-Deficient Mice

DEFF Research Database (Denmark)

Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens

2012-01-01

oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2......RNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor......The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular...

Circadian Rhythms and Clock Genes in Reproduction: Insights From Behavior and the Female Rabbit’s Brain

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Mario Caba

2018-03-01

Full Text Available Clock gene oscillations are necessary for a successful pregnancy and parturition, but little is known about their function during lactation, a period demanding from the mother multiple physiological and behavioral adaptations to fulfill the requirements of the offspring. First, we will focus on circadian rhythms and clock genes in reproductive tissues mainly in rodents. Disruption of circadian rhythms or proper rhythmic oscillations of clock genes provoke reproductive problems, as found in clock gene knockout mice. Then, we will focus mainly on the rabbit doe as this mammal nurses the young just once a day with circadian periodicity. This daily event synchronizes the behavior and the activity of specific brain regions critical for reproductive neuroendocrinology and maternal behavior, like the preoptic area. This region shows strong rhythms of the PER1 protein (product of the Per1 clock gene associated with circadian nursing. Additionally, neuroendocrine cells related to milk production and ejections are also synchronized to daily nursing. A threshold of suckling is necessary to entrain once a day nursing; this process is independent of milk output as even virgin does (behaving maternally following anosmia can display circadian nursing behavior. A timing motivational mechanism may regulate such behavior as mesolimbic dopaminergic cells are entrained by daily nursing. Finally, we will explore about the clinical importance of circadian rhythms. Indeed, women in chronic shift-work schedules show problems in their menstrual cycles and pregnancies and also have a high risk of preterm delivery, making this an important field of translational research.

Cycling of clock genes entrained to the solar rhythm enables plants to tell time: data from arabidopsis

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Yeang, Hoong-Yeet

2015-01-01

Background and Aims An endogenous rhythm synchronized to dawn cannot time photosynthesis-linked genes to peak consistently at noon since the interval between sunrise and noon changes seasonally. In this study, a solar clock model that circumvents this limitation is proposed using two daily timing references synchronized to noon and midnight. Other rhythmic genes that are not directly linked to photosynthesis, and which peak at other times, also find an adaptive advantage in entrainment to the solar rhythm. Methods Fourteen datasets extracted from three published papers were used in a meta-analysis to examine the cyclic behaviour of the Arabidopsis thaliana photosynthesis-related gene CAB2 and the clock oscillator genes TOC1 and LHY in T cycles and N–H cycles. Key Results Changes in the rhythms of CAB2, TOC1 and LHY in plants subjected to non-24-h light:dark cycles matched the hypothesized changes in their behaviour as predicted by the solar clock model, thus validating it. The analysis further showed that TOC1 expression peaked ∼5·5 h after mid-day, CAB2 peaked close to noon, while LHY peaked ∼7·5 h after midnight, regardless of the cycle period, the photoperiod or the light:dark period ratio. The solar clock model correctly predicted the zeitgeber timing of these genes under 11 different lighting regimes comprising combinations of seven light periods, nine dark periods, four cycle periods and four light:dark period ratios. In short cycles that terminated before LHY could be expressed, the solar clock correctly predicted zeitgeber timing of its expression in the following cycle. Conclusions Regulation of gene phases by the solar clock enables the plant to tell the time, by which means a large number of genes are regulated. This facilitates the initiation of gene expression even before the arrival of sunrise, sunset or noon, thus allowing the plant to ‘anticipate’ dawn, dusk or mid-day respectively, independently of the photoperiod. PMID:26070640

Investigation of Seasonal and Latitudinal Effects on the Expression of Clock Genes in Drosophila

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Hosseini, Seyede Sanaz; Nazarimehr, Fahimeh; Jafari, Sajad

The primary goal in this work is to develop a dynamical model capturing the influence of seasonal and latitudinal variations on the expression of Drosophila clock genes. To this end, we study a specific dynamical system with strange attractors that exhibit changes of Drosophila activity in a range of latitudes and across different seasons. Bifurcations of this system are analyzed to peruse the effect of season and latitude on the behavior of clock genes. Existing experimental data collected from the activity of Drosophila melanogaster corroborate the dynamical model.

Suicide attempts in children and adolescents: The place of clock genes and early rhythm dysfunction.

Science.gov (United States)

Olliac, Bertrand; Ouss, Lisa; Charrier, Annaëlle

2016-11-01

Suicide remains one of the leading causes of death among young people, and suicidal ideation and behavior are relatively common in healthy and clinical populations. Suicide risk in childhood and adolescence is often approached from the perspective of nosographic categories to which predictive variables for suicidal acts are often linked. The cascading effects resulting from altered clock genes in a pediatric population could participate in biological rhythm abnormalities and the emergence of suicide attempts through impaired regulation of circadian rhythms and emotional states with neurodevelopmental effects. Also, early trauma and stressful life events can alter the expression of clock genes and contribute to the emergence of suicide attempts. Alteration of clock genes might lead to desynchronized and abnormal circadian rhythms impairing in turn the synchronization between external and internal rhythms and therefore the adaptation of the individual to his/her internal and external environment with the development of psychiatric disorders associated with increased risk for suicide attempts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cycling of clock genes entrained to the solar rhythm enables plants to tell time: data from Arabidopsis.

Science.gov (United States)

Yeang, Hoong-Yeet

2015-07-01

An endogenous rhythm synchronized to dawn cannot time photosynthesis-linked genes to peak consistently at noon since the interval between sunrise and noon changes seasonally. In this study, a solar clock model that circumvents this limitation is proposed using two daily timing references synchronized to noon and midnight. Other rhythmic genes that are not directly linked to photosynthesis, and which peak at other times, also find an adaptive advantage in entrainment to the solar rhythm. Fourteen datasets extracted from three published papers were used in a meta-analysis to examine the cyclic behaviour of the Arabidopsis thaliana photosynthesis-related gene CAB2 and the clock oscillator genes TOC1 and LHY in T cycles and N-H cycles. Changes in the rhythms of CAB2, TOC1 and LHY in plants subjected to non-24-h light:dark cycles matched the hypothesized changes in their behaviour as predicted by the solar clock model, thus validating it. The analysis further showed that TOC1 expression peaked ∼5·5 h after mid-day, CAB2 peaked close to noon, while LHY peaked ∼7·5 h after midnight, regardless of the cycle period, the photoperiod or the light:dark period ratio. The solar clock model correctly predicted the zeitgeber timing of these genes under 11 different lighting regimes comprising combinations of seven light periods, nine dark periods, four cycle periods and four light:dark period ratios. In short cycles that terminated before LHY could be expressed, the solar clock correctly predicted zeitgeber timing of its expression in the following cycle. Regulation of gene phases by the solar clock enables the plant to tell the time, by which means a large number of genes are regulated. This facilitates the initiation of gene expression even before the arrival of sunrise, sunset or noon, thus allowing the plant to 'anticipate' dawn, dusk or mid-day respectively, independently of the photoperiod. © The Author 2015. Published by Oxford University Press on behalf of the

Barley (Hordeum vulgare) circadian clock genes can respond rapidly to temperature in an EARLY FLOWERING 3-dependent manner

Science.gov (United States)

Ford, Brett; Deng, Weiwei; Clausen, Jenni; Oliver, Sandra; Boden, Scott; Hemming, Megan; Trevaskis, Ben

2016-01-01

An increase in global temperatures will impact future crop yields. In the cereal crops wheat and barley, high temperatures accelerate reproductive development, reducing the number of grains per plant and final grain yield. Despite this relationship between temperature and cereal yield, it is not clear what genes and molecular pathways mediate the developmental response to increased temperatures. The plant circadian clock can respond to changes in temperature and is important for photoperiod-dependent flowering, and so is a potential mechanism controlling temperature responses in cereal crops. This study examines the relationship between temperature, the circadian clock, and the expression of flowering-time genes in barley (Hordeum vulgare), a crop model for temperate cereals. Transcript levels of barley core circadian clock genes were assayed over a range of temperatures. Transcript levels of core clock genes CCA1, GI, PRR59, PRR73, PRR95, and LUX are increased at higher temperatures. CCA1 and PRR73 respond rapidly to a decrease in temperature whereas GI and PRR59 respond rapidly to an increase in temperature. The response of GI and the PRR genes to changes in temperature is lost in the elf3 mutant indicating that their response to temperature may be dependent on a functional ELF3 gene. PMID:27580625

Photoperiodic regulation of diapause in linden bugs: are period and Clock genes involved?

Czech Academy of Sciences Publication Activity Database

Syrová, Zdeňka; Doležel, David; Šauman, Ivo; Hodková, Magdalena

2003-01-01

Roč. 60, - (2003), s. 2510-2515 ISSN 1420-682X R&D Projects: GA ČR GA206/02/0900; GA ČR GA204/01/0404 Institutional research plan: CEZ:AV0Z5007907 Keywords : period gene * clock gene * photoperiodism Subject RIV: ED - Physiology Impact factor: 4.995, year: 2003

Moonlight controls lunar-phase-dependency and regular oscillation of clock gene expressions in a lunar-synchronized spawner fish, Goldlined spinefoot.

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Takeuchi, Yuki; Kabutomori, Ryo; Yamauchi, Chihiro; Miyagi, Hitomi; Takemura, Akihiro; Okano, Keiko; Okano, Toshiyuki

2018-04-18

Goldlined spinefoot, Siganus guttatus, inhabits tropical and subtropical waters and synchronizes its spawning around the first quarter moon likely using an hourglass-like lunar timer. In previous studies, we have found that clock genes (Cryptochrome3 and Period1) could play the role of state variable in the diencephalon when determining the lunar phase for spawning. Here, we identified three Cry, two Per, two Clock, and two Bmal genes in S. guttatus and investigated their expression patterns in the diencephalon and pituitary gland. We further evaluated the effect on their expression patterns by daily interruptions of moonlight stimuli for 1 lunar cycle beginning at the new moon. It significantly modified the expression patterns in many of the examined clock(-related) genes including Cry3 in the diencephalon and/or pituitary gland. Acute interruptions of moonlight around the waxing gibbous moon upregulated nocturnal expressions of Cry1b and Cry2 in the diencephalon and pituitary gland, respectively, but did not affect expression levels of the other clock genes. These results highlighted the importance of repetitive moonlight illumination for stable or lunar-phase-specific daily expression of clock genes in the next lunar cycle that may be important for the lunar-phase-synchronized spawning on the next first quarter moon.

Diel pattern of circadian clock and storage protein gene expression in leaves and during seed filling in cowpea (Vigna unguiculata).

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Weiss, Julia; Terry, Marta I; Martos-Fuentes, Marina; Letourneux, Lisa; Ruiz-Hernández, Victoria; Fernández, Juan A; Egea-Cortines, Marcos

2018-02-14

Cowpea (Vigna unguiculata) is an important source of protein supply for animal and human nutrition. The major storage globulins VICILIN and LEGUMIN (LEG) are synthesized from several genes including LEGA, LEGB, LEGJ and CVC (CONVICILIN). The current hypothesis is that the plant circadian core clock genes are conserved in a wide array of species and that primary metabolism is to a large extent controlled by the plant circadian clock. Our aim was to investigate a possible link between gene expression of storage proteins and the circadian clock. We identified cowpea orthologues of the core clock genes VunLHY, VunTOC1, VunGI and VunELF3, the protein storage genes VunLEG, VunLEGJ, and VunCVC as well as nine candidate reference genes used in RT-PCR. ELONGATION FACTOR 1-A (ELF1A) resulted the most suitable reference gene. The clock genes VunELF3, VunGI, VunTOC1 and VunLHY showed a rhythmic expression profile in leaves with a typical evening/night and morning/midday phased expression. The diel patterns were not completely robust and only VungGI and VungELF3 retained a rhythmic pattern under free running conditions of darkness. Under field conditions, rhythmicity and phasing apparently faded during early pod and seed development and was regained in ripening pods for VunTOC1 and VunLHY. Mature seeds showed a rhythmic expression of VunGI resembling leaf tissue under controlled growth chamber conditions. Comparing time windows during developmental stages we found that VunCVC and VunLEG were significantly down regulated during the night in mature pods as compared to intermediate ripe pods, while changes in seeds were non-significant due to high variance. The rhythmic expression under field conditions was lost under growth chamber conditions. The core clock gene network is conserved in cowpea leaves showing a robust diel expression pattern except VunELF3 under growth chamber conditions. There appears to be a clock transcriptional reprogramming in pods and seeds compared to

The Circadian Clock Gene BMAL1 Coordinates Intestinal RegenerationSummary

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Kyle Stokes

2017-07-01

Full Text Available Background & Aims: The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied. Methods: We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture. Results: The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway. Conclusions: Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology. Keywords: Intestine, Circadian Rhythms, Gastrointestinal Syndrome, TNF, Intestinal Stem Cells

Diurnal rhythmicity of the clock genes Per1 and Per2 in the rat ovary.

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Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens; Hindersson, Peter; Gräs, Søren

2006-08-01

Circadian rhythms are generated by endogenous clocks in the central brain oscillator, the suprachiasmatic nucleus, and peripheral tissues. The molecular basis for the circadian clock consists of a number of genes and proteins that form transcriptional/translational feedback loops. In the mammalian gonads, clock genes have been reported in the testes, but the expression pattern is developmental rather than circadian. Here we investigated the daily expression of the two core clock genes, Per1 and Per2, in the rat ovary using real-time RT-PCR, in situ hybridization histochemistry, and immunohistochemistry. Both Per1 and Per2 mRNA displayed a statistically significant rhythmic oscillation in the ovary with a period of 24 h in: 1) a group of rats during proestrus and estrus under 12-h light,12-h dark cycles; 2) a second group of rats representing a mixture of all 4 d of the estrous cycle under 12-h light,12-h dark conditions; and 3) a third group of rats representing a mixture of all 4 d of estrous cycle during continuous darkness. Per1 mRNA was low at Zeitgeber time 0-2 and peaked at Zeitgeber time 12-14, whereas Per2 mRNA was delayed by approximately 4 h relative to Per1. By in situ hybridization histochemistry, Per mRNAs were localized to steroidogenic cells in preantral, antral, and preovulatory follicles; corpora lutea; and interstitial glandular tissue. With newly developed antisera, we substantiated the expression of Per1 and Per2 in these cells by single/double immunohistochemistry. Furthermore, we visualized the temporal intracellular movements of PER1 and PER2 proteins. These findings suggest the existence of an ovarian circadian clock, which may play a role both locally and in the hypothalamo-pituitary-ovarian axis.

Existence of a photoinducible phase for ovarian development and photoperiod-related alteration of clock gene expression in a damselfish.

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Takeuchi, Yuki; Hada, Noriko; Imamura, Satoshi; Hur, Sung-Pyo; Bouchekioua, Selma; Takemura, Akihiro

2015-10-01

The sapphire devil, Chrysiptera cyanea, is a reef-associated damselfish and their ovarian development can be induced by a long photoperiod. In this study, we demonstrated the existence of a photoinducible phase for the photoperiodic ovarian development in the sapphire devil. Induction of ovarian development under night-interruption light schedules and Nanda-Hamner cycles revealed that the photoinducible phase appeared in a circadian manner between ZT12 and ZT13. To characterize the effect of photoperiod on clock gene expression in the brain of this species, we determined the expression levels of the sdPer1, sdPer2, sdCry1, and sdCry2 clock genes under constant light and dark conditions (LL and DD) and photoperiodic (short and long photoperiods). The expression of sdPer1 exhibited clear circadian oscillation under both LL and DD conditions, while sdPer2 and sdCry1 expression levels were lower under DD than under LL conditions and sdCry2 expression was lower under LL than under DD conditions. These results suggest a key role for sdPer1 in circadian clock cycling and that sdPer2, sdCry1, and sdCry2 are light-responsive clock genes in the sapphire devil. After 1 week under a long photoperiod, we observed photoperiod-related changes in sdPer1, sdPer2, and sdCry2 expression, but not in sdCry1 expression. These results suggest that the expression patterns of some clock genes exhibit seasonal variation according to seasonal changes in day length and that such seasonal alteration of clock gene expression may contribute to seasonal recognition by the sapphire devil. Copyright © 2015 Elsevier Inc. All rights reserved.

Photoperiodic Modulation of Circadian Clock and Reproductive Axis Gene Expression in the Pre-Pubertal European Sea Bass Brain.

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Rute S T Martins

Full Text Available The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis.

Evidence for widespread dysregulation of circadian clock progression in human cancer

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Jarrod Shilts

2018-01-01

Full Text Available The ubiquitous daily rhythms in mammalian physiology are guided by progression of the circadian clock. In mice, systemic disruption of the clock can promote tumor growth. In vitro, multiple oncogenes can disrupt the clock. However, due to the difficulties of studying circadian rhythms in solid tissues in humans, whether the clock is disrupted within human tumors has remained unknown. We sought to determine the state of the circadian clock in human cancer using publicly available transcriptome data. We developed a method, called the clock correlation distance (CCD, to infer circadian clock progression in a group of samples based on the co-expression of 12 clock genes. Our method can be applied to modestly sized datasets in which samples are not labeled with time of day and coverage of the circadian cycle is incomplete. We used the method to define a signature of clock gene co-expression in healthy mouse organs, then validated the signature in healthy human tissues. By then comparing human tumor and non-tumor samples from twenty datasets of a range of cancer types, we discovered that clock gene co-expression in tumors is consistently perturbed. Subsequent analysis of data from clock gene knockouts in mice suggested that perturbed clock gene co-expression in human cancer is not caused solely by the inactivation of clock genes. Furthermore, focusing on lung cancer, we found that human lung tumors showed systematic changes in expression in a large set of genes previously inferred to be rhythmic in healthy lung. Our findings suggest that clock progression is dysregulated in many solid human cancers and that this dysregulation could have broad effects on circadian physiology within tumors. In addition, our approach opens the door to using publicly available data to infer circadian clock progression in a multitude of human phenotypes.

Do Caucasian and Asian clocks tick differently?

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A.A. Barbosa

Full Text Available The Period 3 and Clock genes are important components of the mammalian molecular circadian system. Studies have shown association between polymorphisms in these clock genes and circadian phenotypes in different populations. Nevertheless, differences in the pattern of allele frequency and genotyping distribution are systematically observed in studies with different ethnic groups. To investigate and compare the pattern of distribution in a sample of Asian and Caucasian populations living in Brazil, we evaluated two well-studied polymorphisms in the clock genes: a variable number of tandem repeats (VNTR in PER3 and a single nucleotide polymorphism (SNP in CLOCK. The aim of this investigation was to search for clues about human evolutionary processes related to circadian rhythms. We selected 109 Asian and 135 Caucasian descendants. The frequencies of the shorter allele (4 repeats in the PER3 gene and the T allele in the CLOCK gene among Asians (0.86 and 0.84, respectively were significantly higher than among Caucasians (0.69 and 0.71, respectively. Our results directly confirmed the different distribution of these polymorphisms between the Asian and Caucasian ethnic groups. Given the genetic differences found between groups, two points became evident: first, ethnic variations may have implications for the interpretation of results in circadian rhythm association studies, and second, the question may be raised about which evolutionary conditions shaped these genetic clock variations.

Novel transcriptional networks regulated by CLOCK in human neurons.

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Fontenot, Miles R; Berto, Stefano; Liu, Yuxiang; Werthmann, Gordon; Douglas, Connor; Usui, Noriyoshi; Gleason, Kelly; Tamminga, Carol A; Takahashi, Joseph S; Konopka, Genevieve

2017-11-01

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. © 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.

A network of (autonomic) clock outputs

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Kalsbeek, A.; Perreau-Lenz, S.; Buijs, R. M.

2006-01-01

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that

Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia.

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Fenske, Myles P; Hewett Hazelton, Kristen D; Hempton, Andrew K; Shim, Jae Sung; Yamamoto, Breanne M; Riffell, Jeffrey A; Imaizumi, Takato

2015-08-04

Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening-expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia.

FUNCTIONAL IMPLICATIONS OF THE CLOCK 3111T/C SINGLE-NUCLEOTIDE POLYMORPHISM

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Angela Renee Ozburn

2016-04-01

Full Text Available Circadian rhythm disruptions are prominently associated with Bipolar Disorder (BD. Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (Roybal et al., 2007. The Clock 3111T/C single-nucleotide polymorphism (SNP; rs1801260 is a genetic variation of the human Clock gene that is significantly associated with increased frequency of manic episodes in BD patients (Benedetti et al., 2003. The 3111T/C SNP is located in the 3’ untranslated region of the Clock gene. In this study, we sought to examine the functional implications of the human Clock 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock -/- knockout mice with pcDNA plasmids containing the human Clock gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24 hour time period. We found that the Clock3111C SNP resulted in higher mRNA levels than the Clock 3111T SNP. Further, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with Clock 3111C expression, indicating the 3’UTR SNP affects the expression, function and stability of Clock mRNA.

A network of (autonomic) clock outputs

NARCIS (Netherlands)

Kalsbeek, A.; Perreau-Lenz, S.; Buijs, R. M.

2006-01-01

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each of which is dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock

Night-time restricted feeding normalises clock genes and Pai-1 gene expression in the db/db mouse liver.

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Kudo, T; Akiyama, M; Kuriyama, K; Sudo, M; Moriya, T; Shibata, S

2004-08-01

An increase in PAI-1 activity is thought to be a key factor underlying myocardial infarction. Mouse Pai-1 (mPai-1) activity shows a daily rhythm in vivo, and its transcription seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglycerides. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin and triglycerides. Locomotor activity was measured using an infrared detection system. RT-PCR or in situ hybridisation methods were applied to measure gene expression. Humoral factors were measured using measurement kits. The db/ db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely diminished and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, whereas mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery not only from the diminished locomotor activity, but also from the diminished Per2 and advanced mBmal1 mRNA rhythms. Expression of mPai-1 mRNA in db/db mice was reduced to levels far below normal. Pioglitazone treatment slightly normalised glucose and insulin levels, with a slight reduction in mPai-1 gene expression. We demonstrated that Type 2 diabetes impairs the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the diminished locomotor activity, and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food intake may be a useful form of treatment for diabetes.

Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells

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Nakabayashi, Hiroko; Ohta, Yasuharu; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio

2013-01-01

Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1 −/− A y /a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the Arnt

Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells

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Nakabayashi, Hiroko; Ohta, Yasuharu, E-mail: yohta@yamaguchi-u.ac.jp; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio, E-mail: tanizawa@yamaguchi-u.ac.jp

2013-05-03

Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1{sup −/−} A{sup y}/a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the

Analysis of clock-regulated genes in Neurospora reveals widespread posttranscriptional control of metabolic potential

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Hurley, Jennifer M.; Dasgupta, Arko; Emerson, Jillian M.; Zhou, Xiaoying; Ringelberg, Carol S.; Knabe, Nicole; Lipzen, Anna M.; Lindquist, Erika A.; Daum, Christopher G.; Barry, Kerrie W.; Grigoriev, Igor V.; Smith, Kristina M.; Galagan, James E.; Bell-Pedersen, Deborah; Freitag, Michael; Cheng, Chao; Loros, Jennifer J.; Dunlap, Jay C.

2014-01-01

Neurospora crassa has been for decades a principal model for filamentous fungal genetics and physiology as well as for understanding the mechanism of circadian clocks. Eukaryotic fungal and animal clocks comprise transcription-translation–based feedback loops that control rhythmic transcription of a substantial fraction of these transcriptomes, yielding the changes in protein abundance that mediate circadian regulation of physiology and metabolism: Understanding circadian control of gene expression is key to understanding eukaryotic, including fungal, physiology. Indeed, the isolation of clock-controlled genes (ccgs) was pioneered in Neurospora where circadian output begins with binding of the core circadian transcription factor WCC to a subset of ccg promoters, including those of many transcription factors. High temporal resolution (2-h) sampling over 48 h using RNA sequencing (RNA-Seq) identified circadianly expressed genes in Neurospora, revealing that from ∼10% to as much 40% of the transcriptome can be expressed under circadian control. Functional classifications of these genes revealed strong enrichment in pathways involving metabolism, protein synthesis, and stress responses; in broad terms, daytime metabolic potential favors catabolism, energy production, and precursor assembly, whereas night activities favor biosynthesis of cellular components and growth. Discriminative regular expression motif elicitation (DREME) identified key promoter motifs highly correlated with the temporal regulation of ccgs. Correlations between ccg abundance from RNA-Seq, the degree of ccg-promoter activation as reported by ccg-promoter–luciferase fusions, and binding of WCC as measured by ChIP-Seq, are not strong. Therefore, although circadian activation is critical to ccg rhythmicity, posttranscriptional regulation plays a major role in determining rhythmicity at the mRNA level. PMID:25362047

Physiological links of circadian clock and biological clock of aging.

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Liu, Fang; Chang, Hung-Chun

2017-07-01

Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.

Involvement of adenosine monophosphate-activated protein kinase in the influence of timed high-fat evening diet on the hepatic clock and lipogenic gene expression in mice.

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Huang, Yan; Zhu, Zengyan; Xie, Meilin; Xue, Jie

2015-09-01

A high-fat diet may result in changes in hepatic clock gene expression, but potential mechanisms are not yet elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine protein kinase that is recognized as a key regulator of energy metabolism and certain clock genes. Therefore, we hypothesized that AMPK may be involved in the alteration of hepatic clock gene expression under a high-fat environment. This study aimed to examine the effects of timed high-fat evening diet on the activity of hepatic AMPK, clock genes, and lipogenic genes. Mice with hyperlipidemic fatty livers were induced by orally administering high-fat milk via gavage every evening (19:00-20:00) for 6 weeks. Results showed that timed high-fat diet in the evening not only decreased the hepatic AMPK protein expression and activity but also disturbed its circadian rhythm. Accordingly, the hepatic clock genes, including clock, brain-muscle-Arnt-like 1, cryptochrome 2, and period 2, exhibited prominent changes in their expression rhythms and/or amplitudes. The diurnal rhythms of the messenger RNA expression of peroxisome proliferator-activated receptorα, acetyl-CoA carboxylase 1α, and carnitine palmitoyltransferase 1 were also disrupted; the amplitude of peroxisome proliferator-activated receptorγcoactivator 1α was significantly decreased at 3 time points, and fatty liver was observed. These findings demonstrate that timed high-fat diet at night can change hepatic AMPK protein levels, activity, and circadian rhythm, which may subsequently alter the circadian expression of several hepatic clock genes and finally result in the disorder of hepatic lipogenic gene expression and the formation of fatty liver. Copyright © 2015 Elsevier Inc. All rights reserved.

Circadian clock, cell cycle and cancer

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Cansu Özbayer

2011-12-01

Full Text Available There are a few rhythms of our daily lives that we are under the influence. One of them is characterized by predictable changes over a 24-hour timescale called circadian clock. This cellular clock is coordinated by the suprachiasmatic nucleus in the anterior hypothalamus. The clock consist of an autoregulatory transcription-translation feedback loop compose of four genes/proteins; BMAL1, Clock, Cyrptochrome, and Period. BMAL 1 and Clock are transcriptional factors and Period and Cyrptochrome are their targets. Period and Cyrptochrome dimerize in the cytoplasm to enter the nucleus where they inhibit Clock/BMAL activity.It has been demonstrate that circadian clock plays an important role cellular proliferation, DNA damage and repair mechanisms, checkpoints, apoptosis and cancer.

Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver.

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Honma, Kazue; Hikosaka, Maki; Mochizuki, Kazuki; Goda, Toshinao

2016-04-01

Peripheral clock genes show a circadian rhythm is correlated with the timing of feeding in peripheral tissues. It was reported that these clock genes are strongly regulated by insulin action and that a high-fat diet (HFD) intake in C57BL/6J mice for 21days induced insulin secretion during the dark phase and reduced the circadian rhythm of clock genes. In this study, we examined the circadian expression patterns of these clock genes in insulin-resistant animal models with excess secretion of insulin during the day. We examined whether insulin resistance induced by a HFD intake for 80days altered blood parameters (glucose and insulin concentrations) and expression of mRNA and proteins encoded by clock and functional genes in the liver using male ICR mice. Serum insulin concentrations were continuously higher during the day in mice fed a HFD than control mice. Expression of lipogenesis-related genes (Fas and Accβ) and the transcription factor Chrebp peaked at zeitgeber time (ZT)24 in the liver of control mice. A HFD intake reduced the expression of these genes at ZT24 and disrupted the circadian rhythm. Expression of Bmal1 and Clock, transcription factors that compose the core feedback loop, showed circadian variation and were synchronously associated with Fas gene expression in control mice, but not in those fed a HFD. These results indicate that the disruption of the circadian rhythm of insulin secretion by HFD intake is closely associated with the disappearance of circadian expression of lipogenic and clock genes in the liver of mice. Copyright © 2016 Elsevier Inc. All rights reserved.

RNAi of the circadian clock gene period disrupts the circadian rhythm but not the circatidal rhythm in the mangrove cricket

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Takekata, Hiroki; Matsuura, Yu; Goto, Shin G.; Satoh, Aya; Numata, Hideharu

2012-01-01

The clock mechanism for circatidal rhythm has long been controversial, and its molecular basis is completely unknown. The mangrove cricket, Apteronemobius asahinai, shows two rhythms simultaneously in its locomotor activity: a circatidal rhythm producing active and inactive phases as well as a circadian rhythm modifying the activity intensity of circatidal active phases. The role of the clock gene period (per), one of the key components of the circadian clock in insects, was investigated in t...

Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK-BMAL1 and LRH-1

International Nuclear Information System (INIS)

Oiwa, Ako; Kakizawa, Tomoko; Miyamoto, Takahide; Yamashita, Koh; Jiang, Wei; Takeda, Teiji; Suzuki, Satoru; Hashizume, Kiyoshi

2007-01-01

Small heterodimer partner (SHP; NR0B2) is an orphan nuclear receptor and acts as a repressor for wide variety of nuclear hormone receptors. We demonstrated here that mouse SHP mRNA showed a circadian expression pattern in the liver. Transient transfection of the mSHP promoter demonstrated that CLOCK-BMAL1, core circadian clock components, bound to E-box (CACGTG), and stimulated the promoter activity by 4-fold. Liver receptor homologue-1 (LRH-1; NR5A2) stimulated the mSHP promoter, and CLOCK-BMAL1 synergistically enhanced the LRH-1-mediated transactivation. Interestingly, SHP did not affect the CLOCK-BMAL1-mediated promoter activity, but strongly repressed the synergistic activation of CLOCK-BMAL1 and LRH-1. Furthermore, in vitro pull-down assays revealed the existence of direct protein-protein interaction between LRH-1 and CLOCK. In summary, this study shows that CLOCK-BMAL1, LRH-1 and SHP coordinately regulate the mSHP gene to generate the circadian oscillation. The cyclic expression of mSHP may affect daily activity of other nuclear receptors and contribute to circadian liver functions

Human CLOCK gene-associated attention deficit hyperactivity disorder-related features in healthy adults: quantitative association study using Wender Utah Rating Scale.

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Jeong, Seong Hoon; Yu, Je-Chun; Lee, Chang Hwa; Choi, Kyeong-Sook; Choi, Jung-Eun; Kim, Se Hyun; Joo, Eun-Jeong

2014-02-01

Circadian rhythm disturbance is highly prevalent in attention deficit hyperactivity disorder (ADHD). Recently, the association between the CLOCK gene and ADHD has been demonstrated in clinical samples, and the CLOCK gene's role was thought to be mediated by rhythm dysregulation. Meanwhile, ADHD has been suggested as the extreme end of a continuously distributed trait that can be found in the general population. Therefore, we examined two possibilities: (1) an ADHD-related continuous trait may be associated with the CLOCK gene, and (2) this association may be mediated by the degree of individuals' evening preference. To explore these possibilities, we performed a quantitative trait locus association study with a sample of 1,289 healthy adults. The Wender Utah Rating Scale (WURS) and the Composite Scale of Morningness (CSM) were utilized to measure the quantitative traits. Quantitative association analysis was performed using PLINK software. We found that rs1801260 (=T3111C) was associated with WURS scores in both allele-wise (p = 0.018) and haplotype-wise analyses (range of p values: 0.0155-0.0171) in male participants only. After controlling for the CSM total score as a covariate, the strength of the association did not change at all, suggesting that the association was not mediated by evening preference. Despite the very weak association signal, our results provide evidence that the CLOCK gene's association with ADHD in clinical samples may be generalizable to traits measured in the normal population. However, as our results failed to show a mediating role of evening preference, ongoing efforts are needed to identify the mechanisms by which the CLOCK gene determines ADHD-related traits.

Photoperiodic plasticity in circadian clock neurons in insects

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Sakiko eShiga

2013-08-01

Full Text Available Since Bünning’s observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Based on molecular and neuronal studies in Drosophila melanogaster, photoperiodic changes have been reported for expression patterns of the circadian clock genes, subcellular distribution of clock proteins, fiber distribution, or the number of plausible clock neurons in different species. Photoperiod sets peaks of per or tim mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.

The role of circadian clock genes in the photoperiodic timer of the linden bug Pyrrhocoris apterus during the nymphal stage

Czech Academy of Sciences Publication Activity Database

Kotwica-Rolinska, Joanna; Pivarčiová, Lenka; Vaněčková, Hana; Doležel, David

2017-01-01

Roč. 42, č. 3 (2017), s. 266-273 ISSN 0307-6962 R&D Projects: GA ČR GA15-23681S; GA MŠk(CZ) EE2.3.30.0032 EU Projects: European Commission(XE) 316790 - INsecTIME Institutional support: RVO:60077344 Keywords : activity of nympha * circadian clock gene * Clock gene Subject RIV: ED - Physiology OBOR OECD: Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology Impact factor: 1.364, year: 2016 http://onlinelibrary.wiley.com/doi/10.1111/phen.12197/abstract

Molecular cogs of the insect circadian clock.

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Shirasu, Naoto; Shimohigashi, Yasuyuki; Tominaga, Yoshiya; Shimohigashi, Miki

2003-08-01

During the last five years, enormous progress has been made in understanding the molecular basis of circadian systems, mainly by molecular genetic studies using the mouse and fly. Extensive evidence has revealed that the core clock machinery involves "clock genes" and "clock proteins" functioning as molecular cogs. These participate in transcriptional/translational feedback loops and many homologous clock-components in the fruit fly Drosophila are also expressed in mammalian clock tissues with circadian rhythms. Thus, the mechanisms of the central clock seem to be conserved across animal kingdom. However, some recent studies imply that the present widely accepted molecular models of circadian clocks may not always be supported by the experimental evidence.

The Circadian Clock-controlled Transcriptome of Developing Soybean Seeds

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Karen A. Hudson

2010-07-01

Full Text Available A number of metabolic and physiological processes in plants are controlled by the circadian clock, which enables a plant to anticipate daily changes in the environment. Relatively little is known about circadian rhythms in developing seeds, which may be important for determining the extent and timing of nutrient storage in grain. Microarray expression profiling was used to identify genes expressed in developing soybean ( seeds that are controlled by the circadian clock. Genes with predicted functions in protein synthesis, fatty acid metabolism, and photosynthesis totaling 1.8% of the mRNAs detected in seed were found to be expressed in a circadian rhythm. Known circadian and light-controlled promoter elements were identified as over-represented in the promoters of clock-controlled seed genes, with the over-represented elements varying according to the phase of circadian expression. A subset of circadian-regulated genes were found to be expressed in different phases in developing seeds with respect to leaves from the same plants, many of which have roles in photosynthesis and carbon metabolism. These results help to characterize the genes and processes in seeds that may be regulated by the circadian clock, and provide some insight into organ-specific phasing of clock controlled gene expression.

Transcriptome Profiling of the Lungs Reveals Molecular Clock Genes Expression Changes after Chronic Exposure to Ambient Air Particles

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Pengcheng Song

2017-01-01

Full Text Available The symptoms of asthma, breathlessness, insomnia, etc. all have relevance to pulmonary rhythmic disturbances. Epidemiology and toxicology studies have demonstrated that exposure to ambient air particles can result in pulmonary dysfunction. However, there are no data directly supporting a link between air pollution and circadian rhythm disorder. In the present study, we found that breathing highly polluted air resulted in changes of the molecular clock genes expression in lung by transcriptome profiling analyses in a rodent model. Compared to those exposed to filtered air, in both pregnant and offspring rats in the unfiltered group, key clock genes (Per1, Per2, Per3, Rev-erbα and Dbp expression level decreased and Bmal1 expression level increased. In both rat dams and their offspring, after continuous exposure to unfiltered air, we observed significant histologic evidence for both perivascular and peribronchial inflammation, increased tissue and systemic oxidative stress in the lungs. Our results suggest that chronic exposure to particulate matter can induce alterations of clock genes expression, which could be another important pathway for explaining the feedbacks of ambient particle exposure in addition to oxidative stress and inflammation.

Systems approach identifies an organic nitrogen-responsive gene network that is regulated by the master clock control gene CCA1.

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Gutiérrez, Rodrigo A; Stokes, Trevor L; Thum, Karen; Xu, Xiaodong; Obertello, Mariana; Katari, Manpreet S; Tanurdzic, Milos; Dean, Alexis; Nero, Damion C; McClung, C Robertson; Coruzzi, Gloria M

2008-03-25

Understanding how nutrients affect gene expression will help us to understand the mechanisms controlling plant growth and development as a function of nutrient availability. Nitrate has been shown to serve as a signal for the control of gene expression in Arabidopsis. There is also evidence, on a gene-by-gene basis, that downstream products of nitrogen (N) assimilation such as glutamate (Glu) or glutamine (Gln) might serve as signals of organic N status that in turn regulate gene expression. To identify genome-wide responses to such organic N signals, Arabidopsis seedlings were transiently treated with ammonium nitrate in the presence or absence of MSX, an inhibitor of glutamine synthetase, resulting in a block of Glu/Gln synthesis. Genes that responded to organic N were identified as those whose response to ammonium nitrate treatment was blocked in the presence of MSX. We showed that some genes previously identified to be regulated by nitrate are under the control of an organic N-metabolite. Using an integrated network model of molecular interactions, we uncovered a subnetwork regulated by organic N that included CCA1 and target genes involved in N-assimilation. We validated some of the predicted interactions and showed that regulation of the master clock control gene CCA1 by Glu or a Glu-derived metabolite in turn regulates the expression of key N-assimilatory genes. Phase response curve analysis shows that distinct N-metabolites can advance or delay the CCA1 phase. Regulation of CCA1 by organic N signals may represent a novel input mechanism for N-nutrients to affect plant circadian clock function.

Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia.

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Julian Lippert

Full Text Available From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH in comparison to those of healthy controls (HC. Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG and Multiple Sleep Latency Test (MSLT. Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.

Altered dynamics in the circadian oscillation of clock genes in dermal fibroblasts of patients suffering from idiopathic hypersomnia.

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Lippert, Julian; Halfter, Hartmut; Heidbreder, Anna; Röhr, Dominik; Gess, Burkhard; Boentert, Mathias; Osada, Nani; Young, Peter

2014-01-01

From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.

The expression of the clock gene cycle has rhythmic pattern and is affected by photoperiod in the moth Sesamia nonagrioides.

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Kontogiannatos, Dimitrios; Gkouvitsas, Theodoros; Kourti, Anna

2017-06-01

To obtain clues to the link between the molecular mechanism of circadian and photoperiod clocks, we have cloned the circadian clock gene cycle (Sncyc) in the corn stalk borer, Sesamia nonagrioides, which undergoes facultative diapause controlled by photoperiod. Sequence analysis revealed a high degree of conservation among insects for this gene. SnCYC consists of 667 amino acids and structural analysis showed that it contains a BCTR domain in its C-terminal in addition to the common domains found in Drosophila CYC, i.e. bHLH, PAS-A, PAS-B domains. The results revealed that the sequence of Sncyc showed a similarity to that of its mammalian orthologue, Bmal1. We also investigated the expression patterns of Sncyc in the brain of larvae growing under long-day 16L: 8D (LD), constant darkness (DD) and short-day 10L: 14D (SD) conditions using qRT-PCR assays. The mRNAs of Sncyc expression was rhythmic in LD, DD and SD cycles. Also, it is remarkable that the photoperiodic conditions affect the expression patterns and/or amplitudes of circadian clock gene Sncyc. This gene is associated with diapause in S. nonagrioides, because under SD (diapause conditions) the photoperiodic signal altered mRNA accumulation. Sequence and expression analysis of cyc in S. nonagrioides shows interesting differences compared to Drosophila where this gene does not oscillate or change in expression patterns in response to photoperiod, suggesting that this species is an interesting new model to study the molecular control of insect circadian and photoperiodic clocks. Copyright © 2017 Elsevier Inc. All rights reserved.

Circadian regulation of myocardial sarcomeric Titin-cap (Tcap, telethonin: identification of cardiac clock-controlled genes using open access bioinformatics data.

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Peter S Podobed

Full Text Available Circadian rhythms are important for healthy cardiovascular physiology and are regulated at the molecular level by a circadian clock mechanism. We and others previously demonstrated that 9-13% of the cardiac transcriptome is rhythmic over 24 h daily cycles; the heart is genetically a different organ day versus night. However, which rhythmic mRNAs are regulated by the circadian mechanism is not known. Here, we used open access bioinformatics databases to identify 94 transcripts with expression profiles characteristic of CLOCK and BMAL1 targeted genes, using the CircaDB website and JTK_Cycle. Moreover, 22 were highly expressed in the heart as determined by the BioGPS website. Furthermore, 5 heart-enriched genes had human/mouse conserved CLOCK:BMAL1 promoter binding sites (E-boxes, as determined by UCSC table browser, circadian mammalian promoter/enhancer database PEDB, and the European Bioinformatics Institute alignment tool (EMBOSS. Lastly, we validated findings by demonstrating that Titin cap (Tcap, telethonin was targeted by transcriptional activators CLOCK and BMAL1 by showing 1 Tcap mRNA and TCAP protein had a diurnal rhythm in murine heart; 2 cardiac Tcap mRNA was rhythmic in animals kept in constant darkness; 3 Tcap and control Per2 mRNA expression and cyclic amplitude were blunted in Clock(Δ19/Δ19 hearts; 4 BMAL1 bound to the Tcap promoter by ChIP assay; 5 BMAL1 bound to Tcap promoter E-boxes by biotinylated oligonucleotide assay; and 6 CLOCK and BMAL1 induced tcap expression by luciferase reporter assay. Thus this study identifies circadian regulated genes in silico, with validation of Tcap, a critical regulator of cardiac Z-disc sarcomeric structure and function.

An association between clock genes and clock-controlled cell cycle genes in murine colorectal tumors

Czech Academy of Sciences Publication Activity Database

Soták, Matúš; Polidarová, Lenka; Ergang, Peter; Sumová, Alena; Pácha, Jiří

2013-01-01

Roč. 132, č. 5 (2013), s. 1032-1041 ISSN 0020-7136 R&D Projects: GA MZd(CZ) NS9982 Institutional research plan: CEZ:AV0Z50110509 Keywords : cancer * circadian rhythm * peripheral circadian clock Subject RIV: FE - Other Internal Medicine Disciplines Impact factor: 5.007, year: 2013

Melanopsin resets circadian rhythms in cells by inducing clock gene Period1

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Yamashita, Shuhei; Uehara, Tomoe; Matsuo, Minako; Kikuchi, Yo; Numano, Rika

2014-02-01

The biochemical, physiological and behavioral processes are under the control of internal clocks with the period of approximately 24 hr, circadian rhythms. The expression of clock gene Period1 (Per1) oscillates autonomously in cells and is induced immediately after a light pulse. Per1 is an indispensable member of the central clock system to maintain the autonomous oscillator and synchronize environmental light cycle. Per1 expression could be detected by Per1∷luc and Per1∷GFP plasmid DNA in which firefly luciferase and Green Fluorescence Protein were rhythmically expressed under the control of the mouse Per1 promoter in order to monitor mammalian circadian rhythms. Membrane protein, MELANOPSIN is activated by blue light in the morning on the retina and lead to signals transduction to induce Per1 expression and to reset the phase of circadian rhythms. In this report Per1 induction was measured by reporter signal assay in Per1∷luc and Per1∷GFP fibroblast cell at the input process of circadian rhythms. To the result all process to reset the rhythms by Melanopsin is completed in single cell like in the retina projected to the central clock in the brain. Moreover, the phase of circadian rhythm in Per1∷luc cells is synchronized by photo-activated Melanopsin, because the definite peak of luciferase activity in one dish was found one day after light illumination. That is an available means that physiological circadian rhythms could be real-time monitor as calculable reporter (bioluminescent and fluorescent) chronological signal in both single and groups of cells.

Redox rhythm reinforces the circadian clock to gate immune response.

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Zhou, Mian; Wang, Wei; Karapetyan, Sargis; Mwimba, Musoki; Marqués, Jorge; Buchler, Nicolas E; Dong, Xinnian

2015-07-23

Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism's metabolic activities. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant's redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism.

Time-place learning and memory persist in mice lacking functional Per1 and Per2 clock genes.

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Mulder, C; Van Der Zee, E A; Hut, R A; Gerkema, M P

2013-12-01

With time-place learning, animals link a stimulus with the location and the time of day. This ability may optimize resource localization and predator avoidance in daily changing environments. Time-place learning is a suitable task to study the interaction of the circadian system and memory. Previously, we showed that time-place learning in mice depends on the circadian system and Cry1 and/or Cry2 clock genes. We questioned whether time-place learning is Cry specific or also depends on other core molecular clock genes. Here, we show that Per1/Per2 double mutant mice, despite their arrhythmic phenotype, acquire time-place learning similar to wild-type mice. As well as an established role in circadian rhythms, Per genes have also been implicated in the formation and storage of memory. We found no deficiencies in short-term spatial working memory in Per mutant mice compared to wild-type mice. Moreover, both Per mutant and wild-type mice showed similar long-term memory for contextual features of a paradigm (a mild foot shock), measured in trained mice after a 2-month nontesting interval. In contrast, time-place associations were lost in both wild-type and mutant mice after these 2 months, suggesting a lack of maintained long-term memory storage for this type of information. Taken together, Cry-dependent time-place learning does not require Per genes, and Per mutant mice showed no PER-specific short-term or long-term memory deficiencies. These results limit the functional role of Per clock genes in the circadian regulation of time-place learning and memory.

Effects of circadian clock genes and health-related behavior on metabolic syndrome in a Taiwanese population: Evidence from association and interaction analysis.

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Eugene Lin

Full Text Available Increased risk of developing metabolic syndrome (MetS has been associated with the circadian clock genes. In this study, we assessed whether 29 circadian clock-related genes (including ADCYAP1, ARNTL, ARNTL2, BHLHE40, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, GSK3B, HCRTR2, KLF10, NFIL3, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, REV1, RORA, RORB, RORC, SENP3, SERPINE1, TIMELESS, TIPIN, VIP, and VIPR2 are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with several single nucleotide polymorphisms (SNPs in five key circadian clock genes including ARNTL, GSK3B, PER3, RORA, and RORB; but none of these SNPs persisted significantly after performing Bonferroni correction. Moreover, we identified the effect of GSK3B rs2199503 on high fasting glucose (P = 0.0002. Additionally, we found interactions among the ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, RORA rs8034880, and RORB rs972902 SNPs influenced MetS (P < 0.001 ~ P = 0.002. Finally, we investigated the influence of interactions between ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, and RORB rs972902 with environmental factors such as alcohol consumption, smoking status, and physical activity on MetS and its individual components (P < 0.001 ~ P = 0.002. Our study indicates that circadian clock genes such as ARNTL, GSK3B, PER3, RORA, and RORB genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.

The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria.

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Ihara, Tatsuya; Mitsui, Takahiko; Nakamura, Yuki; Kira, Satoru; Miyamoto, Tatsuya; Nakagomi, Hiroshi; Sawada, Norifumi; Hirayama, Yuri; Shibata, Keisuke; Shigetomi, Eiji; Shinozaki, Yoichi; Yoshiyama, Mitsuharu; Andersson, Karl-Erik; Nakao, Atsuhito; Takeda, Masayuki; Koizumi, Schuichi

2017-04-01

The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (Clock Δ19/Δ19 ) mice in order to determine the effects of clock genes on NOC/NP. Male C57BL/6 mice aged 8-12 weeks (WT) and male C57BL/6 Clock Δ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods. No significant differences were observed in behavior patterns between Clock Δ19/Δ19 and WT mice. Clock Δ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in Clock Δ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in Clock Δ19/Δ19 mice than in WT mice. We demonstrated that Clock Δ19/Δ19 mice showed the phenotype of NOC/NP. The Clock Δ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. 36:1034-1038, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus.

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Besing, Rachel C; Paul, Jodi R; Hablitz, Lauren M; Rogers, Courtney O; Johnson, Russell L; Young, Martin E; Gamble, Karen L

2015-04-01

The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprising clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for 2 weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 µM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. © 2015 The Author(s).

The mammalian retina as a clock

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Tosini, Gianluca; Fukuhara, Chiaki

2002-01-01

Many physiological, cellular, and biochemical parameters in the retina of vertebrates show daily rhythms that, in many cases, also persist under constant conditions. This demonstrates that they are driven by a circadian pacemaker. The presence of an autonomous circadian clock in the retina of vertebrates was first demonstrated in Xenopus laevis and then, several years later, in mammals. In X. laevis and in chicken, the retinal circadian pacemaker has been localized in the photoreceptor layer, whereas in mammals, such information is not yet available. Recent advances in molecular techniques have led to the identification of a group of genes that are believed to constitute the molecular core of the circadian clock. These genes are expressed in the retina, although with a slightly different 24-h profile from that observed in the central circadian pacemaker. This result suggests that some difference (at the molecular level) may exist between the retinal clock and the clock located in the suprachiasmatic nuclei of hypothalamus. The present review will focus on the current knowledge of the retinal rhythmicity and the mechanisms responsible for its control.

Clocks do not tick in unison: isolation of Clock and vrille shed new light on the clockwork model of the sand fly Lutzomyia longipalpis.

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Gesto, João Silveira Moledo; Rivas, Gustavo Bueno da Silva; Pavan, Marcio Galvão; Meireles-Filho, Antonio Carlos Alves; Amoretty, Paulo Roberto de; Souza, Nataly Araújo de; Bruno, Rafaela Vieira; Peixoto, Alexandre Afranio

2015-10-06

Behavior rhythms of insect vectors directly interfere with the dynamics of pathogen transmission to humans. The sand fly Lutzomyia longipalpis is the main vector of visceral leishmaniasis in America and concentrates its activity around dusk. Despite the accumulation of behavioral data, very little is known about the molecular bases of the clock mechanism in this species. This study aims to characterize, within an evolutionary perspective, two important circadian clock genes, Clock and vrille. We have cloned and isolated the coding sequence of L. longipalpis' genes Clock and vrille. The former is structured in eight exons and encodes a protein of 696 amino acids, and the latter comprises three exons and translates to a protein of 469 amino acids. When compared to other insects' orthologues, L. longipalpis CLOCK shows a high degree of conservation in the functional domains bHLH and PAS, but a much shorter glutamine-rich (poly-Q) C-terminal region. As for L. longipalpis VRILLE, a high degree of conservation was found in the bZIP domain. To support these observations and provide an elegant view of the evolution of both genes in insects, phylogenetic analyses based on maximum-likelihood and Bayesian inferences were performed, corroborating the previously known insect systematics. The isolation and phylogenetic analyses of Clock and vrille orthologues in L. longipalpis bring novel and important data to characterize this species' circadian clock. Interestingly, the poly-Q shortening observed in CLOCK suggests that its transcription activity might be impaired and we speculate if this effect could be compensated by other clock factors such as CYCLE.

Canonical correlation analysis for gene-based pleiotropy discovery.

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Jose A Seoane

2014-10-01

Full Text Available Genome-wide association studies have identified a wealth of genetic variants involved in complex traits and multifactorial diseases. There is now considerable interest in testing variants for association with multiple phenotypes (pleiotropy and for testing multiple variants for association with a single phenotype (gene-based association tests. Such approaches can increase statistical power by combining evidence for association over multiple phenotypes or genetic variants respectively. Canonical Correlation Analysis (CCA measures the correlation between two sets of multidimensional variables, and thus offers the potential to combine these two approaches. To apply CCA, we must restrict the number of attributes relative to the number of samples. Hence we consider modules of genetic variation that can comprise a gene, a pathway or another biologically relevant grouping, and/or a set of phenotypes. In order to do this, we use an attribute selection strategy based on a binary genetic algorithm. Applied to a UK-based prospective cohort study of 4286 women (the British Women's Heart and Health Study, we find improved statistical power in the detection of previously reported genetic associations, and identify a number of novel pleiotropic associations between genetic variants and phenotypes. New discoveries include gene-based association of NSF with triglyceride levels and several genes (ACSM3, ERI2, IL18RAP, IL23RAP and NRG1 with left ventricular hypertrophy phenotypes. In multiple-phenotype analyses we find association of NRG1 with left ventricular hypertrophy phenotypes, fibrinogen and urea and pleiotropic relationships of F7 and F10 with Factor VII, Factor IX and cholesterol levels.

The role of biological clock in glucose homeostasis 

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Piotr Chrościcki

2013-06-01

Full Text Available The mechanism of the biological clock is based on a rhythmic expression of clock genes and clock-controlled genes. As a result of their transcripto-translational associations, endogenous rhythms in the synthesis of key proteins of various physiological and metabolic processes are created. The major timekeeping mechanism for these rhythms exists in the central nervous system. The master circadian clock, localized in suprachiasmatic nucleus (SCN, regulates multiple metabolic pathways, while feeding behavior and metabolite availability can in turn regulate the circadian clock. It is also suggested that in the brain there is a food entrainable oscillator (FEO or oscillators, resulting in activation of both food anticipatory activity and hormone secretion that control digestion processes. Moreover, most cells and tissues express autonomous clocks. Maintenance of the glucose homeostasis is particularly important for the proper function of the body, as this sugar is the main source of energy for the brain, retina, erythrocytes and skeletal muscles. Thus, glucose production and utilization are synchronized in time. The hypothalamic excited orexin neurons control energy balance of organism and modulate the glucose production and utilization. Deficiency of orexin action results in narcolepsy and weight gain, whereas glucose and amino acids can affect activity of the orexin cells. Large-scale genetic studies in rodents and humans provide evidence for the involvement of disrupted clock gene expression rhythms in the pathogenesis of obesity and type 2 diabetes. In general, the current lifestyle of the developed modern societies disturbs the action of biological clock. 

Age-associated disruption of molecular clock expression in skeletal muscle of the spontaneously hypertensive rat.

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Mitsunori Miyazaki

Full Text Available It is well known that spontaneously hypertensive rats (SHR develop muscle pathologies with hypertension and heart failure, though the mechanism remains poorly understood. Woon et al. (2007 linked the circadian clock gene Bmal1 to hypertension and metabolic dysfunction in the SHR. Building on these findings, we compared the expression pattern of several core-clock genes in the gastrocnemius muscle of aged SHR (80 weeks; overt heart failure compared to aged-matched control WKY strain. Heart failure was associated with marked effects on the expression of Bmal1, Clock and Rora in addition to several non-circadian genes important in regulating skeletal muscle phenotype including Mck, Ttn and Mef2c. We next performed circadian time-course collections at a young age (8 weeks; pre-hypertensive and adult age (22 weeks; hypertensive to determine if clock gene expression was disrupted in gastrocnemius, heart and liver tissues prior to or after the rats became hypertensive. We found that hypertensive/hypertrophic SHR showed a dampening of peak Bmal1 and Rev-erb expression in the liver, and the clock-controlled gene Pgc1α in the gastrocnemius. In addition, the core-clock gene Clock and the muscle-specific, clock-controlled gene Myod1, no longer maintained a circadian pattern of expression in gastrocnemius from the hypertensive SHR. These findings provide a framework to suggest a mechanism whereby chronic heart failure leads to skeletal muscle pathologies; prolonged dysregulation of the molecular clock in skeletal muscle results in altered Clock, Pgc1α and Myod1 expression which in turn leads to the mis-regulation of target genes important for mechanical and metabolic function of skeletal muscle.

The rhythm of feeding : Effect of nutrients on metabolism and the molecular clock

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Oosterman, J.E.

2017-01-01

This thesis describes studies we performed to assess the relationship between nutrients and the circadian clock. We assessed the effects of sugar and fatty acids on the daily rhythmicity of hepatic clock genes and whole-body metabolism in vivo, and on circadian rhythmicity of clock genes in vitro.

Phylogenetic footprint of the plant clock system in angiosperms: evolutionary processes of Pseudo-Response Regulators

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Saito Shigeru

2010-05-01

Full Text Available Abstract Background Plant circadian clocks regulate many photoperiodic and diurnal responses that are conserved among plant species. The plant circadian clock system has been uncovered in the model plant, Arabidopsis thaliana, using genetics and systems biology approaches. However, it is still not clear how the clock system had been organized in the evolutionary history of plants. We recently revealed the molecular phylogeny of LHY/CCA1 genes, one of the essential components of the clock system. The aims of this study are to reconstruct the phylogenetic relationships of angiosperm clock-associated PRR genes, the partner of the LHY/CCA1 genes, and to clarify the evolutionary history of the plant clock system in angiosperm lineages. Results In the present study, to investigate the molecular phylogeny of PRR genes, we performed two approaches: reconstruction of phylogenetic trees and examination of syntenic relationships. Phylogenetic analyses revealed that PRR genes had diverged into three clades prior to the speciation of monocots and eudicots. Furthermore, copy numbers of PRR genes have been independently increased in monocots and eudicots as a result of ancient chromosomal duplication events. Conclusions Based on the molecular phylogenies of both PRR genes and LHY/CCA1 genes, we inferred the evolutionary process of the plant clock system in angiosperms. This scenario provides evolutionary information that a common ancestor of monocots and eudicots had retained the basic components required for reconstructing a clock system and that the plant circadian clock may have become a more elaborate mechanism after the speciation of monocots and eudicots because of the gene expansion that resulted from polyploidy events.

Association study between a polymorphism at the 3'-untranslated region of CLOCK gene and attention deficit hyperactivity disorder

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Xu Xiaohui

2010-08-01

Full Text Available Abstract Background The circadian locomotor output cycles kaput (CLOCK gene encodes protein regulation circadian rhythm and also plays some roles in neural transmitter systems including the dopamine system. Several lines of evidence implicate a relationship between attention-deficit hyperactivity disorder (ADHD, circadian rythmicity and sleeping disturbances. A recent study has reported that a polymorphism (rs1801260 at the 3'-untranslated region of the CLOCK gene is associated with adult ADHD. Methods To investigate the association between the polymorphism (rs1801260 in ADHD, two samples of ADHD probands from the United Kingdom (n = 180 and Taiwan (n = 212 were genotyped and analysed using within-family transmission disequilibrium test (TDT. Bonferroni correction procedures were used to just for multiple comparisons. Results We found evidence of increased transmission of the T allele of the rs1801260 polymorphism in Taiwanese samples (P = 0.010. There was also evidence of preferential transmission of the T allele of the rs1801260 polymorphism in combined samples from the Taiwan and UK (P = 0.008. Conclusion This study provides evidence for the possible involvement of CLOCK in susceptibility to ADHD.

A Circadian Clock Gene, Cry, Affects Heart Morphogenesis and Function in Drosophila as Revealed by Optical Coherence Microscopy.

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Aneesh Alex

Full Text Available Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR and cardiac activity period (CAP of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays

A Circadian Clock Gene, Cry, Affects Heart Morphogenesis and Function in Drosophila as Revealed by Optical Coherence Microscopy

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Zeng, Xianxu; Tate, Rebecca E.; McKee, Mary L.; Capen, Diane E.; Zhang, Zhan; Tanzi, Rudolph E.; Zhou, Chao

2015-01-01

Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry) is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold) in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM) system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR) and cardiac activity period (CAP) of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time) OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays an essential

Expression of the Circadian Clock Gene Period2 in the Hippocampus: Possible Implications for Synaptic Plasticity and Learned Behaviour

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Louisa M-C Wang

2009-05-01

Full Text Available Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2 gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour.

Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study.

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Fan, Zhiliang; Hou, Lei; Wan, Dongjun; Ao, Ran; Zhao, Dengfa; Yu, Shengyuan

2018-01-09

Cluster headache (CH), a rare primary headache disorder, is currently thought to be a genetic susceptibility which play a role in CH susceptibility. A large numbers of genetic association studies have confirmed that the HCRTR2 (Hypocretin Receptor 2) SNP rs2653349, and the ADH4 (Alcohol Dehydrogenase 4) SNP rs1126671 and rs1800759 polymorphisms are linked to CH. In addition, the CLOCK (Circadian Locomotor Output Cycles Kaput) gene is becoming a research hotspot for CH due to encoding a transcription factor that serves as a basic driving force for circadian rhythm in humans. The purpose of this study was to evaluate the association between CH and the HCRTR2, ADH4 and CLOCK genes in a Chinese CH case-control sample. We genotyped polymorphisms of nine single nucleotide polymorphisms (SNPs) in the HCRTR2, ADH4 and CLOCK genes to perform an association study on a Chinese Han CH case-control sample (112 patients and 192 controls),using Sequenom MALDI-TOF mass spectrometry iPLEX platform. The frequencies and distributions of genotypes and haplotypes were statistically compared between the case and control groups to identify associations with CH. The effects of SNPs on CH were further investigated by multiple logistic regression. The frequency of the HCRTR2 SNP rs3800539 GA genotype was significantly higher in cases than in controls (48.2% vs.37.0%). The GA genotypes was associated with a higher CH risk (OR = 1.483, 95% CI: 0.564-3.387, p = 0.038), however, after Bonferroni correction, the association lost statistical significance. Haplotype analysis of the HCRTR2 SNPs showed that among eight haplotypes, only H1-GTGGGG was linked to a reduced CH risk (44.7% vs. 53.1%, OR = 0.689, 95% CI =0.491~0.966, p = 0.030). No significant association of ADH4, CLOCK SNPs with CH was statistically detected in the present study. Association between HCRTR2, ADH4,CLOCK gene polymorphisms and CH was not significant in the present study, however, haplotype analysis indicated

A central role for ubiquitination within a circadian clock protein modification code

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Katarina eStojkovic

2014-08-01

Full Text Available Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation-transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components, but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle.

CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial

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Background Circadian rhythms regulate key biological processes influencing metabolic pathways. Dysregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK...

Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature.

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Riedel, Casper Schwartz; Georg, Birgitte; Jørgensen, Henrik L; Hannibal, Jens; Fahrenkrug, Jan

2018-01-01

Early growth response transcription factor 1 (EGR1) is expressed in the suprachiasmatic nucleus (SCN) after light stimulation. We used EGR1-deficient mice to address the role of EGR1 in the clock function and light-induced resetting of the clock. The diurnal rhythms of expression of the clock genes BMAL1 and PER1 in the SCN were evaluated by semi-quantitative in situ hybridization. We found no difference in the expression of PER1 mRNA between wildtype and EGR1-deficient mice; however, the daily rhythm of BMAL1 mRNA was completely abolished in the EGR1-deficient mice. In addition, we evaluated the circadian running wheel activity, telemetric locomotor activity, and core body temperature of the mice. Loss of EGR1 neither altered light-induced phase shifts at subjective night nor affected negative masking. Overall, circadian light entrainment was found in EGR1-deficient mice but they displayed a reduced locomotor activity and an altered temperature regulation compared to wild type mice. When placed in running wheels, a subpopulation of EGR1-deficient mice displayed a more disrupted activity rhythm with no measurable endogenous period length (tau). In conclusion, the present study provides the first evidence that the circadian clock in the SCN is disturbed in mice deficient of EGR1.

There Is No Association Between the Circadian Clock Gene HPER3 and Cognitive Dysfunction After Noncardiac Surgery

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Voigt Hansen, Melissa; Simon Rasmussen, Lars; Jespersgaard, Cathrine

2012-01-01

The specific clock-gene PERIOD3 is important with regard to circadian rhythmicity, sleep homeostasis, and cognitive function. The allele PER3(5/5) has been associated with worse cognitive performance in response to sleep deprivation. We hypothesized that patients with the PER3(5/5) genotype would...

Cycling of clock genes entrained to the solar rhythm enables plants to tell time: data from arabidopsis

OpenAIRE

Yeang, Hoong-Yeet

2015-01-01

Background and Aims An endogenous rhythm synchronized to dawn cannot time photosynthesis-linked genes to peak consistently at noon since the interval between sunrise and noon changes seasonally. In this study, a solar clock model that circumvents this limitation is proposed using two daily timing references synchronized to noon and midnight. Other rhythmic genes that are not directly linked to photosynthesis, and which peak at other times, also find an adaptive advantage in entrainment to the...

Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

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Yaoming Yang

2012-06-01

Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2 in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1. USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues.

Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver.

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Wang, Danfeng; Chen, Siyu; Liu, Mei; Liu, Chang

2015-06-01

Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.

Speed control: cogs and gears that drive the circadian clock.

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Zheng, Xiangzhong; Sehgal, Amita

2012-09-01

In most organisms, an intrinsic circadian (~24-h) timekeeping system drives rhythms of physiology and behavior. Within cells that contain a circadian clock, specific transcriptional activators and repressors reciprocally regulate each other to generate a basic molecular oscillator. A mismatch of the period generated by this oscillator with the external environment creates circadian disruption, which can have adverse effects on neural function. Although several clock genes have been extensively characterized, a fundamental question remains: how do these genes work together to generate a ~24-h period? Period-altering mutations in clock genes can affect any of multiple regulated steps in the molecular oscillator. In this review, we examine the regulatory mechanisms that contribute to setting the pace of the circadian oscillator. Copyright © 2012 Elsevier Ltd. All rights reserved.

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

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Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

2016-07-15

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

Relations between canonical and non-canonical inflation

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Gwyn, Rhiannon [Max-Planck-Institut fuer Gravitationsphysik (Albert-Einstein-Institut), Potsdam (Germany); Rummel, Markus [Hamburg Univ. (Germany). 2. Inst. fuer Theoretische Physik; Westphal, Alexander [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group

2012-12-15

We look for potential observational degeneracies between canonical and non-canonical models of inflation of a single field {phi}. Non-canonical inflationary models are characterized by higher than linear powers of the standard kinetic term X in the effective Lagrangian p(X,{phi}) and arise for instance in the context of the Dirac-Born-Infeld (DBI) action in string theory. An on-shell transformation is introduced that transforms non-canonical inflationary theories to theories with a canonical kinetic term. The 2-point function observables of the original non-canonical theory and its canonical transform are found to match in the case of DBI inflation.

Sex-Specific Diurnal Immobility Induced by Forced Swim Test in Wild Type and Clock Gene Deficient Mice

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Ningyue Li

2015-03-01

Full Text Available Objective: The link between alterations in circadian rhythms and depression are well established, but the underlying mechanisms are far less elucidated. We investigated the circadian characteristics of immobility behavior in wild type (WT mice and mice with mutations in core Clock genes. Methods: All mice were tested with forced swim test (FST at 4 h intervals. Results: These experiments revealed significant diurnal rhythms associated with immobility behavior in both male and female WT mice with sex-different circadian properties. In addition, male mice showed significantly less immobility during the night phase in comparison to female mice. Female Per1Brdm1 mice also showed significant rhythmicity. However, the timing of rhythmicity was very different from that observed in female wild type mice. Male Per1Brdm1 mice showed a pattern of rhythmicity similar to that of wild type mice. Furthermore, female Per1Brdm1 mice showed higher duration of immobility in comparison to male Per1Brdm1 mice in both daytime and early night phases. Neither Per2Brdm1 nor ClockΔ19 mice showed significant rhythmicity, but both female Per2Brdm1 and ClockΔ19 mice had lower levels of immobility, compared to males. Conclusions: This study highlights the differences in the circadian characteristics of immobility induced by FST in WT, ClockΔ19, Per1, and Per2 deficient mice.

α1B-Adrenergic receptor signaling controls circadian expression of Tnfrsf11b by regulating clock genes in osteoblasts

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Takao Hirai

2015-11-01

Full Text Available Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG, was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1 and Bmal1 (Bmal1, also known as Arntl, which are components of the core loop of the circadian clock in osteoblasts.

Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver.

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Zhang, Wenxiang; Wang, Peng; Chen, Siyu; Zhang, Zhao; Liang, Tingming; Liu, Chang

2016-06-01

Circadian clocks orchestrate daily oscillations in mammalian behaviors, physiology, and gene expression. MicroRNAs (miRNAs) play a crucial role in fine-tuning of the circadian system. However, little is known about the direct regulation of the clock genes by specific miRNAs. In this study, we found that miR-27b-3p exhibits rhythmic expression in the metabolic tissues of the mice subjected to constant darkness. MiR-27b-3p's expression is induced in livers of unfed and ob/ob mice. In addition, the oscillation phases of miR-27b-3p can be reversed by restricted feeding, suggesting a role of peripheral clock in regulating its rhythmicity. Bioinformatics analysis indicated that aryl hydrocarbon receptor nuclear translocator-like (also known as Bmal1) may be a direct target of miR-27b-3p. Luciferase reporter assay showed that miR-27b-3p suppressed Bmal1 3' UTR activity in a dose-dependent manner, and mutagenesis of their binding site abolished this suppression. Furthermore, overexpression of miR-27b-3p dose-dependently reduced the protein expression levels of BMAL1 and impaired the endogenous BMAL1 and gluconeogenic protein rhythmicity. Collectively, our results suggest that miR-27b-3p plays an important role in the posttranscriptional regulation of BMAL1 protein in the liver. MiR-27b-3p may serve as a novel node to integrate the circadian clock and energy metabolism.-Zhang, W., Wang, P., Chen, S., Zhang, Z., Liang, T., Liu, C. Rhythmic expression of miR-27b-3p targets the clock gene Bmal1 at the posttranscriptional level in the mouse liver. © FASEB.

Glucose Alters Per2 Rhythmicity Independent of AMPK, Whereas AMPK Inhibitor Compound C Causes Profound Repression of Clock Genes and AgRP in mHypoE-37 Hypothalamic Neurons.

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Johanneke E Oosterman

Full Text Available Specific neurons in the hypothalamus are regulated by peripheral hormones and nutrients to maintain proper metabolic control. It is unclear if nutrients can directly control clock gene expression. We have therefore utilized the immortalized, hypothalamic cell line mHypoE-37, which exhibits robust circadian rhythms of core clock genes. mHypoE-37 neurons were exposed to 0.5 or 5.5 mM glucose, comparable to physiological levels in the brain. Per2 and Bmal1 mRNAs were assessed every 3 hours over 36 hours. Incubation with 5.5 mM glucose significantly shortened the period and delayed the phase of Per2 mRNA levels, but had no effect on Bmal1. Glucose had no significant effect on phospho-GSK3β, whereas AMPK phosphorylation was altered. Thus, the AMPK inhibitor Compound C was utilized, and mRNA levels of Per2, Bmal1, Cryptochrome1 (Cry1, agouti-related peptide (AgRP, carnitine palmitoyltransferase 1C (Cpt1c, and O-linked N-acetylglucosamine transferase (Ogt were measured. Remarkably, Compound C dramatically reduced transcript levels of Per2, Bmal1, Cry1, and AgRP, but not Cpt1c or Ogt. Because AMPK was not inhibited at the same time or concentrations as the clock genes, we suggest that the effect of Compound C on gene expression occurs through an AMPK-independent mechanism. The consequences of inhibition of the rhythmic expression of clock genes, and in turn downstream metabolic mediators, such as AgRP, could have detrimental effects on overall metabolic processes. Importantly, the effects of the most commonly used AMPK inhibitor Compound C should be interpreted with caution, considering its role in AMPK-independent repression of specific genes, and especially clock gene rhythm dysregulation.

Glucose Alters Per2 Rhythmicity Independent of AMPK, Whereas AMPK Inhibitor Compound C Causes Profound Repression of Clock Genes and AgRP in mHypoE-37 Hypothalamic Neurons.

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Oosterman, Johanneke E; Belsham, Denise D

2016-01-01

Specific neurons in the hypothalamus are regulated by peripheral hormones and nutrients to maintain proper metabolic control. It is unclear if nutrients can directly control clock gene expression. We have therefore utilized the immortalized, hypothalamic cell line mHypoE-37, which exhibits robust circadian rhythms of core clock genes. mHypoE-37 neurons were exposed to 0.5 or 5.5 mM glucose, comparable to physiological levels in the brain. Per2 and Bmal1 mRNAs were assessed every 3 hours over 36 hours. Incubation with 5.5 mM glucose significantly shortened the period and delayed the phase of Per2 mRNA levels, but had no effect on Bmal1. Glucose had no significant effect on phospho-GSK3β, whereas AMPK phosphorylation was altered. Thus, the AMPK inhibitor Compound C was utilized, and mRNA levels of Per2, Bmal1, Cryptochrome1 (Cry1), agouti-related peptide (AgRP), carnitine palmitoyltransferase 1C (Cpt1c), and O-linked N-acetylglucosamine transferase (Ogt) were measured. Remarkably, Compound C dramatically reduced transcript levels of Per2, Bmal1, Cry1, and AgRP, but not Cpt1c or Ogt. Because AMPK was not inhibited at the same time or concentrations as the clock genes, we suggest that the effect of Compound C on gene expression occurs through an AMPK-independent mechanism. The consequences of inhibition of the rhythmic expression of clock genes, and in turn downstream metabolic mediators, such as AgRP, could have detrimental effects on overall metabolic processes. Importantly, the effects of the most commonly used AMPK inhibitor Compound C should be interpreted with caution, considering its role in AMPK-independent repression of specific genes, and especially clock gene rhythm dysregulation.

Clocking In Time to Gate Memory Processes: The Circadian Clock Is Part of the Ins and Outs of Memory

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Oliver Rawashdeh

2018-01-01

Full Text Available Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA/protein kinase C (PKC/mitogen-activated protein kinase (MAPK/cyclic adenosine monophosphate response element-binding protein (CREB signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2. Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1 as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.

Non-circadian expression masking clock-driven weak transcription rhythms in U2OS cells.

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Julia Hoffmann

Full Text Available U2OS cells harbor a circadian clock but express only a few rhythmic genes in constant conditions. We identified 3040 binding sites of the circadian regulators BMAL1, CLOCK and CRY1 in the U2OS genome. Most binding sites even in promoters do not correlate with detectable rhythmic transcript levels. Luciferase fusions reveal that the circadian clock supports robust but low amplitude transcription rhythms of representative promoters. However, rhythmic transcription of these potentially clock-controlled genes is masked by non-circadian transcription that overwrites the weaker contribution of the clock in constant conditions. Our data suggest that U2OS cells harbor an intrinsically rather weak circadian oscillator. The oscillator has the potential to regulate a large number of genes. The contribution of circadian versus non-circadian transcription is dependent on the metabolic state of the cell and may determine the apparent complexity of the circadian transcriptome.

A circadian clock in Antarctic krill: an endogenous timing system governs metabolic output rhythms in the euphausid species Euphausia superba.

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Mathias Teschke

Full Text Available Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9-12 h period in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9-12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle.

Development and entrainment of the colonic circadian clock during ontogenesis

Czech Academy of Sciences Publication Activity Database

Polidarová, Lenka; Olejníková, Lucie; Paušlyová, Lucia; Sládek, Martin; Soták, Matúš; Pácha, Jiří; Sumová, Alena

2014-01-01

Roč. 306, č. 4 (2014), G346-G356 ISSN 0193-1857 R&D Projects: GA ČR(CZ) GAP303/12/1108 Institutional support: RVO:67985823 Keywords : circadian clock * clock gene * ontogenesis * circadian entrainment Subject RIV: ED - Physiology Impact factor: 3.798, year: 2014

Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

DEFF Research Database (Denmark)

Yang, Yaoming; Duguay, David; Bédard, Nathalie

2012-01-01

Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock...

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks.

Science.gov (United States)

de Assis, Leonardo Vinícius Monteiro; Moraes, Maria Nathália; Magalhães-Marques, Keila Karoline; Kinker, Gabriela Sarti; da Silveira Cruz-Machado, Sanseray; Castrucci, Ana Maria de Lauro

2018-04-03

The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism's biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks

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Leonardo Vinícius Monteiro de Assis

2018-04-01

Full Text Available The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME and macro-environments (TMaE in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis, and the suprachiasmatic nucleus (SCN were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism’s biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Influence of simulated microgravity on clock genes expression rhythmicity and underlying blood circulating miRNAs-mRNA co-expression regulatory mechanism in C57BL/6J mice

Science.gov (United States)

Lv, Ke; Qu, Lina

Purpose: It is vital for astronauts to maintain the optimal alertness and neurobehavioral function. Among various factors that exist in the space flight and long-duration mission environment, gravity changes may probably an essential environmental factor to interfere with internal circadian rhythms homeostasis and sleep quality, but the underlying mechanism is unclear. Mammals' biological clock is controlled by the suprachiasmatic nucleus (SCN), and peripheral organs adjust their own rhythmicity with the central signals. Nevertheless the mechanism underlying this synchronizition process is still unknown. microRNAs (miRNAs) are about 19˜22nt long regulatory RNAs that serve as critical modulators of post-transcriptional gene regulation. Recently, circulating miRNAs were found to have the regulatory role between cells and peripheral tissues, besides its function inside the cells. This study aims to investigate the regulatory signal transduction role of miRNAs between SCN and peripheral biological clock effecter tissues and to further decipher the mechanism of circadian disturbance under microgravity. Method: Firstly, based on the assumption that severe alterations in the expression of genes known to be involved in circadian rhythms may affect the expression of other genes, the labeled cDNA from liver and suprachiasmatic nucleus (SCN) of clock-knockout mice and control mice in different time points were cohybridized to microarrays. The fold change exceeding 2 (FC>2) was used to identify genes with altered expression levels in the knockout mice compared with control mice. Secondly, male C57BL/6J mice at 8 weeks of age were individually caged and acclimatized to the laboratory conditions (12h light/dark cycle) before being used for continuous core body temperature and activity monitoring. The mice were individually caged and tail suspended using a strip of adhesive surgical tape attached to a chain hanging from a pulley. Peripheral blood and liver tissues collection

Loss of circadian clock accelerates aging in neurodegeneration-prone mutants.

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Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S; Wentzell, Jill S; Kretzschmar, Doris; Giebultowicz, Jadwiga M

2012-03-01

Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per(01)) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni(1)), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni(1) mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per(01)sni(1) flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per(01) mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws(1)), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of Photoperiod Extension on Clock Gene and Neuropeptide RNA Expression in the SCN of the Soay Sheep.

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Hugues Dardente

Full Text Available In mammals, changing daylength (photoperiod is the main synchronizer of seasonal functions. The photoperiodic information is transmitted through the retino-hypothalamic tract to the suprachiasmatic nuclei (SCN, site of the master circadian clock. To investigate effects of day length change on the sheep SCN, we used in-situ hybridization to assess the daily temporal organization of expression of circadian clock genes (Per1, Per2, Bmal1 and Fbxl21 and neuropeptides (Vip, Grp and Avp in animals acclimated to a short photoperiod (SP; 8h of light and at 3 or 15 days following transfer to a long photoperiod (LP3, LP15, respectively; 16h of light, achieved by an acute 8-h delay of lights off. We found that waveforms of SCN gene expression conformed to those previously seen in LP acclimated animals within 3 days of transfer to LP. Mean levels of expression for Per1-2 and Fbxl21 were nearly 2-fold higher in the LP15 than in the SP group. The expression of Vip was arrhythmic and unaffected by photoperiod, while, in contrast to rodents, Grp expression was not detectable within the sheep SCN. Expression of the circadian output gene Avp cycled robustly in all photoperiod groups with no detectable change in phasing. Overall these data suggest that synchronizing effects of light on SCN circadian organisation proceed similarly in ungulates and in rodents, despite differences in neuropeptide gene expression.

Rapid resetting of human peripheral clocks by phototherapy during simulated night shift work.

Science.gov (United States)

Cuesta, Marc; Boudreau, Philippe; Cermakian, Nicolas; Boivin, Diane B

2017-11-24

A majority of night shift workers have their circadian rhythms misaligned to their atypical schedule. While bright light exposure at night is known to reset the human central circadian clock, the behavior of peripheral clocks under conditions of shift work is more elusive. The aim of the present study was to quantify the resetting effects of bright light exposure on both central (plasma cortisol and melatonin) and peripheral clocks markers (clock gene expression in peripheral blood mononuclear cells, PBMCs) in subjects living at night. Eighteen healthy subjects were enrolled to either a control (dim light) or a bright light group. Blood was sampled at baseline and on the 4 th day of simulated night shift. In response to a night-oriented schedule, the phase of PER1 and BMAL1 rhythms in PBMCs was delayed by ~2.5-3 h (P shift was observed for the other clock genes and the central markers. Three cycles of 8-h bright light induced significant phase delays (P night-oriented schedule and a rapid resetting effect of nocturnal bright light exposure on peripheral clocks.

[Associations between chronotype, road accidents and polymorphisms in genes linked with biological clock and dopaminergic system].

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Taranov, A O; Puchkova, A N; Slominsky, P A; Tupitsyna, T V; Dementiyenko, V V; Dorokhov, V B

2017-01-01

Public transport driving is a highly demanding activity requiring high skills and responsibility. Shift work, problems with regular sleep schedule negatively impact psychomotor reactions, cognitive functions and ability to react appropriately to the changing environment. For professional drivers all these factors may lead to the increased risk of a road accident. Individual differences in chronotype, cognitive and emotional control are partially genetically determined. Our study aimed to investigate the possible associations between chronotype parameters, traffic accident history and single nucleotide polymorphisms (SNPs) in a number of genes: RORA (rs1159814), CLOCK (rs12649507), PER3 (rs2640909), NPSR1 (rs324981), NPAS2 (rs4851377), DRD3 (rs6280), SLC6A3 (rs6347), DBH (rs1611125). We have studied 303 professional bus drivers working on rolling shifts in the Moscow region who had a recorded history of road accidents. The studied group was genotyped on selected SNPs and has filled out two chronotype questionnaires: MCTQ and shortened SWPAQ (Putilov A.A, 2014). A mixed chronotype with high levels of morning and evening alertness prevailed in the group. A prominent social jetlag caused by shift work was found. For SNP in PER3 gene there was an association with morning activation. SNP in CLOCK gene was associated with social jetlag and the risk to cause a crash. Minor alleles of SNPs in NPSR1and SLC6A3 correlated with later chronotype and increased risk of a road accident. We suppose that these polymorphisms may be amongst the genetic factors connecting chronotype and road accident risk.

The Molecular Circadian Clock and Alcohol-Induced Liver Injury

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Uduak S. Udoh

2015-10-01

Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

Temporal Gradient in the Clock Gene and Cell-Cycle Checkpoint Kinase Wee1 Expression along the Gut

Czech Academy of Sciences Publication Activity Database

Polidarová, Lenka; Soták, Matúš; Sládek, Martin; Pácha, Jiří; Sumová, Alena

2009-01-01

Roč. 26, č. 4 (2009), s. 607-620 ISSN 0742-0528 R&D Projects: GA AV ČR(CZ) IAA500110605; GA ČR(CZ) GA305/09/0321; GA MŠk(CZ) LC554 EU Projects: European Commission(XE) 18741 - EUCLOCK Institutional research plan: CEZ:AV0Z50110509 Keywords : intestine epithelium * circadian clock gene * cell cycle Subject RIV: ED - Physiology Impact factor: 3.987, year: 2009

Lego clocks: building a clock from parts.

Science.gov (United States)

Brunner, Michael; Simons, Mirre J P; Merrow, Martha

2008-06-01

A new finding opens up speculation that the molecular mechanism of circadian clocks in Synechococcus elongatus is composed of multiple oscillator systems (Kitayama and colleagues, this issue, pp. 1513-1521), as has been described in many eukaryotic clock model systems. However, an alternative intepretation is that the pacemaker mechanism-as previously suggested-lies primarily in the rate of ATP hydrolysis by the clock protein KaiC.

Neurogenetics of Drosophila circadian clock: expect the unexpected.

Science.gov (United States)

Jarabo, Patricia; Martin, Francisco A

2017-12-01

Daily biological rhythms (i.e. circadian) are a fundamental part of animal behavior. Numerous reports have shown disruptions of the biological clock in neurodegenerative disorders and cancer. In the latter case, only recently we have gained insight into the molecular mechanisms. After 45 years of intense study of the circadian rhtythms, we find surprising similarities among species on the molecular clock that governs biological rhythms. Indeed, Drosophila is one of the most widely used models in the study of chronobiology. Recent studies in the fruit fly have revealed unpredicted roles for the clock machinery in different aspects of behavior and physiology. Not only the central pacemaker cells do have non-classical circadian functions but also circadian genes work in other cells and tissues different from central clock neurons. In this review, we summarize these new evidences. We also recapitulate the most basic features of Drosophila circadian clock, including recent data about the inputs and outputs that connect the central pacemaker with other regions of the brain. Finally, we discuss the advantages and drawbacks of using natural versus laboratory conditions.

Influence of night-shift and napping at work on urinary melatonin, 17-β-estradiol and clock gene expression in pre-menopausal nurses.

Science.gov (United States)

Bracci, M; Copertaro, A; Manzella, N; Staffolani, S; Strafella, E; Nocchi, L; Barbaresi, M; Copertaro, B; Rapisarda, V; Valentino, M; Santarelli, L

2013-01-01

Night-workers experience disruption of the sleep-wake cycle and light at night which may increase breast cancer risk by suppressing the nocturnal melatonin surge, resulting in higher levels of circulating estrogens. Night-work may also deregulate peripheral clock genes which have been found to be altered in breast cancer. This study investigated urinary 6-sulfatoxymelatonin (aMT6s), serum 17-beta-estradiol levels in premenopausal shift nurses at the end of the night-shift compared to a control group of daytime nurses. Peripheral clock gene expression in lymphocytes were also investigated. All participants were sampled in the follicular phase of the menstrual cycle. The effect of nurses’ ability to take a short nap during the night-shift was also explored. The shift-work group had significantly lower aMT6s levels than daytime nurses independently of a nap. Night-shift napping significantly influences 17-beta-estradiol levels resulting in higher outcomes in nurses who do not take a nap compared to napping group and daytime workers. Peripheral clock genes expression investigated was not significantly different among the groups. Our findings suggest that shift nurses experience changes in aMT6s levels after a night-shift. Napping habits influence 17-beta-estradiol levels at the end of a night-shift. These findings might be related to the increased cancer risk reported in night-shift workers and suggest that a short nap during night-shifts may exert a positive effect.

Thermodynamics in Neurodegenerative Diseases: Interplay Between Canonical WNT/Beta-Catenin Pathway-PPAR Gamma, Energy Metabolism and Circadian Rhythms.

Science.gov (United States)

Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

2018-03-23

Entropy production rate is increased by several metabolic and thermodynamics abnormalities in neurodegenerative diseases (NDs). Irreversible processes are quantified by changes in the entropy production rate. This review is focused on the opposing interactions observed in NDs between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In amyotrophic lateral sclerosis and Huntington's disease, WNT/beta-catenin pathway is upregulated, whereas PPAR gamma is downregulated. In Alzheimer's disease and Parkinson's disease, WNT/beta-catenin pathway is downregulated while PPAR gamma is upregulated. The dysregulation of the canonical WNT/beta-catenin pathway is responsible for the modification of thermodynamics behaviors of metabolic enzymes. Upregulation of WNT/beta-catenin pathway leads to aerobic glycolysis, named Warburg effect, through activated enzymes, such as glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactic dehydrogenase kinase-A (LDH-A) and inactivation of pyruvate dehydrogenase complex (PDH). Downregulation of WNT/beta-catenin pathway leads to oxidative stress and cell death through inactivation of Glut, PKM2, PDK1, MCT-1, LDH-A but activation of PDH. In addition, in NDs, PPAR gamma is dysregulated, whereas it contributes to the regulation of several key circadian genes. NDs show many dysregulation in the mediation of circadian clock genes and so of circadian rhythms. Thermodynamics rhythms operate far-from-equilibrium and partly regulate interactions between WNT/beta-catenin pathway and PPAR gamma. In NDs, metabolism, thermodynamics and circadian rhythms are tightly interrelated.

Geography of the circadian gene clock and photoperiodic response in western North American populations of the three-spined stickleback Gasterosteus aculeatus.

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O'Brien, C; Unruh, L; Zimmerman, C; Bradshaw, W E; Holzapfel, C M; Cresko, W A

2013-03-01

Controlled laboratory experiments were used to show that Oregon and Alaskan three-spined stickleback Gasterosteus aculeatus, collected from locations differing by 18° of latitude, exhibited no significant variation in length of the polyglutamine domain of the clock protein or in photoperiodic response within or between latitudes despite the fact that male and female G. aculeatus are photoperiodic at both latitudes. Hence, caution is urged when interpreting variation in the polyglutamine repeat (PolyQ) domain of the gene clock in the context of seasonal activities or in relationship to photoperiodism along geographical gradients. © 2013 The Authors. Journal of Fish Biology © 2013 The Fisheries Society of the British Isles.

Interrelationship between 3,5,3´-triiodothyronine and the circadian clock in the rodent heart.

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Peliciari-Garcia, Rodrigo Antonio; Prévide, Rafael Maso; Nunes, Maria Tereza; Young, Martin Elliot

2016-01-01

Triiodothyronine (T3) is an important modulator of cardiac metabolism and function, often through modulation of gene expression. The cardiomyocyte circadian clock is a transcriptionally based molecular mechanism capable of regulating cardiac processes, in part by modulating responsiveness of the heart to extra-cardiac stimuli/stresses in a time-of-day (TOD)-dependent manner. Although TOD-dependent oscillations in circulating levels of T3 (and its intermediates) have been established, oscillations in T3 sensitivity in the heart is unknown. To investigate the latter possibility, euthyroid male Wistar rats were treated with vehicle or T3 at distinct times of the day, after which induction of known T3 target genes were assessed in the heart (4-h later). The expression of mRNA was assessed by real-time quantitative polymerase chain reaction (qPCR). Here, we report greater T3 induction of transcript levels at the end of the dark phase. Surprisingly, use of cardiomyocyte-specific clock mutant (CCM) mice revealed that TOD-dependent oscillations in T3 sensitivity were independent of this cell autonomous mechanism. Investigation of genes encoding for proteins that affect T3 sensitivity revealed that Dio1, Dio2 and Thrb1 exhibited TOD-dependent variations in the heart, while Thra1 and Thra2 did not. Of these, Dio1 and Thrb1 were increased in the heart at the end of the dark phase. Interestingly, we observed that T3 acutely altered the expression of core clock components (e.g. Bmal1) in the rat heart. To investigate this further, rats were injected with a single dose of T3, after which expression of clock genes was interrogated at 3-h intervals over the subsequent 24-h period. These studies revealed robust effects of T3 on oscillations of both core clock components and clock-controlled genes. In summary, the current study exposed TOD-dependent sensitivity to T3 in the heart and its effects in the circadian clock genes expression.

Far-red fluorescent probes for canonical and non-canonical nucleic acid structures: current progress and future implications.

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Suseela, Y V; Narayanaswamy, Nagarjun; Pratihar, Sumon; Govindaraju, Thimmaiah

2018-02-05

The structural diversity and functional relevance of nucleic acids (NAs), mainly deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are indispensable for almost all living organisms, with minute aberrations in their structure and function becoming causative factors in numerous human diseases. The standard structures of NAs, termed canonical structures, are supported by Watson-Crick hydrogen bonding. Under special physiological conditions, NAs adopt distinct spatial organisations, giving rise to non-canonical conformations supported by hydrogen bonding other than the Watson-Crick type; such non-canonical structures have a definite function in controlling gene expression and are considered as novel diagnostic and therapeutic targets. Development of molecular probes for these canonical and non-canonical DNA/RNA structures has been an active field of research. Among the numerous probes studied, probes with turn-on fluorescence in the far-red (600-750 nm) region are highly sought-after due to minimal autofluorescence and cellular damage. Far-red fluorescent probes are vital for real-time imaging of NAs in live cells as they provide good resolution and minimal perturbation of the cell under investigation. In this review, we present recent advances in the area of far-red fluorescent probes of DNA/RNA and non-canonical G-quadruplex structures. For the sake of continuity and completeness, we provide a brief overview of visible fluorescent probes. Utmost importance is given to design criteria, characteristic properties and biological applications, including in cellulo imaging, apart from critical discussion on limitations of the far-red fluorescent probes. Finally, we offer current and future prospects in targeting canonical and non-canonical NAs specific to cellular organelles, through sequence- and conformation-specific far-red fluorescent probes. We also cover their implications in chemical and molecular biology, with particular focus on decoding various disease

The canonical and grand canonical models for nuclear ...

Indian Academy of Sciences (India)

Many observables seen in intermediate energy heavy-ion collisions can be explained on the basis of statistical equilibrium. Calculations based on statistical equilibrium can be implemented in microcanonical ensemble, canonical ensemble or grand canonical ensemble. This paper deals with calculations with canonical ...

Relativistic Ideal Clock

OpenAIRE

Bratek, Łukasz

2015-01-01

Two particularly simple ideal clocks exhibiting intrinsic circular motion with the speed of light and opposite spin alignment are described. The clocks are singled out by singularities of an inverse Legendre transformation for relativistic rotators of which mass and spin are fixed parameters. Such clocks work always the same way, no matter how they move. When subject to high accelerations or falling in strong gravitational fields of black holes, the clocks could be used to test the clock hypo...

Localization and expression of putative circadian clock transcripts in the brain of the nudibranch Melibe leonina.

Science.gov (United States)

Duback, Victoria E; Sabrina Pankey, M; Thomas, Rachel I; Huyck, Taylor L; Mbarani, Izhar M; Bernier, Kyle R; Cook, Geoffrey M; O'Dowd, Colleen A; Newcomb, James M; Watson, Winsor H

2018-09-01

The nudibranch, Melibe leonina, expresses a circadian rhythm of locomotion, and we recently determined the sequences of multiple circadian clock transcripts that may play a role in controlling these daily patterns of behavior. In this study, we used these genomic data to help us: 1) identify putative clock neurons using fluorescent in situ hybridization (FISH); and 2) determine if there is a daily rhythm of expression of clock transcripts in the M. leonina brain, using quantitative PCR. FISH indicated the presence of the clock-related transcripts clock, period, and photoreceptive and non-photoreceptive cryptochrome (pcry and npcry, respectively) in two bilateral neurons in each cerebropleural ganglion and a group of <10 neurons in the anterolateral region of each pedal ganglion. Double-label experiments confirmed colocalization of all four clock transcripts with each other. Quantitative PCR demonstrated that the genes clock, period, pcry and npcry exhibited significant differences in expression levels over 24 h. These data suggest that the putative circadian clock network in M. leonina consists of a small number of identifiable neurons that express circadian genes with a daily rhythm. Copyright © 2018 Elsevier Inc. All rights reserved.

Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues.

Science.gov (United States)

Castellano, Leandro; Stebbing, Justin

2013-03-01

MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. They are characterized by specific maturation processes defined by canonical and non-canonical biogenic pathways. Analysis of ∼0.5 billion sequences from mouse data sets derived from different tissues, developmental stages and cell types, partly characterized by either ablation or mutation of the main proteins belonging to miRNA processor complexes, reveals 66 high-confidence new genomic loci coding for miRNAs that could be processed in a canonical or non-canonical manner. A proportion of the newly discovered miRNAs comprises mirtrons, for which we define a new sub-class. Notably, some of these newly discovered miRNAs are generated from untranslated and open reading frames of coding genes, and we experimentally validate these. We also show that many annotated miRNAs do not present miRNA-like features, as they are neither processed by known processing complexes nor loaded on AGO2; this indicates that the current miRNA miRBase database list should be refined and re-defined. Accordingly, a group of them map on ribosomal RNA molecules, whereas others cannot undergo genuine miRNA biogenesis. Notably, a group of annotated miRNAs are Dgcr8 independent and DICER dependent endogenous small interfering RNAs that derive from a unique hairpin formed from a short interspersed nuclear element.

Conserved and divergent rhythms of crassulacean acid metabolism-related and core clock gene expression in the cactus Opuntia ficus-indica.

Science.gov (United States)

Mallona, Izaskun; Egea-Cortines, Marcos; Weiss, Julia

2011-08-01

The cactus Opuntia ficus-indica is a constitutive Crassulacean acid metabolism (CAM) species. Current knowledge of CAM metabolism suggests that the enzyme phosphoenolpyruvate carboxylase kinase (PPCK) is circadian regulated at the transcriptional level, whereas phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), NADP-malic enzyme (NADP-ME), and pyruvate phosphate dikinase (PPDK) are posttranslationally controlled. As little transcriptomic data are available from obligate CAM plants, we created an expressed sequence tag database derived from different organs and developmental stages. Sequences were assembled, compared with sequences in the National Center for Biotechnology Information nonredundant database for identification of putative orthologs, and mapped using Kyoto Encyclopedia of Genes and Genomes Orthology and Gene Ontology. We identified genes involved in circadian regulation and CAM metabolism for transcriptomic analysis in plants grown in long days. We identified stable reference genes for quantitative polymerase chain reaction and found that OfiSAND, like its counterpart in Arabidopsis (Arabidopsis thaliana), and OfiTUB are generally appropriate standards for use in the quantification of gene expression in O. ficus-indica. Three kinds of expression profiles were found: transcripts of OfiPPCK oscillated with a 24-h periodicity; transcripts of the light-active OfiNADP-ME and OfiPPDK genes adapted to 12-h cycles, while transcript accumulation patterns of OfiPEPC and OfiMDH were arrhythmic. Expression of the circadian clock gene OfiTOC1, similar to Arabidopsis, oscillated with a 24-h periodicity, peaking at night. Expression of OfiCCA1 and OfiPRR9, unlike in Arabidopsis, adapted best to a 12-h rhythm, suggesting that circadian clock gene interactions differ from those of Arabidopsis. Our results indicate that the evolution of CAM metabolism could be the result of modified circadian regulation at both the transcriptional and posttranscriptional

Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

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Zordan, Mauro Agostino; Sandrelli, Federica

2015-01-01

There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.

Circadian clock dysfunction and psychiatric disease: could fruit flies have a say?

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Mauro Agostino Zordan

2015-04-01

Full Text Available There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system lead to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e. a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.

Daily rhythm variations of the clock gene PER1 and cancer-related genes during various stages of carcinogenesis in a golden hamster model of buccal mucosa carcinoma

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Ye H

2015-06-01

Full Text Available Hua Ye, Kai Yang, Xue-Mei Tan, Xiao-Juan Fu, Han-Xue LiDepartment of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaBackground: Recent studies have demonstrated that the clock gene PER1 regulates various tumor-related genes. Abnormal expressions and circadian rhythm alterations of PER1 are closely related to carcinogenesis. However, the dynamic circadian variations of PER1 and tumor-related genes at different stages of carcinogenesis remain unknown. This study was conducted to investigate the daily rhythm variation of PER1 and expression of tumor-related genes VEGF, KI67, C-MYC, and P53 in different stages of carcinogenesis.Materials and methods: Dimethylbenzanthracene was used to establish a golden hamster model of buccal mucosa carcinogenesis. Hamsters with normal buccal mucosa, precancerous lesion, and cancerous lesion were sacrificed at six different time points during a 24-hour period of a day. Pathological examination was conducted using routine hematoxylin and eosin staining. PER1, VEGF, KI67, C-MYC, and P53 mRNAs were detected by real-time reverse transcriptase polymerase chain reaction, and a cosinor analysis was applied to analyze the daily rhythm.Results: PER1, VEGF, C-MYC, and P53 mRNA exhibited daily rhythmic expression in three carcinogenesis stages, and KI67 mRNA exhibited daily rhythmic expression in the normal and precancerous stages. The daily rhythmic expression of KI67 was not observed in cancerous stages. The mesor and amplitude of PER1 and P53 mRNA expression decreased upon the development of cancer (P<0.05, whereas the mesor and amplitude of VEGF, KI67, and C-MYC mRNA increased upon the development of cancer (P<0.05. Compared with the normal tissues, the acrophases of PER1, VEGF, and C-MYC mRNA occurred earlier, whereas the acrophases of P53 and KI67 mRNA lagged remarkably in the precancerous lesions. In the cancer stage, the acrophases

Stress affects expression of the clock gene Bmal1 in the suprachiasmatic nucleus of neonatal rats via glucocorticoid‐dependent mechanism

Czech Academy of Sciences Publication Activity Database

Olejníková, Lucie; Polidarová, Lenka; Sumová, Alena

2018-01-01

Roč. 223, č. 1 (2018), č. článku e13020. ISSN 1748-1708 R&D Projects: GA ČR(CZ) GA16-03932S Institutional support: RVO:67985823 Keywords : clock genes * development * glucocorticoids * mifepristone * restricted feeding * stress * suprachiasmatic nuclei Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) Impact factor: 4.867, year: 2016

Expression of the clock genes Per1 and Bmal1 during follicle development in the rat ovary. Effects of gonadotropin stimulation and hypophysectomy

DEFF Research Database (Denmark)

Gräs, Søren; Georg, Birgitte; Jørgensen, Henrik L

2012-01-01

rhythms in the rat ovary to the luteinising hormone receptor and suggest a functional link to androgen and progesterone production. In hypophysectomised animals, rhythmic clock gene expression is also observed in the corpora lutea and in secondary interstitial cells demonstrating that...

Coordination of the maize transcriptome by a conserved circadian clock

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Harmon Frank G

2010-06-01

Full Text Available Abstract Background The plant circadian clock orchestrates 24-hour rhythms in internal physiological processes to coordinate these activities with daily and seasonal changes in the environment. The circadian clock has a profound impact on many aspects of plant growth and development, including biomass accumulation and flowering time. Despite recent advances in understanding the circadian system of the model plant Arabidopsis thaliana, the contribution of the circadian oscillator to important agronomic traits in Zea mays and other cereals remains poorly defined. To address this deficit, this study investigated the transcriptional landscape of the maize circadian system. Results Since transcriptional regulation is a fundamental aspect of circadian systems, genes exhibiting circadian expression were identified in the sequenced maize inbred B73. Of the over 13,000 transcripts examined, approximately 10 percent displayed circadian expression patterns. The majority of cycling genes had peak expression at subjective dawn and dusk, similar to other plant circadian systems. The maize circadian clock organized co-regulation of genes participating in fundamental physiological processes, including photosynthesis, carbohydrate metabolism, cell wall biogenesis, and phytohormone biosynthesis pathways. Conclusions Circadian regulation of the maize genome was widespread and key genes in several major metabolic pathways had circadian expression waveforms. The maize circadian clock coordinated transcription to be coincident with oncoming day or night, which was consistent with the circadian oscillator acting to prepare the plant for these major recurring environmental changes. These findings highlighted the multiple processes in maize plants under circadian regulation and, as a result, provided insight into the important contribution this regulatory system makes to agronomic traits in maize and potentially other C4 plant species.

clockwork orange encodes a transcriptional repressor important for circadian clock amplitude in Drosophila

OpenAIRE

Lim, Chunghun; Chung, Brian Y.; Pitman, Jena L.; McGill, Jermaine J.; Pradhan, Suraj; Lee, Jongbin; Keegan, Kevin P.; Choe, Joonho; Allada, Ravi

2007-01-01

Gene transcription is a central timekeeping process in animal clocks. In Drosophila, the basic helix-loop helix (bHLH)-PAS transcription factor heterodimer, CLOCK (CLK)/CYCLE(CYC) transcriptionally activates the clock components period (per), timeless (tim), Par domain protein 1 (Pdp1), and vrille (vri) that feedback and regulate distinct features of CLK/CYC function [1]. Microarray studies have identified numerous rhythmically expressed transcripts [2-7], some of which are potential direct C...

Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health

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Ribas-Latre, Aleix; Eckel-Mahan, Kristin

2016-01-01

Background While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. Scope of review This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively

Alteration of the Circadian Clock in Children with Smith-Magenis Syndrome

Czech Academy of Sciences Publication Activity Database

Nováková, Marta; Nevšímalová, S.; Příhodová, I.; Sládek, Martin; Sumová, Alena

2012-01-01

Roč. 97, č. 2 (2012), E312-E318 ISSN 0021-972X R&D Projects: GA MZd(CZ) NT11474 Grant - others:GA ČR(CZ) GD309/08/H079 Institutional research plan: CEZ:AV0Z50110509 Keywords : melatonin * circadian clock * clock genes * Smith-Magenis syndrome Subject RIV: FH - Neurology Impact factor: 6.430, year: 2012

Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

International Nuclear Information System (INIS)

Perkins, Timothy N.; Dentener, Mieke A.; Stassen, Frank R.; Rohde, Gernot G.; Mossman, Brooke T.; Wouters, Emiel F.M.; Reynaert, Niki L.

2016-01-01

Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Perkins, Timothy N.; Dentener, Mieke A. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Stassen, Frank R. [Department of Medical Microbiology, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Rohde, Gernot G. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Mossman, Brooke T. [Department of Pathology, University of Vermont College of Medicine, Burlington, VT (United States); Wouters, Emiel F.M. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Reynaert, Niki L., E-mail: n.reynaert@maastrichtuniversity.nl [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands)

2016-06-15

Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

DEFF Research Database (Denmark)

Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.

2014-01-01

Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-s...

A canonical correlation analysis-based dynamic bayesian network prior to infer gene regulatory networks from multiple types of biological data.

Science.gov (United States)

Baur, Brittany; Bozdag, Serdar

2015-04-01

One of the challenging and important computational problems in systems biology is to infer gene regulatory networks (GRNs) of biological systems. Several methods that exploit gene expression data have been developed to tackle this problem. In this study, we propose the use of copy number and DNA methylation data to infer GRNs. We developed an algorithm that scores regulatory interactions between genes based on canonical correlation analysis. In this algorithm, copy number or DNA methylation variables are treated as potential regulator variables, and expression variables are treated as potential target variables. We first validated that the canonical correlation analysis method is able to infer true interactions in high accuracy. We showed that the use of DNA methylation or copy number datasets leads to improved inference over steady-state expression. Our results also showed that epigenetic and structural information could be used to infer directionality of regulatory interactions. Additional improvements in GRN inference can be gleaned from incorporating the result in an informative prior in a dynamic Bayesian algorithm. This is the first study that incorporates copy number and DNA methylation into an informative prior in dynamic Bayesian framework. By closely examining top-scoring interactions with different sources of epigenetic or structural information, we also identified potential novel regulatory interactions.

Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

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Gaora Peadar Ó

2010-10-01

Full Text Available Abstract Background Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of

Circadian oscillations of molecular clock components in the cerebellar cortex of the rat

DEFF Research Database (Denmark)

Rath, Martin Fredensborg; Rohde, Kristian; Møller, Morten

2012-01-01

these genes, Per1, Per2, Per3, Cry1, Arntl, Nr1d1, and Dbp were found to exhibit circadian rhythms in a sequential temporal manner similar to that of the SCN, but with several hours of delay. The results of lesion studies indicate that the molecular oscillatory profiles of Per1, Per2, and Cry1......The central circadian clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the circadian clockwork of the SCN constitutes a self-sustained autoregulatory feedback mechanism reflected by the rhythmic expression of clock genes. However...... in the cerebellum are controlled, though possibly indirectly, by the central clock of the SCN. These data support the presence of a circadian oscillator in the cortex of the rat cerebellum....

PDF and cAMP enhance PER stability in Drosophila clock neurons

Science.gov (United States)

Li, Yue; Guo, Fang; Shen, James; Rosbash, Michael

2014-01-01

The neuropeptide PDF is important for Drosophila circadian rhythms: pdf01 (pdf-null) animals are mostly arrhythmic or short period in constant darkness and have an advanced activity peak in light–dark conditions. PDF contributes to the amplitude, synchrony, as well as the pace of circadian rhythms within clock neurons. PDF is known to increase cAMP levels in PDR receptor (PDFR)-containing neurons. However, there is no known connection of PDF or of cAMP with the Drosophila molecular clockworks. We discovered that the mutant period gene perS ameliorates the phenotypes of pdf-null flies. The period protein (PER) is a well-studied repressor of clock gene transcription, and the perS protein (PERS) has a markedly short half-life. The result therefore suggests that the PDF-mediated increase in cAMP might lengthen circadian period by directly enhancing PER stability. Indeed, increasing cAMP levels and cAMP-mediated protein kinase A (PKA) activity stabilizes PER, in S2 tissue culture cells and in fly circadian neurons. Adding PDF to fly brains in vitro has a similar effect. Consistent with these relationships, a light pulse causes more prominent PER degradation in pdf01 circadian neurons than in wild-type neurons. The results indicate that PDF contributes to clock neuron synchrony by increasing cAMP and PKA, which enhance PER stability and decrease clock speed in intrinsically fast-paced PDFR-containing clock neurons. We further suggest that the more rapid degradation of PERS bypasses PKA regulation and makes the pace of clock neurons more uniform, allowing them to avoid much of the asynchrony caused by the absence of PDF. PMID:24707054

Peripheral CLOCK Regulates Target-Tissue Glucocorticoid Receptor Transcriptional Activity in a Circadian Fashion in Man

Science.gov (United States)

Charmandari, Evangelia; Chrousos, George P.; Lambrou, George I.; Pavlaki, Aikaterini; Koide, Hisashi; Ng, Sinnie Sin Man; Kino, Tomoshige

2011-01-01

Context and Objective Circulating cortisol fluctuates diurnally under the control of the “master” circadian CLOCK, while the peripheral “slave” counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. Design and Participants We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. Results GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. Conclusions Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night. PMID:21980503

Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man.

Directory of Open Access Journals (Sweden)

Evangelia Charmandari

Full Text Available Circulating cortisol fluctuates diurnally under the control of the "master" circadian CLOCK, while the peripheral "slave" counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans.We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs as non-synchronized controls.GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo.Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night.

Differentiation of PC12 Cells Results in Enhanced VIP Expression and Prolonged Rhythmic Expression of Clock Genes

DEFF Research Database (Denmark)

Pretzmann, C.P.; Fahrenkrug, J.; Georg, B.

2008-01-01

To examine for circadian rhythmicity, the messenger RNA (mRNA) amount of the clock genes Per1 and Per2 was measured in undifferentiated and nerve-growth-factor-differentiated PC12 cells harvested every fourth hour. Serum shock was needed to induce circadian oscillations, which in undifferentiated...... PC12 cultures lasted only one 24-h period, while in differentiated cultures, the rhythms continued for at least 3 days. Thus, neuronal differentiation provided PC12 cells the ability to maintain rhythmicity for an extended period. Both vasoactive intestinal polypeptide (VIP) and its receptor VPAC(2...

Circadian Stress Regimes Affect the Circadian Clock and Cause Jasmonic Acid-Dependent Cell Death in Cytokinin-Deficient Arabidopsis Plants[OPEN

Science.gov (United States)

Nitschke, Silvia; Cortleven, Anne; Iven, Tim; Havaux, Michel; Schmülling, Thomas

2016-01-01

The circadian clock helps plants measure daylength and adapt to changes in the day-night rhythm. We found that changes in the light-dark regime triggered stress responses, eventually leading to cell death, in leaves of Arabidopsis thaliana plants with reduced cytokinin levels or defective cytokinin signaling. Prolonged light treatment followed by a dark period induced stress and cell death marker genes while reducing photosynthetic efficiency. This response, called circadian stress, is also characterized by altered expression of clock and clock output genes. In particular, this treatment strongly reduced the expression of CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Intriguingly, similar changes in gene expression and cell death were observed in clock mutants lacking proper CCA1 and LHY function. Circadian stress caused strong changes in reactive oxygen species- and jasmonic acid (JA)-related gene expression. The activation of the JA pathway, involving the accumulation of JA metabolites, was crucial for the induction of cell death, since the cell death phenotype was strongly reduced in the jasmonate resistant1 mutant background. We propose that adaptation to circadian stress regimes requires a normal cytokinin status which, acting primarily through the AHK3 receptor, supports circadian clock function to guard against the detrimental effects of circadian stress. PMID:27354555

High Precision Clock Bias Prediction Model in Clock Synchronization System

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Zan Liu

2016-01-01

Full Text Available Time synchronization is a fundamental requirement for many services provided by a distributed system. Clock calibration through the time signal is the usual way to realize the synchronization among the clocks used in the distributed system. The interference to time signal transmission or equipment failures may bring about failure to synchronize the time. To solve this problem, a clock bias prediction module is paralleled in the clock calibration system. And for improving the precision of clock bias prediction, the first-order grey model with one variable (GM(1,1 model is proposed. In the traditional GM(1,1 model, the combination of parameters determined by least squares criterion is not optimal; therefore, the particle swarm optimization (PSO is used to optimize GM(1,1 model. At the same time, in order to avoid PSO getting stuck at local optimization and improve its efficiency, the mechanisms that double subgroups and nonlinear decreasing inertia weight are proposed. In order to test the precision of the improved model, we design clock calibration experiments, where time signal is transferred via radio and wired channel, respectively. The improved model is built on the basis of clock bias acquired in the experiments. The results show that the improved model is superior to other models both in precision and in stability. The precision of improved model increased by 66.4%~76.7%.

Effects of chronotherapy of benazepril on the diurnal profile of RAAS and clock genes in the kidney of 5/6 nephrectomy rats.

Science.gov (United States)

Huang, Xiao-mei; Yuan, Jing-ping; Zeng, Xing-ruo; Peng, Cai-xia; Mei, Qi-hui; Chen, Wen-li

2013-06-01

This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system (RAAS) and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy (STNx) were established. Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril group (MB) and evening benazepril group (EB). Benazepril was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.

Altered energy intake and the amplitude of the body temperature rhythm are associated with changes in phase, but not amplitude, of clock gene expression in the rat suprachiasmatic nucleus in vivo.

Science.gov (United States)

Goh, Grace H; Mark, Peter J; Maloney, Shane K

2016-01-01

Circadian rhythms in mammals are driven by a central clock in the suprachiasmatic nucleus (SCN). In vitro, temperature cycles within the physiological range can act as potent entraining cues for biological clocks. We altered the body temperature (Tc) rhythm in rats by manipulating energy intake (EI) to determine whether EI-induced changes in Tc oscillations are associated with changes in SCN clock gene rhythms in vivo. Male Wistar rats (n = 16 per diet) were maintained on either an ad libitum diet (CON), a high energy cafeteria diet (CAF), or a calorie restricted diet (CR), and Tc was recorded every 30 min for 6-7 weeks. SCN tissue was harvested from rats at zeitgeber time (ZT) 0, ZT6, ZT12, or ZT18. Expression of the clock genes Bmal1, Per2, Cry1, and Rev-erbα, the heat shock transcription factor Hsf1, and the heat shock protein Hsp90aa1, were determined using qPCR. The circadian profile of gene expression for each gene was characterized using cosinor analysis. Compared to the CON rats, the amplitude of Tc was decreased in CAF rats by 0.1 °C (p  0.25). Compared to CON, phase advances of the Tc, Bmal1, and Per2 rhythms were observed with CR feeding (p < 0.05), but CAF feeding elicited no significant changes in phase. The present results indicate that in vivo, the SCN is largely resistant to entrainment by EI-induced changes in the Tc rhythm, although some phase entrainment may occur.

Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri.

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Quentin Thommen

Full Text Available The development of systemic approaches in biology has put emphasis on identifying genetic modules whose behavior can be modeled accurately so as to gain insight into their structure and function. However, most gene circuits in a cell are under control of external signals and thus, quantitative agreement between experimental data and a mathematical model is difficult. Circadian biology has been one notable exception: quantitative models of the internal clock that orchestrates biological processes over the 24-hour diurnal cycle have been constructed for a few organisms, from cyanobacteria to plants and mammals. In most cases, a complex architecture with interlocked feedback loops has been evidenced. Here we present the first modeling results for the circadian clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock genes have been shown to play a central role in the Ostreococcus clock. We find that their expression time profiles can be accurately reproduced by a minimal model of a two-gene transcriptional feedback loop. Remarkably, best adjustment of data recorded under light/dark alternation is obtained when assuming that the oscillator is not coupled to the diurnal cycle. This suggests that coupling to light is confined to specific time intervals and has no dynamical effect when the oscillator is entrained by the diurnal cycle. This intriguing property may reflect a strategy to minimize the impact of fluctuations in daylight intensity on the core circadian oscillator, a type of perturbation that has been rarely considered when assessing the robustness of circadian clocks.

DNA Replication Is Required for Circadian Clock Function by Regulating Rhythmic Nucleosome Composition.

Science.gov (United States)

Liu, Xiao; Dang, Yunkun; Matsu-Ura, Toru; He, Yubo; He, Qun; Hong, Christian I; Liu, Yi

2017-07-20

Although the coupling between circadian and cell cycles allows circadian clocks to gate cell division and DNA replication in many organisms, circadian clocks were thought to function independently of cell cycle. Here, we show that DNA replication is required for circadian clock function in Neurospora. Genetic and pharmacological inhibition of DNA replication abolished both overt and molecular rhythmicities by repressing frequency (frq) gene transcription. DNA replication is essential for the rhythmic changes of nucleosome composition at the frq promoter. The FACT complex, known to be involved in histone disassembly/reassembly, is required for clock function and is recruited to the frq promoter in a replication-dependent manner to promote replacement of histone H2A.Z by H2A. Finally, deletion of H2A.Z uncoupled the dependence of the circadian clock on DNA replication. Together, these results establish circadian clock and cell cycle as interdependent coupled oscillators and identify DNA replication as a critical process in the circadian mechanism. Published by Elsevier Inc.

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators▿

Science.gov (United States)

Bertolucci, Cristiano; Cavallari, Nicola; Colognesi, Ilaria; Aguzzi, Jacopo; Chen, Zheng; Caruso, Pierpaolo; Foá, Augusto; Tosini, Gianluca; Bernardi, Francesco; Pinotti, Mirko

2008-01-01

The mechanisms underlying the circadian control of gene expression in peripheral tissues and influencing many biological pathways are poorly defined. Factor VII (FVII), the protease triggering blood coagulation, represents a valuable model to address this issue in liver since its plasma levels oscillate in a circadian manner and its promoter contains E-boxes, which are putative DNA-binding sites for CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers and hallmarks of circadian regulation. The peaks of FVII mRNA levels in livers of wild-type mice preceded those in plasma, indicating a transcriptional regulation, and were abolished in Clock−/−; Npas2−/− mice, thus demonstrating a role for CLOCK and NPAS2 circadian transcription factors. The investigation of Npas2−/− and ClockΔ19/Δ19 mice, which express functionally defective heterodimers, revealed robust rhythms of FVII expression in both animal models, suggesting a redundant role for NPAS2 and CLOCK. The molecular bases of these observations were established through reporter gene assays. FVII transactivation activities of the NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers were (i) comparable (a fourfold increase), (ii) dampened by the negative circadian regulators PER2 and CRY1, and (iii) abolished upon E-box mutagenesis. Our data provide the first evidence in peripheral oscillators for an overlapping role of CLOCK and NPAS2 in the regulation of circadianly controlled genes. PMID:18316400

Minimal tool set for a prokaryotic circadian clock.

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Schmelling, Nicolas M; Lehmann, Robert; Chaudhury, Paushali; Beck, Christian; Albers, Sonja-Verena; Axmann, Ilka M; Wiegard, Anika

2017-07-21

Circadian clocks are found in organisms of almost all domains including photosynthetic Cyanobacteria, whereby large diversity exists within the protein components involved. In the model cyanobacterium Synechococcus elongatus PCC 7942 circadian rhythms are driven by a unique KaiABC protein clock, which is embedded in a network of input and output factors. Homologous proteins to the KaiABC clock have been observed in Bacteria and Archaea, where evidence for circadian behavior in these domains is accumulating. However, interaction and function of non-cyanobacterial Kai-proteins as well as homologous input and output components remain mainly unclear. Using a universal BLAST analyses, we identified putative KaiC-based timing systems in organisms outside as well as variations within Cyanobacteria. A systematic analyses of publicly available microarray data elucidated interesting variations in circadian gene expression between different cyanobacterial strains, which might be correlated to the diversity of genome encoded clock components. Based on statistical analyses of co-occurrences of the clock components homologous to Synechococcus elongatus PCC 7942, we propose putative networks of reduced and fully functional clock systems. Further, we studied KaiC sequence conservation to determine functionally important regions of diverged KaiC homologs. Biochemical characterization of exemplary cyanobacterial KaiC proteins as well as homologs from two thermophilic Archaea demonstrated that kinase activity is always present. However, a KaiA-mediated phosphorylation is only detectable in KaiC1 orthologs. Our analysis of 11,264 genomes clearly demonstrates that components of the Synechococcus elongatus PCC 7942 circadian clock are present in Bacteria and Archaea. However, all components are less abundant in other organisms than Cyanobacteria and KaiA, Pex, LdpA, and CdpA are only present in the latter. Thus, only reduced KaiBC-based or even simpler, solely KaiC-based timing systems

Cryptochromes define a novel circadian clock mechanism in monarch butterflies that may underlie sun compass navigation.

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Haisun Zhu

2008-01-01

Full Text Available The circadian clock plays a vital role in monarch butterfly (Danaus plexippus migration by providing the timing component of time-compensated sun compass orientation, a process that is important for successful navigation. We therefore evaluated the monarch clockwork by focusing on the functions of a Drosophila-like cryptochrome (cry, designated cry1, and a vertebrate-like cry, designated cry2, that are both expressed in the butterfly and by placing these genes in the context of other relevant clock genes in vivo. We found that similar temporal patterns of clock gene expression and protein levels occur in the heads, as occur in DpN1 cells, of a monarch cell line that contains a light-driven clock. CRY1 mediates TIMELESS degradation by light in DpN1 cells, and a light-induced TIMELESS decrease occurs in putative clock cells in the pars lateralis (PL in the brain. Moreover, monarch cry1 transgenes partially rescue both biochemical and behavioral light-input defects in cry(b mutant Drosophila. CRY2 is the major transcriptional repressor of CLOCK:CYCLE-mediated transcription in DpN1 cells, and endogenous CRY2 potently inhibits transcription without involvement of PERIOD. CRY2 is co-localized with clock proteins in the PL, and there it translocates to the nucleus at the appropriate time for transcriptional repression. We also discovered CRY2-positive neural projections that oscillate in the central complex. The results define a novel, CRY-centric clock mechanism in the monarch in which CRY1 likely functions as a blue-light photoreceptor for entrainment, whereas CRY2 functions within the clockwork as the transcriptional repressor of a negative transcriptional feedback loop. Our data further suggest that CRY2 may have a dual role in the monarch butterfly's brain-as a core clock element and as an output that regulates circadian activity in the central complex, the likely site of the sun compass.

Clock Drawing in Spatial Neglect: A Comprehensive Analysis of Clock Perimeter, Placement, and Accuracy

Science.gov (United States)

Chen, Peii; Goedert, Kelly M.

2012-01-01

Clock drawings produced by right-brain-damaged (RBD) individuals with spatial neglect often contain an abundance of empty space on the left while numbers and hands are placed on the right. However, the clock perimeter is rarely compromised in neglect patients’ drawings. By analyzing clock drawings produced by 71 RBD and 40 healthy adults, this study investigated whether the geometric characteristics of the clock perimeter reveal novel insights to understanding spatial neglect. Neglect participants drew smaller clocks than either healthy or non-neglect RBD participants. While healthy participants’ clock perimeter was close to circular, RBD participants drew radially extended ellipses. The mechanisms for these phenomena were investigated by examining the relation between clock-drawing characteristics and performance on six subtests of the Behavioral Inattention Test (BIT). The findings indicated that the clock shape was independent of any BIT subtest or the drawing placement on the test sheet and that the clock size was significantly predicted by one BIT subtest: the poorer the figure and shape copying, the smaller the clock perimeter. Further analyses revealed that in all participants, clocks decreased in size as they were placed farther from the center of the paper. However, even when neglect participants placed their clocks towards the center of the page, they were smaller than those produced by healthy or non-neglect RBD participants. These results suggest a neglect-specific reduction in the subjectively available workspace for graphic production from memory, consistent with the hypothesis that neglect patients are impaired in the ability to enlarge the attentional aperture. PMID:22390278

Inhibition of adipocytogenesis by canonical WNT signaling in human mesenchymal stem cells

International Nuclear Information System (INIS)

Shen, Longxiang; Glowacki, Julie; Zhou, Shuanhu

2011-01-01

The WNT signaling pathway plays important roles in the self-renewal and differentiation of mesenchymal stem cells (MSCs). Little is known about WNT signaling in adipocyte differentiation of human MSCs. In this study, we tested the hypothesis that canonical and non-canonical WNTs differentially regulate in vitro adipocytogenesis in human MSCs. The expression of adipocyte gene PPARγ2, lipoprotein lipase, and adipsin increased during adipocytogenesis of hMSCs. Simultaneously, the expression of canonical WNT2, 10B, 13, and 14 decreased, whereas non-canonical WNT4 and 11 increased, and WNT5A was unchanged. A small molecule WNT mimetic, SB-216763, increased accumulation of β-catenin protein, inhibited induction of WNT4 and 11 and inhibited adipocytogenesis. In contrast, knockdown of β-catenin with siRNA resulted in spontaneous adipocytogenesis. These findings support the view that canonical WNT signaling inhibits and non-canonical WNT signaling promotes adipocytogenesis in adult human marrow-derived mesenchymal stem cells.

Differential effects of diet composition and timing of feeding behavior on rat brown adipose tissue and skeletal muscle peripheral clocks

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Paul de Goede

2018-01-01

Full Text Available The effects of feeding behavior and diet composition, as well as their possible interactions, on daily (clock gene expression rhythms have mainly been studied in the liver, and to a lesser degree in white adipose tissue (WAT, but hardly in other metabolic tissues such as skeletal muscle (SM and brown adipose tissues (BAT. We therefore subjected male Wistar rats to a regular chow or free choice high-fat-high sugar (fcHFHS diet in combination with time restricted feeding (TRF to either the light or dark phase. In SM, all tested clock genes lost their rhythmic expression in the chow light fed group. In the fcHFHS light fed group rhythmic expression for some, but not all, clock genes was maintained, but shifted by several hours. In BAT the daily rhythmicity of clock genes was maintained for the light fed groups, but expression patterns were shifted as compared with ad libitum and dark fed groups, whilst the fcHFHS diet made the rhythmicity of clock genes become more pronounced. Most of the metabolic genes in BAT tissue tested did not show any rhythmic expression in either the chow or fcHFHS groups. In SM Pdk4 and Ucp3 were phase-shifted, but remained rhythmically expressed in the chow light fed groups. Rhythmic expression was lost for Ucp3 whilst on the fcHFHS diet during the light phase. In summary, both feeding at the wrong time of day and diet composition disturb the peripheral clocks in SM and BAT, but to different degrees and thereby result in a further desynchronization between metabolically active tissues such as SM, BAT, WAT and liver.

Conserved and Divergent Rhythms of Crassulacean Acid Metabolism-Related and Core Clock Gene Expression in the Cactus Opuntia ficus-indica1[C][W

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Mallona, Izaskun; Egea-Cortines, Marcos; Weiss, Julia

2011-01-01

The cactus Opuntia ficus-indica is a constitutive Crassulacean acid metabolism (CAM) species. Current knowledge of CAM metabolism suggests that the enzyme phosphoenolpyruvate carboxylase kinase (PPCK) is circadian regulated at the transcriptional level, whereas phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), NADP-malic enzyme (NADP-ME), and pyruvate phosphate dikinase (PPDK) are posttranslationally controlled. As little transcriptomic data are available from obligate CAM plants, we created an expressed sequence tag database derived from different organs and developmental stages. Sequences were assembled, compared with sequences in the National Center for Biotechnology Information nonredundant database for identification of putative orthologs, and mapped using Kyoto Encyclopedia of Genes and Genomes Orthology and Gene Ontology. We identified genes involved in circadian regulation and CAM metabolism for transcriptomic analysis in plants grown in long days. We identified stable reference genes for quantitative polymerase chain reaction and found that OfiSAND, like its counterpart in Arabidopsis (Arabidopsis thaliana), and OfiTUB are generally appropriate standards for use in the quantification of gene expression in O. ficus-indica. Three kinds of expression profiles were found: transcripts of OfiPPCK oscillated with a 24-h periodicity; transcripts of the light-active OfiNADP-ME and OfiPPDK genes adapted to 12-h cycles, while transcript accumulation patterns of OfiPEPC and OfiMDH were arrhythmic. Expression of the circadian clock gene OfiTOC1, similar to Arabidopsis, oscillated with a 24-h periodicity, peaking at night. Expression of OfiCCA1 and OfiPRR9, unlike in Arabidopsis, adapted best to a 12-h rhythm, suggesting that circadian clock gene interactions differ from those of Arabidopsis. Our results indicate that the evolution of CAM metabolism could be the result of modified circadian regulation at both the transcriptional and posttranscriptional

A GPS Satellite Clock Offset Prediction Method Based on Fitting Clock Offset Rates Data

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WANG Fuhong

2016-12-01

Full Text Available It is proposed that a satellite atomic clock offset prediction method based on fitting and modeling clock offset rates data. This method builds quadratic model or linear model combined with periodic terms to fit the time series of clock offset rates, and computes the model coefficients of trend with the best estimation. The clock offset precisely estimated at the initial prediction epoch is directly adopted to calculate the model coefficient of constant. The clock offsets in the rapid ephemeris (IGR provided by IGS are used as modeling data sets to perform certain experiments for different types of GPS satellite clocks. The results show that the clock prediction accuracies of the proposed method for 3, 6, 12 and 24 h achieve 0.43, 0.58, 0.90 and 1.47 ns respectively, which outperform the traditional prediction method based on fitting original clock offsets by 69.3%, 61.8%, 50.5% and 37.2%. Compared with the IGU real-time clock products provided by IGS, the prediction accuracies of the new method have improved about 15.7%, 23.7%, 27.4% and 34.4% respectively.

The retinal clock in mammals: role in health and disease

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Felder-Schmittbuhl MP

2017-05-01

fundamental processes, the coherence from cell to tissue is critical for circadian functions, and disruption of retinal clock organization or its response to light can potentially have a major impact on retinal pathophysiology and vision. Keywords: retina, clock gene, circadian, ipRGC, photoreceptor, light

Prediction of GNSS satellite clocks

International Nuclear Information System (INIS)

Broederbauer, V.

2010-01-01

This thesis deals with the characterisation and prediction of GNSS-satellite-clocks. A prerequisite to develop powerful algorithms for the prediction of clock-corrections is the thorough study of the behaviour of the different clock-types of the satellites. In this context the predicted part of the IGU-clock-corrections provided by the Analysis Centers (ACs) of the IGS was compared to the IGS-Rapid-clock solutions to determine reasonable estimates of the quality of already existing well performing predictions. For the shortest investigated interval (three hours) all ACs obtain almost the same accuracy of 0,1 to 0,4 ns. For longer intervals the individual predictions results start to diverge. Thus, for a 12-hours- interval the differences range from nearly 10 ns (GFZ, CODE) until up to some 'tens of ns'. Based on the estimated clock corrections provided via the IGS Rapid products a simple quadratic polynomial turns out to be sufficient to describe the time series of Rubidium-clocks. On the other hand Cesium-clocks show a periodical behaviour (revolution period) with an amplitude of up to 6 ns. A clear correlation between these amplitudes and the Sun elevation angle above the orbital planes can be demonstrated. The variability of the amplitudes is supposed to be caused by temperature-variations affecting the oscillator. To account for this periodical behaviour a quadratic polynomial with an additional sinus-term was finally chosen as prediction model both for the Cesium as well as for the Rubidium clocks. The three polynomial-parameters as well as amplitude and phase shift of the periodic term are estimated within a least-square-adjustment by means of program GNSS-VC/static. Input-data are time series of the observed part of the IGU clock corrections. With the estimated parameters clock-corrections are predicted for various durations. The mean error of the prediction of Rubidium-clock-corrections for an interval of six hours reaches up to 1,5 ns. For the 12-hours

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

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Kalkman Hans

2012-10-01

Full Text Available Abstract Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8. Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity.

Feeding cycle-dependent circulating insulin fluctuation is not a dominant Zeitgeber for mouse peripheral clocks except in the liver: Differences between endogenous and exogenous insulin effects.

Science.gov (United States)

Oishi, Katsutaka; Yasumoto, Yuki; Higo-Yamamoto, Sayaka; Yamamoto, Saori; Ohkura, Naoki

2017-01-29

The master clock in the suprachiasmatic nucleus synchronizes peripheral clocks via humoral and neural signals in mammals. Insulin is thought to be a critical Zeitgeber (synchronizer) for peripheral clocks because it induces transient clock gene expression in cultured cells. However, the extent to which fluctuations in feeding-dependent endogenous insulin affect the temporal expression of clock genes remains unclear. We therefore investigated the temporal expression profiles of clock genes in the peripheral tissues of mice fed for 8 h during either the daytime (DF) or the nighttime (NF) for one week to determine the involvement of feeding cycle-dependent endogenous insulin rhythms in the circadian regulation of peripheral clocks. The phase of circulating insulin fluctuations was reversed in DF compared with NF mice, although those of circulating corticosterone fluctuations and nocturnal locomotor activity were identical between these mice. The reversed feeding cycle affected the circadian phases of Per1 and Per2 gene expression in the liver and not in heart, lung, white adipose and skeletal muscle tissues. On the other hand, injected exogenous insulin significantly induced Akt phosphorylation in the heart and skeletal muscle as well as the liver, and significantly induced Per1 and Per2 gene expression in all examined tissues. These findings suggest that feeding cycles and feeding cycle-dependent endogenous insulin fluctuations are not dominant entrainment signals for peripheral clocks other than the liver, although exogenous insulin might reset peripheral oscillators in mammals. Copyright © 2016 Elsevier Inc. All rights reserved.

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

DEFF Research Database (Denmark)

Bugge, Anne Skovsø; Feng, Dan; Everett, Logan J

2012-01-01

of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast......-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set...

El canon literario peruano

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Carlos García-Bedoya Maguiña

2011-05-01

Full Text Available Canon es un concepto clave en la historia literaria. En el presente artículo,se revisa la evolución histórica del canon literario peruano. Es solo con la llamada República Aristocrática, en las primeras décadas del siglo XX, que cabe hablar en el caso peruano de la formación de un auténtico canon nacional. El autor denomina a esta primera versión del canon literario peruano como canon oligárquico y destaca la importancia de la obra de Riva Agüero y de Ventura García Calderón en su configuración. Es solo más tarde, desde los años 20 y de modo definitivo desde los años 50, que puede hablarse de la emergencia de un nuevo canon literarioal que el autor propone determinar canon posoligárquico.

New methods to assess circadian clocks in humans

Czech Academy of Sciences Publication Activity Database

Nováková, Marta; Sumová, Alena

2014-01-01

Roč. 52, č. 5 (2014), s. 404-412 ISSN 0019-5189 R&D Projects: GA MZd(CZ) NT11474 Grant - others:Univerzita Karlova(CZ) 22810 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : circadian * clock gene * melatonin * human Subject RIV: ED - Physiology Impact factor: 0.835, year: 2014

The Canon is el Boom, et. al., or the Hispanic Difference

OpenAIRE

Bell-Villada, Gene H.

2002-01-01

In his article, Gene H. Bell-Villada's "The Canon is el Boom, et. al., or the Hispanic Difference," argues that the rich, globally acclaimed, foundational yet contestatory prose literature produced in Latin America allows teachers and scholars of Spanish to teach what is essentially the "canon" via work that is still fresh, yet historically provocative. Bell-Villada argues that in a time of reconsidering the importance of literature in literature programs, programs of Spanish language and cul...

Peripheral Skin Temperature and Circadian Biological Clock in Shift Nurses after a Day off

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Massimo Bracci

2016-04-01

Full Text Available The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for 24 h after a day off. Significant differences were observed in peripheral skin temperature and cortisol levels between shift and daytime nurses. No differences in melatonin levels were obtained. Per2 maximum values were significantly different between the two groups. Shift nurses exhibited lower circadian variations compared to daytime nurses, and this may indicate an adjustment of the circadian biological clock to continuous shift schedules. Non-invasive procedures, such as peripheral skin temperature measurement, determination of cortisol and melatonin in saliva, and analysis of clock genes in hair follicle cells, may be effective approaches to extensively study the circadian clock in shift workers.

Whose Canon? Culturalization versus Democratization

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Erling Bjurström

2012-06-01

Full Text Available Current accounts – and particularly the critique – of canon formation are primarily based on some form of identity politics. In the 20th century a representational model of social identities replaced cultivation as the primary means to democratize the canons of the fine arts. In a parallel development, the discourse on canons has shifted its focus from processes of inclusion to those of exclusion. This shift corresponds, on the one hand, to the construction of so-called alternative canons or counter-canons, and, on the other hand, to attempts to restore the authority of canons considered to be in a state of crisis or decaying. Regardless of the democratic stance of these efforts, the construction of alternatives or the reestablishment of decaying canons does not seem to achieve their aims, since they break with the explicit and implicit rules of canon formation. Politically motivated attempts to revise or restore a specific canon make the workings of canon formation too visible, transparent and calculated, thereby breaking the spell of its imaginary character. Retracing the history of the canonization of the fine arts reveals that it was originally tied to the disembedding of artists and artworks from social and worldly affairs, whereas debates about canons of the fine arts since the end of the 20th century are heavily dependent on their social, cultural and historical reembedding. The latter has the character of disenchantment, but has also fettered the canon debate in notions of “our” versus “their” culture. However, by emphasizing the dedifferentiation of contemporary processes of culturalization, the advancing canonization of popular culture seems to be able to break with identity politics that foster notions of “our” culture in the present thinking on canons, and push it in a more transgressive, syncretic or hybrid direction.

Probing the canonicity of the Wnt/Wingless signaling pathway.

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Alexandra Franz

2017-04-01

Full Text Available The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a genome-wide scale the requirement for Armadillo (Arm, Drosophila beta-catenin and Pangolin (Pan, Drosophila TCF in the Wnt/Wingless(Wg-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, we demonstrate that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing we identified Wnt/Wg-responsive enhancer elements and found that all responsive enhancers depend on Pan. Together, our results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.

Effects of different per translational kinetics on the dynamics of a core circadian clock model.

Science.gov (United States)

Nieto, Paula S; Revelli, Jorge A; Garbarino-Pico, Eduardo; Condat, Carlos A; Guido, Mario E; Tamarit, Francisco A

2015-01-01

Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis.

Divergence time estimates of mammals from molecular clocks and ...

Indian Academy of Sciences (India)

Prakash

2009-10-30

Oct 30, 2009 ... Keywords. Cretaceous; Eocene; Indian Plate; molecular clocks; placental mammals ... variation is known to occur among loci on a gene, between branches on a tree, ... been proposed to explain placental mammal diversification with respect .... Figure 1. Three models (a, explosive, b, long fuse, c, short fuse).

Entanglement of quantum clocks through gravity.

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Castro Ruiz, Esteban; Giacomini, Flaminia; Brukner, Časlav

2017-03-21

In general relativity, the picture of space-time assigns an ideal clock to each world line. Being ideal, gravitational effects due to these clocks are ignored and the flow of time according to one clock is not affected by the presence of clocks along nearby world lines. However, if time is defined operationally, as a pointer position of a physical clock that obeys the principles of general relativity and quantum mechanics, such a picture is, at most, a convenient fiction. Specifically, we show that the general relativistic mass-energy equivalence implies gravitational interaction between the clocks, whereas the quantum mechanical superposition of energy eigenstates leads to a nonfixed metric background. Based only on the assumption that both principles hold in this situation, we show that the clocks necessarily get entangled through time dilation effect, which eventually leads to a loss of coherence of a single clock. Hence, the time as measured by a single clock is not well defined. However, the general relativistic notion of time is recovered in the classical limit of clocks.

Circadian clock gene aryl hydrocarbon receptor nuclear translocator-like polymorphisms are associated with seasonal affective disorder: An Indian family study.

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Rajendran, Bhagya; Janakarajan, Veeramahali Natarajan

2016-01-01

Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms. In this study, 30 members of close-knit family with SAD, 30 age- and sex-matched controls of the same caste with no prior history of psychiatric illness and 30 age- and sex-matched controls belonging to 17 different castes with no prior history of psychiatric illness were genotyped for five different single nucleotide polymorphisms (SNPs) in ARNTL gene by TaqMan allele-specific genotyping assay. Statistical significance was assessed by more powerful quasi-likelihood score test-XM. Most of the family members carried the risk alleles and we observed a highly significant SNP rs2279287 (A/G) in ARNTL gene with an allelic frequency of 0.75. Polymorphisms in ARNTL gene disrupt circadian rhythms causing SAD and genetic predisposition becomes more deleterious in the presence of adverse environment.

Inferring clocks when lacking rocks: the variable rates of molecular evolution in bacteria

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Ochman Howard

2009-09-01

Full Text Available Abstract Background Because bacteria do not have a robust fossil record, attempts to infer the timing of events in their evolutionary history requires comparisons of molecular sequences. This use of molecular clocks is based on the assumptions that substitution rates for homologous genes or sites are fairly constant through time and across taxa. Violation of these conditions can lead to erroneous inferences and result in estimates that are off by orders of magnitude. In this study, we examine the consistency of substitution rates among a set of conserved genes in diverse bacterial lineages, and address the questions regarding the validity of molecular dating. Results By examining the evolution of 16S rRNA gene in obligate endosymbionts, which can be calibrated by the fossil record of their hosts, we found that the rates are consistent within a clade but varied widely across different bacterial lineages. Genome-wide estimates of nonsynonymous and synonymous substitutions suggest that these two measures are highly variable in their rates across bacterial taxa. Genetic drift plays a fundamental role in determining the accumulation of substitutions in 16S rRNA genes and at nonsynonymous sites. Moreover, divergence estimates based on a set of universally conserved protein-coding genes also exhibit low correspondence to those based on 16S rRNA genes. Conclusion Our results document a wide range of substitution rates across genes and bacterial taxa. This high level of variation cautions against the assumption of a universal molecular clock for inferring divergence times in bacteria. However, by applying relative-rate tests to homologous genes, it is possible to derive reliable local clocks that can be used to calibrate bacterial evolution. Reviewers This article was reviewed by Adam Eyre-Walker, Simonetta Gribaldo and Tal Pupko (nominated by Dan Graur.

A laboratory simulation of Arabidopsis seed dormancy cycling provides new insight into its regulation by clock genes and the dormancy-related genes DOG1, MFT, CIPK23 and PHYA.

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Footitt, Steven; Ölçer-Footitt, Hülya; Hambidge, Angela J; Finch-Savage, William E

2017-08-01

Environmental signals drive seed dormancy cycling in the soil to synchronize germination with the optimal time of year, a process essential for species' fitness and survival. Previous correlation of transcription profiles in exhumed seeds with annual environmental signals revealed the coordination of dormancy-regulating mechanisms with the soil environment. Here, we developed a rapid and robust laboratory dormancy cycling simulation. The utility of this simulation was tested in two ways: firstly, using mutants in known dormancy-related genes [DELAY OF GERMINATION 1 (DOG1), MOTHER OF FLOWERING TIME (MFT), CBL-INTERACTING PROTEIN KINASE 23 (CIPK23) and PHYTOCHROME A (PHYA)] and secondly, using further mutants, we test the hypothesis that components of the circadian clock are involved in coordination of the annual seed dormancy cycle. The rate of dormancy induction and relief differed in all lines tested. In the mutants, dog1-2 and mft2, dormancy induction was reduced but not absent. DOG1 is not absolutely required for dormancy. In cipk23 and phyA dormancy, induction was accelerated. Involvement of the clock in dormancy cycling was clear when mutants in the morning and evening loops of the clock were compared. Dormancy induction was faster when the morning loop was compromised and delayed when the evening loop was compromised. © 2017 The Authors Plant, Cell & Environment Published by John Wiley & Sons Ltd.

A Light Clock Satisfying the Clock Hypothesis of Special Relativity

Science.gov (United States)

West, Joseph

2007-01-01

The design of the FMEL, a floor-mirrored Einstein-Langevin "light clock", is introduced. The clock provides a physically intuitive manner to calculate and visualize the time dilation effects for a spatially extended set of observers (an accelerated "frame") undergoing unidirectional acceleration or observers on a rotating cylinder of constant…

Dynamics of the Drosophila circadian clock: theoretical anti-jitter network and controlled chaos.

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Hassan M Fathallah-Shaykh

Full Text Available BACKGROUND: Electronic clocks exhibit undesirable jitter or time variations in periodic signals. The circadian clocks of humans, some animals, and plants consist of oscillating molecular networks with peak-to-peak time of approximately 24 hours. Clockwork orange (CWO is a transcriptional repressor of Drosophila direct target genes. METHODOLOGY/PRINCIPAL FINDINGS: Theory and data from a model of the Drosophila circadian clock support the idea that CWO controls anti-jitter negative circuits that stabilize peak-to-peak time in light-dark cycles (LD. The orbit is confined to chaotic attractors in both LD and dark cycles and is almost periodic in LD; furthermore, CWO diminishes the Euclidean dimension of the chaotic attractor in LD. Light resets the clock each day by restricting each molecular peak to the proximity of a prescribed time. CONCLUSIONS/SIGNIFICANCE: The theoretical results suggest that chaos plays a central role in the dynamics of the Drosophila circadian clock and that a single molecule, CWO, may sense jitter and repress it by its negative loops.

Canonical Information Analysis

DEFF Research Database (Denmark)

Vestergaard, Jacob Schack; Nielsen, Allan Aasbjerg

2015-01-01

is replaced by the information theoretical, entropy based measure mutual information, which is a much more general measure of association. We make canonical information analysis feasible for large sample problems, including for example multispectral images, due to the use of a fast kernel density estimator......Canonical correlation analysis is an established multivariate statistical method in which correlation between linear combinations of multivariate sets of variables is maximized. In canonical information analysis introduced here, linear correlation as a measure of association between variables...... for entropy estimation. Canonical information analysis is applied successfully to (1) simple simulated data to illustrate the basic idea and evaluate performance, (2) fusion of weather radar and optical geostationary satellite data in a situation with heavy precipitation, and (3) change detection in optical...

Study of the association between 3111T/C polymorphism of the CLOCK gene and the presence of overweight in schoolchildren

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Nayara P. Giovaninni

2014-09-01

Full Text Available Objectives: To evaluate the association between 3111T/C polymorphism of the CLOCK gene and the presence of obesity and sleep duration in children aged 6‐13 years. In adults, this genetic variant has been associated with duration of sleep, ghrelin levels, weight, and eating habits. Although short sleep duration has been linked to obesity in children, no study has aimed to identify the possible molecular mechanisms of this association to date. Methods: Weight, height, and circumferences were transformed into Z‐scores for age and gender. Genotyping was performed using TaqMan methodology. A questionnaire regarding hours of sleep was provided to parents. The appropriate statistical tests were performed. Results: This study evaluated 370 children (45% males, 55% females, mean age 8.5 ± 1.5 years. The prevalence of overweight was 18%. The duration of sleep was, on average, 9.7 hours, and was inversely related to age (p < 0.001. Genotype distribution was: 4% CC, 31% CT, and 65% TT. There was a trend toward higher prevalence of overweight in children who slept less than nine hours (23% when compared to those who slept more than ten hours (16%, p = 0.06. Genotype was not significantly correlated to any of the assessed outcomes. Conclusions: The CLOCK 3111T/C polymorphism was not significantly associated with overweight or sleep duration in children in this city. Resumo: Objetivos: Avaliar a relação entre o polimorfismo 3111 T/C do gene CLOCK (rs1801260 e a presença de obesidade, bem como a duração do sono, em crianças de 6 a 13 anos. Em adultos, essa variante genética foi associada à duração do sono, níveis de grelina, peso e padrão alimentar. Embora, em crianças, a curta duração do sono tenha sido relacionada à obesidade, até o momento nenhum estudo foi direcionado no sentido de identificar possíveis mecanismos moleculares dessa associação. Métodos: Peso, altura e circunferências foram transformados em escores‐Z para

Early transcriptomic changes induced by magnesium deficiency in Arabidopsis thaliana reveal the alteration of circadian clock gene expression in roots and the triggering of abscisic acid-responsive genes.

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Hermans, Christian; Vuylsteke, Marnik; Coppens, Frederik; Craciun, Adrian; Inzé, Dirk; Verbruggen, Nathalie

2010-07-01

*Plant growth and development ultimately depend on environmental variables such as the availability of essential minerals. Unravelling how nutrients affect gene expression will help to understand how they regulate plant growth. *This study reports the early transcriptomic response to magnesium (Mg) deprivation in Arabidopsis. Whole-genome transcriptome was studied in the roots and young mature leaves 4, 8 and 28 h after the removal of Mg from the nutrient solution. *The highest number of regulated genes was first observed in the roots. Contrary to other mineral deficiencies, Mg depletion did not induce a higher expression of annotated genes in Mg uptake. Remarkable responses include the perturbation of the central oscillator of the circadian clock in roots and the triggering of abscisic acid (ABA) signalling, with half of the up-regulated Mg genes in leaves being ABA-responsive. However, no change in ABA content was observed. *The specificity of the response of some Mg-regulated genes was challenged by studying their expression after other mineral deficiencies and environmental stresses. The possibility to develop markers for Mg incipient deficiency is discussed here.

Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

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Marina Pasca di Magliano

2007-11-01

Full Text Available Pancreatic ductal adenocarcinoma (PDA is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma.

[Circadian rhythm variation of the clock genes Per1 and cell cycle related genes in different stages of carcinogenesis of buccal mucosa in animal model].

Science.gov (United States)

Tan, Xuemei; Ye, Hua; Yang, Kai; Chen, Dan; Tang, Hong

2015-07-01

To investigate the expression and circadian rhythm variation of biological clock gene Per1 and cell cycle genes p53, CyclinD1, cyclin-dependent kinases (CDK1), CyclinB1 in different stages of carcinogenesis in buccal mucosa and its relationship with the development of buccal mucosa carcinoma. Ninety golden hamsters were housed under 12 hours light-12 hours dark cycles, and the model of buccal squamous cell carcinoma was established by using the dimethylbenzanthracene (DMBA) to smear the golden hamster buccal mucosa. Before the DMBA was used and after DMBA was used 6 weeks and 14 weeks respectively, the golden hamsters were sacrificed at 6 different time points (5 rats per time point) within 24 hour, including 4, 8, 12, 16, 20 and 24 hour after lights onset (HALO), and the normal buccal mucosa, precancerous lesions and cancer tissue were obtained, respectively. HE stained sections were prepared to observe the canceration of each tissue. Real time RT-PCR was used to detect the mRNA expression of Per1, p53, CyclinD1, CDK1 and CyclinB1, and a cosine analysis method was applied to determine the circadian rhythm variation of Per1, p53, CyclinD1, CDK1 and CyclinB1 mRNA expression, which were characterized by median, amplitude and acrophase. The expression of Per1, p53, CDK1 and CyclinD1 mRNA in 6 different time points within 24 hours in the tissues of three different stages of carcinogenesis had circadian rhythm, respectively. However, the CyclinB1 mRNA was expressed with circadian rhythm just in normal and cancer tissue (P circadian rhythm was in disorder (P > 0.05). As the development of carcinoma, the median of Per1 and p53 mRNA expression were significantly decreased (P circadian rhythm of clock gene Per1 and cell cycle genes p53, CyclinD1, CDK1, CyclinB1 expression remarkably varied with the occurrence and development of carcinoma. Further research into the interaction between circadian and cell cycle of two cycle activity and relationship with the carcinogenesis may

Stochastic models of cellular circadian rhythms in plants help to understand the impact of noise on robustness and clock structure

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Maria Luisa eGuerriero

2014-10-01

Full Text Available Rhythmic behavior is essential for plants; for example, daily (circadian rhythms control photosynthesis and seasonal rhythms regulate their life cycle. The core of the circadian clock is a genetic network that coordinates the expression of specific clock genes in a circadian rhythm reflecting the 24-hour day/night cycle.Circadian clocks exhibit stochastic noise due to the low copy numbers of clock genes and the consequent cell-to-cell variation: this intrinsic noise plays a major role in circadian clocks by inducing more robust oscillatory behavior. Another source of noise is the environment, which causes variation in temperature and light intensity: this extrinsic noise is part of the requirement for the structural complexity of clock networks.Advances in experimental techniques now permit single-cell measurements and the development of single-cell models. Here we present some modeling studies showing the importance of considering both types of noise in understanding how plants adapt to regular and irregular light variations. Stochastic models have proven useful for understanding the effect of regular variations. By contrast, the impact of irregular variations and the interaction of different noise sources are less studied.

General anesthesia alters time perception by phase shifting the circadian clock.

Science.gov (United States)

Cheeseman, James F; Winnebeck, Eva C; Millar, Craig D; Kirkland, Lisa S; Sleigh, James; Goodwin, Mark; Pawley, Matt D M; Bloch, Guy; Lehmann, Konstantin; Menzel, Randolf; Warman, Guy R

2012-05-01

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87° in the Southern Hemisphere and a clockwise shift in flight direction of 58° in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.

The dark sector from interacting canonical and non-canonical scalar fields

International Nuclear Information System (INIS)

De Souza, Rudinei C; Kremer, Gilberto M

2010-01-01

In this work general models with interactions between two canonical scalar fields and between one non-canonical (tachyon type) and one canonical scalar field are investigated. The potentials and couplings to the gravity are selected through the Noether symmetry approach. These general models are employed to describe interactions between dark energy and dark matter, with the fields being constrained by the astronomical data. The cosmological solutions of some cases are compared with the observed evolution of the late Universe.

Expression patterns of a circadian clock gene are associated with age-related polyethism in harvester ants, Pogonomyrmex occidentalis

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Ingram Krista K

2009-04-01

Full Text Available Abstract Background Recent advances in sociogenomics allow for comparative analyses of molecular mechanisms regulating the development of social behavior. In eusocial insects, one key aspect of their sociality, the division of labor, has received the most attention. Age-related polyethism, a derived form of division of labor in ants and bees where colony tasks are allocated among distinct behavioral phenotypes, has traditionally been assumed to be a product of convergent evolution. Previous work has shown that the circadian clock is associated with the development of behavior and division of labor in honeybee societies. We cloned the ortholog of the clock gene, period, from a harvester ant (Pogonomyrmex occidentalis and examined circadian rhythms and daily activity patterns in a species that represents an evolutionary origin of eusociality independent of the honeybee. Results Using real time qPCR analyses, we determined that harvester ants have a daily cyclic expression of period and this rhythm is endogenous (free-running under dark-dark conditions. Cyclic expression of period is task-specific; foragers have strong daily fluctuations but nest workers inside the nest do not. These patterns correspond to differences in behavior as activity levels of foragers show a diurnal pattern while nest workers tend to exhibit continuous locomotor activity at lower levels. In addition, we found that foragers collected in the early fall (relative warm, long days exhibit a delay in the nightly peak of period expression relative to foragers collected in the early spring (relative cold, short days. Conclusion The association of period mRNA expression levels with harvester ant task behaviors suggests that the development of circadian rhythms is associated with the behavioral development of ants. Thus, the circadian clock pathway may represent a conserved 'genetic toolkit' that has facilitated the parallel evolution of age-related polyethism and task allocation in

Canonical and Non-Canonical Aspects of JAK-STAT Signaling: Lessons from Interferons for Cytokine Responses.

Science.gov (United States)

Majoros, Andrea; Platanitis, Ekaterini; Kernbauer-Hölzl, Elisabeth; Rosebrock, Felix; Müller, Mathias; Decker, Thomas

2017-01-01

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK-STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1.

Both canonical and non-canonical Wnt signaling independently promote stem cell growth in mammospheres.

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Alexander M Many

Full Text Available The characterization of mammary stem cells, and signals that regulate their behavior, is of central importance in understanding developmental changes in the mammary gland and possibly for targeting stem-like cells in breast cancer. The canonical Wnt/β-catenin pathway is a signaling mechanism associated with maintenance of self-renewing stem cells in many tissues, including mammary epithelium, and can be oncogenic when deregulated. Wnt1 and Wnt3a are examples of ligands that activate the canonical pathway. Other Wnt ligands, such as Wnt5a, typically signal via non-canonical, β-catenin-independent, pathways that in some cases can antagonize canonical signaling. Since the role of non-canonical Wnt signaling in stem cell regulation is not well characterized, we set out to investigate this using mammosphere formation assays that reflect and quantify stem cell properties. Ex vivo mammosphere cultures were established from both wild-type and Wnt1 transgenic mice and were analyzed in response to manipulation of both canonical and non-canonical Wnt signaling. An increased level of mammosphere formation was observed in cultures derived from MMTV-Wnt1 versus wild-type animals, and this was blocked by treatment with Dkk1, a selective inhibitor of canonical Wnt signaling. Consistent with this, we found that a single dose of recombinant Wnt3a was sufficient to increase mammosphere formation in wild-type cultures. Surprisingly, we found that Wnt5a also increased mammosphere formation in these assays. We confirmed that this was not caused by an increase in canonical Wnt/β-catenin signaling but was instead mediated by non-canonical Wnt signals requiring the receptor tyrosine kinase Ror2 and activity of the Jun N-terminal kinase, JNK. We conclude that both canonical and non-canonical Wnt signals have positive effects promoting stem cell activity in mammosphere assays and that they do so via independent signaling mechanisms.

Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma

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Alexandre Vallée

2017-05-01

Full Text Available Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1 and monocarboxylate lactate transporter 1 (MCT-1. Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH. Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.

Controllable clock circuit design in PEM system

International Nuclear Information System (INIS)

Sun Yunhua; Wang Peihua; Hu Tingting; Feng Baotong; Shuai Lei; Huang Huan; Wei Shujun; Li Ke; Zhao Jingwei; Wei Long

2011-01-01

A high-precision synchronized clock circuit design will be presented, which can supply steady, reliable and anti-jamming clock signal for the data acquirement (DAQ) system of Positron Emission Mammography (PEM). This circuit design is based on the Single-Chip Microcomputer and high-precision clock chip, and can achieve multiple controllable clock signals. The jamming between the clock signals can be reduced greatly with the differential transmission. Meanwhile, the adoption of CAN bus control in the clock circuit can prompt the clock signals to be transmitted or masked simultaneously when needed. (authors)

Controllable clock circuit design in PEM system

International Nuclear Information System (INIS)

Sun Yunhua; Wang Peilin; Hu Tingting; Feng Baotong; Shuai Lei; Huang Huan; Wei Shujun; Li Ke; Zhao Jingwei; Wei Long

2010-01-01

A high-precision synchronized clock circuit design will be presented, which can supply steady, reliable and anti-jamming clock signal for the data acquirement (DAQ) system of Positron Emission Mammography (PEM). This circuit design is based on the Single-Chip Microcomputer and high-precision clock chip, and can achieve multiple controllable clock signals. The jamming between the clock signals can be reduced greatly with the differential transmission. Meanwhile, the adoption of CAN bus control in the clock circuit can prompt the clock signals to be transmitted or masked simultaneously when needed. (authors)

GPS Composite Clock Analysis

OpenAIRE

Wright, James R.

2008-01-01

The GPS composite clock defines GPS time, the timescale used today in GPS operations. GPS time is illuminated by examination of its role in the complete estimation and control problem relative to UTC/TAI. The phase of each GPS clock is unobservable from GPS pseudorange measurements, and the mean phase of the GPS clock ensemble (GPS time) is unobservable. A new and useful observability definition is presented, together with new observability theorems, to demonstrate explicitly that GPS time is...

Defence responses of arabidopsis thaliana to infection by pseudomonas syringae are regulated by the circadian clock

KAUST Repository

Bhardwaj, Vaibhav

2011-10-31

The circadian clock allows plants to anticipate predictable daily changes in abiotic stimuli, such as light; however, whether the clock similarly allows plants to anticipate interactions with other organisms is unknown. Here we show that Arabidopsis thaliana (Arabidopsis) has circadian clock-mediated variation in resistance to the virulent bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), with plants being least susceptible to infection in the subjective morning. We suggest that the increased resistance to Pst DC3000 observed in the morning in Col-0 plants results from clock-mediated modulation of pathogen associated molecular pattern (PAMP)-triggered immunity. Analysis of publicly available microarray data revealed that a large number of Arabidopsis defence-related genes showed both diurnal- and circadian-regulation, including genes involved in the perception of the PAMP flagellin which exhibit a peak in expression in the morning. Accordingly, we observed that PAMP-triggered callose deposition was significantly higher in wild-type plants inoculated with Pst DC3000 hrpA in the subjective morning than in the evening, while no such temporal difference was evident in arrhythmic plants. Our results suggest that PAMP-triggered immune responses are modulated by the circadian clock and that temporal regulation allows plants to anticipate and respond more effectively to pathogen challenges in the daytime. © 2011 Bhardwaj et al.

Three dimensional canonical transformations

International Nuclear Information System (INIS)

Tegmen, A.

2010-01-01

A generic construction of canonical transformations is given in three-dimensional phase spaces on which Nambu bracket is imposed. First, the canonical transformations are defined as based on cannonade transformations. Second, it is shown that determination of the generating functions and the transformation itself for given generating function is possible by solving correspondent Pfaffian differential equations. Generating functions of type are introduced and all of them are listed. Infinitesimal canonical transformations are also discussed as the complementary subject. Finally, it is shown that decomposition of canonical transformations is also possible in three-dimensional phase spaces as in the usual two-dimensional ones.

Canonical methods in classical and quantum gravity: An invitation to canonical LQG

Science.gov (United States)

Reyes, Juan D.

2018-04-01

Loop Quantum Gravity (LQG) is a candidate quantum theory of gravity still under construction. LQG was originally conceived as a background independent canonical quantization of Einstein’s general relativity theory. This contribution provides some physical motivations and an overview of some mathematical tools employed in canonical Loop Quantum Gravity. First, Hamiltonian classical methods are reviewed from a geometric perspective. Canonical Dirac quantization of general gauge systems is sketched next. The Hamiltonian formultation of gravity in geometric ADM and connection-triad variables is then presented to finally lay down the canonical loop quantization program. The presentation is geared toward advanced undergradute or graduate students in physics and/or non-specialists curious about LQG.

Automatic control of clock duty cycle

Science.gov (United States)

Feng, Xiaoxin (Inventor); Roper, Weston (Inventor); Seefeldt, James D. (Inventor)

2010-01-01

In general, this disclosure is directed to a duty cycle correction (DCC) circuit that adjusts a falling edge of a clock signal to achieve a desired duty cycle. In some examples, the DCC circuit may generate a pulse in response to a falling edge of an input clock signal, delay the pulse based on a control voltage, adjust the falling edge of the input clock signal based on the delayed pulse to produce an output clock signal, and adjust the control voltage based on the difference between a duty cycle of the output clock signal and a desired duty cycle. Since the DCC circuit adjusts the falling edge of the clock cycle to achieve a desired duty cycle, the DCC may be incorporated into existing PLL control loops that adjust the rising edge of a clock signal without interfering with the operation of such PLL control loops.

The Circadian Clock Modulates Global Daily Cycles of mRNA Ribosome Loading[OPEN

Science.gov (United States)

Missra, Anamika; Ernest, Ben; Jia, Qidong; Ke, Kenneth

2015-01-01

Circadian control of gene expression is well characterized at the transcriptional level, but little is known about diel or circadian control of translation. Genome-wide translation state profiling of mRNAs in Arabidopsis thaliana seedlings grown in long day was performed to estimate ribosome loading per mRNA. The experiments revealed extensive translational regulation of key biological processes. Notably, translation of mRNAs for ribosomal proteins and mitochondrial respiration peaked at night. Central clock mRNAs are among those subject to fluctuations in ribosome loading. There was no consistent phase relationship between peak translation states and peak transcript levels. The overlay of distinct transcriptional and translational cycles can be expected to alter the waveform of the protein synthesis rate. Plants that constitutively overexpress the clock gene CCA1 showed phase shifts in peak translation, with a 6-h delay from midnight to dawn or from noon to evening being particularly common. Moreover, cycles of ribosome loading that were detected under continuous light in the wild type collapsed in the CCA1 overexpressor. Finally, at the transcript level, the CCA1-ox strain adopted a global pattern of transcript abundance that was broadly correlated with the light-dark environment. Altogether, these data demonstrate that gene-specific diel cycles of ribosome loading are controlled in part by the circadian clock. PMID:26392078

Atomic and gravitational clocks

International Nuclear Information System (INIS)

Canuto, V.M.; City Coll., New York; Goldman, I.

1982-01-01

Atomic and gravitational clocks are governed by the laws of electrodynamics and gravity respectively. While the strong equivalence principle (SEP) assumes that the two clocks have been synchronous at all times, recent planetary data seem to suggest a possible violation of the SEP. Past analysis of the implications of an SEP violation on different physical phenomena revealed no disagreement. However, these studies assumed that the two different clocks can be consistently constructed within the framework. The concept of scale invariance, and the physical meaning of different systems of units, are now reviewed and the construction of two clocks that do not remain synchronous-whose rates are related by a non-constant function βsub(a)-is demonstrated. The cosmological character of βsub(a) is also discussed. (author)

Egyptian "Star Clocks"

Science.gov (United States)

Symons, Sarah

Diagonal, transit, and Ramesside star clocks are tables of astronomical information occasionally found in ancient Egyptian temples, tombs, and papyri. The tables represent the motions of selected stars (decans and hour stars) throughout the Egyptian civil year. Analysis of star clocks leads to greater understanding of ancient Egyptian constellations, ritual astronomical activities, observational practices, and pharaonic chronology.

NPAS2 and PER2 are linked to risk factors of the metabolic syndrome

Directory of Open Access Journals (Sweden)

Aromaa Arpo

2009-05-01

Full Text Available Abstract Background Mammalian circadian clocks control multiple physiological events. The principal circadian clock generates seasonal variations in behavior as well. Seasonality elevates the risk for metabolic syndrome, and evidence suggests that disruption of the clockwork can lead to alterations in metabolism. Our aim was to analyze whether circadian clock polymorphisms contribute to seasonal variations in behavior and to the metabolic syndrome. Methods We genotyped 39 single-nucleotide polymorphisms (SNP from 19 genes which were either canonical circadian clock genes or genes related to the circadian clockwork from 517 individuals drawn from a nationwide population-based sample. Associations between these SNPs and seasonality, metabolic syndrome and its risk factors were analyzed using regression analysis. The p-values were corrected for multiple testing. Results Our findings link circadian gene variants to the risk factors of the metabolic syndrome, since Npas2 was associated with hypertension (P-value corrected for multiple testing = 0.0024 and Per2 was associated with high fasting blood glucose (P-value corrected for multiple testing = 0.049. Conclusion Our findings support the view that relevant relationships between circadian clocks and the metabolic syndrome in humans exist.

Frequency-based time-series gene expression recomposition using PRIISM

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Rosa Bruce A

2012-06-01

Full Text Available Abstract Background Circadian rhythm pathways influence the expression patterns of as much as 31% of the Arabidopsis genome through complicated interaction pathways, and have been found to be significantly disrupted by biotic and abiotic stress treatments, complicating treatment-response gene discovery methods due to clock pattern mismatches in the fold change-based statistics. The PRIISM (Pattern Recomposition for the Isolation of Independent Signals in Microarray data algorithm outlined in this paper is designed to separate pattern changes induced by different forces, including treatment-response pathways and circadian clock rhythm disruptions. Results Using the Fourier transform, high-resolution time-series microarray data is projected to the frequency domain. By identifying the clock frequency range from the core circadian clock genes, we separate the frequency spectrum to different sections containing treatment-frequency (representing up- or down-regulation by an adaptive treatment response, clock-frequency (representing the circadian clock-disruption response and noise-frequency components. Then, we project the components’ spectra back to the expression domain to reconstruct isolated, independent gene expression patterns representing the effects of the different influences. By applying PRIISM on a high-resolution time-series Arabidopsis microarray dataset under a cold treatment, we systematically evaluated our method using maximum fold change and principal component analyses. The results of this study showed that the ranked treatment-frequency fold change results produce fewer false positives than the original methodology, and the 26-hour timepoint in our dataset was the best statistic for distinguishing the most known cold-response genes. In addition, six novel cold-response genes were discovered. PRIISM also provides gene expression data which represents only circadian clock influences, and may be useful for circadian clock studies

Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis

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Vincent van den Boom

2016-01-01

Full Text Available Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34+ cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability.

A VMEbus clock system for accelerator control

International Nuclear Information System (INIS)

Beechy, D.G.; McClure, C.R.

1992-01-01

Because an accelerator has many systems which must operate with a high degree of synchronization, a clock signal is typically generated which carries timing information to the various accelerator components. This paper discusses two VMEbus modules designed to generate and receive this clock signal. Together they implement a clock system which can generate timing markers with 200 nanosecond resolution and can generate timing delays of over one hour with one microsecond resolution. The Clock Generator module contains both a time line generator programmed to produce clock events at specific times and eight programmable input channels to produce clock events when externally triggered. Additional clock events are generated directly from the VMEbus. Generators can be cascaded for added capability. The Clock Timer module receives the signal from the generator. It can be programmed to recognize specific clock events which act as triggers to the eight timing channels on the module. Each timing channel is programmed with a 32-bit delay value. The channels are clocked at 1 MHz. At the end of the delay period, a timer channel produces an output pulse and optionally can generate a bus interrupt

An analysis of clock-shift experiments: is scatter increased and deflection reduced in clock-shifted homing pigeons?

Science.gov (United States)

Chappell

1997-01-01

Clock-shifting (altering the phase of the internal clock) in homing pigeons leads to a deflection in the vanishing bearing of the clock-shifted group relative to controls. However, two unexplained phenomena are common in clock-shift experiments: the vanishing bearings of the clock-shifted group are often more scattered (with a shorter vector length) than those of the control group, and the deflection of the mean bearing of the clock-shifted group from that of the controls is often smaller than expected theoretically. Here, an analysis of 55 clock-shift experiments performed in four countries over 21 years is reported. The bearings of the clock-shifted groups were significantly more scattered than those of controls and less deflected than expected, but these effects were not significantly different at familiar and unfamiliar sites. The possible causes of the effects are discussed and evaluated with reference to this analysis and other experiments. The most likely causes appear to be conflict between the directions indicated by the sun compass and either unshifted familiar visual landmarks (at familiar sites only) or the unshifted magnetic compass (possible at both familiar and unfamiliar sites).

High Performance Clocks and Gravity Field Determination

Science.gov (United States)

Müller, J.; Dirkx, D.; Kopeikin, S. M.; Lion, G.; Panet, I.; Petit, G.; Visser, P. N. A. M.

2018-02-01

Time measured by an ideal clock crucially depends on the gravitational potential and velocity of the clock according to general relativity. Technological advances in manufacturing high-precision atomic clocks have rapidly improved their accuracy and stability over the last decade that approached the level of 10^{-18}. This notable achievement along with the direct sensitivity of clocks to the strength of the gravitational field make them practically important for various geodetic applications that are addressed in the present paper. Based on a fully relativistic description of the background gravitational physics, we discuss the impact of those highly-precise clocks on the realization of reference frames and time scales used in geodesy. We discuss the current definitions of basic geodetic concepts and come to the conclusion that the advances in clocks and other metrological technologies will soon require the re-definition of time scales or, at least, clarification to ensure their continuity and consistent use in practice. The relative frequency shift between two clocks is directly related to the difference in the values of the gravity potential at the points of clock's localization. According to general relativity the relative accuracy of clocks in 10^{-18} is equivalent to measuring the gravitational red shift effect between two clocks with the height difference amounting to 1 cm. This makes the clocks an indispensable tool in high-precision geodesy in addition to laser ranging and space geodetic techniques. We show how clock measurements can provide geopotential numbers for the realization of gravity-field-related height systems and can resolve discrepancies in classically-determined height systems as well as between national height systems. Another application of clocks is the direct use of observed potential differences for the improved recovery of regional gravity field solutions. Finally, clock measurements for space-borne gravimetry are analyzed along with

Causes and consequences of hyperexcitation in central clock neurons.

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Casey O Diekman

Full Text Available Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs, have been observed in neurons of the suprachiasmatic nuclei (SCN, the site of the central mammalian circadian (~24-hour clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus.

NONO couples the circadian clock to the cell cycle.

Science.gov (United States)

Kowalska, Elzbieta; Ripperger, Juergen A; Hoegger, Dominik C; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A

2013-01-29

Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.

Robustness from flexibility in the fungal circadian clock

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Akman Ozgur E

2010-06-01

Full Text Available Abstract Background Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa. Results The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq gene inhibits its transcriptional activator white collar-1 (wc-1, interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on

Canonical transformations of Kepler trajectories

International Nuclear Information System (INIS)

Mostowski, Jan

2010-01-01

In this paper, canonical transformations generated by constants of motion in the case of the Kepler problem are discussed. It is shown that canonical transformations generated by angular momentum are rotations of the trajectory. Particular attention is paid to canonical transformations generated by the Runge-Lenz vector. It is shown that these transformations change the eccentricity of the orbit. A method of obtaining elliptic trajectories from the circular ones with the help of canonical trajectories is discussed.

The Canonical Immediate Early 3 Gene Product pIE611 of Mouse Cytomegalovirus Is Dispensable for Viral Replication but Mediates Transcriptional and Posttranscriptional Regulation of Viral Gene Products.

Science.gov (United States)

Rattay, Stephanie; Trilling, Mirko; Megger, Dominik A; Sitek, Barbara; Meyer, Helmut E; Hengel, Hartmut; Le-Trilling, Vu Thuy Khanh

2015-08-01

Transcription of mouse cytomegalovirus (MCMV) immediate early ie1 and ie3 is controlled by the major immediate early promoter/enhancer (MIEP) and requires differential splicing. Based on complete loss of genome replication of an MCMV mutant carrying a deletion of the ie3-specific exon 5, the multifunctional IE3 protein (611 amino acids; pIE611) is considered essential for viral replication. Our analysis of ie3 transcription resulted in the identification of novel ie3 isoforms derived from alternatively spliced ie3 transcripts. Construction of an IE3-hemagglutinin (IE3-HA) virus by insertion of an in-frame HA epitope sequence allowed detection of the IE3 isoforms in infected cells, verifying that the newly identified transcripts code for proteins. This prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Δie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication. To determine the role of pIE611 for viral gene expression during MCMV infection in an unbiased global approach, we used label-free quantitative mass spectrometry to delineate pIE611-dependent changes of the MCMV proteome. Interestingly, further analysis revealed transcriptional as well as posttranscriptional regulation of MCMV gene products by pIE611. Cytomegaloviruses are pathogenic betaherpesviruses persisting in a lifelong latency from which reactivation can occur under conditions of immunosuppression, immunoimmaturity, or inflammation. The switch from latency to reactivation requires expression of immediate early genes. Therefore, understanding of immediate early gene regulation might add insights into viral pathogenesis. The mouse cytomegalovirus (MCMV) immediate early 3 protein (611 amino acids; pIE611) is considered essential for viral replication. The identification of novel protein isoforms derived from alternatively spliced ie3 transcripts prompted

Canonical quantum gravity and consistent discretizations

Indian Academy of Sciences (India)

Abstract. This paper covers some developments in canonical quantum gravity that ... derstanding the real Ashtekar variables four dimensionally [4], or the recent work ... Traditionally, canonical formulations of general relativity considered as canonical variables the metric on a spatial slice qab and a canonically conjugate.

Hypothalamic expression and moonlight-independent changes of Cry3 and Per4 implicate their roles in lunar clock oscillators of the lunar-responsive Goldlined spinefoot.

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Riko Toda

Full Text Available Lunar cycle-associated physiology has been found in a wide variety of organisms. Studies suggest the presence of a circalunar clock in some animals, but the location of the lunar clock is unclear. We previously found lunar-associated expression of transcripts for Cryptochrome3 gene (SgCry3 in the brain of a lunar phase-responsive fish, the Goldlined spinefoot (Siganus guttatus. Then we proposed a photoperiodic model for the lunar phase response, in which SgCry3 might function as a phase-specific light response gene and/or an oscillatory factor in unidentified circalunar clock. In this study, we have developed an anti-SgCRY3 antibody to identify SgCRY3-immunoreactive cells in the brain. We found immunoreactions in the subependymal cells located in the mediobasal region of the diencephalon, a crucial site for photoperiodic seasonal responses in birds. For further assessment of the lunar-responding mechanism and the circalunar clock, we investigated mRNA levels of Cry3 as well as those of the other clock(-related genes, Period (Per2 and Per4, in S. guttatus reared under nocturnal moonlight interruption or natural conditions. Not only SgCry3 but SgPer4 mRNA levels showed lunar phase-dependent variations in the diencephalon without depending on light condition during the night. These results suggest that the expressions of SgCry3 and SgPer4 are not directly regulated by moonlight stimulation but endogenously mediated in the brain, and implicate that circadian clock(-related genes may be involved in the circalunar clock locating within the mediobasal region of the diencephalon.

Hypothalamic expression and moonlight-independent changes of Cry3 and Per4 implicate their roles in lunar clock oscillators of the lunar-responsive Goldlined spinefoot.

Science.gov (United States)

Toda, Riko; Okano, Keiko; Takeuchi, Yuki; Yamauchi, Chihiro; Fukushiro, Masato; Takemura, Akihiro; Okano, Toshiyuki

2014-01-01

Lunar cycle-associated physiology has been found in a wide variety of organisms. Studies suggest the presence of a circalunar clock in some animals, but the location of the lunar clock is unclear. We previously found lunar-associated expression of transcripts for Cryptochrome3 gene (SgCry3) in the brain of a lunar phase-responsive fish, the Goldlined spinefoot (Siganus guttatus). Then we proposed a photoperiodic model for the lunar phase response, in which SgCry3 might function as a phase-specific light response gene and/or an oscillatory factor in unidentified circalunar clock. In this study, we have developed an anti-SgCRY3 antibody to identify SgCRY3-immunoreactive cells in the brain. We found immunoreactions in the subependymal cells located in the mediobasal region of the diencephalon, a crucial site for photoperiodic seasonal responses in birds. For further assessment of the lunar-responding mechanism and the circalunar clock, we investigated mRNA levels of Cry3 as well as those of the other clock(-related) genes, Period (Per2 and Per4), in S. guttatus reared under nocturnal moonlight interruption or natural conditions. Not only SgCry3 but SgPer4 mRNA levels showed lunar phase-dependent variations in the diencephalon without depending on light condition during the night. These results suggest that the expressions of SgCry3 and SgPer4 are not directly regulated by moonlight stimulation but endogenously mediated in the brain, and implicate that circadian clock(-related) genes may be involved in the circalunar clock locating within the mediobasal region of the diencephalon.

Canonical and Non-Canonical Aspects of JAK–STAT Signaling: Lessons from Interferons for Cytokine Responses

Science.gov (United States)

Majoros, Andrea; Platanitis, Ekaterini; Kernbauer-Hölzl, Elisabeth; Rosebrock, Felix; Müller, Mathias; Decker, Thomas

2017-01-01

Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK–STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1. PMID:28184222

Atomic clocks for geodesy

Science.gov (United States)

Mehlstäubler, Tanja E.; Grosche, Gesine; Lisdat, Christian; Schmidt, Piet O.; Denker, Heiner

2018-06-01

We review experimental progress on optical atomic clocks and frequency transfer, and consider the prospects of using these technologies for geodetic measurements. Today, optical atomic frequency standards have reached relative frequency inaccuracies below 10‑17, opening new fields of fundamental and applied research. The dependence of atomic frequencies on the gravitational potential makes atomic clocks ideal candidates for the search for deviations in the predictions of Einstein’s general relativity, tests of modern unifying theories and the development of new gravity field sensors. In this review, we introduce the concepts of optical atomic clocks and present the status of international clock development and comparison. Besides further improvement in stability and accuracy of today’s best clocks, a large effort is put into increasing the reliability and technological readiness for applications outside of specialized laboratories with compact, portable devices. With relative frequency uncertainties of 10‑18, comparisons of optical frequency standards are foreseen to contribute together with satellite and terrestrial data to the precise determination of fundamental height reference systems in geodesy with a resolution at the cm-level. The long-term stability of atomic standards will deliver excellent long-term height references for geodetic measurements and for the modelling and understanding of our Earth.

Epigenetic control and the circadian clock: linking metabolism to neuronal responses.

Science.gov (United States)

Orozco-Solis, R; Sassone-Corsi, P

2014-04-04

Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape. Published by Elsevier Ltd.

CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock.

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Teruya Tamaru

Full Text Available Intracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we established a pivotal role for casein kinase (CK-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P in regulating central and peripheral core clocks. Subsequent analysis of the underlying mechanism showed a novel role of CRY as a repressor for protein kinase. Co-immunoprecipitation experiments and real-time monitoring of protein-protein interactions revealed that CRY-mediated periodic binding of CK2β to BMAL1 inhibits BMAL1-Ser90 phosphorylation by CK2α. The FAD binding domain of CRY1, two C-terminal BMAL1 domains, and particularly BMAL1-Lys537 acetylation/deacetylation by CLOCK/SIRT1, were shown to be critical for CRY-mediated BMAL1-CK2β binding. Reciprocally, BMAL1-Ser90 phosphorylation is prerequisite for BMAL1-Lys537 acetylation. We propose a dual negative-feedback model in which a CRY-dependent CK2-driven posttranslational BMAL1-P-BMAL1 loop is an integral part of the core clock oscillator.

Light and the human circadian clock

NARCIS (Netherlands)

Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V

2013-01-01

The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the

Age-Related Changes in the Expression of the Circadian Clock Protein PERIOD in Drosophila Glial Cells

OpenAIRE

Long, Dani M.; Giebultowicz, Jadwiga M.

2018-01-01

Circadian clocks consist of molecular negative feedback loops that coordinate physiological, neurological, and behavioral variables into “circa” 24-h rhythms. Rhythms in behavioral and other circadian outputs tend to weaken during aging, as evident in progressive disruptions of sleep-wake cycles in aging organisms. However, less is known about the molecular changes in the expression of clock genes and proteins that may lead to the weakening of circadian outputs. Western blot studies have demo...

Towards Self-Clocked Gated OCDMA Receiver

Science.gov (United States)

Idris, S.; Osadola, T.; Glesk, I.

2013-02-01

A novel incoherent OCDMA receiver with incorporated all-optical clock recovery for self-synchronization of a time gate for the multi access interferences (MAI) suppression and minimizing the effect of data time jitter in incoherent OCDMA system was successfully developed and demonstrated. The solution was implemented and tested in a multiuser environment in an out of the laboratory OCDMA testbed with two-dimensional wavelength-hopping time-spreading coding scheme and OC-48 (2.5 Gbp/s) data rate. The self-clocked all-optical time gate uses SOA-based fibre ring laser optical clock, recovered all-optically from the received OCDMA traffic to control its switching window for cleaning the autocorrelation peak from the surrounding MAI. A wider eye opening was achieved when the all-optically recovered clock from received data was used for synchronization if compared to a static approach with the RF clock being generated by a RF synthesizer. Clean eye diagram was also achieved when recovered clock is used to drive time gating.

Feeding period restriction alters the expression of peripheral circadian rhythm genes without changing body weight in mice.

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Hagoon Jang

Full Text Available Accumulating evidence suggests that the circadian clock is closely associated with metabolic regulation. However, whether an impaired circadian clock is a direct cause of metabolic dysregulation such as body weight gain is not clearly understood. In this study, we demonstrate that body weight gain in mice is not significantly changed by restricting feeding period to daytime or nighttime. The expression of peripheral circadian clock genes was altered by feeding period restriction, while the expression of light-regulated hypothalamic circadian clock genes was unaffected by either a normal chow diet (NCD or a high-fat diet (HFD. In the liver, the expression pattern of circadian clock genes, including Bmal1, Clock, and Per2, was changed by different feeding period restrictions. Moreover, the expression of lipogenic genes, gluconeogenic genes, and fatty acid oxidation-related genes in the liver was also altered by feeding period restriction. Given that feeding period restriction does not affect body weight gain with a NCD or HFD, it is likely that the amount of food consumed might be a crucial factor in determining body weight. Collectively, these data suggest that feeding period restriction modulates the expression of peripheral circadian clock genes, which is uncoupled from light-sensitive hypothalamic circadian clock genes.

Could Atomic clocks be affected by neutrinos?

CERN Document Server

Hanafi, Hanaa

2016-01-01

An atomic clock is a clock device that uses an electronic transition frequency of the electromagnetic spectrum of atoms as a frequency standard in order to derive a time standard since time is the reciprocal of frequency. If the electronic transition frequencies are in an "optical region", we are talking in this case about optical atomic clocks. If they are in an "microwave region" these atomic clocks are made of the metallic element cesium so they are called Cesium atomic clocks. Atomic clocks are the most accurate time and frequency standards known despite the different perturbations that can affect them, a lot of researches were made in this domain to show how the transitions can be different for different type of perturbations..Since atomic clocks are very sensitive devices, based on coherent states (A coherent state tends to loose coherence after interacting). One question can arise (from a lot of questions) which is why cosmic neutrinos are not affecting these clocks? The answer to this question requir...

Time-of-Day Effects on Metabolic and Clock-Related Adjustments to Cold

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Frederico Sander Mansur Machado

2018-04-01

Full Text Available BackgroundDaily cyclic changes in environmental conditions are key signals for anticipatory and adaptive adjustments of most living species, including mammals. Lower ambient temperature stimulates the thermogenic activity of brown adipose tissue (BAT and skeletal muscle. Given that the molecular components of the endogenous biological clock interact with thermal and metabolic mechanisms directly involved in the defense of body temperature, the present study evaluated the differential homeostatic responses to a cold stimulus at distinct time-windows of the light/dark-cycle.MethodsMale Wistar rats were subjected to a single episode of 3 h cold ambient temperature (4°C at one of 6 time-points starting at Zeitgeber Times 3, 7, 11, 15, 19, and 23. Metabolic rate, core body temperature, locomotor activity (LA, feeding, and drinking behaviors were recorded during control and cold conditions at each time-point. Immediately after the stimulus, rats were euthanized and both the soleus and BAT were collected for real-time PCR.ResultsDuring the light phase (i.e., inactive phase, cold exposure resulted in a slight hyperthermia (p < 0.001. Light phase cold exposure also increased metabolic rate and LA (p < 0.001. In addition, the prevalence of fat oxidative metabolism was attenuated during the inactive phase (p < 0.001. These metabolic changes were accompanied by time-of-day and tissue-specific changes in core clock gene expression, such as DBP (p < 0.0001 and REV-ERBα (p < 0.01 in the BAT and CLOCK (p < 0.05, PER2 (p < 0.05, CRY1 (p < 0.05, CRY2 (p < 0.01, and REV-ERBα (p < 0.05 in the soleus skeletal muscle. Moreover, genes involved in substrate oxidation and thermogenesis were affected in a time-of-day and tissue-specific manner by cold exposure.ConclusionThe time-of-day modulation of substrate mobilization and oxidation during cold exposure provides a clear example of the circadian modulation of physiological

Biological Clocks & Circadian Rhythms

Science.gov (United States)

Robertson, Laura; Jones, M. Gail

2009-01-01

The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…

Circadian clocks, epigenetics, and cancer

KAUST Repository

Masri, Selma; Kinouchi, Kenichiro; Sassone-Corsi, Paolo

2015-01-01

The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

Pitfalls of Insulin Pump Clocks

Science.gov (United States)

Reed, Amy J.

2014-01-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

Circadian clock genes Per1 and Per2 regulate the response of metabolism-associated transcripts to sleep disruption.

Directory of Open Access Journals (Sweden)

Jana Husse

Full Text Available Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction--TSR. We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects

GPS satellite clock determination in case of inter-frequency clock biases for triple-frequency precise point positioning

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Guo, Jiang; Geng, Jianghui

2017-12-01

Significant time-varying inter-frequency clock biases (IFCBs) within GPS observations prevent the application of the legacy L1/L2 ionosphere-free clock products on L5 signals. Conventional approaches overcoming this problem are to estimate L1/L5 ionosphere-free clocks in addition to their L1/L2 counterparts or to compute IFCBs between the L1/L2 and L1/L5 clocks which are later modeled through a harmonic analysis. In contrast, we start from the undifferenced uncombined GNSS model and propose an alternative approach where a second satellite clock parameter dedicated to the L5 signals is estimated along with the legacy L1/L2 clock. In this manner, we do not need to rely on the correlated L1/L2 and L1/L5 ionosphere-free observables which complicates triple-frequency GPS stochastic models, or account for the unfavorable time-varying hardware biases in undifferenced GPS functional models since they can be absorbed by the L5 clocks. An extra advantage over the ionosphere-free model is that external ionosphere constraints can potentially be introduced to improve PPP. With 27 days of triple-frequency GPS data from globally distributed stations, we find that the RMS of the positioning differences between our GPS model and all conventional models is below 1 mm for all east, north and up components, demonstrating the effectiveness of our model in addressing triple-frequency observations and time-varying IFCBs. Moreover, we can combine the L1/L2 and L5 clocks derived from our model to calculate precisely the L1/L5 clocks which in practice only depart from their legacy counterparts by less than 0.006 ns in RMS. Our triple-frequency GPS model proves convenient and efficient in combating time-varying IFCBs and can be generalized to more than three frequency signals for satellite clock determination.

Adrenal clocks and the role of adrenal hormones in the regulation of circadian physiology.

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Leliavski, Alexei; Dumbell, Rebecca; Ott, Volker; Oster, Henrik

2015-02-01

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) and subordinate clocks that disseminate time information to various central and peripheral tissues. While the function of the SCN in circadian rhythm regulation has been extensively studied, we still have limited understanding of how peripheral tissue clock function contributes to the regulation of physiological processes. The adrenal gland plays a special role in this context as adrenal hormones show strong circadian secretion rhythms affecting downstream physiological processes. At the same time, they have been shown to affect clock gene expression in various other tissues, thus mediating systemic entrainment to external zeitgebers and promoting internal circadian alignment. In this review, we discuss the function of circadian clocks in the adrenal gland, how they are reset by the SCN and may further relay time-of-day information to other tissues. Focusing on glucocorticoids, we conclude by outlining the impact of adrenal rhythm disruption on neuropsychiatric, metabolic, immune, and malignant disorders. © 2014 The Author(s).

Decamp Clock Board Firmware

Energy Technology Data Exchange (ETDEWEB)

Vicente, J. de; Castilla, J.; Martinez, G.

2007-09-27

Decamp (Dark Energy Survey Camera) is a new instrument designed to explore the universe aiming to reveal the nature of Dark Energy. The camera consists of 72 CCDs and 520 Mpixels. The readout electronics of DECam is based on the Monsoon system. Monsoon is a new image acquisition system developed by the NOAO (National Optical Astronomical Observatory) for the new generation of astronomical cameras. The Monsoon system uses three types of boards inserted in a Eurocard format based crate: master control board, acquisition board and clock board. The direct use of the Monsoon system for DECam readout electronics requires nine crates mainly due to the high number of clock boards needed. Unfortunately, the available space for DECam electronics is constrained to four crates at maximum. The major drawback to achieve such desired compaction degree resides in the clock board signal density. This document describes the changes performed at CIEMAT on the programmable logic of the Monsoon clock board aiming to meet such restricted space constraints. (Author) 5 refs.

Decamp Clock Board Firmware

International Nuclear Information System (INIS)

Vicente, J. de; Castilla, J.; Martinez, G.

2007-01-01

Decamp (Dark Energy Survey Camera) is a new instrument designed to explore the universe aiming to reveal the nature of Dark Energy. The camera consists of 72 CCDs and 520 Mpixels. The readout electronics of DECam is based on the Monsoon system. Monsoon is a new image acquisition system developed by the NOAO (National Optical Astronomical Observatory) for the new generation of astronomical cameras. The Monsoon system uses three types of boards inserted in a Eurocard format based crate: master control board, acquisition board and clock board. The direct use of the Monsoon system for DECam readout electronics requires nine crates mainly due to the high number of clock boards needed. Unfortunately, the available space for DECam electronics is constrained to four crates at maximum. The major drawback to achieve such desired compaction degree resides in the clock board signal density. This document describes the changes performed at CIEMAT on the programmable logic of the Monsoon clock board aiming to meet such restricted space constraints. (Author) 5 refs

Canonical vs. micro-canonical sampling methods in a 2D Ising model

International Nuclear Information System (INIS)

Kepner, J.

1990-12-01

Canonical and micro-canonical Monte Carlo algorithms were implemented on a 2D Ising model. Expressions for the internal energy, U, inverse temperature, Z, and specific heat, C, are given. These quantities were calculated over a range of temperature, lattice sizes, and time steps. Both algorithms accurately simulate the Ising model. To obtain greater than three decimal accuracy from the micro-canonical method requires that the more complicated expression for Z be used. The overall difference between the algorithms is small. The physics of the problem under study should be the deciding factor in determining which algorithm to use. 13 refs., 6 figs., 2 tabs

The Importance of the Circadian Clock in Regulating Plant Metabolism

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Jin A Kim

2017-12-01

Full Text Available Carbohydrates are the primary energy source for plant development. Plants synthesize sucrose in source organs and transport them to sink organs during plant growth. This metabolism is sensitive to environmental changes in light quantity, quality, and photoperiod. In the daytime, the synthesis of sucrose and starch accumulates, and starch is degraded at nighttime. The circadian clock genes provide plants with information on the daily environmental changes and directly control many developmental processes, which are related to the path of primary metabolites throughout the life cycle. The circadian clock mechanism and processes of metabolism controlled by the circadian rhythm were studied in the model plant Arabidopsis and in the crops potato and rice. However, the translation of molecular mechanisms obtained from studies of model plants to crop plants is still difficult. Crop plants have specific organs such as edible seed and tuber that increase the size or accumulate valuable metabolites by harvestable metabolic components. Human consumers are interested in the regulation and promotion of these agriculturally significant crops. Circadian clock manipulation may suggest various strategies for the increased productivity of food crops through using environmental signal or overcoming environmental stress.

Toward A Neutral Mercury Optical Lattice Clock: Determination of the Magic Wavelength for the Ultraviolet clock Transition

International Nuclear Information System (INIS)

Mejri, Sinda

2012-01-01

A lattice clock combines the advantages of ion and neutral atom based clocks, namely the recoil and first order Doppler free spectroscopy allowed by the Lamb-Dicke regime. This lattice light field shifts the energy levels of the clock transition. However a wavelength can be found where the light-shift of the clock states cancelled to first order. In this thesis, we present the latest advances in optical lattice clock with mercury atoms developed at LNE-SYRTE. After a review of the current performances of different optical clock are currently under development, we focus on the concept of optical lattice clock and the features of the mercury that make him an excellent candidate for the realization of an optical lattice clock achievement the uncertainty of the level of 10 -17 . The second part is devoted to the characterization of the mercury MOT, using a sensitive detection system, which allowed us to evaluate the temperature of different isotopes present in the MOT and have a good evidence of sub-Doppler cooling for the fermionic isotopes. The third part of this these, present the experimental aspects of the implementation and the development of the laser source required for trapping mercury atoms operating near the predicted magic wavelength. Finally, we report on the Lamb-Dicke spectroscopy of the 1S0 →3 P0 clock transition in the 199 Hg atoms confined in lattice trap. With use of the ultra-stable laser system, linked to LNE-SYRTE primary frequency reference, we have determined the center frequency of the transition for a range of lattice wavelengths and different lattice depths. Analyzing these measurement, we have carried out the first experimental determination of the magic wavelength, which is the crucial step towards achieving a highly accurate frequency standard using mercury. (author)

Titchmarsh-Weyl theory for canonical systems

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Keshav Raj Acharya

2014-11-01

Full Text Available The main purpose of this paper is to develop Titchmarsh- Weyl theory of canonical systems. To this end, we first observe the fact that Schrodinger and Jacobi equations can be written into canonical systems. We then discuss the theory of Weyl m-function for canonical systems and establish the relation between the Weyl m-functions of Schrodinger equations and that of canonical systems which involve Schrodinger equations.

Mini Screening of Kinase Inhibitors Affecting Period-length of Mammalian Cellular Circadian Clock

International Nuclear Information System (INIS)

Yagita, Kazuhiro; Yamanaka, Iori; Koinuma, Satoshi; Shigeyoshi, Yasufumi; Uchiyama, Yasuo

2009-01-01

In mammalian circadian rhythms, the transcriptional-translational feedback loop (TTFL) consisting of a set of clock genes is believed to elicit the circadian clock oscillation. The TTFL model explains that the accumulation and degradation of mPER and mCRY proteins control the period-length (tau) of the circadian clock. Although recent studies revealed that the Casein Kinase Iεδ (CKIεδ) regurates the phosphorylation of mPER proteins and the circadian period-length, other kinases are also likely to contribute the phosphorylation of mPER. Here, we performed small scale screening using 84 chemical compounds known as kinase inhibitors to identify candidates possibly affecting the circadian period-length in mammalian cells. Screening by this high-throughput real-time bioluminescence monitoring system revealed that the several chemical compounds apparently lengthened the cellular circadian clock oscillation. These compounds are known as inhibitors against kinases such as Casein Kinase II (CKII), PI3-kinase (PI3K) and c-Jun N-terminal Kinase (JNK) in addition to CKIεδ. Although these kinase inhibitors may have some non-specific effects on other factors, our mini screening identified new candidates contributing to period-length control in mammalian cells

A non-canonical transferred DNA insertion at the BRI1 locus in Arabidopsis thaliana.

Science.gov (United States)

Zhao, Zhong; Zhu, Yan; Erhardt, Mathieu; Ruan, Ying; Shen, Wen-Hui

2009-04-01

Agrobacterium-mediated transformation is widely used in transgenic plant engineering and has been proven to be a powerful tool for insertional mutagenesis of the plant genome. The transferred DNA (T-DNA) from Agrobacterium is integrated into the plant genome through illegitimate recombination between the T-DNA and the plant DNA. Contrasting to the canonical insertion, here we report on a locus showing a complex mutation associated with T-DNA insertion at the BRI1 gene in Arabidopsis thaliana. We obtained a mutant line, named salade for its phenotype of dwarf stature and proliferating rosette. Molecular characterization of this mutant revealed that in addition to T-DNA a non-T-DNA-localized transposon from bacteria was inserted in the Arabidopsis genome and that a region of more than 11.5 kb of the Arabidopsis genome was deleted at the insertion site. The deleted region contains the brassinosteroid receptor gene BRI1 and the transcription factor gene WRKY13. Our finding reveals non-canonical T-DNA insertion, implicating horizontal gene transfer and cautioning the use of T-DNA as mutagen in transgenic research.

Sleep quality and diurnal preference in a sample of young adults: associations with 5HTTLPR, PER3, and CLOCK 3111.

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Barclay, Nicola L; Eley, Thalia C; Mill, Jonathan; Wong, Chloe C Y; Zavos, Helena M S; Archer, Simon N; Gregory, Alice M

2011-09-01

Research investigating associations between specific genes and individual differences with regards to the quality and timing of sleep has primarily focussed on serotonin-related and clock genes. However, there are only a few studies of this type and most of those to date have not considered the possibility of gene-environment interaction. Here, we describe associations between sleep quality and diurnal preference and three functional polymorphisms: 5HTTLPR, PERIOD3, and CLOCK 3111. Furthermore, we assessed whether associations between genotypes and sleep phenotypes were moderated by negative life events-a test of gene-environment interaction. DNA from buccal swabs was collected from 947 individuals [mean age = 20.3 years (SD = 1.77), age range = 18-27 years; 61.8% female] and genotyped for the three polymorphisms. Participants completed the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. There was a significant main effect of 5HTTLPR on sleep quality, indicating that "long-long" homozygotes experienced significantly poorer sleep quality (mean = 6.35, SD = 3.36) than carriers of at least one "short" allele (mean = 5.67, SD = 2.96; β = -0.34, P = 0.005). There were no main effects of 5HTTLPR on diurnal preference; no main effects of PERIOD3 or CLOCK on sleep quality or diurnal preference; and no significant interactions with negative life events. The main effect of the "long" 5HTTLPR allele contradicts previous research, suggesting that perhaps the effects of this gene are heterogeneous in different populations. Failure to replicate previous research in relation to PERIOD3 and CLOCK concurs with previous research suggesting that the effects of these genes are small and may be related to population composition. Copyright © 2011 Wiley-Liss, Inc.

Internal Clock Drift Estimation in Computer Clusters

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Hicham Marouani

2008-01-01

Full Text Available Most computers have several high-resolution timing sources, from the programmable interrupt timer to the cycle counter. Yet, even at a precision of one cycle in ten millions, clocks may drift significantly in a single second at a clock frequency of several GHz. When tracing the low-level system events in computer clusters, such as packet sending or reception, each computer system records its own events using an internal clock. In order to properly understand the global system behavior and performance, as reported by the events recorded on each computer, it is important to estimate precisely the clock differences and drift between the different computers in the system. This article studies the clock precision and stability of several computer systems, with different architectures. It also studies the typical network delay characteristics, since time synchronization algorithms rely on the exchange of network packets and are dependent on the symmetry of the delays. A very precise clock, based on the atomic time provided by the GPS satellite network, was used as a reference to measure clock drifts and network delays. The results obtained are of immediate use to all applications which depend on computer clocks or network time synchronization accuracy.

Iterative Calibration: A Novel Approach for Calibrating the Molecular Clock Using Complex Geological Events.

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Loeza-Quintana, Tzitziki; Adamowicz, Sarah J

2018-02-01

During the past 50 years, the molecular clock has become one of the main tools for providing a time scale for the history of life. In the era of robust molecular evolutionary analysis, clock calibration is still one of the most basic steps needing attention. When fossil records are limited, well-dated geological events are the main resource for calibration. However, biogeographic calibrations have often been used in a simplistic manner, for example assuming simultaneous vicariant divergence of multiple sister lineages. Here, we propose a novel iterative calibration approach to define the most appropriate calibration date by seeking congruence between the dates assigned to multiple allopatric divergences and the geological history. Exploring patterns of molecular divergence in 16 trans-Bering sister clades of echinoderms, we demonstrate that the iterative calibration is predominantly advantageous when using complex geological or climatological events-such as the opening/reclosure of the Bering Strait-providing a powerful tool for clock dating that can be applied to other biogeographic calibration systems and further taxa. Using Bayesian analysis, we observed that evolutionary rate variability in the COI-5P gene is generally distributed in a clock-like fashion for Northern echinoderms. The results reveal a large range of genetic divergences, consistent with multiple pulses of trans-Bering migrations. A resulting rate of 2.8% pairwise Kimura-2-parameter sequence divergence per million years is suggested for the COI-5P gene in Northern echinoderms. Given that molecular rates may vary across latitudes and taxa, this study provides a new context for dating the evolutionary history of Arctic marine life.

USP2-45 Is a Circadian Clock Output Effector Regulating Calcium Absorption at the Post-Translational Level.

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Daniel Pouly

Full Text Available The mammalian circadian clock influences most aspects of physiology and behavior through the transcriptional control of a wide variety of genes, mostly in a tissue-specific manner. About 20 clock-controlled genes (CCGs oscillate in virtually all mammalian tissues and are generally considered as core clock components. One of them is Ubiquitin-Specific Protease 2 (Usp2, whose status remains controversial, as it may be a cogwheel regulating the stability or activity of core cogwheels or an output effector. We report here that Usp2 is a clock output effector related to bodily Ca2+ homeostasis, a feature that is conserved across evolution. Drosophila with a whole-body knockdown of the orthologue of Usp2, CG14619 (dUsp2-kd, predominantly die during pupation but are rescued by dietary Ca2+ supplementation. Usp2-KO mice show hyperabsorption of dietary Ca2+ in small intestine, likely due to strong overexpression of the membrane scaffold protein NHERF4, a regulator of the Ca2+ channel TRPV6 mediating dietary Ca2+ uptake. In this tissue, USP2-45 is found in membrane fractions and negatively regulates NHERF4 protein abundance in a rhythmic manner at the protein level. In clock mutant animals (Cry1/Cry2-dKO, rhythmic USP2-45 expression is lost, as well as the one of NHERF4, confirming the inverse relationship between USP2-45 and NHERF4 protein levels. Finally, USP2-45 interacts in vitro with NHERF4 and endogenous Clathrin Heavy Chain. Taken together these data prompt us to define USP2-45 as the first clock output effector acting at the post-translational level at cell membranes and possibly regulating membrane permeability of Ca2+.

Canonical variate regression.

Science.gov (United States)

Luo, Chongliang; Liu, Jin; Dey, Dipak K; Chen, Kun

2016-07-01

In many fields, multi-view datasets, measuring multiple distinct but interrelated sets of characteristics on the same set of subjects, together with data on certain outcomes or phenotypes, are routinely collected. The objective in such a problem is often two-fold: both to explore the association structures of multiple sets of measurements and to develop a parsimonious model for predicting the future outcomes. We study a unified canonical variate regression framework to tackle the two problems simultaneously. The proposed criterion integrates multiple canonical correlation analysis with predictive modeling, balancing between the association strength of the canonical variates and their joint predictive power on the outcomes. Moreover, the proposed criterion seeks multiple sets of canonical variates simultaneously to enable the examination of their joint effects on the outcomes, and is able to handle multivariate and non-Gaussian outcomes. An efficient algorithm based on variable splitting and Lagrangian multipliers is proposed. Simulation studies show the superior performance of the proposed approach. We demonstrate the effectiveness of the proposed approach in an [Formula: see text] intercross mice study and an alcohol dependence study. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain

NARCIS (Netherlands)

Sen, Satish; Raingard, Hélène; Dumont, Stéphanie; Kalsbeek, A.; Vuillez, Patrick; Challet, Etienne

2017-01-01

Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock

From Classical to Quantum: New Canonical Tools for the Dynamics of Gravity

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Höhn, P. A.

2012-05-01

second part of this thesis, the paradigm of relational dynamics is considered. Dynamical observables in gravity are relational. Unfortunately, their construction and evaluation is notoriously difficult, especially in the quantum theory. An effective canonical framework is devised which permits to evaluate the semiclassical relational dynamics of constrained quantum systems by sidestepping technical problems associated with explicit constructions of physical Hilbert spaces. This effective approach is well-geared for addressing the concept of relational evolution in general quantum cosmological models since it (i) allows to depart from idealized relational `clock references’ and, instead, to employ generic degrees of freedom as imperfect relational `clocks’, (ii) enables one to systematically switch between different such `clocks’ and (iii) yields a consistent (temporally) local time evolution with transient observables so long as semiclassicality holds. These techniques are illustrated by toy models and, finally, are applied to a non-integrable cosmological model. It is argued that relational evolution is generically only a transient and semiclassical phenomenon

Variation in candidate genes CLOCK and ADCYAP1 does not consistently predict differences in migratory behavior in the songbird genus Junco [v1; ref status: indexed, http://f1000r.es/11p

Directory of Open Access Journals (Sweden)

Mark P Peterson

2013-04-01

Full Text Available Recent studies exploring the molecular genetic basis for migratory variation in animals have identified polymorphisms in two genes (CLOCK and ADCYAP1 that are linked to circadian rhythms and correlate with migratory propensity and phenology among individuals and populations. Results from these initial studies are mixed, however, and additional data are needed to assess the generality and diversity of the molecular mechanisms that regulate the biology of migration. We sequenced CLOCK and ADCYAP1 in 15 populations across the two species of the avian genus Junco, a North American lineage in which multiple recently diverged subspecies and populations range from sedentary to long-distance migrants. We found no consistent associations between allele length and migratory status across the genus for either CLOCK or ADCYAP1. However, within two subspecies groups, populations that migrate longer distances have longer CLOCK alleles on average. Additionally, there was a positive relationship between ADCYAP1 allele length and migratory restlessness (zugunruhe among individuals within one of two captive populations studied—a result similar to those reported previously within captive blackcaps (Sylvia atricapilla. We conclude that, while both ADCYAP1 and CLOCK may correlate with migratory propensity within or among certain populations or species, previously identified relationships between migratory behavior and sequence variants cannot be easily generalized across taxa.

Rhythms of mammalian body temperature can sustain peripheral circadian clocks.

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Brown, Steven A; Zumbrunn, Gottlieb; Fleury-Olela, Fabienne; Preitner, Nicolas; Schibler, Ueli

2002-09-17

Low-amplitude temperature oscillations can entrain the phase of circadian rhythms in several unicellular and multicellular organisms, including Neurospora and Drosophila. Because mammalian body temperature is subject to circadian variations of 1 degrees C-4 degrees C, we wished to determine whether these temperature cycles could serve as a Zeitgeber for circadian gene expression in peripheral cell types. In RAT1 fibroblasts cultured in vitro, circadian gene expression could be established by a square wave temperature rhythm with a (Delta)T of 4 degrees C (12 hr 37 degrees C/12 hr 33 degrees C). To examine whether natural body temperature rhythms can also affect circadian gene expression, we first measured core body temperature cycles in the peritoneal cavities of mice by radiotelemetry. We then reproduced these rhythms with high precision in the liquid medium of cultured fibroblasts for several days by means of a homemade computer-driven incubator. While these "in vivo" temperature rhythms were incapable of establishing circadian gene expression de novo, they could maintain previously induced rhythms for multiple days; by contrast, the rhythms of control cells kept at constant temperature rapidly dampened. Moreover, circadian oscillations of environmental temperature could reentrain circadian clocks in the livers of mice, probably via the changes they imposed upon both body temperature and feeding behavior. Interestingly, these changes in ambient temperature did not affect the phase of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. We postulate that both endogenous and environmental temperature cycles can participate in the synchronization of peripheral clocks in mammals.

An optical clock to go

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Ludlow, Andrew D.

2018-05-01

Bringing next-generation atomic clocks out of the lab is not an easy task, but doing so will unlock many new possibilities. As a crucial first step, a portable atomic clock has now been deployed for relativistic geodesy measurements in the Alps.

Identification of novel light-induced genes in the suprachiasmatic nucleus

Directory of Open Access Journals (Sweden)

Piontkivska Helen

2007-11-01

Full Text Available Abstract Background The transmission of information about the photic environment to the circadian clock involves a complex array of neurotransmitters, receptors, and second messenger systems. Exposure of an animal to light during the subjective night initiates rapid transcription of a number of immediate-early genes in the suprachiasmatic nucleus of the hypothalamus. Some of these genes have known roles in entraining the circadian clock, while others have unknown functions. Using laser capture microscopy, microarray analysis, and quantitative real-time PCR, we performed a comprehensive screen for changes in gene expression immediately following a 30 minute light pulse in suprachiasmatic nucleus of mice. Results The results of the microarray screen successfully identified previously known light-induced genes as well as several novel genes that may be important in the circadian clock. Newly identified light-induced genes include early growth response 2, proviral integration site 3, growth-arrest and DNA-damage-inducible 45 beta, and TCDD-inducible poly(ADP-ribose polymerase. Comparative analysis of promoter sequences revealed the presence of evolutionarily conserved CRE and associated TATA box elements in most of the light-induced genes, while other core clock genes generally lack this combination of promoter elements. Conclusion The photic signalling cascade in the suprachiasmatic nucleus activates an array of immediate-early genes, most of which have unknown functions in the circadian clock. Detected evolutionary conservation of CRE and TATA box elements in promoters of light-induced genes suggest that the functional role of these elements has likely remained the same over evolutionary time across mammalian orders.

Processing of visually presented clock times.

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Goolkasian, P; Park, D C

1980-11-01

The encoding and representation of visually presented clock times was investigated in three experiments utilizing a comparative judgment task. Experiment 1 explored the effects of comparing times presented in different formats (clock face, digit, or word), and Experiment 2 examined angular distance effects created by varying positions of the hands on clock faces. In Experiment 3, encoding and processing differences between clock faces and digitally presented times were directly measured. Same/different reactions to digitally presented times were faster than to times presented on a clock face, and this format effect was found to be a result of differences in processing that occurred after encoding. Angular separation also had a limited effect on processing. The findings are interpreted within the framework of theories that refer to the importance of representational codes. The applicability to the data of Bank's semantic-coding theory, Paivio's dual-coding theory, and the levels-of-processing view of memory are discussed.

Functional Multiple-Set Canonical Correlation Analysis

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Hwang, Heungsun; Jung, Kwanghee; Takane, Yoshio; Woodward, Todd S.

2012-01-01

We propose functional multiple-set canonical correlation analysis for exploring associations among multiple sets of functions. The proposed method includes functional canonical correlation analysis as a special case when only two sets of functions are considered. As in classical multiple-set canonical correlation analysis, computationally, the…

The Implementation of E1 Clock Recovery

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Wang Ziyu

2016-01-01

Full Text Available Clock transform and recovery is of significant importance in microwave TDM service, and it is always extracted from the E1 line data stream in most cases. However, intrinsically uncertain delay and jitter caused by packet transmission of E1 data information, may lead to the indexes of the data recovery clock exceed the clock performance template. Through analysis of the E1 clock indexes and measuring methods, this paper proposes a new clock recovery method. The method employs two buffers, the first RAM is used as a buffer to deduct excess information, and the second FIFO is used as a buffer to recovery the clock and data. The first buffer has a feedback from the second one, and is able to actively respond to changes in the data link and requests from the second one. The test results validate the effectiveness of the method, and the corresponding scheme is also valuable for the other communication systems.

A model of guarded recursion with clock synchronisation

DEFF Research Database (Denmark)

Bizjak, Aleš; Møgelberg, Rasmus Ejlers

2015-01-01

productivity to be captured in types. The calculus uses clocks representing time streams and clock quantifiers which allow limited and controlled elimination of modalities. The calculus has since been extended to dependent types by Møgelberg. Both works give denotational semantics but no rewrite semantics....... In previous versions of this calculus, different clocks represented separate time streams and clock synchronisation was prohibited. In this paper we show that allowing clock synchronisation is safe by constructing a new model of guarded recursion and clocks. This result will greatly simplify the type theory...... by removing freshness restrictions from typing rules, and is a necessary step towards defining rewrite semantics, and ultimately implementing the calculus....

Study of the association between 3111T/C polymorphism of the CLOCK gene and the presence of overweight in schoolchildren,

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Nayara P. Giovaninni

2014-09-01

Full Text Available Objectives: To evaluate the association between 3111T/C polymorphism of the CLOCK gene and the presence of obesity and sleep duration in children aged 6-13 years. In adults, this genetic variant has been associated with duration of sleep, ghrelin levels, weight, and eating habits. Although short sleep duration has been linked to obesity in children, no study has aimed to identify the possible molecular mechanisms of this association to date. Methods: Weight, height, and circumferences were transformed into Z-scores for age and gender. Genotyping was performed using TaqMan methodology. A questionnaire regarding hours of sleep was provided to parents. The appropriate statistical tests were performed. Results: This study evaluated 370 children (45% males, 55% females, mean age 8.5 ± 1.5 years. The prevalence of overweight was 18%. The duration of sleep was, on average, 9.7 hours, and was inversely related to age (p < 0.001. Genotype distribution was: 4% CC, 31% CT, and 65% TT. There was a trend toward higher prevalence of overweight in children who slept less than nine hours (23% when compared to those who slept more than ten hours (16%, p = 0.06. Genotype was not significantly correlated to any of the assessed outcomes. Conclusions: The CLOCK 3111T/C polymorphism was not significantly associated with overweight or sleep duration in children in this city.

Global synchronization of parallel processors using clock pulse width modulation

Science.gov (United States)

Chen, Dong; Ellavsky, Matthew R.; Franke, Ross L.; Gara, Alan; Gooding, Thomas M.; Haring, Rudolf A.; Jeanson, Mark J.; Kopcsay, Gerard V.; Liebsch, Thomas A.; Littrell, Daniel; Ohmacht, Martin; Reed, Don D.; Schenck, Brandon E.; Swetz, Richard A.

2013-04-02

A circuit generates a global clock signal with a pulse width modification to synchronize processors in a parallel computing system. The circuit may include a hardware module and a clock splitter. The hardware module may generate a clock signal and performs a pulse width modification on the clock signal. The pulse width modification changes a pulse width within a clock period in the clock signal. The clock splitter may distribute the pulse width modified clock signal to a plurality of processors in the parallel computing system.

Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish.

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Elbaz, Idan; Foulkes, Nicholas S; Gothilf, Yoav; Appelbaum, Lior

2013-01-01

The circadian clock and homeostatic processes are fundamental mechanisms that regulate sleep. Surprisingly, despite decades of research, we still do not know why we sleep. Intriguing hypotheses suggest that sleep regulates synaptic plasticity and consequently has a beneficial role in learning and memory. However, direct evidence is still limited and the molecular regulatory mechanisms remain unclear. The zebrafish provides a powerful vertebrate model system that enables simple genetic manipulation, imaging of neuronal circuits and synapses in living animals, and the monitoring of behavioral performance during day and night. Thus, the zebrafish has become an attractive model to study circadian and homeostatic processes that regulate sleep. Zebrafish clock- and sleep-related genes have been cloned, neuronal circuits that exhibit circadian rhythms of activity and synaptic plasticity have been studied, and rhythmic behavioral outputs have been characterized. Integration of this data could lead to a better understanding of sleep regulation. Here, we review the progress of circadian clock and sleep studies in zebrafish with special emphasis on the genetic and neuroendocrine mechanisms that regulate rhythms of melatonin secretion, structural synaptic plasticity, locomotor activity and sleep.

Explaining the imperfection of the molecular clock of hominid mitochondria.

Directory of Open Access Journals (Sweden)

Eva-Liis Loogväli

Full Text Available The molecular clock of mitochondrial DNA has been extensively used to date various genetic events. However, its substitution rate among humans appears to be higher than rates inferred from human-chimpanzee comparisons, limiting the potential of interspecies clock calibrations for intraspecific dating. It is not well understood how and why the substitution rate accelerates. We have analyzed a phylogenetic tree of 3057 publicly available human mitochondrial DNA coding region sequences for changes in the ratios of mutations belonging to different functional classes. The proportion of non-synonymous and RNA genes substitutions has reduced over hundreds of thousands of years. The highest mutation ratios corresponding to fast acceleration in the apparent substitution rate of the coding sequence have occurred after the end of the Last Ice Age. We recalibrate the molecular clock of human mtDNA as 7990 years per synonymous mutation over the mitochondrial genome. However, the distribution of substitutions at synonymous sites in human data significantly departs from a model assuming a single rate parameter and implies at least 3 different subclasses of sites. Neutral model with 3 synonymous substitution rates can explain most, if not all, of the apparent molecular clock difference between the intra- and interspecies levels. Our findings imply the sluggishness of purifying selection in removing the slightly deleterious mutations from the human as well as the Neandertal and chimpanzee populations. However, for humans, the weakness of purifying selection has been further exacerbated by the population expansions associated with the out-of Africa migration and the end of the Last Ice Age.

Derivation of Mayer Series from Canonical Ensemble

International Nuclear Information System (INIS)

Wang Xian-Zhi

2016-01-01

Mayer derived the Mayer series from both the canonical ensemble and the grand canonical ensemble by use of the cluster expansion method. In 2002, we conjectured a recursion formula of the canonical partition function of a fluid (X.Z. Wang, Phys. Rev. E 66 (2002) 056102). In this paper we give a proof for this formula by developing an appropriate expansion of the integrand of the canonical partition function. We further derive the Mayer series solely from the canonical ensemble by use of this recursion formula. (paper)

Derivation of Mayer Series from Canonical Ensemble

Science.gov (United States)

Wang, Xian-Zhi

2016-02-01

Mayer derived the Mayer series from both the canonical ensemble and the grand canonical ensemble by use of the cluster expansion method. In 2002, we conjectured a recursion formula of the canonical partition function of a fluid (X.Z. Wang, Phys. Rev. E 66 (2002) 056102). In this paper we give a proof for this formula by developing an appropriate expansion of the integrand of the canonical partition function. We further derive the Mayer series solely from the canonical ensemble by use of this recursion formula.

Space experiments with high stability clocks

International Nuclear Information System (INIS)

Vessot, R.F.C.

1993-01-01

Modern metrology depends increasingly on the accuracy and frequency stability of atomic clocks. Applications of such high-stability oscillators (or clocks) to experiments performed in space are described and estimates of the precision of these experiments are made in terms of clock performance. Methods using time-correlation to cancel localized disturbances in very long signal paths and a proposed space borne four station VLBI system are described. (TEC). 30 refs., 14 figs., 1 tab

CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet

Science.gov (United States)

Introduction: The success of obesity therapy is dependent on the genetic background of the patient. Circadian Locomotor Output Cycles Kaput (CLOCK), one of the transcription factors from the positive limb of the molecular clock, is involved in metabolic alterations. Objective: To investigate whethe...

Geodesy and metrology with a transportable optical clock

Science.gov (United States)

Grotti, Jacopo; Koller, Silvio; Vogt, Stefan; Häfner, Sebastian; Sterr, Uwe; Lisdat, Christian; Denker, Heiner; Voigt, Christian; Timmen, Ludger; Rolland, Antoine; Baynes, Fred N.; Margolis, Helen S.; Zampaolo, Michel; Thoumany, Pierre; Pizzocaro, Marco; Rauf, Benjamin; Bregolin, Filippo; Tampellini, Anna; Barbieri, Piero; Zucco, Massimo; Costanzo, Giovanni A.; Clivati, Cecilia; Levi, Filippo; Calonico, Davide

2018-05-01

Optical atomic clocks, due to their unprecedented stability1-3 and uncertainty3-6, are already being used to test physical theories7,8 and herald a revision of the International System of Units9,10. However, to unlock their potential for cross-disciplinary applications such as relativistic geodesy11, a major challenge remains: their transformation from highly specialized instruments restricted to national metrology laboratories into flexible devices deployable in different locations12-14. Here, we report the first field measurement campaign with a transportable 87Sr optical lattice clock12. We use it to determine the gravity potential difference between the middle of a mountain and a location 90 km away, exploiting both local and remote clock comparisons to eliminate potential clock errors. A local comparison with a 171Yb lattice clock15 also serves as an important check on the international consistency of independently developed optical clocks. This campaign demonstrates the exciting prospects for transportable optical clocks.

Long-Term Clock Behavior of GPS IIR Satellites

National Research Council Canada - National Science Library

Epstein, Marvin; Dass, Todd; Rajan, John; Gilmour, Paul

2007-01-01

.... Rubidium clocks, as opposed to cesium clocks, have significant long-term drift. The current literature describes an initial model of drift aging for rubidium atomic clocks followed by a long-term characteristic...

Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery.

Science.gov (United States)

Degan, Massimo; Bomben, Riccardo; Bo, Michele Dal; Zucchetto, Antonella; Nanni, Paola; Rupolo, Maurizio; Steffan, Agostino; Attadia, Vincenza; Ballerini, Pier Ferruccio; Damiani, Daniela; Pucillo, Carlo; Poeta, Giovanni Del; Colombatti, Alfonso; Gattei, Valter

2004-07-01

Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H) genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H) mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgV(H) gene per cent mutations above or below the 2% cut-off. sM B-CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgV(H) genes. sM, nsM and UM B-CLL were also characterized for the biased usage of IgV(H) families, intraclonal IgV(H) gene diversification, preference of mutations to target-specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase zeta and eta and activation-induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B-CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B-CLL.

Insights into the role of the habenular circadian clock in addiction

Directory of Open Access Journals (Sweden)

Nora L Salaberry

2016-01-01

Full Text Available Drug addiction is a brain disease involving alterations in anatomy and functional neural communication. Drug intake and toxicity show daily rhythms in both humans and rodents. Evidence concerning the role of clock genes in drug intake has been previously reported. However, the implication of a timekeeping brain locus is much less known. The epithalamic lateral habenula (LHb is now emerging as a key nucleus in drug intake and addiction. This brain structure modulates the activity of dopaminergic neurons from the ventral tegmental area, a central part of the reward system. Moreover, the LHb has circadian properties: LHb cellular activity (i.e., firing rate and clock genes expression oscillates in a 24h range, and the nucleus is affected by photic stimulation and has anatomical connections with the main circadian pacemaker, the suprachiasmatic nucleus. Here, we describe the current insights on the role of the LHb as a circadian oscillator and its possible implications on the rhythmic regulation of the dopaminergic activity and drug intake. This data could inspire new strategies to treat drug addiction, considering circadian timing as a principal factor.

Sound Clocks and Sonic Relativity

Science.gov (United States)

Todd, Scott L.; Menicucci, Nicolas C.

2017-10-01

Sound propagation within certain non-relativistic condensed matter models obeys a relativistic wave equation despite such systems admitting entirely non-relativistic descriptions. A natural question that arises upon consideration of this is, "do devices exist that will experience the relativity in these systems?" We describe a thought experiment in which `acoustic observers' possess devices called sound clocks that can be connected to form chains. Careful investigation shows that appropriately constructed chains of stationary and moving sound clocks are perceived by observers on the other chain as undergoing the relativistic phenomena of length contraction and time dilation by the Lorentz factor, γ , with c the speed of sound. Sound clocks within moving chains actually tick less frequently than stationary ones and must be separated by a shorter distance than when stationary to satisfy simultaneity conditions. Stationary sound clocks appear to be length contracted and time dilated to moving observers due to their misunderstanding of their own state of motion with respect to the laboratory. Observers restricted to using sound clocks describe a universe kinematically consistent with the theory of special relativity, despite the preferred frame of their universe in the laboratory. Such devices show promise in further probing analogue relativity models, for example in investigating phenomena that require careful consideration of the proper time elapsed for observers.

The Pyrexia transient receptor potential channel mediates circadian clock synchronization to low temperature cycles in Drosophila melanogaster.

Science.gov (United States)

Wolfgang, Werner; Simoni, Alekos; Gentile, Carla; Stanewsky, Ralf

2013-10-07

Circadian clocks are endogenous approximately 24 h oscillators that temporally regulate many physiological and behavioural processes. In order to be beneficial for the organism, these clocks must be synchronized with the environmental cycles on a daily basis. Both light : dark and the concomitant daily temperature cycles (TCs) function as Zeitgeber ('time giver') and efficiently entrain circadian clocks. The temperature receptors mediating this synchronization have not been identified. Transient receptor potential (TRP) channels function as thermo-receptors in animals, and here we show that the Pyrexia (Pyx) TRP channel mediates temperature synchronization in Drosophila melanogaster. Pyx is expressed in peripheral sensory organs (chordotonal organs), which previously have been implicated in temperature synchronization. Flies deficient for Pyx function fail to synchronize their behaviour to TCs in the lower range (16-20°C), and this deficit can be partially rescued by introducing a wild-type copy of the pyx gene. Synchronization to higher TCs is not affected, demonstrating a specific role for Pyx at lower temperatures. In addition, pyx mutants speed up their clock after being exposed to TCs. Our results identify the first TRP channel involved in temperature synchronization of circadian clocks.

Quaternion Linear Canonical Transform Application

OpenAIRE

Bahri, Mawardi

2015-01-01

Quaternion linear canonical transform (QLCT) is a generalization of the classical linear canonical transfom (LCT) using quaternion algebra. The focus of this paper is to introduce an application of the QLCT to study of generalized swept-frequency filter

Canonical transformations and generating functionals

NARCIS (Netherlands)

Broer, L.J.F.; Kobussen, J.A.

1972-01-01

It is shown that canonical transformations for field variables in hamiltonian partial differential equations can be obtained from generating functionals in the same way as classical canonical transformations from generating functions. A simple proof of the relation between infinitesimal invariant

Log canonical thresholds of smooth Fano threefolds

International Nuclear Information System (INIS)

Cheltsov, Ivan A; Shramov, Konstantin A

2008-01-01

The complex singularity exponent is a local invariant of a holomorphic function determined by the integrability of fractional powers of the function. The log canonical thresholds of effective Q-divisors on normal algebraic varieties are algebraic counterparts of complex singularity exponents. For a Fano variety, these invariants have global analogues. In the former case, it is the so-called α-invariant of Tian; in the latter case, it is the global log canonical threshold of the Fano variety, which is the infimum of log canonical thresholds of all effective Q-divisors numerically equivalent to the anticanonical divisor. An appendix to this paper contains a proof that the global log canonical threshold of a smooth Fano variety coincides with its α-invariant of Tian. The purpose of the paper is to compute the global log canonical thresholds of smooth Fano threefolds (altogether, there are 105 deformation families of such threefolds). The global log canonical thresholds are computed for every smooth threefold in 64 deformation families, and the global log canonical thresholds are computed for a general threefold in 20 deformation families. Some bounds for the global log canonical thresholds are computed for 14 deformation families. Appendix A is due to J.-P. Demailly.

Circadian expression profiles of chromatin remodeling factor genes in Arabidopsis.

Science.gov (United States)

Lee, Hong Gil; Lee, Kyounghee; Jang, Kiyoung; Seo, Pil Joon

2015-01-01

The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock.

Classifying Linear Canonical Relations

OpenAIRE

Lorand, Jonathan

2015-01-01

In this Master's thesis, we consider the problem of classifying, up to conjugation by linear symplectomorphisms, linear canonical relations (lagrangian correspondences) from a finite-dimensional symplectic vector space to itself. We give an elementary introduction to the theory of linear canonical relations and present partial results toward the classification problem. This exposition should be accessible to undergraduate students with a basic familiarity with linear algebra.

Are neoclassical canons valid for southern Chinese faces?

Directory of Open Access Journals (Sweden)

Yasas S N Jayaratne

Full Text Available BACKGROUND: Proportions derived from neoclassical canons, initially described by Renaissance sculptors and painters, are still being employed as aesthetic guidelines during the clinical assessment of the facial morphology. OBJECTIVE: 1. to determine the applicability of neoclassical canons for Southern Chinese faces and 2. to explore gender differences in relation to the applicability of the neoclassical canons and their variants. METHODOLOGY: 3-D photographs acquired from 103 young adults (51 males and 52 females without facial dysmorphology were used to test applicability of four neoclassical canons. Standard anthropometric measurements that determine the facial canons were made on these 3-D images. The validity of the canons as well as their different variants were quantified. PRINCIPAL FINDINGS: The neoclassical cannons seldom applied to these individuals, and facial three-section and orbital canons did not apply at all. The orbitonasal canon was most frequently applicable, with a frequency of 19%. Significant sexual dimorphism was found relative to the prevalence of the variants of facial three-section and orbitonasal canons. CONCLUSION: The neoclassical canons did not appear to apply to our sample when rigorous quantitative measurements were employed. Thus, they should not be used as esthetic goals for craniofacial surgical interventions.

Naming analog clocks conceptually facilitates naming digital clocks

NARCIS (Netherlands)

Meeuwissen, M.H.W.; Roelofs, A.P.A.; Levelt, W.J.M.

2004-01-01

Naming digital clocks (e.g., 2:45, say "quarter to three") requires conceptual operations on the minute and hour information displayed in the input for producing the correct relative time expression. The interplay of these conceptual operations was investigated using a repetition priming paradigm.

Optical lattice clock with Strontium atoms

International Nuclear Information System (INIS)

Baillard, X.

2008-01-01

This thesis presents the latest achievements regarding the optical lattice clock with Strontium atoms developed at LNE-SYRTE. After a review of the different types of optical clocks that are currently under development, we stress on the concept of optical lattice clock which was first imagined for Sr 87 using the 1 S 0 → 3 P 0 transition. We exhibit the features of this atom, in particular the concept of magic wavelength for the trap, and the achievable performances for this kind of clock. The second part presents the experimental aspects, insisting particularly on the ultra-stable laser used for the interrogation of the atoms which is a central part of the experiment. Among the latest improvements, an optical pumping phase and an interrogation phase using a magnetic field have been added in order to refine the evaluation of the Zeeman effect. Finally, the last part presents the experimental results. The last evaluation of the clock using Sr 87 atoms allowed us to reach a frequency accuracy of 2.6*10 -15 and a measurement in agreement with the one made at JILA (Tokyo university) at the 10 -15 level. On another hand, thanks to recent theoretical proposals, we made a measurement using the bosonic isotope Sr 88 by adapting the experimental setup. This measurement represents the first evaluation for this type of clock, with a frequency accuracy of 7*10 -14 . (author)

Transcripts from the Circadian Clock: Telling Time and Season

NARCIS (Netherlands)

K. Brand (Karl)

2011-01-01

textabstractWe all know it when we wake mere moments before an alarm clock is scheduled to wake us: our body clock made the alarm clock redundant. This phenomenon is driven by an endogenous timer known as the biological, or circadian clock. Each revolution of the Earth about its own axis produces

Genome-wide analysis of SREBP1 activity around the clock reveals its combined dependency on nutrient and circadian signals.

Directory of Open Access Journals (Sweden)

Federica Gilardi

2014-03-01

Full Text Available In mammals, the circadian clock allows them to anticipate and adapt physiology around the 24 hours. Conversely, metabolism and food consumption regulate the internal clock, pointing the existence of an intricate relationship between nutrient state and circadian homeostasis that is far from being understood. The Sterol Regulatory Element Binding Protein 1 (SREBP1 is a key regulator of lipid homeostasis. Hepatic SREBP1 function is influenced by the nutrient-response cycle, but also by the circadian machinery. To systematically understand how the interplay of circadian clock and nutrient-driven rhythm regulates SREBP1 activity, we evaluated the genome-wide binding of SREBP1 to its targets throughout the day in C57BL/6 mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding pattern. In particular, different expression phases were observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. Binding sites for Hepatocyte Nuclear Factor 4 (HNF4 were specifically enriched in the close proximity of SREBP1 peaks of genes, whose expression was shifted by about 8 hours with respect to SREBP1 binding. Thus, the cross-talk between hepatic HNF4 and SREBP1 may underlie the expression timing of this subgroup of SREBP1 targets. Interestingly, the proper temporal expression profile of these genes was dramatically changed in Bmal1-/- mice upon time-restricted feeding, for which a rhythmic, but slightly delayed, binding of SREBP1 was maintained. Collectively, our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity, strongly dependent from the circadian clock, exists. This system allows us to fine tune the expression timing of SREBP1

Genome-Wide Analysis of SREBP1 Activity around the Clock Reveals Its Combined Dependency on Nutrient and Circadian Signals

Science.gov (United States)

Naldi, Aurélien; Baruchet, Michaël; Canella, Donatella; Le Martelot, Gwendal; Guex, Nicolas; Desvergne, Béatrice; Delorenzi, Mauro; Deplancke, Bart; Desvergne, Béatrice; Guex, Nicolas; Herr, Winship; Naef, Felix; Rougemont, Jacques; Schibler, Ueli; Deplancke, Bart; Guex, Nicolas; Herr, Winship; Guex, Nicolas; Andersin, Teemu; Cousin, Pascal; Gilardi, Federica; Gos, Pascal; Martelot, Gwendal Le; Lammers, Fabienne; Canella, Donatella; Gilardi, Federica; Raghav, Sunil; Fabbretti, Roberto; Fortier, Arnaud; Long, Li; Vlegel, Volker; Xenarios, Ioannis; Migliavacca, Eugenia; Praz, Viviane; Guex, Nicolas; Naef, Felix; Rougemont, Jacques; David, Fabrice; Jarosz, Yohan; Kuznetsov, Dmitry; Liechti, Robin; Martin, Olivier; Delafontaine, Julien; Sinclair, Lucas; Cajan, Julia; Krier, Irina; Leleu, Marion; Migliavacca, Eugenia; Molina, Nacho; Naldi, Aurélien; Rey, Guillaume; Symul, Laura; Guex, Nicolas; Naef, Felix; Rougemont, Jacques; Bernasconi, David; Delorenzi, Mauro; Andersin, Teemu; Canella, Donatella; Gilardi, Federica; Martelot, Gwendal Le; Lammers, Fabienne; Baruchet, Michaël; Raghav, Sunil

2014-01-01

In mammals, the circadian clock allows them to anticipate and adapt physiology around the 24 hours. Conversely, metabolism and food consumption regulate the internal clock, pointing the existence of an intricate relationship between nutrient state and circadian homeostasis that is far from being understood. The Sterol Regulatory Element Binding Protein 1 (SREBP1) is a key regulator of lipid homeostasis. Hepatic SREBP1 function is influenced by the nutrient-response cycle, but also by the circadian machinery. To systematically understand how the interplay of circadian clock and nutrient-driven rhythm regulates SREBP1 activity, we evaluated the genome-wide binding of SREBP1 to its targets throughout the day in C57BL/6 mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding pattern. In particular, different expression phases were observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. Binding sites for Hepatocyte Nuclear Factor 4 (HNF4) were specifically enriched in the close proximity of SREBP1 peaks of genes, whose expression was shifted by about 8 hours with respect to SREBP1 binding. Thus, the cross-talk between hepatic HNF4 and SREBP1 may underlie the expression timing of this subgroup of SREBP1 targets. Interestingly, the proper temporal expression profile of these genes was dramatically changed in Bmal1 −/− mice upon time-restricted feeding, for which a rhythmic, but slightly delayed, binding of SREBP1 was maintained. Collectively, our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity, strongly dependent from the circadian clock, exists. This system allows us to fine tune the expression timing of SREBP1 target genes

Biological timing and the clock metaphor: oscillatory and hourglass mechanisms.

Science.gov (United States)

Rensing, L; Meyer-Grahle, U; Ruoff, P

2001-05-01

Living organisms have developed a multitude of timing mechanisms--"biological clocks." Their mechanisms are based on either oscillations (oscillatory clocks) or unidirectional processes (hourglass clocks). Oscillatory clocks comprise circatidal, circalunidian, circadian, circalunar, and circannual oscillations--which keep time with environmental periodicities--as well as ultradian oscillations, ovarian cycles, and oscillations in development and in the brain, which keep time with biological timescales. These clocks mainly determine time points at specific phases of their oscillations. Hourglass clocks are predominantly found in development and aging and also in the brain. They determine time intervals (duration). More complex timing systems combine oscillatory and hourglass mechanisms, such as the case for cell cycle, sleep initiation, or brain clocks, whereas others combine external and internal periodicities (photoperiodism, seasonal reproduction). A definition of a biological clock may be derived from its control of functions external to its own processes and its use in determining temporal order (sequences of events) or durations. Biological and chemical oscillators are characterized by positive and negative feedback (or feedforward) mechanisms. During evolution, living organisms made use of the many existing oscillations for signal transmission, movement, and pump mechanisms, as well as for clocks. Some clocks, such as the circadian clock, that time with environmental periodicities are usually compensated (stabilized) against temperature, whereas other clocks, such as the cell cycle, that keep time with an organismic timescale are not compensated. This difference may be related to the predominance of negative feedback in the first class of clocks and a predominance of positive feedback (autocatalytic amplification) in the second class. The present knowledge of a compensated clock (the circadian oscillator) and an uncompensated clock (the cell cycle), as well

The Square Light Clock and Special Relativity

Science.gov (United States)

Galli, J. Ronald; Amiri, Farhang

2012-01-01

A thought experiment that includes a square light clock is similar to the traditional vertical light beam and mirror clock, except it is made up of four mirrors placed at a 45[degree] angle at each corner of a square of length L[subscript 0], shown in Fig. 1. Here we have shown the events as measured in the rest frame of the square light clock. By…

A precise clock distribution network for MRPC-based experiments

International Nuclear Information System (INIS)

Wang, S.; Cao, P.; Shang, L.; An, Q.

2016-01-01

In high energy physics experiments, the MRPC (Multi-Gap Resistive Plate Chamber) detectors are widely used recently which can provide higher-resolution measurement for particle identification. However, the application of MRPC detectors leads to a series of challenges in electronics design with large number of front-end electronic channels, especially for distributing clock precisely. To deal with these challenges, this paper presents a universal scheme of clock transmission network for MRPC-based experiments with advantages of both precise clock distribution and global command synchronization. For precise clock distributing, the clock network is designed into a tree architecture with two stages: the first one has a point-to-multipoint long range bidirectional distribution with optical channels and the second one has a fan-out structure with copper link inside readout crates. To guarantee the precision of clock frequency or phase, the r-PTP (reduced Precision Time Protocol) and the DDMTD (digital Dual Mixer Time Difference) methods are used for frequency synthesis, phase measurement and adjustment, which is implemented by FPGA (Field Programmable Gate Array) in real-time. In addition, to synchronize global command execution, based upon this clock distribution network, synchronous signals are coded with clock for transmission. With technique of encoding/decoding and clock data recovery, signals such as global triggers or system control commands, can be distributed to all front-end channels synchronously, which greatly simplifies the system design. The experimental results show that both the clock jitter (RMS) and the clock skew can be less than 100 ps.

Minimal canonical comprehensive Gröbner systems

OpenAIRE

Manubens, Montserrat; Montes, Antonio

2009-01-01

This is the continuation of Montes' paper "On the canonical discussion of polynomial systems with parameters''. In this paper, we define the Minimal Canonical Comprehensive Gröbner System of a parametric ideal and fix under which hypothesis it exists and is computable. An algorithm to obtain a canonical description of the segments of the Minimal Canonical CGS is given, thus completing the whole MCCGS algorithm (implemented in Maple and Singular). We show its high utility for applications, suc...

Relativity theory and time perception: single or multiple clocks?

Science.gov (United States)

Buhusi, Catalin V; Meck, Warren H

2009-07-22

Current theories of interval timing assume that humans and other animals time as if using a single, absolute stopwatch that can be stopped or reset on command. Here we evaluate the alternative view that psychological time is represented by multiple clocks, and that these clocks create separate temporal contexts by which duration is judged in a relative manner. Two predictions of the multiple-clock hypothesis were tested. First, that the multiple clocks can be manipulated (stopped and/or reset) independently. Second, that an event of a given physical duration would be perceived as having different durations in different temporal contexts, i.e., would be judged differently by each clock. Rats were trained to time three durations (e.g., 10, 30, and 90 s). When timing was interrupted by an unexpected gap in the signal, rats reset the clock used to time the "short" duration, stopped the "medium" duration clock, and continued to run the "long" duration clock. When the duration of the gap was manipulated, the rats reset these clocks in a hierarchical order, first the "short", then the "medium", and finally the "long" clock. Quantitative modeling assuming re-allocation of cognitive resources in proportion to the relative duration of the gap to the multiple, simultaneously timed event durations was used to account for the results. These results indicate that the three event durations were effectively timed by separate clocks operated independently, and that the same gap duration was judged relative to these three temporal contexts. Results suggest that the brain processes the duration of an event in a manner similar to Einstein's special relativity theory: A given time interval is registered differently by independent clocks dependent upon the context.

Relativity theory and time perception: single or multiple clocks?

Directory of Open Access Journals (Sweden)

Catalin V Buhusi

2009-07-01

Full Text Available Current theories of interval timing assume that humans and other animals time as if using a single, absolute stopwatch that can be stopped or reset on command. Here we evaluate the alternative view that psychological time is represented by multiple clocks, and that these clocks create separate temporal contexts by which duration is judged in a relative manner. Two predictions of the multiple-clock hypothesis were tested. First, that the multiple clocks can be manipulated (stopped and/or reset independently. Second, that an event of a given physical duration would be perceived as having different durations in different temporal contexts, i.e., would be judged differently by each clock.Rats were trained to time three durations (e.g., 10, 30, and 90 s. When timing was interrupted by an unexpected gap in the signal, rats reset the clock used to time the "short" duration, stopped the "medium" duration clock, and continued to run the "long" duration clock. When the duration of the gap was manipulated, the rats reset these clocks in a hierarchical order, first the "short", then the "medium", and finally the "long" clock. Quantitative modeling assuming re-allocation of cognitive resources in proportion to the relative duration of the gap to the multiple, simultaneously timed event durations was used to account for the results.These results indicate that the three event durations were effectively timed by separate clocks operated independently, and that the same gap duration was judged relative to these three temporal contexts. Results suggest that the brain processes the duration of an event in a manner similar to Einstein's special relativity theory: A given time interval is registered differently by independent clocks dependent upon the context.

Robust canonical correlations: A comparative study

OpenAIRE

Branco, JA; Croux, Christophe; Filzmoser, P; Oliveira, MR

2005-01-01

Several approaches for robust canonical correlation analysis will be presented and discussed. A first method is based on the definition of canonical correlation analysis as looking for linear combinations of two sets of variables having maximal (robust) correlation. A second method is based on alternating robust regressions. These methods axe discussed in detail and compared with the more traditional approach to robust canonical correlation via covariance matrix estimates. A simulation study ...

A Novel Method of Clock Synchronization in Distributed Systems

Science.gov (United States)

Li, Gun; Niu, Meng-jie; Chai, Yang-shun; Chen, Xin; Ren, Yan-qiu

2017-04-01

Time synchronization plays an important role in the spacecraft formation flight and constellation autonomous navigation, etc. For the application of clock synchronization in a network system, it is not always true that all the observed nodes in the network are interconnected, therefore, it is difficult to achieve the high-precision time synchronization of a network system in the condition that a certain node can only obtain the measurement information of clock from a single neighboring node, but cannot obtain it from other nodes. Aiming at this problem, a novel method of high-precision time synchronization in a network system is proposed. In this paper, each clock is regarded as a node in the network system, and based on the definition of different topological structures of a distributed system, the three control algorithms of time synchronization under the following three cases are designed: without a master clock (reference clock), with a master clock (reference clock), and with a fixed communication delay in the network system. And the validity of the designed clock synchronization protocol is proved by both stability analysis and numerical simulation.

Physical Layer Ethernet Clock Synchronization

Science.gov (United States)

2010-11-01

42 nd Annual Precise Time and Time Interval (PTTI) Meeting 77 PHYSICAL LAYER ETHERNET CLOCK SYNCHRONIZATION Reinhard Exel, Georg...oeaw.ac.at Nikolaus Kerö Oregano Systems, Mohsgasse 1, 1030 Wien, Austria E-mail: nikolaus.keroe@oregano.at Abstract Clock synchronization ...is a service widely used in distributed networks to coordinate data acquisition and actions. As the requirement to achieve tighter synchronization

A canonical approach to forces in molecules

Energy Technology Data Exchange (ETDEWEB)

Walton, Jay R. [Department of Mathematics, Texas A& M University, College Station, TX 77843-3368 (United States); Rivera-Rivera, Luis A., E-mail: rivera@chem.tamu.edu [Department of Chemistry, Texas A& M University, College Station, TX 77843-3255 (United States); Lucchese, Robert R.; Bevan, John W. [Department of Chemistry, Texas A& M University, College Station, TX 77843-3255 (United States)

2016-08-02

Highlights: • Derivation of canonical representation of molecular force. • Correlation of derivations with accurate results from Born–Oppenheimer potentials. • Extension of methodology to Mg{sub 2}, benzene dimer, and water dimer. - Abstract: In previous studies, we introduced a generalized formulation for canonical transformations and spectra to investigate the concept of canonical potentials strictly within the Born–Oppenheimer approximation. Data for the most accurate available ground electronic state pairwise intramolecular potentials in H{sub 2}{sup +}, H{sub 2}, HeH{sup +}, and LiH were used to rigorously establish such conclusions. Now, a canonical transformation is derived for the molecular force, F(R), with H{sub 2}{sup +} as molecular reference. These transformations are demonstrated to be inherently canonical to high accuracy but distinctly different from those corresponding to the respective potentials of H{sub 2}, HeH{sup +}, and LiH. In this paper, we establish the canonical nature of the molecular force which is key to fundamental generalization of canonical approaches to molecular bonding. As further examples Mg{sub 2}, benzene dimer and to water dimer are also considered within the radial limit as applications of the current methodology.

Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish

Directory of Open Access Journals (Sweden)

Idan eElbaz

2013-02-01

Full Text Available The circadian clock and homeostatic processes are fundamental mechanisms that regulate sleep. Surprisingly, despite decades of research, we still do not know why we sleep. Intriguing hypotheses suggest that sleep regulates synaptic plasticity and consequently has a beneficial role in learning and memory. However, direct evidence is still limited and the molecular regulatory mechanisms remain unclear. The zebrafish provides a powerful vertebrate model system that enables simple genetic manipulation, imaging of neuronal circuits and synapses in living animals, and the monitoring of behavioral performance during day and night. Thus, the zebrafish has become an attractive model to study circadian and homeostatic processes that regulate sleep. Zebrafish clock- and sleep-related genes have been cloned, neuronal circuits that exhibit circadian rhythms of activity and synaptic plasticity have been studied, and rhythmic behavioral outputs have been characterized. Integration of this data could lead to a better understanding of sleep regulation. Here, we review the progress of circadian clock and sleep studies in zebrafish with special emphasis on the genetic and neuroendocrine mechanisms that regulate rhythms of melatonin secretion, structural synaptic plasticity, locomotor activity and sleep.

Ramadan fasting in Saudi Arabia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in cardiometabolic risk factors.

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Ghada M A Ajabnoor

Full Text Available During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance.To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors.Healthy young volunteers (5 females, 18 males; mean age +SEM = 23.2 +1.2 years were evaluated before Ramadan and two weeks into it. Blood samples were collected at 9 am (±1 hour and twelve hours later for determination of serum lipid profile, high sensitivity CRP (hsCRP, and adiponectin. The expression of CLOCK, DUSP1 and IL-1α was evaluated in circulating leukocytes.Mean levels of GGT and morning adiponectin decreased, while those of LDL-c/ HDL-c and atherogenic index (AI increased significantly in Ramadan compared to Shabaan. There was no significant difference between morning and evening adiponectin during Ramadan, while the diurnal rhythm of hsCRP was lost. CLOCK gene expression mean was significantly higher in morning than in evening during Shabaan. Mean morning and evening DUSP1 mRNA levels showed significant increase during Ramadan compared to Shabaan, however, its diurnal rhythm was maintained. Morning IL-1α mRNA expression remained significantly higher than in the evening during Ramadan, but was markedly decreased compared to Shabaan.Ramadan fasting in Saudi Arabia is associated with improvements in some cardiometabolic risk factors, such as circulating GGT and hsCRP and leukocyte expression of IL-1α mRNA, suggesting that intermittent fasting might have a beneficial component. These benefits may be offset by the previously reported dysregulation in the circadian rhythm, excess glucocorticoid levels and action

A clock network for geodesy and fundamental science.

Science.gov (United States)

Lisdat, C; Grosche, G; Quintin, N; Shi, C; Raupach, S M F; Grebing, C; Nicolodi, D; Stefani, F; Al-Masoudi, A; Dörscher, S; Häfner, S; Robyr, J-L; Chiodo, N; Bilicki, S; Bookjans, E; Koczwara, A; Koke, S; Kuhl, A; Wiotte, F; Meynadier, F; Camisard, E; Abgrall, M; Lours, M; Legero, T; Schnatz, H; Sterr, U; Denker, H; Chardonnet, C; Le Coq, Y; Santarelli, G; Amy-Klein, A; Le Targat, R; Lodewyck, J; Lopez, O; Pottie, P-E

2016-08-09

Leveraging the unrivalled performance of optical clocks as key tools for geo-science, for astronomy and for fundamental physics beyond the standard model requires comparing the frequency of distant optical clocks faithfully. Here, we report on the comparison and agreement of two strontium optical clocks at an uncertainty of 5 × 10(-17) via a newly established phase-coherent frequency link connecting Paris and Braunschweig using 1,415 km of telecom fibre. The remote comparison is limited only by the instability and uncertainty of the strontium lattice clocks themselves, with negligible contributions from the optical frequency transfer. A fractional precision of 3 × 10(-17) is reached after only 1,000 s averaging time, which is already 10 times better and more than four orders of magnitude faster than any previous long-distance clock comparison. The capability of performing high resolution international clock comparisons paves the way for a redefinition of the unit of time and an all-optical dissemination of the SI-second.

Canonical Labelling of Site Graphs

Directory of Open Access Journals (Sweden)

Nicolas Oury

2013-06-01

Full Text Available We investigate algorithms for canonical labelling of site graphs, i.e. graphs in which edges bind vertices on sites with locally unique names. We first show that the problem of canonical labelling of site graphs reduces to the problem of canonical labelling of graphs with edge colourings. We then present two canonical labelling algorithms based on edge enumeration, and a third based on an extension of Hopcroft's partition refinement algorithm. All run in quadratic worst case time individually. However, one of the edge enumeration algorithms runs in sub-quadratic time for graphs with "many" automorphisms, and the partition refinement algorithm runs in sub-quadratic time for graphs with "few" bisimulation equivalences. This suite of algorithms was chosen based on the expectation that graphs fall in one of those two categories. If that is the case, a combined algorithm runs in sub-quadratic worst case time. Whether this expectation is reasonable remains an interesting open problem.

Programmable Clock Waveform Generation for CCD Readout

Energy Technology Data Exchange (ETDEWEB)

Vicente, J. de; Castilla, J.; Martinez, G.; Marin, J.

2006-07-01

Charge transfer efficiency in CCDs is closely related to the clock waveform. In this paper, an experimental framework to explore different FPGA based clock waveform generator designs is described. Two alternative design approaches for controlling the rise/fall edge times and pulse width of the CCD clock signal have been implemented: level-control and time-control. Both approaches provide similar characteristics regarding the edge linearity and noise. Nevertheless, dissimilarities have been found with respect to the area and frequency range of application. Thus, while the time-control approach consumes less area, the level control approach provides a wider range of clock frequencies since it does not suffer capacitor discharge effect. (Author) 8 refs.

Canonical forms for single-qutrit Clifford+T operators

OpenAIRE

Glaudell, Andrew N.; Ross, Neil J.; Taylor, Jacob M.

2018-01-01

We introduce canonical forms for single qutrit Clifford+T circuits and prove that every single-qutrit Clifford+T operator admits a unique such canonical form. We show that our canonical forms are T-optimal in the sense that among all the single-qutrit Clifford+T circuits implementing a given operator our canonical form uses the least number of T gates. Finally, we provide an algorithm which inputs the description of an operator (as a matrix or a circuit) and constructs the canonical form for ...

Using Integer Clocks to Verify the Timing-Sync Sensor Network Protocol

Science.gov (United States)

Huang, Xiaowan; Singh, Anu; Smolka, Scott A.

2010-01-01

We use the UPPAAL model checker for Timed Automata to verify the Timing-Sync time-synchronization protocol for sensor networks (TPSN). The TPSN protocol seeks to provide network-wide synchronization of the distributed clocks in a sensor network. Clock-synchronization algorithms for sensor networks such as TPSN must be able to perform arithmetic on clock values to calculate clock drift and network propagation delays. They must be able to read the value of a local clock and assign it to another local clock. Such operations are not directly supported by the theory of Timed Automata. To overcome this formal-modeling obstacle, we augment the UPPAAL specification language with the integer clock derived type. Integer clocks, which are essentially integer variables that are periodically incremented by a global pulse generator, greatly facilitate the encoding of the operations required to synchronize clocks as in the TPSN protocol. With this integer-clock-based model of TPSN in hand, we use UPPAAL to verify that the protocol achieves network-wide time synchronization and is devoid of deadlock. We also use the UPPAAL Tracer tool to illustrate how integer clocks can be used to capture clock drift and resynchronization during protocol execution

Cryptochrome mediates light-dependent magnetosensitivity of Drosophila's circadian clock.

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Taishi Yoshii

2009-04-01

Full Text Available Since 1960, magnetic fields have been discussed as Zeitgebers for circadian clocks, but the mechanism by which clocks perceive and process magnetic information has remained unknown. Recently, the radical-pair model involving light-activated photoreceptors as magnetic field sensors has gained considerable support, and the blue-light photoreceptor cryptochrome (CRY has been proposed as a suitable molecule to mediate such magnetosensitivity. Since CRY is expressed in the circadian clock neurons and acts as a critical photoreceptor of Drosophila's clock, we aimed to test the role of CRY in magnetosensitivity of the circadian clock. In response to light, CRY causes slowing of the clock, ultimately leading to arrhythmic behavior. We expected that in the presence of applied magnetic fields, the impact of CRY on clock rhythmicity should be altered. Furthermore, according to the radical-pair hypothesis this response should be dependent on wavelength and on the field strength applied. We tested the effect of applied static magnetic fields on the circadian clock and found that flies exposed to these fields indeed showed enhanced slowing of clock rhythms. This effect was maximal at 300 muT, and reduced at both higher and lower field strengths. Clock response to magnetic fields was present in blue light, but absent under red-light illumination, which does not activate CRY. Furthermore, cry(b and cry(OUT mutants did not show any response, and flies overexpressing CRY in the clock neurons exhibited an enhanced response to the field. We conclude that Drosophila's circadian clock is sensitive to magnetic fields and that this sensitivity depends on light activation of CRY and on the applied field strength, consistent with the radical pair mechanism. CRY is widespread throughout biological systems and has been suggested as receptor for magnetic compass orientation in migratory birds. The present data establish the circadian clock of Drosophila as a model system

A strontium lattice clock with reduced blackbody radiation shift

Energy Technology Data Exchange (ETDEWEB)

Al-Masoudi, Ali Khalas Anfoos

2016-09-30

Optical clocks have been quickly moving to the forefront of the frequency standards field due to their high spectral resolution, and therefore the potential high stability and accuracy. The accuracy and stability of the optical clocks are nowadays two orders of magnitude better than microwave Cs clocks, which realize the SI second. Envisioned applications of highly accurate optical clocks are to perform tests of fundamental physics, for example, searching for temporal drifts of the fine structure constant α, violations of the Local Position Invariance (LPI), dark matter and dark energy, or to performance relativistic geodesy. In this work, the uncertainty of a strontium lattice clock, based on the {sup 1}S{sub 0}-{sup 3}P{sub 0} transition in {sup 87}Sr, due to the blackbody radiation (BBR) shift has been reduced to less than 1 x 10{sup -18} by more than one order of magnitude compared to the previous evaluation of the BBR shift uncertainty in this clock. The BBR shift has been reduced by interrogating the atoms in a cryogenic environment. The systematic uncertainty of the cryogenic lattice clock is evaluated to be 1.3 x 10{sup -17} which is dominated by the uncertainty of the AC Stark shift of the lattice laser and the uncertainty contribution of the BBR shift is negligible. Concerning the instability of the clock, the detection noise of the clock has been measured, and a model linking noise and clock instability has been developed. This noise model shows that, in our lattice clock, quantum projection noise is reached if more than 130 atoms are interrogated. By combining the noise model with the degradation due to the Dick effect reflecting the frequency noise of the interrogation laser, the instability of the clock is estimated to be 1.6 x 10{sup -16}/√(τ/s) in regular operation. During this work, several high-accuracy comparisons to other atomic clocks have been performed, including several absolute frequency measurements. The Sr clock transition frequency

NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators.

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Dominic Landgraf

2016-02-01

Full Text Available Heterodimers of CLOCK and BMAL1 are the major transcriptional activators of the mammalian circadian clock. Because the paralog NPAS2 can substitute for CLOCK in the suprachiasmatic nucleus (SCN, the master circadian pacemaker, CLOCK-deficient mice maintain circadian rhythms in behavior and in tissues in vivo. However, when isolated from the SCN, CLOCK-deficient peripheral tissues are reportedly arrhythmic, suggesting a fundamental difference in circadian clock function between SCN and peripheral tissues. Surprisingly, however, using luminometry and single-cell bioluminescence imaging of PER2 expression, we now find that CLOCK-deficient dispersed SCN neurons and peripheral cells exhibit similarly stable, autonomous circadian rhythms in vitro. In CLOCK-deficient fibroblasts, knockdown of Npas2 leads to arrhythmicity, suggesting that NPAS2 can compensate for loss of CLOCK in peripheral cells as well as in SCN. Our data overturn the notion of an SCN-specific role for NPAS2 in the molecular circadian clock, and instead indicate that, at the cellular level, the core loops of SCN neuron and peripheral cell circadian clocks are fundamentally similar.

On the coupling of statistic sum of canonical and large canonical ensemble of interacting particles

International Nuclear Information System (INIS)

Vall, A.N.

2000-01-01

Potentiality of refining the known result based on analytic properties of a great statistical sum, as a function of the absolute activity of the boundary integral contribution into statistical sum, is considered. A strict asymptotic ratio between statistical sums of canonical and large canonical ensemble of interacting particles was derived [ru

Daily changes in temperature, not the circadian clock, regulate growth rate in Brachypodium distachyon.

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Dominick A Matos

Full Text Available Plant growth is commonly regulated by external cues such as light, temperature, water availability, and internal cues generated by the circadian clock. Changes in the rate of growth within the course of a day have been observed in the leaves, stems, and roots of numerous species. However, the relative impact of the circadian clock on the growth of grasses has not been thoroughly characterized. We examined the influence of diurnal temperature and light changes, and that of the circadian clock on leaf length growth patterns in Brachypodium distachyon using high-resolution time-lapse imaging. Pronounced changes in growth rate were observed under combined photocyles and thermocycles or with thermocycles alone. A considerably more rapid growth rate was observed at 28°C than 12°C, irrespective of the presence or absence of light. In spite of clear circadian clock regulated gene expression, plants exhibited no change in growth rate under conditions of constant light and temperature, and little or no effect under photocycles alone. Therefore, temperature appears to be the primary cue influencing observed oscillations in growth rate and not the circadian clock or photoreceptor activity. Furthermore, the size of the leaf meristem and final cell length did not change in response to changes in temperature. Therefore, the nearly five-fold difference in growth rate observed across thermocycles can be attributed to proportionate changes in the rate of cell division and expansion. A better understanding of the growth cues in B. distachyon will further our ability to model metabolism and biomass accumulation in grasses.

Fast Clock Recovery for Digital Communications

Science.gov (United States)

Tell, R. G.

1985-01-01

Circuit extracts clock signal from random non-return-to-zero data stream, locking onto clock within one bit period at 1-gigabitper-second data rate. Circuit used for synchronization in opticalfiber communications. Derives speed from very short response time of gallium arsenide metal/semiconductor field-effect transistors (MESFET's).

The Literary Canon in the Age of New Media

DEFF Research Database (Denmark)

Backe, Hans-Joachim

2015-01-01

and mediality of the canon. In a development that has largely gone unnoticed outside German speaking countries, new approaches for discussing current and future processes of canonization have been developed in recent years. One pivotal element of this process has been a thorough re-evaluation new media......The article offers a comparative overview of the diverging courses of the canon debate in Anglophone and Germanophone contexts. While the Anglophone canon debate has focused on the politics of canon composition, the Germanophone canon debate has been more concerned with the malleability...

Age-Related Changes in the Expression of the Circadian Clock Protein PERIOD in Drosophila Glial Cells

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Dani M. Long

2018-01-01

Full Text Available Circadian clocks consist of molecular negative feedback loops that coordinate physiological, neurological, and behavioral variables into “circa” 24-h rhythms. Rhythms in behavioral and other circadian outputs tend to weaken during aging, as evident in progressive disruptions of sleep-wake cycles in aging organisms. However, less is known about the molecular changes in the expression of clock genes and proteins that may lead to the weakening of circadian outputs. Western blot studies have demonstrated that the expression of the core clock protein PERIOD (PER declines in the heads of aged Drosophila melanogaster flies. This age-related decline in PER does not occur in the central pacemaker neurons but has been demonstrated so far in retinal photoreceptors. Besides photoreceptors, clock proteins are also expressed in fly glia, which play important roles in neuronal homeostasis and are further categorized into subtypes based on morphology and function. While previous studies of mammalian glial cells have demonstrated the presence of functional clocks in astrocytes and microglia, it is not known which glial cell types in Drosophila express clock proteins and how their expression may change in aged individuals. Here, we conducted immunocytochemistry experiments to identify which glial subtypes express PER protein suggestive of functional circadian clocks. Glial cell subtypes that showed night-time accumulation and day-time absence in PER consistent with oscillations reported in the pacemaker neurons were selected to compare the level of PER protein between young and old flies. Our data demonstrate that some glial subtypes show rhythmic PER expression and the relative PER levels become dampened with advanced age. Identification of glial cell types that display age-related dampening of PER levels may help to understand the cellular changes that contribute to the loss of homeostasis in the aging brain.

Transmission delays in hardware clock synchronization

Science.gov (United States)

Shin, Kang G.; Ramanathan, P.

1988-01-01

Various methods, both with software and hardware, have been proposed to synchronize a set of physical clocks in a system. Software methods are very flexible and economical but suffer an excessive time overhead, whereas hardware methods require no time overhead but are unable to handle transmission delays in clock signals. The effects of nonzero transmission delays in synchronization have been studied extensively in the communication area in the absence of malicious or Byzantine faults. The authors show that it is easy to incorporate the ideas from the communication area into the existing hardware clock synchronization algorithms to take into account the presence of both malicious faults and nonzero transmission delays.

Comparisons of mental clocks.

Science.gov (United States)

Paivio, A

1978-02-01

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

A New Trapped Ion Clock Based on Hg-201(+)

Science.gov (United States)

Taghavi-Larigani, S.; Burt, E. A.; Lea, S. N.; Prestage, J. D.; Tjoelker, R. L.

2009-01-01

There are two stable odd isotopes of mercury with singly ionized hyperfine structure suitable for a microwave clock: Hg-199(+) and Hg-201(+). Virtually all trapped mercury ion clocks to date have used the 199 isotope. We have begun to investigate the viability of a trapped ion clock based on Hg-201(+). We have measured the unperturbed frequency of the (S-2)(sub 1/2) F = 1, m(sub F) = 0 to (S-2)(sub 1/2) F = 2, m(sub F) = 0 clock transition to be 29.9543658211(2) GHz. In this paper we describe initial measurements with Hg-201(+) and new applications to clocks and fundamental physics.

Clinical Trials With Large Numbers of Variables: Important Advantages of Canonical Analysis.

Science.gov (United States)

Cleophas, Ton J

2016-01-01

Canonical analysis assesses the combined effects of a set of predictor variables on a set of outcome variables, but it is little used in clinical trials despite the omnipresence of multiple variables. The aim of this study was to assess the performance of canonical analysis as compared with traditional multivariate methods using multivariate analysis of covariance (MANCOVA). As an example, a simulated data file with 12 gene expression levels and 4 drug efficacy scores was used. The correlation coefficient between the 12 predictor and 4 outcome variables was 0.87 (P = 0.0001) meaning that 76% of the variability in the outcome variables was explained by the 12 covariates. Repeated testing after the removal of 5 unimportant predictor and 1 outcome variable produced virtually the same overall result. The MANCOVA identified identical unimportant variables, but it was unable to provide overall statistics. (1) Canonical analysis is remarkable, because it can handle many more variables than traditional multivariate methods such as MANCOVA can. (2) At the same time, it accounts for the relative importance of the separate variables, their interactions and differences in units. (3) Canonical analysis provides overall statistics of the effects of sets of variables, whereas traditional multivariate methods only provide the statistics of the separate variables. (4) Unlike other methods for combining the effects of multiple variables such as factor analysis/partial least squares, canonical analysis is scientifically entirely rigorous. (5) Limitations include that it is less flexible than factor analysis/partial least squares, because only 2 sets of variables are used and because multiple solutions instead of one is offered. We do hope that this article will stimulate clinical investigators to start using this remarkable method.

cGMP-phosphodiesterase inhibition enhances photic responses and synchronization of the biological circadian clock in rodents.

Directory of Open Access Journals (Sweden)

Santiago A Plano

Full Text Available The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN and is synchronized by several environmental stimuli, mainly the light-dark (LD cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2. The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC, cGMP and its related protein kinase (PKG. Pharmacological manipulation of cGMP by phosphodiesterase (PDE inhibition (e.g., sildenafil increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.

Regulation of mesenchymal stromal cells through fine tuning of canonical Wnt signaling

Directory of Open Access Journals (Sweden)

Jin-A Kim

2015-05-01

Full Text Available Mesenchymal stromal cells (MSCs have been extensively utilized for various cell therapeutic trials, but the signals regulating their stromal function remain largely unclear. Here, we show that canonical Wnt signals distinctively regulate MSCs in a biphasic manner depending on signal intensity, i.e., MSCs exhibit proliferation and progenitor self-renewal under low Wnt/β-catenin signaling, whereas they exhibit enhanced osteogenic differentiation with priming to osteoblast-like lineages under high Wnt/β-catenin signaling. Moreover, low or high levels of β-catenin in MSCs distinctly regulated the hematopoietic support of MSCs to promote proliferation or the undifferentiated state of hematopoietic progenitors, respectively. A gene expression study demonstrated that different intracellular levels of β-catenin in MSCs induce distinct transcriptomic changes in subsets of genes belonging to different gene function categories. Different β-catenin levels also induced differences in intracellular levels of the β-catenin co-factors, Tcf-1 and Lef-1. Moreover, nano-scale mass spectrometry of proteins that co-precipitated with β-catenin revealed distinctive spectra of proteins selectively interacting with β-catenin at specific expression levels. Together, these results show that Wnt/β-catenin signals can coax distinct transcription milieu to induce different transcription profiles in MSCs depending on the signal intensity and that fine-tuning of the canonical Wnt signaling intensity can regulate the phase-specific functionality of MSCs.

Post-transcriptional control of the mammalian circadian clock: implications for health and disease.

Science.gov (United States)

Preußner, Marco; Heyd, Florian

2016-06-01

Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease.

Vane clocking effects in an embedded compressor stage

Science.gov (United States)

Key, Nicole Leanne

The objective of this research was to experimentally investigate the effects of vane clocking, the circumferential indexing of adjacent vane rows with similar vane counts, in an embedded compressor stage. Experiments were performed in the Purdue 3-Stage Compressor, which consists of an IGV followed by three stages. The IGV, Stator 1, and Stator 2 have identical vane counts of 44, and the effects of clocking were studied on Stage 2. The clocking configuration that located the upstream vane wake on the Stator 2 leading edge was identified with total pressure measurements at the inlet to Stator 2 and confirmed with measurements at the exit of Stator 2. For both loading conditions, the total temperature results showed that there was no measurable change associated with vane clocking in the amount of work done on the flow. At design loading, the change in stage efficiency with vane clocking was 0.27 points between the maximum and minimum efficiency clocking configurations. The maximum efficiency configuration was the case where the Stator 1 wake impinged on the Stator 2 leading edge. This condition produced a shallower and thinner Stator 2 wake compared to the clocking configuration that located the wake in the middle of the Stator 2 passage. By locating the Stator 1 wake at the leading edge, it dampened the Stator 2 boundary layer response to inlet fluctuations associated with the Rotor 2 wakes. At high loading, the change in Stage 2 efficiency increased to 1.07 points; however, the maximum efficiency clocking configuration was the case where the Stator 1 wake passed through the middle of the downstream vane passage. At high loading, the flow physics associated with vane clocking were different than at design loading because the location of the Stator 1 wake fluid on the Stator 2 leading edge triggered a boundary layer separation on the suction side of Stator 2 producing a wider and deeper wake. Vane clocking essentially affects the amount of interaction between the

Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

Directory of Open Access Journals (Sweden)

Silvia Mazzotta

2016-10-01

Full Text Available Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

An introduction to the theory of canonical matrices

CERN Document Server

Turnbull, H W

2004-01-01

Thorough and self-contained, this penetrating study of the theory of canonical matrices presents a detailed consideration of all the theory's principal features. Topics include elementary transformations and bilinear and quadratic forms; canonical reduction of equivalent matrices; subgroups of the group of equivalent transformations; and rational and classical canonical forms. The final chapters explore several methods of canonical reduction, including those of unitary and orthogonal transformations. 1952 edition. Index. Appendix. Historical notes. Bibliographies. 275 problems.

Math Clock: Perangkat Penunjuk Waktu Kreatif untuk Olahraga Otak

Directory of Open Access Journals (Sweden)

Galuh Boy Hertantyo

2014-11-01

Full Text Available Brain is one of the most vital parts for humans, with the number of brain function that is needed for the body, the brain becomes a very important part of the human body. If there is damage to the brain will certainly cause the performance of the human body will not run properly. Because of that, it’s very important to maintain brain health. There is a way to maintain brain health, for example is by doing brain exercise. Examples of brain exercise is to do simple math calculations or doing brain games like sudoku. Because of that, created a tool that can help the brain to maintain brain exercise. The tool is called math clock. Making math clock tool consists of hardware and software. The hardware consists of RTC as real time data input, ATmega328 as microcontroller and dot matrix 32x16 as a tool to display the output that has been processed by the microcontroller. The software is built using C with Arduino IDE. Math clock will process the data from RTC then processed it, in microcontroller so when output displayed on dot matrix, output will be simple mathematical operation with real time clock data on it. Test results show that, math clock is capable of displaying a simple mathematical calculation operations such as addition, subtraction, multiplication and division. The mathematical operation that display on math clock, appears to be random, so it’s not triggered by same mathematical operation. In math clock the display will change every 20 second, so in 1 minute there are 3 different kinds of mathematical operations. The results of questionnaires of 10 different students, showed 9 out of 10 students said math clock is a tool that easy to use as a clock. Math clock will be alternative for doing brain exercise every day.

Electromagnetic synchronisation of clocks with finite separation in a rotating system

International Nuclear Information System (INIS)

Cohen, J.M.; Moses, H.E.; Rosenblum, A.; Temple Univ., Philadelphia, PA

1984-01-01

For clocks on the vertices of a triangle, it is shown that clock synchronisation using electromagnetic signals between finitely spaced clocks in a rotating frame leads to the same synchronisation error as a closely spaced band of clocks along the same light path. In addition, the above result is generalised to n equally spaced clocks. (author)

Fan fiction, early Greece, and the historicity of canon

Directory of Open Access Journals (Sweden)

Ahuvia Kahane

2016-03-01

Full Text Available The historicity of canon is considered with an emphasis on contemporary fan fiction and early Greek oral epic traditions. The essay explores the idea of canon by highlighting historical variance, exposing wider conceptual isomorphisms, and formulating a revised notion of canonicity. Based on an analysis of canon in early Greece, the discussion moves away from the idea of canon as a set of valued works and toward canon as a practice of containment in response to inherent states of surplus. This view of canon is applied to the practice of fan fiction, reestablishing the idea of canonicity in fluid production environments within a revised, historically specific understanding in early oral traditions on the one hand and in digital cultures and fan fiction on the other. Several examples of early epigraphic Greek texts embedded in oral environments are analyzed and assessed in terms of their implications for an understanding of fan fiction and its modern contexts.

Synthesizing genetic sequential logic circuit with clock pulse generator.

Science.gov (United States)

Chuang, Chia-Hua; Lin, Chun-Liang

2014-05-28

Rhythmic clock widely occurs in biological systems which controls several aspects of cell physiology. For the different cell types, it is supplied with various rhythmic frequencies. How to synthesize a specific clock signal is a preliminary but a necessary step to further development of a biological computer in the future. This paper presents a genetic sequential logic circuit with a clock pulse generator based on a synthesized genetic oscillator, which generates a consecutive clock signal whose frequency is an inverse integer multiple to that of the genetic oscillator. An analogous electronic waveform-shaping circuit is constructed by a series of genetic buffers to shape logic high/low levels of an oscillation input in a basic sinusoidal cycle and generate a pulse-width-modulated (PWM) output with various duty cycles. By controlling the threshold level of the genetic buffer, a genetic clock pulse signal with its frequency consistent to the genetic oscillator is synthesized. A synchronous genetic counter circuit based on the topology of the digital sequential logic circuit is triggered by the clock pulse to synthesize the clock signal with an inverse multiple frequency to the genetic oscillator. The function acts like a frequency divider in electronic circuits which plays a key role in the sequential logic circuit with specific operational frequency. A cascaded genetic logic circuit generating clock pulse signals is proposed. Based on analogous implement of digital sequential logic circuits, genetic sequential logic circuits can be constructed by the proposed approach to generate various clock signals from an oscillation signal.

Lattice-induced nonadiabatic frequency shifts in optical lattice clocks

International Nuclear Information System (INIS)

Beloy, K.

2010-01-01

We consider the frequency shift in optical lattice clocks which arises from the coupling of the electronic motion to the atomic motion within the lattice. For the simplest of three-dimensional lattice geometries this coupling is shown to affect only clocks based on blue-detuned lattices. We have estimated the size of this shift for the prospective strontium lattice clock operating at the 390-nm blue-detuned magic wavelength. The resulting fractional frequency shift is found to be on the order of 10 -18 and is largely overshadowed by the electric quadrupole shift. For lattice clocks based on more complex geometries or other atomic systems, this shift could potentially be a limiting factor in clock accuracy.

Improvement of an Atomic Clock using Squeezed Vacuum

DEFF Research Database (Denmark)

Kruse, I.; Lange, K; Peise, Jan

2016-01-01

, the vacuum noise restricts the precision of the interferometer to the standard quantum limit (SQL). Here, we propose and experimentally demonstrate a novel clock configuration that surpasses the SQL by squeezing the vacuum in the empty input state. We create a squeezed vacuum state containing an average of 0.......75 atoms to improve the clock sensitivity of 10000 atoms by 2.05+0.34−0.37  dB. The SQL poses a significant limitation for today’s microwave fountain clocks, which serve as the main time reference. We evaluate the major technical limitations and challenges for devising a next generation of fountain clocks...

Sleep Deprivation Influences Circadian Gene Expression in the Lateral Habenula.

Science.gov (United States)

Zhang, Beilin; Gao, Yanxia; Li, Yang; Yang, Jing; Zhao, Hua

2016-01-01

Sleep is governed by homeostasis and the circadian clock. Clock genes play an important role in the generation and maintenance of circadian rhythms but are also involved in regulating sleep homeostasis. The lateral habenular nucleus (LHb) has been implicated in sleep-wake regulation, since LHb gene expression demonstrates circadian oscillation characteristics. This study focuses on the participation of LHb clock genes in regulating sleep homeostasis, as the nature of their involvement is unclear. In this study, we observed changes in sleep pattern following sleep deprivation in LHb-lesioned rats using EEG recording techniques. And then the changes of clock gene expression (Per1, Per2, and Bmal1) in the LHb after 6 hours of sleep deprivation were detected by using real-time quantitative PCR (qPCR). We found that sleep deprivation increased the length of Non-Rapid Eye Movement Sleep (NREMS) and decreased wakefulness. LHb-lesioning decreased the amplitude of reduced wake time and increased NREMS following sleep deprivation in rats. qPCR results demonstrated that Per2 expression was elevated after sleep deprivation, while the other two genes were unaffected. Following sleep recovery, Per2 expression was comparable to the control group. This study provides the basis for further research on the role of LHb Per2 gene in the regulation of sleep homeostasis.

Canonical cortical circuits: current evidence and theoretical implications

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Capone F

2016-04-01

Full Text Available Fioravante Capone,1,2 Matteo Paolucci,1,2 Federica Assenza,1,2 Nicoletta Brunelli,1,2 Lorenzo Ricci,1,2 Lucia Florio,1,2 Vincenzo Di Lazzaro1,2 1Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy; 2Fondazione Alberto Sordi – Research Institute for Aging, Rome, ItalyAbstract: Neurophysiological and neuroanatomical studies have found that the same basic structural and functional organization of neuronal circuits exists throughout the cortex. This kind of cortical organization, termed canonical circuit, has been functionally demonstrated primarily by studies involving visual striate cortex, and then, the concept has been extended to different cortical areas. In brief, the canonical circuit is composed of superficial pyramidal neurons of layers II/III receiving different inputs and deep pyramidal neurons of layer V that are responsible for cortex output. Superficial and deep pyramidal neurons are reciprocally connected, and inhibitory interneurons participate in modulating the activity of the circuit. The main intuition of this model is that the entire cortical network could be modeled as the repetition of relatively simple modules composed of relatively few types of excitatory and inhibitory, highly interconnected neurons. We will review the origin and the application of the canonical cortical circuit model in the six sections of this paper. The first section (The origins of the concept of canonical circuit: the cat visual cortex reviews the experiments performed in the cat visual cortex, from the origin of the concept of canonical circuit to the most recent developments in the modelization of cortex. The second (The canonical circuit in neocortex and third (Toward a canonical circuit in agranular cortex sections try to extend the concept of canonical circuit to other cortical areas, providing some significant examples of circuit functioning in different cytoarchitectonic

The canon as text for a biblical theology

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James A. Loader

2005-10-01

Full Text Available The novelty of the canonical approach is questioned and its fascination at least partly traced to the Reformation, as well as to the post-Reformation’s need for a clear and authoritative canon to perform the function previously performed by the church. This does not minimise the elusiveness and deeply contradictory positions both within the canon and triggered by it. On the one hand, the canon itself is a centripetal phenomenon and does play an important role in exegesis and theology. Even so, on the other hand, it not only contains many difficulties, but also causes various additional problems of a formal as well as a theological nature. The question is mooted whether the canonical approach alleviates or aggravates the dilemma. Since this approach has become a major factor in Christian theology, aspects of the Christian canon are used to gauge whether “canon” is an appropriate category for eliminating difficulties that arise by virtue of its own existence. Problematic uses and appropriations of several Old Testament canons are advanced, as well as evidence in the New Testament of a consciousness that the “old” has been surpassed(“Überbietungsbewußtsein”. It is maintained that at least the Childs version of the canonical approach fails to smooth out these and similar difficulties. As a method it can cater for the New Testament’s (superior role as the hermeneutical standard for evaluating the Old, but flounders on its inability to create the theological unity it claims can solve religious problems exposed by Old Testament historical criticism. It is concluded that canon as a category cannot be dispensed with, but is useful for the opposite of the purpose to which it is conventionally put: far from bringing about theological “unity” or producing a standard for “correct” exegesis, it requires different readings of different canons.

Epigenetic and Posttranslational Modifications in Light Signal Transduction and the Circadian Clock in Neurospora crassa

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Marco Proietto

2015-07-01

Full Text Available Blue light, a key abiotic signal, regulates a wide variety of physiological processes in many organisms. One of these phenomena is the circadian rhythm presents in organisms sensitive to the phase-setting effects of blue light and under control of the daily alternation of light and dark. Circadian clocks consist of autoregulatory alternating negative and positive feedback loops intimately connected with the cellular metabolism and biochemical processes. Neurospora crassa provides an excellent model for studying the molecular mechanisms involved in these phenomena. The White Collar Complex (WCC, a blue-light receptor and transcription factor of the circadian oscillator, and Frequency (FRQ, the circadian clock pacemaker, are at the core of the Neurospora circadian system. The eukaryotic circadian clock relies on transcriptional/translational feedback loops: some proteins rhythmically repress their own synthesis by inhibiting the activity of their transcriptional factors, generating self-sustained oscillations over a period of about 24 h. One of the basic mechanisms that perpetuate self-sustained oscillations is post translation modification (PTM. The acronym PTM generically indicates the addition of acetyl, methyl, sumoyl, or phosphoric groups to various types of proteins. The protein can be regulatory or enzymatic or a component of the chromatin. PTMs influence protein stability, interaction, localization, activity, and chromatin packaging. Chromatin modification and PTMs have been implicated in regulating circadian clock function in Neurospora. Research into the epigenetic control of transcription factors such as WCC has yielded new insights into the temporal modulation of light-dependent gene transcription. Here we report on epigenetic and protein PTMs in the regulation of the Neurospora crassa circadian clock. We also present a model that illustrates the molecular mechanisms at the basis of the blue light control of the circadian clock.

High-precision multi-node clock network distribution.

Science.gov (United States)

Chen, Xing; Cui, Yifan; Lu, Xing; Ci, Cheng; Zhang, Xuesong; Liu, Bo; Wu, Hong; Tang, Tingsong; Shi, Kebin; Zhang, Zhigang

2017-10-01

A high precision multi-node clock network for multiple users was built following the precise frequency transmission and time synchronization of 120 km fiber. The network topology adopts a simple star-shaped network structure. The clock signal of a hydrogen maser (synchronized with UTC) was recovered from a 120 km telecommunication fiber link and then was distributed to 4 sub-stations. The fractional frequency instability of all substations is in the level of 10 -15 in a second and the clock offset instability is in sub-ps in root-mean-square average.

A Canonical Approach to the Argument/Adjunct Distinction

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Diana Forker

2014-01-01

Full Text Available This paper provides an account of the argument/adjunct distinction implementing the 'canonical approach'. I identify five criteria (obligatoriness, latency, co-occurrence restrictions, grammatical relations, and iterability and seven diagnostic tendencies that can be used to distinguish canonical arguments from canonical adjuncts. I then apply the criteria and tendencies to data from the Nakh-Daghestanian language Hinuq. Hinuq makes extensive use of spatial cases for marking adjunct-like and argument-like NPs. By means of the criteria and tendencies it is possible to distinguish spatial NPs that come close to canonical arguments from those that are canonical adjuncts, and to place the remaining NPs bearing spatial cases within the argument-adjunct continuum.

A high-precision synchronization circuit for clock distribution

International Nuclear Information System (INIS)

Lu Chong; Tan Hongzhou; Duan Zhikui; Ding Yi

2015-01-01

In this paper, a novel structure of a high-precision synchronization circuit, HPSC, using interleaved delay units and a dynamic compensation circuit is proposed. HPSCs are designed for synchronization of clock distribution networks in large-scale integrated circuits, where high-quality clocks are required. The application of a hybrid structure of a coarse delay line and dynamic compensation circuit performs roughly the alignment of the clock signal in two clock cycles, and finishes the fine tuning in the next three clock cycles with the phase error suppressed under 3.8 ps. The proposed circuit is implemented and fabricated using a SMIC 0.13 μm 1P6M process with a supply voltage at 1.2 V. The allowed operation frequency ranges from 200 to 800 MHz, and the duty cycle ranges between [20%, 80%]. The active area of the core circuits is 245 × 134 μm 2 , and the power consumption is 1.64 mW at 500 MHz. (paper)

Diverse development and higher sensitivity of the circadian clocks to changes in maternal-feeding regime in a rat model of cardio-metabolic disease

Czech Academy of Sciences Publication Activity Database

Olejníková, Lucie; Polidarová, Lenka; Paušlyová, Lucia; Sládek, Martin; Sumová, Alena

2015-01-01

Roč. 32, č. 4 (2015), s. 531-547 ISSN 0742-0528 R&D Projects: GA ČR(CZ) GAP303/12/1108 Grant - others:Program interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111202 Institutional support: RVO:67985823 Keywords : circadian clock * clock gene * colon * liver * SHR * supraciasmatic nucleus Subject RIV: ED - Physiology Impact factor: 3.540, year: 2015

[Elevated expression of CLOCK is associated with poor prognosis in hepatocellular carcinoma].

Science.gov (United States)

Li, Bo; Yang, Xiliang; Li, Jiaqi; Yang, Yi; Yan, Zhaoyong; Zhang, Hongxin; Mu, Jiao

2018-02-01

Objective To evaluate the expression of circadian locomotor output cycles kaput (CLOCK) and its effects on cell growth in hepatocellular carcinoma (HCC). Methods The expression of CLOCK in 158 pairs of human HCC tissues and matched noncancerous samples was detected by immunohistochemical (IHC) staining. The expression of CLOCK in HCC patients was also verified using the data from GEO and TCGA (a total of 356 cases). The relationship between CLOCK expression and clinicopathological features of HCC patients was analyzed by single factor statistical analysis. Kaplan-Meier survival curves of HCC patients were drawn to study the relationship between the expression level of CLOCK and the survival state. The effect of CLOCK on the growth of HepG2 cells was detected by MTS assay. Results The expression of CLOCK in HCC tissues was significantly higher than that in the adjacent tissues, and the up-regulation of CLOCK expression in HCC tissue was also confirmed in the public data of HCC (356 cases). HCC patients were divided into low CLOCK expression group and high CLOCK expression group. Univariate analysis showed that the expression of CLOCK was related to tumor size, TNM stage, and portal vein invasion in HCC patients. HCC patients with low CLOCK expression had longer overall survival time and relapse-free survival time than those with high CLOCK expression. The proliferation of cells significantly decreased after the expression of CLOCK was knocked down in HepG2 cells. Conclusion The expression of CLOCK in HCC tissues was much higher than that in normal liver tissues, and the high expression of CLOCK indicated the poor prognosis. The knockdown of CLOCK in HCC cells could inhibit the proliferation of HepG2 cells.

Circadian rhythm genes mediate fenvalerate-induced inhibition of testosterone synthesis in mouse Leydig cells.

Science.gov (United States)

Guo, Yichen; Shen, Ouxi; Han, Jingjing; Duan, Hongyu; Yang, Siyuan; Zhu, Zhenghong; Tong, Jian; Zhang, Jie

2017-01-01

Fenvalerate (Fen), a widely used pesticide, is known to impair male reproductive functions by mechanisms that remain to be elucidated. Recent studies indicated that circadian clock genes may play an important role in successful male reproduction. The aim of this study was to determine the effects of Fen on circadian clock genes involved in the biosynthesis of testosterone using TM3 cells derived from mouse Leydig cells. Data demonstrated that the circadian rhythm of testosterone synthesis in TM3 cells was disturbed following Fen treatment as evidenced by changes in the circadian rhythmicity of core clock genes (Bmal1, Rev-erbα, Rorα). Further, the observed altered rhythms were accompanied by increased intracellular Ca 2+ levels and modified steroidogenic acute regulatory (StAR) mRNA expression. Thus, data suggested that Fen inhibits testosterone synthesis via pathways involving intracellular Ca 2+ and clock genes (Bmal1, Rev-Erbα, Rorα) as well as StAR mRNA expression in TM3 cells.

A clock synchronization skeleton based on RTAI

NARCIS (Netherlands)

Huang, Y.; Visser, P.M.; Broenink, Johannes F.

2006-01-01

This paper presents a clock synchronization skeleton based on RTAI (Real Time Application Interface). The skeleton is a thin layer that provides unified but extendible interfaces to the underlying operating system, the synchronization algorithms and the upper level applications in need of clock

Shining a light on the Arabidopsis circadian clock.

Science.gov (United States)

Oakenfull, Rachael J; Davis, Seth J

2017-11-01

The circadian clock provides essential timing information to ensure optimal growth to prevailing external environmental conditions. A major time-setting mechanism (zeitgeber) in clock synchronization is light. Differing light wavelengths, intensities, and photoperiodic duration are processed for the clock-setting mechanism. Many studies on light-input pathways to the clock have focused on Arabidopsis thaliana. Photoreceptors are specific chromic proteins that detect light signals and transmit this information to the central circadian oscillator through a number of different signalling mechanisms. The most well-characterized clock-mediating photoreceptors are cryptochromes and phytochromes, detecting blue, red, and far-red wavelengths of light. Ultraviolet and shaded light are also processed signals to the oscillator. Notably, the clock reciprocally generates rhythms of photoreceptor action leading to so-called gating of light responses. Intermediate proteins, such as Phytochrome interacting factors (PIFs), constitutive photomorphogenic 1 (COP1) and EARLY FLOWERING 3 (ELF3), have been established in signalling pathways downstream of photoreceptor activation. However, the precise details for these signalling mechanisms are not fully established. This review highlights both historical and recent efforts made to understand overall light input to the oscillator, first looking at how each wavelength of light is detected, this is then related to known input mechanisms and their interactions. © 2017 John Wiley & Sons Ltd.

Time without clocks - an attempt

International Nuclear Information System (INIS)

Karpman, G.

1978-01-01

A definition of time intervals separating two states of systems of elementary particles and observers is attempted. The definition is founded on the notion of instant state of the system and uses no information connected with the use of a clock. Applying the definition to a classical clock and to a sample of unstable particles, results are obtained in agreement with experiment. However, if the system contains 'few' elementary particles, the properties of the time interval present some different features. (author)

The Mechanics of Mechanical Watches and Clocks

CERN Document Server

Du, Ruxu

2013-01-01

"The Mechanics of Mechanical Watches and Clocks" presents historical views and mathematical models of mechanical watches and clocks. Although now over six hundred years old, mechanical watches and clocks are still popular luxury items that fascinate many people around the world. However few have examined the theory of how they work as presented in this book. The illustrations and computer animations are unique and have never been published before. It will be of significant interest to researchers in mechanical engineering, watchmakers and clockmakers, as well as people who have an engineering background and are interested in mechanical watches and clocks. It will also inspire people in other fields of science and technology, such as mechanical engineering and electronics engineering, to advance their designs. Professor Ruxu Du works at the Chinese University of Hong Kong, China. Assistant Professor Longhan Xie works at the South China University of Technology, China.

The mammalian circadian clock and its entrainment by stress and exercise.

Science.gov (United States)

Tahara, Yu; Aoyama, Shinya; Shibata, Shigenobu

2017-01-01

The mammalian circadian clock regulates day-night fluctuations in various physiological processes. The circadian clock consists of the central clock in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks in peripheral tissues. External environmental cues, including light/dark cycles, food intake, stress, and exercise, provide important information for adjusting clock phases. This review focuses on stress and exercise as potent entrainment signals for both central and peripheral clocks, especially in regard to the timing of stimuli, types of stressors/exercises, and differences in the responses of rodents and humans. We suggest that the common signaling pathways of clock entrainment by stress and exercise involve sympathetic nervous activation and glucocorticoid release. Furthermore, we demonstrate that physiological responses to stress and exercise depend on time of day. Therefore, using exercise to maintain the circadian clock at an appropriate phase and amplitude might be effective for preventing obesity, diabetes, and cardiovascular disease.

Toward a detailed computational model for the mammalian circadian clock

Science.gov (United States)

Leloup, Jean-Christophe; Goldbeter, Albert

2003-06-01

We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erb and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.

Precision Clock Evaluation Facility

Data.gov (United States)

Federal Laboratory Consortium — FUNCTION: Tests and evaluates high-precision atomic clocks for spacecraft, ground, and mobile applications. Supports performance evaluation, environmental testing,...

The clock paradox as a cosmological problem

International Nuclear Information System (INIS)

Fu, K.Y.

1975-01-01

In this paper the clock paradox is discussed within the framework of the general theory of relativity. It is shown that in general the aging asymmetry exists. It is also argued that the clock paradox, according to Mach's principle, is essentially a cosmological problem. (author)

HPRT deficiency coordinately dysregulates canonical Wnt and presenilin-1 signaling: a neuro-developmental regulatory role for a housekeeping gene?

Directory of Open Access Journals (Sweden)

Tae Hyuk Kang

2011-01-01

Full Text Available We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO and Gene Set Enrichment Analysis (GSEA as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock.

Science.gov (United States)

Narasimamurthy, Rajesh; Virshup, David M

2017-01-01

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

Directory of Open Access Journals (Sweden)

David M. Virshup

2017-04-01

Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

A model of individualized canonical microcircuits supporting cognitive operations.

Directory of Open Access Journals (Sweden)

Tim Kunze

Full Text Available Major cognitive functions such as language, memory, and decision-making are thought to rely on distributed networks of a large number of basic elements, called canonical microcircuits. In this theoretical study we propose a novel canonical microcircuit model and find that it supports two basic computational operations: a gating mechanism and working memory. By means of bifurcation analysis we systematically investigate the dynamical behavior of the canonical microcircuit with respect to parameters that govern the local network balance, that is, the relationship between excitation and inhibition, and key intrinsic feedback architectures of canonical microcircuits. We relate the local behavior of the canonical microcircuit to cognitive processing and demonstrate how a network of interacting canonical microcircuits enables the establishment of spatiotemporal sequences in the context of syntax parsing during sentence comprehension. This study provides a framework for using individualized canonical microcircuits for the construction of biologically realistic networks supporting cognitive operations.

Sparse canonical methods for biological data integration: application to a cross-platform study

Directory of Open Access Journals (Sweden)

Robert-Granié Christèle

2009-01-01

Full Text Available Abstract Background In the context of systems biology, few sparse approaches have been proposed so far to integrate several data sets. It is however an important and fundamental issue that will be widely encountered in post genomic studies, when simultaneously analyzing transcriptomics, proteomics and metabolomics data using different platforms, so as to understand the mutual interactions between the different data sets. In this high dimensional setting, variable selection is crucial to give interpretable results. We focus on a sparse Partial Least Squares approach (sPLS to handle two-block data sets, where the relationship between the two types of variables is known to be symmetric. Sparse PLS has been developed either for a regression or a canonical correlation framework and includes a built-in procedure to select variables while integrating data. To illustrate the canonical mode approach, we analyzed the NCI60 data sets, where two different platforms (cDNA and Affymetrix chips were used to study the transcriptome of sixty cancer cell lines. Results We compare the results obtained with two other sparse or related canonical correlation approaches: CCA with Elastic Net penalization (CCA-EN and Co-Inertia Analysis (CIA. The latter does not include a built-in procedure for variable selection and requires a two-step analysis. We stress the lack of statistical criteria to evaluate canonical correlation methods, which makes biological interpretation absolutely necessary to compare the different gene selections. We also propose comprehensive graphical representations of both samples and variables to facilitate the interpretation of the results. Conclusion sPLS and CCA-EN selected highly relevant genes and complementary findings from the two data sets, which enabled a detailed understanding of the molecular characteristics of several groups of cell lines. These two approaches were found to bring similar results, although they highlighted the same

Reduced Kalman Filters for Clock Ensembles

Science.gov (United States)

Greenhall, Charles A.

2011-01-01

This paper summarizes the author's work ontimescales based on Kalman filters that act upon the clock comparisons. The natural Kalman timescale algorithm tends to optimize long-term timescale stability at the expense of short-term stability. By subjecting each post-measurement error covariance matrix to a non-transparent reduction operation, one obtains corrected clocks with improved short-term stability and little sacrifice of long-term stability.

Clock face drawing test performance in children with ADHD.

Science.gov (United States)

Ghanizadeh, Ahmad; Safavi, Salar; Berk, Michael

2013-01-01

The utility and discriminatory pattern of the clock face drawing test in ADHD is unclear. This study therefore compared Clock Face Drawing test performance in children with ADHD and controls. 95 school children with ADHD and 191 other children were matched for gender ratio and age. ADHD symptoms severities were assessed using DSM-IV ADHD checklist and their intellectual functioning was assessed. The participants completed three clock-drawing tasks, and the following four functions were assessed: Contour score, Numbers score, Hands setting score, and Center score. All the subscales scores of the three clock drawing tests of the ADHD group were lower than that of the control group. In ADHD children, inattention and hyperactivity/ impulsivity scores were not related to free drawn clock test scores. When pre-drawn contour test was performed, inattentiveness score was statistically associated with Number score while none of the other variables of age, gender, intellectual functioning, and hand use preference were associated with that kind of score. In pre-drawn clock, no association of ADHD symptoms with any CDT subscales found significant. In addition, more errors are observed with free drawn clock and Pre-drawn contour than pre-drawn clock. Putting Numbers and Hands setting are more sensitive measures to screen ADHD than Contour and Center drawing. Test performance, except Hands setting, may have already reached a developmental plateau. It is probable that Hand setting deficit in children with ADHD may not decrease from age 8 to 14 years. Performance of children with ADHD is associated with complexity of CDT.

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

International Nuclear Information System (INIS)

Yano, Fumiko; Kugimiya, Fumitaka; Ohba, Shinsuke; Ikeda, Toshiyuki; Chikuda, Hirotaka; Ogasawara, Toru; Ogata, Naoshi; Takato, Tsuyoshi; Nakamura, Kozo; Kawaguchi, Hiroshi; Chung, Ung-il

2005-01-01

To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (Canada) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of β-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

Restoring canonical partition functions from imaginary chemical potential

Science.gov (United States)

Bornyakov, V. G.; Boyda, D.; Goy, V.; Molochkov, A.; Nakamura, A.; Nikolaev, A.; Zakharov, V. I.

2018-03-01

Using GPGPU techniques and multi-precision calculation we developed the code to study QCD phase transition line in the canonical approach. The canonical approach is a powerful tool to investigate sign problem in Lattice QCD. The central part of the canonical approach is the fugacity expansion of the grand canonical partition functions. Canonical partition functions Zn(T) are coefficients of this expansion. Using various methods we study properties of Zn(T). At the last step we perform cubic spline for temperature dependence of Zn(T) at fixed n and compute baryon number susceptibility χB/T2 as function of temperature. After that we compute numerically ∂χ/∂T and restore crossover line in QCD phase diagram. We use improved Wilson fermions and Iwasaki gauge action on the 163 × 4 lattice with mπ/mρ = 0.8 as a sandbox to check the canonical approach. In this framework we obtain coefficient in parametrization of crossover line Tc(µ2B) = Tc(C-ĸµ2B/T2c) with ĸ = -0.0453 ± 0.0099.

Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.

Science.gov (United States)

Pistocchi, A; Fazio, G; Cereda, A; Ferrari, L; Bettini, L R; Messina, G; Cotelli, F; Biondi, A; Selicorni, A; Massa, V

2013-10-17

Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

The Bargmann transform and canonical transformations

International Nuclear Information System (INIS)

Villegas-Blas, Carlos

2002-01-01

This paper concerns a relationship between the kernel of the Bargmann transform and the corresponding canonical transformation. We study this fact for a Bargmann transform introduced by Thomas and Wassell [J. Math. Phys. 36, 5480-5505 (1995)]--when the configuration space is the two-sphere S 2 and for a Bargmann transform that we introduce for the three-sphere S 3 . It is shown that the kernel of the Bargmann transform is a power series in a function which is a generating function of the corresponding canonical transformation (a classical analog of the Bargmann transform). We show in each case that our canonical transformation is a composition of two other canonical transformations involving the complex null quadric in C 3 or C 4 . We also describe quantizations of those two other canonical transformations by dealing with spaces of holomorphic functions on the aforementioned null quadrics. Some of these quantizations have been studied by Bargmann and Todorov [J. Math. Phys. 18, 1141-1148 (1977)] and the other quantizations are related to the work of Guillemin [Integ. Eq. Operator Theory 7, 145-205 (1984)]. Since suitable infinite linear combinations of powers of the generating functions are coherent states for L 2 (S 2 ) or L 2 (S 3 ), we show finally that the studied Bargmann transforms are actually coherent states transforms

Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8-deficient embryonic stem cells

International Nuclear Information System (INIS)

Kim, Byeong-Moo; Choi, Michael Y.

2012-01-01

Highlights: ► Embryonic stem cells (ESCs) lacking non-canonical miRNAs proliferate slower. ► miR-320 and miR-702 are two non-canonical miRNAs expressed in ESCs. ► miR-320 and miR-702 promote proliferation of Dgcr8-deficient ESCs. ► miR-320 targets p57 and helps to release Dgcr8-deficient ESCs from G1 arrest. ► miR-702 targets p21 and helps to release Dgcr8-deficient ESCs from G1 arrest. -- Abstract: MicroRNAs are known to contribute significantly to stem cell phenotype by post-transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generate mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non-canonical microRNAs have much more severe proliferation defect than Dgcr8-deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3′-untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs.

Gene-by-environment interactions of the CLOCK, PEMT, and GHRELIN loci with average sleep duration in relation to obesity traits using a cohort of 643 New Zealand European children.

Science.gov (United States)

Krishnan, Mohanraj; Shelling, Andrew N; Wall, Clare R; Mitchell, Edwin A; Murphy, Rinki; McCowan, Lesley M E; Thompson, John M D

2017-09-01

Modern technology may have desensitised the 'biological clock' to environmental cues, disrupting the appropriate co-ordination of metabolic processes. Susceptibility to misalignment of circadian rhythms may be partly genetically influenced and effects on sleep quality and duration could predispose to poorer health outcomes. Shorter sleep duration is associated with obesity traits, which are brought on by an increased opportunity to eat and/or a shift of hormonal profile promoting hunger. We hypothesised that increased sleep duration will offset susceptible genetic effects, resulting in reduced obesity risk. We recruited 643 (male: 338; female: 305) European children born to participants in the New Zealand centre of the International Screening for Pregnancy Endpoints sleep study. Ten genes directly involved in the circadian rhythm machinery and a further 20 genes hypothesised to be driven by cyclic oscillations were evaluated by Sequenom assay. Multivariable regression was performed to test the interaction between gene variants and average sleep length (derived from actigraphy), in relation to obesity traits (body mass index (BMI) z-scores and percentage body fat (PBF)). No association was found between average sleep length and BMI z-scores (p = 0.056) or PBF (p = 0.609). Uncorrected genotype associations were detected between STAT-rs8069645 (p = 0.0052) and ADIPOQ-rs266729 (p = 0.019) with differences in average sleep duration. Evidence for uncorrected gene-by-sleep interactions of the CLOCK-rs4864548 (p = 0.0039), PEMT-936108 (p = 0.016) and GHRELIN-rs696217 (p = 0.046) were found in relation to BMI z-scores but not for PBF. Our results indicate that children may have different genetic susceptibility to the effects of sleep duration on obesity. Further confirmatory studies are required in other population cohorts of different age groups. Copyright © 2017 Elsevier B.V. All rights reserved.

Canonical ensembles and nonzero density quantum chromodynamics

International Nuclear Information System (INIS)

Hasenfratz, A.; Toussaint, D.

1992-01-01

We study QCD with nonzero chemical potential on 4 4 lattices by averaging over the canonical partition functions, or sectors with fixed quark number. We derive a condensed matrix of size 2x3xL 3 whose eigenvalues can be used to find the canonical partition functions. We also experiment with a weight for configuration generation which respects the Z(3) symmetry which forces the canonical partition function to be zero for quark numbers that are not multiples of three. (orig.)

USP2 Regulates the Intracellular Localization of PER1 and Circadian Gene Expression

DEFF Research Database (Denmark)

Yang, Yaoming; Duguay, David; Fahrenkrug, Jan

2014-01-01

. Although Per1 mRNA expression rhythm remained intact in the Usp2 KO MEFs, the expression profiles of other core clock genes were altered. This was also true for the expression of clock-controlled genes (e.g., Dbp, Tef, Hlf, E4bp4). A similar phase advance of PER1 nuclear localization rhythm and alteration...

Initial atomic coherences and Ramsey frequency pulling in fountain clocks

Science.gov (United States)

Gerginov, Vladislav; Nemitz, Nils; Weyers, Stefan

2014-09-01

In the uncertainty budget of primary atomic cesium fountain clocks, evaluations of frequency-pulling shifts of the hyperfine clock transition caused by unintentional excitation of its nearby transitions (Rabi and Ramsey pulling) have been based so far on an approach developed for cesium beam clocks. We re-evaluate this type of frequency pulling in fountain clocks and pay particular attention to the effect of initial coherent atomic states. We find significantly enhanced frequency shifts caused by Ramsey pulling due to sublevel population imbalance and corresponding coherences within the state-selected hyperfine component of the initial atom ground state. Such shifts are experimentally investigated in an atomic fountain clock and quantitative agreement with the predictions of the model is demonstrated.

Backlund transformations as canonical transformations

International Nuclear Information System (INIS)

Villani, A.; Zimerman, A.H.

1977-01-01

Toda and Wadati as well as Kodama and Wadati have shown that the Backlund transformations, for the exponential lattice equation, sine-Gordon equation, K-dV (Korteweg de Vries) equation and modifies K-dV equation, are canonical transformation. It is shown that the Backlund transformation for the Boussinesq equation, for a generalized K-dV equation, for a model equation for shallow water waves and for the nonlinear Schroedinger equation are also canonical transformations [pt

El Escritor y las Normas del Canon Literario (The Writer and the Norms of the Literary Canon).

Science.gov (United States)

Policarpo, Alcibiades

This paper speculates about whether a literary canon exists in contemporary Latin American literature, particularly in the prose genre. The paper points to Carlos Fuentes, Gabriel Garcia Marquez, and Mario Vargas Llosa as the three authors who might form this traditional and liberal canon with their works "La Muerte de Artemio Cruz"…

Clock Face Drawing Test Performance in Children with ADHD

Directory of Open Access Journals (Sweden)

Ahmad Ghanizadeh

2013-01-01

Full Text Available  Introduction: The utility and discriminatory pattern of the clock face drawing test in ADHD is unclear. This study therefore compared Clock Face Drawing test performance in children with ADHD and controls.   Material & methods: 95 children with ADHD and 191 school children were matched for gender ratio and age. ADHD symptoms severities were assessed using DSM-IV ADHD checklist and their intellectual functioning was assessed. The participants completed three clock-drawing tasks, and the following four functions were assessed: Contour score, Numbers score, Hands setting score, and Center score    Results: All the subscales scores of the three clock drawing tests of the ADHD group were lower than that of the control group. In ADHD children, inattention and hyperactivity/impulsivity scores were not related with free drawn clock test scores. When pre-drawn contour test was performed, inattentiveness score was statistically associated with Number score. None of the other variables of age, gender, intellectual functioning, and hand use preference were associated with Numbers score. In pre-drawn clock, no association of ADHD symptoms with any CDT subscales was significant. In addition, more errors are observed with free drawn clock and Pre-drawn contour than pre-drawn clock.    Conclusion: Putting Numbers and Hands setting are more sensitive measures to screen ADHD than Contour and Center drawing. Test performance, except Hands setting, may have already reached a developmental plateau. It is probable that Hand setting deficit in children with ADHD may not decrease from age 8 to 14 years. Performance of children with ADHD is associated with the complexity of CDT.

Periodicity, the Canon and Sport

Directory of Open Access Journals (Sweden)

Thomas F. Scanlon

2015-10-01

Full Text Available The topic according to this title is admittedly a broad one, embracing two very general concepts of time and of the cultural valuation of artistic products. Both phenomena are, in the present view, largely constructed by their contemporary cultures, and given authority to a great extent from the prestige of the past. The antiquity of tradition brings with it a certain cachet. Even though there may be peripheral debates in any given society which question the specifics of periodization or canonicity, individuals generally accept the consensus designation of a sequence of historical periods and they accept a list of highly valued artistic works as canonical or authoritative. We will first examine some of the processes of periodization and of canon-formation, after which we will discuss some specific examples of how these processes have worked in the sport of two ancient cultures, namely Greece and Mesoamerica.

Pnrc2 regulates 3'UTR-mediated decay of segmentation clock-associated transcripts during zebrafish segmentation.

Science.gov (United States)

Gallagher, Thomas L; Tietz, Kiel T; Morrow, Zachary T; McCammon, Jasmine M; Goldrich, Michael L; Derr, Nicolas L; Amacher, Sharon L

2017-09-01

Vertebrate segmentation is controlled by the segmentation clock, a molecular oscillator that regulates gene expression and cycles rapidly. The expression of many genes oscillates during segmentation, including hairy/Enhancer of split-related (her or Hes) genes, which encode transcriptional repressors that auto-inhibit their own expression, and deltaC (dlc), which encodes a Notch ligand. We previously identified the tortuga (tor) locus in a zebrafish forward genetic screen for genes involved in cyclic transcript regulation and showed that cyclic transcripts accumulate post-splicing in tor mutants. Here we show that cyclic mRNA accumulation in tor mutants is due to loss of pnrc2, which encodes a proline-rich nuclear receptor co-activator implicated in mRNA decay. Using an inducible in vivo reporter system to analyze transcript stability, we find that the her1 3'UTR confers Pnrc2-dependent instability to a heterologous transcript. her1 mRNA decay is Dicer-independent and likely employs a Pnrc2-Upf1-containing mRNA decay complex. Surprisingly, despite accumulation of cyclic transcripts in pnrc2-deficient embryos, we find that cyclic protein is expressed normally. Overall, we show that Pnrc2 promotes 3'UTR-mediated decay of developmentally-regulated segmentation clock transcripts and we uncover an additional post-transcriptional regulatory layer that ensures oscillatory protein expression in the absence of cyclic mRNA decay. Copyright © 2017 Elsevier Inc. All rights reserved.

Constructing canonical bases of quantized enveloping algebras

OpenAIRE

Graaf, W.A. de

2001-01-01

An algorithm for computing the elements of a given weight of the canonical basis of a quantized enveloping algebra is described. Subsequently, a similar algorithm is presented for computing the canonical basis of a finite-dimensional module.

Canonical and Non-Canonical NF-κB Signaling Promotes Breast Cancer Tumor-Initiating Cells

Science.gov (United States)

Kendellen, Megan F.; Bradford, Jennifer W.; Lawrence, Cortney L.; Clark, Kelly S.; Baldwin, Albert S.

2014-01-01

Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors, and the development of metastases. TICs have been identified in various tumors, including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the NF-κB family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition (EMT) and by upregulating the expression of the inflammatory cytokines IL-1β and IL-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. PMID:23474754

Early Chronotype and Tissue-Specific Alterations of Circadian Clock Function in Spontaneously Hypertensive Rats

Czech Academy of Sciences Publication Activity Database

Sládek, Martin; Polidarová, Lenka; Nováková, Marta; Parkanová, Daniela; Sumová, Alena

2012-01-01

Roč. 7, č. 10 (2012), e46951 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP303/11/0668; GA ČR(CZ) GPP305/10/P244 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : SHR * circadian system * clock gene * metabolism * colon * liver * suprachiasmatic nucleus Subject RIV: ED - Physiology Impact factor: 3.730, year: 2012

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

OpenAIRE

David M. Virshup; Rajesh Narasimamurthy

2017-01-01

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entr...

‘Canonization in early twentieth-century Chinese art history’

Directory of Open Access Journals (Sweden)

Guo Hui

2014-06-01

Full Text Available Since the 1980s, the discussion of canons has been a dominant theme in the discipline of Western art history. Various concerns have emerged regarding ‘questions of artistic judgment’, ‘the history genesis of masterpieces’, ‘variations in taste’, ‘the social instruments of canonicity’, and ‘how canons disappear’. Western art historians have considered how the canon’s appearance in Western visual art embodies aesthetic, ideological, cultural, social, and symbolic values. In Chinese art history, the idea of a canon including masterpieces, important artists, and forms of art, dates back to the mid ninth century when Zhang Yanyuan wrote his painting history Record of Famous Painters of All the Dynasties. Faced with quite different political, economic, and social conditions amid the instability of the early twentieth century, Chinese scholars attempted to discover new canons for cultural orthodoxy and authority. Modern means for canonization, such as museums and exhibition displays, cultural and academic institutions, and massive art publications with image reproduction in good quality, brought the process up to an unprecedented speed. It is true that most of these means have comparable counterparts in pre-modern times. However, their enormous scope and overwhelming influence are far beyond the reach of their imperial counterparts. Through an inter-textual reading of the publications on Chinese art history in early twentieth-century China, this paper explores the transformation of canons in order to shed light on why and how canonical formation happened during the Republican period of China. Despite the diverse styles and strategies which Chinese writers used in their narratives, Chinese art historical books produced during the Republican period canonized and de-canonized artworks. In this paper, the discussion of these texts, with reference to other art historical works, comprises three parts: 1 canon formation of artistic forms

Hanle Detection for Optical Clocks

Directory of Open Access Journals (Sweden)

Xiaogang Zhang

2015-01-01

Full Text Available Considering the strong inhomogeneous spatial polarization and intensity distribution of spontaneous decay fluorescence due to the Hanle effect, we propose and demonstrate a universe Hanle detection configuration of electron-shelving method for optical clocks. Experimental results from Ca atomic beam optical frequency standard with electron-shelving method show that a designed Hanle detection geometry with optimized magnetic field direction, detection laser beam propagation and polarization direction, and detector position can improve the fluorescence collection rate by more than one order of magnitude comparing with that of inefficient geometry. With the fixed 423 nm fluorescence, the improved 657 nm optical frequency standard signal intensity is presented. The potential application of the Hanle detection geometry designed for facilitating the fluorescence collection for optical lattice clock with a limited solid angle of the fluorescence collection has been discussed. The Hanle detection geometry is also effective for ion detection in ion optical clock and quantum information experiments. Besides, a cylinder fluorescence collection structure is designed to increase the solid angle of the fluorescence collection in Ca atomic beam optical frequency standard.

The degeneracy problem in non-canonical inflation

International Nuclear Information System (INIS)

Easson, Damien A.; Powell, Brian A.

2013-01-01

While attempting to connect inflationary theories to observational physics, a potential difficulty is the degeneracy problem: a single set of observables maps to a range of different inflaton potentials. Two important classes of models affected by the degeneracy problem are canonical and non-canonical models, the latter marked by the presence of a non-standard kinetic term that generates observables beyond the scalar and tensor two-point functions on CMB scales. The degeneracy problem is manifest when these distinguishing observables go undetected. We quantify the size of the resulting degeneracy in this case by studying the most well-motivated non-canonical theory having Dirac-Born-Infeld Lagrangian. Beyond the scalar and tensor two-point functions on CMB scales, we then consider the possible detection of equilateral non-Gaussianity at Planck-precision and a measurement of primordial gravitational waves from prospective space-based laser interferometers. The former detection breaks the degeneracy with canonical inflation but results in poor reconstruction prospects, while the latter measurement enables a determination of n T which, while not breaking the degeneracy, can be shown to greatly improve the non-canonical reconstruction

Spanish Literature and Spectrality : Notes on a Haunted Canon

NARCIS (Netherlands)

Valdivia, Pablo

In Spanish Literature, Crisis and Spectrality: Notes on a Haunted Canon, Prof. Dr. Pablo Valdivia analyses the contradictions and complexities of the Spanish traditional canon from a transnational approach. Valdivia explores this particular canon as a 'haunted house' by focusing on the specific

Generalized canonical correlation analysis with missing values

NARCIS (Netherlands)

M. van de Velden (Michel); Y. Takane

2012-01-01

textabstractGeneralized canonical correlation analysis is a versatile technique that allows the joint analysis of several sets of data matrices. The generalized canonical correlation analysis solution can be obtained through an eigenequation and distributional assumptions are not required. When

Time measurement - technical importance of most exact clocks

International Nuclear Information System (INIS)

Goebel, E.O.; Riehle, F.

2004-01-01