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Sample records for human clock associate

  1. Glucocorticoids entrain molecular clock components in human peripheral cells.

    Science.gov (United States)

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

    2015-04-01

    In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work-associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2-3 and BMAL1 expression in PBMCs were shifted by ∼ 9.5-11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet-lag travelers, combining synchronizing agents for the central and peripheral clocks.

  2. Human intestinal circadian clock: expression of clock genes in colonocytes lining the crypt.

    Science.gov (United States)

    Pardini, L; Kaeffer, B; Trubuil, A; Bourreille, A; Galmiche, J-P

    2005-01-01

    Biological clock components have been detected in many epithelial tissues of the digestive tract of mammals (oral mucosa, pancreas, and liver), suggesting the existence of peripheral circadian clocks that may be entrainable by food. Our aim was to investigate the expression of main peripheral clock genes in colonocytes of healthy humans and in human colon carcinoma cell lines. The presence of clock components was investigated in single intact colonic crypts isolated by chelation from the biopsies of 25 patients (free of any sign of colonic lesions) undergoing routine colonoscopy and in cell lines of human colon carcinoma (Caco2 and HT29 clone 19A). Per-1, per-2, and clock mRNA were detected by real-time RT-PCR. The three-dimensional distributions of PER-1, PER-2, CLOCK, and BMAL1 proteins were recorded along colonic crypts by immunofluorescent confocal imaging. We demonstrate the presence of per-1, per-2, and clock mRNA in samples prepared from colonic crypts of 5 patients and in all cell lines. We also demonstrate the presence of two circadian clock proteins, PER-1 and CLOCK, in human colonocytes on crypts isolated from 20 patients (15 patients for PER-1 and 6 for CLOCK) and in colon carcinoma cells. Establishing the presence of clock proteins in human colonic crypts is the first step toward the study of the regulation of the intestinal circadian clock by nutrients and feeding rhythms.

  3. 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

  4. 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 f

  5. Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants

    DEFF Research Database (Denmark)

    Dashti, Hassan S; Follis, Jack L; Smith, Caren E

    2015-01-01

    BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake. OBJECTIVES: We...

  6. Regulation of the clock gene expression in human adipose tissue by weight loss.

    Science.gov (United States)

    Pivovarova, O; Gögebakan, Ö; Sucher, S; Groth, J; Murahovschi, V; Kessler, K; Osterhoff, M; Rudovich, N; Kramer, A; Pfeiffer, A F H

    2016-06-01

    The circadian clock coordinates numerous metabolic processes to adapt physiological responses to light-dark and feeding regimens and is itself regulated by metabolic cues. The implication of the circadian clock in the regulation of energy balance and body weight is widely studied in rodents but not in humans. Here we investigated (1) whether the expression of clock genes in human adipose tissue is changed by weight loss and (2) whether these alterations are associated with metabolic parameters. Subcutaneous adipose tissue (SAT) samples were collected before and after 8 weeks of weight loss on an 800 kcal per day hypocaloric diet (plus 200 g per day vegetables) at the same time of the day. Fifty overweight subjects who lost at least 8% weight after 8 weeks were selected for the study. The expression of 10 clock genes and key metabolic and inflammatory genes in adipose tissue was determined by quantitative real-time PCR. The expression of core clock genes PER2 and NR1D1 was increased after the weight loss. Correlations of PERIOD expression with body mass index (BMI) and serum total, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol levels and of NR1D1 expression with total and LDL cholesterol were found that became non-significant after correction for multiple testing. Clock gene expression levels and their weight loss-induced changes tightly correlated with each other and with genes involved in fat metabolism (FASN, CPT1A, LPL, PPARG, PGC1A, ADIPOQ), energy metabolism (SIRT1), autophagy (LC3A, LC3B) and inflammatory response (NFKB1, NFKBIA, NLRP3, EMR1). Clock gene expression in human SAT is regulated by body weight changes and associated with BMI, serum cholesterol levels and the expression of metabolic and inflammatory genes. Our data confirm the tight crosstalk between molecular clock and metabolic and inflammatory pathways involved in adapting adipose tissue metabolism to changes of the energy intake in humans.

  7. Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters

    Indian Academy of Sciences (India)

    Malcolm Von Schantz

    2008-12-01

    Circadian rhythms and sleep are two separate but intimately related processes. Circadian rhythms are generated through the precisely controlled, cyclic expression of a number of genes designated clock genes. Genetic variability in these genes has been associated with a number of phenotypic differences in circadian as well as sleep parameters, both in mouse models and in humans. Diurnal preferences as determined by the selfreported Horne–Östberg (HÖ) questionnaire, has been associated with polymorphisms in the human genes CLOCK, PER1, PER2 and PER3. Circadian rhythm-related sleep disorders have also been associated with mutations and polymorphisms in clock genes, with the advanced type cosegrating in an autosomal dominant inheritance pattern with mutations in the genes PER2 and CSNK1D, and the delayed type associating without discernible Mendelian inheritance with polymorphisms in CLOCK and PER3. Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep loss, confirming the close association between the processes of circadian rhythms and sleep at the genetic level.

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

    Science.gov (United States)

    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.

  9. Life between Clocks : Daily Temporal Patterns of Human Chronotypes

    NARCIS (Netherlands)

    Roenneberg, Till; Wirz-Justice, Anna; Merrow, Martha

    2003-01-01

    Human behavior shows large interindividual variation in temporal organization. Extreme “larks” wake up when extreme “owls” fall asleep. These chronotypes are attributed to differences in the circadian clock, and in animals, the genetic basis of similar phenotypic differences is well established. To

  10. Entrainment of the human circadian clock to the natural light-dark cycle.

    Science.gov (United States)

    Wright, Kenneth P; McHill, Andrew W; Birks, Brian R; Griffin, Brandon R; Rusterholz, Thomas; Chinoy, Evan D

    2013-08-19

    The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle [1], and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.

  11. Correcting for purifying selection: an improved human mitochondrial molecular clock.

    Science.gov (United States)

    Soares, Pedro; Ermini, Luca; Thomson, Noel; Mormina, Maru; Rito, Teresa; Röhl, Arne; Salas, Antonio; Oppenheimer, Stephen; Macaulay, Vincent; Richards, Martin B

    2009-06-01

    There is currently no calibration available for the whole human mtDNA genome, incorporating both coding and control regions. Furthermore, as several authors have pointed out recently, linear molecular clocks that incorporate selectable characters are in any case problematic. We here confirm a modest effect of purifying selection on the mtDNA coding region and propose an improved molecular clock for dating human mtDNA, based on a worldwide phylogeny of > 2000 complete mtDNA genomes and calibrating against recent evidence for the divergence time of humans and chimpanzees. We focus on a time-dependent mutation rate based on the entire mtDNA genome and supported by a neutral clock based on synonymous mutations alone. We show that the corrected rate is further corroborated by archaeological dating for the settlement of the Canary Islands and Remote Oceania and also, given certain phylogeographic assumptions, by the timing of the first modern human settlement of Europe and resettlement after the Last Glacial Maximum. The corrected rate yields an age of modern human expansion in the Americas at approximately 15 kya that-unlike the uncorrected clock-matches the archaeological evidence, but continues to indicate an out-of-Africa dispersal at around 55-70 kya, 5-20 ky before any clear archaeological record, suggesting the need for archaeological research efforts focusing on this time window. We also present improved rates for the mtDNA control region, and the first comprehensive estimates of positional mutation rates for human mtDNA, which are essential for defining mutation models in phylogenetic analyses.

  12. Putative melatonin receptors in a human biological clock

    Energy Technology Data Exchange (ETDEWEB)

    Reppert, S.M.; Weaver, D.R.; Rivkees, S.A.; Stopa, E.G.

    1988-10-07

    In vitro autoradiography with /sup 125/I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific /sup 125/I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific /sup 125/I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completely inhibited specific /sup 125/I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.

  13. Epidemiology of the human circadian clock

    NARCIS (Netherlands)

    Roenneberg, Till; Kuehnle, Tim; Juda, Myriam; Kantermann, Thomas; Allebrandt, Karla; Gordijn, Marijke; Merrow, Martha

    2007-01-01

    Humans show large inter-individual differences in organising their behaviour within the 24-h day-this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late

  14. Activity clocks: spreading dynamics on temporal networks of human contact

    CERN Document Server

    Gauvin, Laetitia; Cattuto, Ciro; Barrat, Alain

    2013-01-01

    Dynamical processes on time-varying complex networks are key to un- derstanding and modeling a broad variety of processes in socio-technical systems. Here we focus on empirical temporal networks of human proxim- ity and we aim at understanding the factors that, in simulation, shape the arrival time distribution of simple spreading processes. Abandoning the notion of wall-clock time in favour of node-specific clocks based on activ- ity exposes robust statistical patterns in the arrival times across different social contexts. Using randomization strategies and generative models constrained by data, we show that these patterns can be understood in terms of heterogeneous inter-event time distributions coupled with hetero- geneous numbers of events per edge. We also show, both empirically and by using a synthetic dataset, that significant deviations from the above behavior can be caused by the presence of edge classes with strong activity correlations.

  15. Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants

    Science.gov (United States)

    Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake. We examined associations betw...

  16. Relative clock demonstrates the endogenous heterogeneity of human dynamics

    CERN Document Server

    Zhou, Tao; Yang, Zimo; Zhou, Changsong

    2011-01-01

    The heavy-tailed inter-event time distributions are widely observed in many human-activated systems, which may result from both endogenous mechanisms like the highest-priority-first protocol and exogenous factors like the varying global activity versus time. To distinguish the effects on temporal statistics from different mechanisms is this of theoretical significance. In this Letter, we propose a new timing method by using a relative clock, where the time length between two consecutive events of an individual is counted as the number of other individuals' events appeared during this interval. We propose a model, in which agents act either in a constant rate or with a power-law inter-event time distribution, and the global activity either keeps unchanged or varies periodically versus time. Our analysis shows that the heavy tails caused by the heterogeneity of global activity can be eliminated by setting the relative clock, yet the heterogeneity due to real individual behaviors still exists. We perform extensi...

  17. Noninvasive method for assessing the human circadian clock using hair follicle cells

    National Research Council Canada - National Science Library

    Makoto Akashi; Haruhiko Soma; Takuro Yamamoto; Asuka Tsugitomi; Shiko Yamashita; Takuya Yamamoto; Eisuke Nishida; Akio Yasuda; James K. Liao; Koichi Node; Joseph S. Takahashi

    2010-01-01

    .... This limitation has greatly hampered our understanding of human circadian rhythm. Here we report a convenient, reliable, and less invasive method for detecting human clock gene expression using biopsy samples of hair follicle cells from the head or chin...

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

    Science.gov (United States)

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

    2016-01-01

    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 in cca1 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. PMID:26941090

  19. Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

    Science.gov (United States)

    Cadenas, Cristina; van de Sandt, Leonie; Edlund, Karolina; Lohr, Miriam; Hellwig, Birte; Marchan, Rosemarie; Schmidt, Marcus; Rahnenführer, Jörg; Oster, Henrik; Hengstler, Jan G

    2014-01-01

    Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.

  20. Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle.

    Directory of Open Access Journals (Sweden)

    Jonathan A Hardman

    Full Text Available The human hair follicle (HF exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1 prolonging active hair growth (anagen and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4 also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2 were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock-related disease.

  1. Molecular clocks and the human condition: approaching their characterization in human physiology and disease.

    Science.gov (United States)

    Fitzgerald, G A; Yang, G; Paschos, G K; Liang, X; Skarke, C

    2015-09-01

    Molecular clockworks knit together diverse biological networks and compelling evidence from model systems infers their importance in metabolism, immunological and cardiovascular function. Despite this and the diurnal variation in many aspects of human physiology and the phenotypic expression of disease, our understanding of the role and importance of clock function and dysfunction in humans is modest. There are tantalizing hints of connection across the translational divide and some correlative evidence of gene variation and human disease but most of what we know derives from forced desynchrony protocols in controlled environments. We now have the ability to monitor quantitatively ex vivo or in vivo the genome, metabolome, proteome and microbiome of humans in the wild. Combining this capability, with the power of mobile telephony and the evolution of remote sensing, affords a new opportunity for deep phenotyping, including the characterization of diurnal behaviour and the assessment of the impact of the clock on approved drug function.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Miyazaki, Mitsunori; Schroder, Elizabeth; Edelmann, Stephanie E; Hughes, Michael E; Kornacker, Karl; Balke, C William; Esser, Karyn A

    2011-01-01

    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.

  5. Association between circadian clock genes and diapause incidence in Drosophila triauraria.

    Directory of Open Access Journals (Sweden)

    Hirokazu Yamada

    Full Text Available Diapause is an adaptive response triggered by seasonal photoperiodicity to overcome unfavorable seasons. The photoperiodic clock is a system that controls seasonal physiological processes, but our knowledge about its physiological mechanisms and genetic architecture remains incomplete. The circadian clock is another system that controls daily rhythmic physiological phenomena. It has been argued that there is a connection between the two clocks. To examine the genetic connection between them, we analyzed the associations of five circadian clock genes (period, timeless, Clock, cycle and cryptochrome with the occurrence of diapause in Drosophila triauraria, which shows a robust reproductive diapause with clear photoperiodicity. Non-diapause strains found in low latitudes were compared in genetic crosses with the diapause strain, in which the diapause trait is clearly dominant. Single nucleotide polymorphism and deletion analyses of the five circadian clock genes in backcross progeny revealed that allelic differences in timeless and cryptochrome between the strains were additively associated with the differences in the incidence of diapause. This suggests that there is a molecular link between certain circadian clock genes and the occurrence of diapause.

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

    Directory of Open Access Journals (Sweden)

    Purificación Gómez-Abellán

    Full Text Available AIMS: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  7. 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

  8. CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses.

    Science.gov (United States)

    Lai, Alvina Grace; Doherty, Colleen J; Mueller-Roeber, Bernd; Kay, Steve A; Schippers, Jos H M; Dijkwel, Paul P

    2012-10-16

    Organisms have evolved endogenous biological clocks as internal timekeepers to coordinate metabolic processes with the external environment. Here, we seek to understand the mechanism of synchrony between the oscillator and products of metabolism known as Reactive Oxygen Species (ROS) in Arabidopsis thaliana. ROS-responsive genes exhibit a time-of-day-specific phase of expression under diurnal and circadian conditions, implying a role of the circadian clock in transcriptional regulation of these genes. Hydrogen peroxide production and scavenging also display time-of-day phases. Mutations in the core-clock regulator, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress. Mis-expression of EARLY FLOWERING 3, LUX ARRHYTHMO, and TIMING OF CAB EXPRESSION 1 affect ROS production and transcription, indicating a global effect of the clock on the ROS network. We propose CCA1 as a master regulator of ROS homeostasis through association with the Evening Element in promoters of ROS genes in vivo to coordinate time-dependent responses to oxidative stress. We also find that ROS functions as an input signal that affects the transcriptional output of the clock, revealing an important link between ROS signaling and circadian output. Temporal coordination of ROS signaling by CCA1 and the reciprocal control of circadian output by ROS reveal a mechanistic link that allows plants to master oxidative stress responses.

  9. The biological clock modulates the human cortisol response in a multiplicative fashion

    NARCIS (Netherlands)

    van de Werken, Maan; Booij, Sanne H.; van der Zwan, J Esi; Simons, Mirre J. P.; Gordijn, Marijke C. M.; Beersma, Domien G. M.

    2014-01-01

    Human cortisol levels follow a clear circadian rhythm. We investigated the contribution of alternation of sleep and wakefulness and the circadian clock, using forced desynchrony. Cortisol levels were best described by a multiplication of a circadian and a wake-time component. The human cortisol resp

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

    NARCIS (Netherlands)

    K. Lech (Karolina); K. Ackermann (Katrin); V.L. Revell (Victoria); O.S.C.A.R. Lao; D.J. Skene (Debra); M.H. Kayser (Manfred)

    2016-01-01

    textabstractThe 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

  11. Changes of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans.

    Science.gov (United States)

    Pivovarova, Olga; Jürchott, Karsten; Rudovich, Natalia; Hornemann, Silke; Ye, Lu; Möckel, Simona; Murahovschi, Veronica; Kessler, Katharina; Seltmann, Anne-Cathrin; Maser-Gluth, Christiane; Mazuch, Jeannine; Kruse, Michael; Busjahn, Andreas; Kramer, Achim; Pfeiffer, Andreas F H

    2015-06-01

    The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.

  12. CLOCK Gene Variants Associate with Sleep Duration in Two Independent Populations

    NARCIS (Netherlands)

    Allebrandt, Karla V.; Teder-Laving, Maris; Akyol, Mahmut; Pichler, Irene; Mueller-Myhsok, Bertram; Pramstaller, Peter; Merrow, Martha; Meitinger, Thomas; Metspalu, Andreas; Roenneberg, Till; Müller-Myhsok, Bertram

    2010-01-01

    Background: Sleep is an active and complex behavior, yet it has two straightforward properties-timing and duration. Clock genes are associated with dysfunctional timing of sleep, mood, and obesity disorders, which are commonly associated with sleep duration. Methods: Sleep duration was assessed in C

  13. The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts.

    Directory of Open Access Journals (Sweden)

    Lucia Pagani

    Full Text Available BACKGROUND: Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls", clock properties measured in human fibroblasts correlated with extreme diurnal behavior. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. CONCLUSIONS/SIGNIFICANCE: We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness.

  14. Association between the CLOCK gene 3111 T > C polymorphism and an irregular menstrual cycle in Korean adolescents.

    Science.gov (United States)

    Kim, Kye-Hyun; Kim, Yunsin; Ha, Juwon; Shin, Dong-Won; Shin, Young-Chul; Oh, Kang-Seob; Woo, Hee-Yeon; Lim, Se-Won

    2015-01-01

    The menstrual cycle is an example of a human infradian rhythm, but an altered sleep-wake cycle or a disrupted circadian rhythm can change the regularity of the menstrual cycle. In this study, we investigated whether an irregular menstrual cycle is associated with polymorphisms in the CLOCK (3111T > C) and/or PER3 (variable number tandem repeat, VNTR) genes, which are known to have an impact on the circadian rhythm. One hundred ninety-seven postmenarchal, adolescent girls from two girls' high schools in Seoul, Korea, were studied. All participants were requested to complete the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) to assess the emotional distress that might cause menstrual irregularity. Every participant donated a blood sample from which DNA was extracted and genotyped for the CLOCK 3111T > C and PER3 VNTR polymorphisms. A significant association was found between the CLOCK 3111T > C genotype and irregular menstrual cycles. Subjects with the 3111T > C genotype had a high risk of an irregular menstrual cycle compared with 3111T/T homozygous subjects (odds ratio [OR] = 2.88; 95% confidence interval [CI]: 1.26-6.55). When multivariate logistic regression analysis was performed to adjust for age, PSS, STAI, BDI and BMI, subjects with the 3111T > C polymorphism showed a significantly increased OR for irregular menstrual cycles (OR = 3.09; 95% CI: 1.32-7.21). There was no significant association between the PER3 VNTR polymorphism and the irregularity of the menstrual cycle (p > 0.05). The results of this study suggest that the CLOCK 3111T > C polymorphism could be an independent risk factor for irregular menstrual cycles, irrespective of psychological distress and endocrine or metabolic conditions, and could be used as a molecular marker for gynecological studies on this aspect.

  15. Phase-Shifting Effect of Light and Exercise on the Human Circadian Clock.

    Science.gov (United States)

    1992-02-29

    E. A twin study of the circadian and pulsatile variations of plasma cortisol: evidence for genetic control of the human circadian clock. Am J Physiol...Conference on Chronobiology , Irsee, Germany, September 29-October 4, 1991. Van Cauter, E. Effects of sleep on glucose regulation. Invited Speaker. Founding

  16. A self-regulatory circuit of CIRCADIAN CLOCK-ASSOCIATED1 underlies the circadian clock regulation of temperature responses in Arabidopsis.

    Science.gov (United States)

    Seo, Pil Joon; Park, Mi-Jeong; Lim, Mi-Hye; Kim, Sang-Gyu; Lee, Minyoung; Baldwin, Ian T; Park, Chung-Mo

    2012-06-01

    The circadian clock synchronizes biological processes to daily cycles of light and temperature. Clock components, including CIRCADIAN CLOCK-ASSOCIATED1 (CCA1), are also associated with cold acclimation. However, it is unknown how CCA1 activity is modulated in coordinating circadian rhythms and cold acclimation. Here, we report that self-regulation of Arabidopsis thaliana CCA1 activity by a splice variant, CCA1β, links the clock to cold acclimation. CCA1β interferes with the formation of CCA1α-CCA1α and LATE ELONGATED HYPOCOTYL (LHY)-LHY homodimers, as well as CCA1α-LHY heterodimers, by forming nonfunctional heterodimers with reduced DNA binding affinity. Accordingly, the periods of circadian rhythms were shortened in CCA1β-overexpressing transgenic plants (35S:CCA1β), as observed in the cca1 lhy double mutant. In addition, the elongated hypocotyl and leaf petiole phenotypes of CCA1α-overexpressing transgenic plants (35S:CCA1α) were repressed by CCA1β coexpression. Notably, low temperatures suppressed CCA1 alternative splicing and thus reduced CCA1β production. Consequently, whereas the 35S:CCA1α transgenic plants exhibited enhanced freezing tolerance, the 35S:CCA1β transgenic plants were sensitive to freezing, indicating that cold regulation of CCA1 alternative splicing contributes to freezing tolerance. On the basis of these findings, we propose that dynamic self-regulation of CCA1 underlies the clock regulation of temperature responses in Arabidopsis.

  17. Daily oscillation and photoresponses of clock gene, Clock, and clock-associated gene, arylalkylamine N-acetyltransferase gene transcriptions in the rat pineal gland.

    Science.gov (United States)

    Wang, Guo-Qing; Du, Yu-Zhen; Tong, Jian

    2007-01-01

    This study was conducted to investigate the circadian rhythms and light responses of Clock and arylalkylamine N-acetyltransferase (NAT) gene expressions in the rat pineal gland under the environmental conditions of a 12 h light (05:00-17:00 h): 12 h-dark (17:00-05:00 h) cycle (LD) and constant darkness (DD). The pineal gland of Sprague-Dawley rats housed under a LD regime (n=42) for four weeks and of a regime (n=42) for eight weeks were sampled at six different times, every 4 h (n=7 animals per time point), during a 24 h period. Total RNA was extracted from each sample, and the semiquantitative reverse transcription polymerase chain reaction (RT-PCR) was used to determine temporal changes in mRNA levels of Clock and NAT genes during different circadian or zeitgeber times. The data and parameters were analyzed by the cosine function software, Clock Lab software, and the amplitude F test was used to reveal the circadian rhythm. In the DD or LD condition, both the Clock and NAT mRNA levels in the pineal gland showed robust circadian oscillation (ppineal gland were significantly reduced (ppineal gland (p>0.05). These findings indicate that the transcriptions of Clock and NAT genes in the pineal gland not only show remarkably synchronous endogenous circadian rhythmic changes, but also respond to the ambient light signal in a reduced manner.

  18. A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock.

    Science.gov (United States)

    Al-Nuaimi, Yusur; Hardman, Jonathan A; Bíró, Tamás; Haslam, Iain S; Philpott, Michael P; Tóth, Balázs I; Farjo, Nilofer; Farjo, Bessam; Baier, Gerold; Watson, Rachel E B; Grimaldi, Benedetto; Kloepper, Jennifer E; Paus, Ralf

    2014-03-01

    The hair follicle (HF) is a continuously remodeled mini organ that cycles between growth (anagen), regression (catagen), and relative quiescence (telogen). As the anagen-to-catagen transformation of microdissected human scalp HFs can be observed in organ culture, it permits the study of the unknown controls of autonomous, rhythmic tissue remodeling of the HF, which intersects developmental, chronobiological, and growth-regulatory mechanisms. The hypothesis that the peripheral clock system is involved in hair cycle control, i.e., the anagen-to-catagen transformation, was tested. Here we show that in the absence of central clock influences, isolated, organ-cultured human HFs show circadian changes in the gene and protein expression of core clock genes (CLOCK, BMAL1, and Period1) and clock-controlled genes (c-Myc, NR1D1, and CDKN1A), with Period1 expression being hair cycle dependent. Knockdown of either BMAL1 or Period1 in human anagen HFs significantly prolonged anagen. This provides evidence that peripheral core clock genes modulate human HF cycling and are an integral component of the human hair cycle clock. Specifically, our study identifies BMAL1 and Period1 as potential therapeutic targets for modulating human hair growth.

  19. Effects of bright light exposure during daytime on peripheral clock gene expression in humans

    Science.gov (United States)

    Sato, Maki; Wakamura, Tomoko; Morita, Takeshi; Okamoto, Akihiko; Akashi, Makoto; Matsui, Takuya; Sato, Motohiko

    2016-12-01

    Light is the strongest synchronizer controlling circadian rhythms. The intensity and duration of light change throughout the year, thereby influencing body weight, food preferences, and melatonin secretion in humans and animals. Although the expression of clock genes has been examined using human samples, it currently remains unknown whether bright light during the daytime affects the expression of these genes in humans. Therefore, we herein investigated the effects of bright light exposure during the daytime on clock gene expression in the hair follicular and root cells of the human scalp. Seven healthy men (20.4 ± 2.2 years old; 172.3 ± 5.8 cm; 64.3 ± 8.5 kg; BMI 21.7 ± 3.1 kg/m2, mean ± SD) participated in this study. Subjects completed 3-day experimental sessions twice in 1 month during which they were exposed to bright and dim light conditions. The mRNA expression of Per1-3, Cry1-2, Rev-erb-α (Nr1d1), Rev-erb-β (Nr1d2), and Dec1 was analyzed using branched DNA probes. No significant changes were observed in the expression of Per1, Per2, Per3, Cry1, Cry2, Rev-erb-α (Nr1d1), or Dec1 following exposure to bright light conditions. However, the expression of Rev-erb-β (Nr1d2) tended to be stronger under bright light than dim light conditions. These results suggest that the bright light stimulus did not influence the expression of clock genes in humans. Long-lasting bright light exposure during the daytime may be required to change the expression of clock genes in humans.

  20. Clock genes, pancreatic function, and diabetes.

    Science.gov (United States)

    Vieira, Elaine; Burris, Thomas P; Quesada, Ivan

    2014-12-01

    Circadian physiology is responsible for the temporal regulation of metabolism to optimize energy homeostasis throughout the day. Disturbances in the light/dark cycle, sleep/wake schedule, or feeding/activity behavior can affect the circadian function of the clocks located in the brain and peripheral tissues. These alterations have been associated with impaired glucose tolerance and type 2 diabetes. Animal models with molecular manipulation of clock genes and genetic studies in humans also support these links. It has been demonstrated that the endocrine pancreas has an intrinsic self-sustained clock, and recent studies have revealed an important role of clock genes in pancreatic β cells, glucose homeostasis, and diabetes.

  1. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Gustavo Casta(n)o; Carolina Gemma; Tomas Fernández Gianotti; Carlos Jose Pirola

    2007-01-01

    AIM: To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity.METHODS: A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4and representing 115 polymorphic sites (r2>0.8) were genotyped.RESULTS: rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722(empiric P = 0.0229) and rs6850524 (empiric P =0.00899) and between fibrosis score and rs1554483(empiric P = 0.02697), rs6843722 (empiric P = 0.01898)and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097).CONCLUSION: Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.

  2. Human Germline Mutation and the Erratic Evolutionary Clock

    Science.gov (United States)

    Przeworski, Molly

    2016-01-01

    Our understanding of the chronology of human evolution relies on the “molecular clock” provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not “a mutation rate” but a precise characterization of how mutations accumulate in development in males and females—knowledge that remains elusive. PMID:27760127

  3. Circadian Clock Genes Modulate Human Bone Marrow Mesenchymal Stem Cell Differentiation, Migration and Cell Cycle.

    Science.gov (United States)

    Boucher, Helene; Vanneaux, Valerie; Domet, Thomas; Parouchev, Alexandre; Larghero, Jerome

    2016-01-01

    Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties.

  4. Cellular circadian clocks in mood disorders.

    Science.gov (United States)

    McCarthy, Michael J; Welsh, David K

    2012-10-01

    Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks

  5. EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock.

    Science.gov (United States)

    Mi, Yashi; Qi, Guoyuan; Fan, Rong; Ji, Xiaohua; Liu, Zhigang; Liu, Xuebo

    2017-06-01

    In response to the daily light-dark (LD) cycle, organisms on Earth have evolved with the approximately 24-h endogenous oscillations to coordinate behavioral and physiological processes, including feeding, sleep, and metabolism homeostasis. Circadian desynchrony triggered by an energy-dense diet rich in fats and fructose is intimately connected with a series of metabolic disorders. Previous studies revealed that (-)-Epigallocatechin-3-gallate (EGCG) could mitigate metabolic misalignment; however, only a few reports have focused on its potential effect on directly manipulating circadian rhythms to ameliorate metabolic syndrome. Our goal was to investigate the regulating effect of EGCG treatment on metabolic misalignment triggered by a high-fat and high-fructose diet (HFFD) associating with the circadian clock. Our results indicated that HFFD treatment partially exhibited poor circadian oscillations of the core clock gene and the clock-controlled gene in the liver and fat relative to the control group. EGCG administration may ameliorate the diet-dependent decline in circadian function by controlling the Sirt1-PGC1αloop, implying the existence of an EGCG-entrainable oscillator. Subsequently, reducing fatty acid synthesis and elevating β-oxidation in the liver coupled with the increasing brown adipose tissue (BAT) energy expenditure observed in the EGCG group of mice prevented the adipocyte hypertrophy and fat accumulations common to BAT and white adipose tissue (WAT) derived from the HFFD mice. This study is the first to provide compelling evidences that EGCG may ameliorate diet-induced metabolic misalignment by regulating the rhythmic expression of the circadian clock genes in the liver and fat. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition.

    Science.gov (United States)

    Menon, Ramkumar; Bonney, Elizabeth A; Condon, Jennifer; Mesiano, Sam; Taylor, Robert N

    2016-09-01

    The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the

  7. Circadian rhythm genes CLOCK and PER3 polymorphisms and morning gastric motility in humans.

    Directory of Open Access Journals (Sweden)

    Mitsue Yamaguchi

    Full Text Available Clock genes regulate circadian rhythm and are involved in various physiological processes, including digestion. We therefore investigated the association between the CLOCK 3111T/C single nucleotide polymorphism and the Period3 (PER3 variable-number tandem-repeat polymorphism (either 4 or 5 repeats 54 nt in length with morning gastric motility.Lifestyle questionnaires and anthropometric measurements were performed with 173 female volunteers (mean age, 19.4 years. Gastric motility, evaluated by electrogastrography (EGG, blood pressure, and heart rate levels were measured at 8:30 a.m. after an overnight fast. For gastric motility, the spectral powers (% normal power and dominant frequency (DF, peak of the power spectrum of the EGG were evaluated. The CLOCK and PER3 polymorphisms were determined by polymerase chain reaction (PCR restriction fragment length polymorphism analysis.Subjects with the CLOCK C allele (T/C or C/C genotypes: n = 59 showed a significantly lower DF (mean, 2.56 cpm than those with the T/T genotype (n = 114, 2.81 cpm, P < 0.05. Subjects with the longer PER3 allele (PER34/5 or PER35/5 genotypes: n = 65 also showed a significantly lower DF (2.55 cpm than those with the shorter PER34/4 genotype (n = 108, 2.83 cpm, P < 0.05. Furthermore, subjects with both the T/C or C/C and PER34/5 or PER35/5 genotypes showed a significantly lower DF (2.43 cpm, P < 0.05 than subjects with other combinations of the alleles (T/T and PER34/4 genotype, T/C or C/C and PER34/4 genotypes, and T/T and PER34/5 or PER35/5 genotypes.These results suggest that minor polymorphisms of the circadian rhythm genes CLOCK and PER3 may be associated with poor morning gastric motility, and may have a combinatorial effect. The present findings may offer a new viewpoint on the role of circadian rhythm genes on the peripheral circadian systems, including the time-keeping function of the gut.

  8. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition

    Science.gov (United States)

    Menon, Ramkumar; Bonney, Elizabeth A.; Condon, Jennifer; Mesiano, Sam; Taylor, Robert N.

    2016-01-01

    The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments. In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the

  9. Body Clock

    Institute of Scientific and Technical Information of China (English)

    刘洪毓

    2000-01-01

    “Body clocks” are biological methods of controling body activities.Every living thing has one. In humans, a body clock controls normal periods of sleeping and waking. It controls the time swhen you are most likely to feel pain.Eating, sleeping and exercising at about the same time each day will help keep body activities normal. But changes in your life, a new job, for example, destroy the balance and thus cause health problems.

  10. Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes.

    NARCIS (Netherlands)

    Hansen, J.; Timmers, S.; Moonen-Kornips, E.; Duez, H.; Staels, B.; Hesselink, M.K.; Schrauwen, P.

    2016-01-01

    Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type

  11. Clock gene variation is associated with breeding phenology and maybe under directional selection in the migratory barn swallow.

    Directory of Open Access Journals (Sweden)

    Manuela Caprioli

    Full Text Available BACKGROUND: In diverse taxa, photoperiodic responses that cause seasonal physiological and behavioural shifts are controlled by genes, including the vertebrate Clock orthologues, that encode for circadian oscillator mechanisms. While the genetic network behind circadian rhythms is well described, relatively few reports exist of the phenological consequences of and selection on Clock genes in the wild. Here, we investigated variation in breeding phenology in relation to Clock genetic diversity in a long-distance migratory bird, the barn swallow (Hirundo rustica. METHODOLOGY/PRINCIPAL FINDINGS: In a sample of 922 adult barn swallows from a single population breeding in Italy we found one very common (Q(7 and three rare (Q(5, Q(6, Q(8 length variants of a functionally significant polyglutamine repeat. Rare (2.9% Q(7/Q(8 heterozygous females, but not males, bred significantly later than common (91.5% Q(7/Q(7 females, consistent with the expectation that 'long' alleles cause late breeding, as observed in a resident population of another bird species. Because breeding date depends on arrival date from migration, present results suggest that the association between breeding date and Clock might be mediated by migration phenology. In addition, fecundity selection appears to be operating against Q(7/Q(8 because late migrating/breeding swallows have fewer clutches per season, and late breeding has additional negative selection effects via reduced offspring longevity. Genotype frequencies varied marginally non-significantly with age, as Q(7/Q(8 frequency showed a 4-fold reduction in old individuals. This result suggests negative viability selection against Q(7/Q(8, possibly mediated by costs of late breeding. CONCLUSIONS/SIGNIFICANCE: This is the first study of migratory birds showing an association between breeding phenology and Clock genotype and suggesting that negative selection occurs on a phenologically deviant genotype. Low polymorphism at Clock may

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

    DEFF Research Database (Denmark)

    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...

  13. The human circadian clock's seasonal adjustment is disrupted by daylight saving time

    NARCIS (Netherlands)

    Kantermann, Thomas; Juda, Myriam; Merrow, Martha; Roenneberg, Till

    2007-01-01

    A quarter of the world's population is subjected to a 1 hr time change twice a year (daylight saving time, DST). This reflects a change in social clocks, not environmental ones (e.g., dawn). The impact of DST is poorly understood. Circadian clocks use daylight to synchronize (entrain) to the organis

  14. Regulation of molecular clock oscillations and phagocytic activity via muscarinic Ca2+ signaling in human retinal pigment epithelial cells

    Science.gov (United States)

    Ikarashi, Rina; Akechi, Honami; Kanda, Yuzuki; Ahmad, Alsawaf; Takeuchi, Kouhei; Morioka, Eri; Sugiyama, Takashi; Ebisawa, Takashi; Ikeda, Masaaki; Ikeda, Masayuki

    2017-01-01

    Vertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). The hRPE-YC cells demonstrated circadian rhythms in Bmal1 transcription. Also, these cells represented circadian rhythms in Ca2+-spiking frequencies, which were canceled by dominant-negative Bmal1 transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted Bmal1 transcriptional rhythms with a type-1 phase response curve. This is consistent with significant M3 muscarinic receptor expression and little photo-sensor (Cry2 and Opn4) expression in these cells. Moreover, forskolin phase-shifted Bmal1 transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative Bmal1 transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca2+ signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks. PMID:28276525

  15. SIRT1 and CLOCK 3111T greater than C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity

    Science.gov (United States)

    Background: A new negative feedback loop has been proposed, which suggests connections between the circadian clock and SIRTUIN1 (SIRT1)-dependent functions associated with cell survival, development and metabolism. Objective: To develop a SIRT1 and circadian locomotor output cycles kaput (CLOCK) com...

  16. Millisecond flashes of light phase delay the human circadian clock during sleep

    Science.gov (United States)

    Zeitzer, Jamie M.; Fisicaro, Ryan A.; Ruby, Norman F.; Heller, H. Craig

    2016-01-01

    The human circadian timing system is most sensitive to the phase shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a two-week circadian stabilization protocol followed by a two-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n=7) or a sequence of 2-msec light flashes given every 30 seconds (n=6) from hours 2–3 after habitual bed time. Changes in circadian timing (phase), micro- and macroarchitecture of sleep were all assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm as compared to the control dark condition (P0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 seconds of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether there is an effect of these light flashes on sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. PMID:25227334

  17. Light modulation of human sleep depends on a polymorphism in the clock gene Period3.

    Science.gov (United States)

    Chellappa, Sarah L; Viola, Antoine U; Schmidt, Christina; Bachmann, Valérie; Gabel, Virginie; Maire, Micheline; Reichert, Carolin F; Valomon, Amandine; Landolt, Hans-Peter; Cajochen, Christian

    2014-09-01

    Non-image-forming (NIF) responses to light powerfully modulate human physiology. However, it remains scarcely understood how NIF responses to light modulate human sleep and its EEG hallmarks, and if there are differences across individuals. Here we investigated NIF responses to light on sleep in individuals genotyped for the PERIOD3 (PER3) variable-number tandem-repeat (VNTR) polymorphism. Eighteen healthy young men (20-28 years; mean ± SEM: 25.9 ± 1.2) homozygous for the PER3 polymorphism were matched by age, body-mass index, and ethnicity. The study protocol comprised a balanced cross-over design during the winter, during which participants were exposed to either light of 40 lx at 6,500 K (blue-enriched) or light at 2,500 K (non-blue enriched), during 2h in the evening. Compared to light at 2,500 K, light at 6,500 K induced a significant increase in all-night NREM sleep slow-wave activity (SWA: 1.0-4.5 Hz) in the occipital cortex for PER3(5/5) individuals, but not for PER3(4/4) volunteers. Dynamics of SWA across sleep cycles revealed increased occipital NREM sleep SWA for virtually all sleep episode only for PER3(5/5) individuals. Furthermore, they experienced light at 6,500 K as significantly brighter. Intriguingly, this subjective perception of brightness significantly predicted their increased occipital SWA throughout the sleep episode. Our data indicate that humans homozygous for the PER3(5/5) allele are more sensitive to NIF light effects, as indexed by specific changes in sleep EEG activity. Ultimately, individual differences in NIF light responses on sleep may depend on a clock gene polymorphism involved in sleep-wake regulation.

  18. Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes

    Science.gov (United States)

    Hansen, Jan; Timmers, Silvie; Moonen-Kornips, Esther; Duez, Helene; Staels, Bart; Hesselink, Matthijs K. C.; Schrauwen, Patrick

    2016-01-01

    Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status. PMID:27756900

  19. Circadian Clock Is Involved in Regulation of Hepatobiliary Transport Mediated by Multidrug Resistance-Associated Protein 2.

    Science.gov (United States)

    Oh, Ju-Hee; Lee, Joo Hyun; Han, Dong-Hee; Cho, Sehyung; Lee, Young-Joo

    2017-09-01

    There has been a growing interest in circadian regulation of the expression and function of drug transporters. In this study, we investigated circadian rhythm in the expression and function of multidrug resistance-associated protein 2 (Mrp2) in mouse liver and involvement of circadian clock in their regulations by using the circadian clock genes (period 1 and period 2) knockout mice. The mRNA and protein expression of Mrp2, P-glycoprotein, and breast cancer resistance protein was measured in the mouse liver at different times of the day. Circadian variation of hepatobiliary excretion of phenolsulfonphthalein, a model substrate of Mrp2, was also investigated in mice. Circadian oscillation of Mrp2 protein expression was clearly observed in the mouse liver with levels down at the light phase and up at the dark phase. The cumulative biliary excretion and biliary clearance of phenolsulfonphthalein from the liver to the bile was 2.37- and 1.74-fold greater in mice administered during the dark phase than in those administered during the light phase, respectively. The circadian oscillation in mRNA expression of Mrp2 disappeared in period 1 and period 2 double knockout mice. These results suggest that the expression and function of Mrp2 show the circadian rhythm, controlled by circadian clock genes. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Circadian regulation of cell cycle: Molecular connections between aging and the circadian clock.

    Science.gov (United States)

    Khapre, Rohini V; Samsa, William E; Kondratov, Roman V

    2010-09-01

    The circadian clock generates oscillations in physiology and behavior, known as circadian rhythms. Links between the circadian clock genes Periods, Bmal1, and Cryptochromes and aging and cancer are emerging. Circadian clock gene expression is changed in human pathologies, and transgenic mice with mutations in clock genes develop cancer and premature aging. Control of genome integrity and cell proliferation play key roles in the development of age-associated pathologies and carcinogenesis. Here, we review recent data on the connection between the circadian clock and control of the cell cycle. The circadian clock regulates the activity and expression of several critical cell cycle and cell cycle check-point-related proteins, and in turn cell cycle-associated proteins regulate circadian clock proteins. DNA damage can reset the circadian clock, which provides a molecular mechanism for reciprocal regulation between the circadian clock and the cell cycle. This circadian clock-dependent control of cell proliferation, together with other known physiological functions of the circadian clock such as the control of metabolism, oxidative and genotoxic stress response, and DNA repair, opens new horizons for understanding the mechanisms behind aging and carcinogenesis.

  2. Chronotype is associated with the timing of the circadian clock and sleep in toddlers.

    Science.gov (United States)

    Simpkin, Charles T; Jenni, Oskar G; Carskadon, Mary A; Wright, Kenneth P; Akacem, Lameese D; Garlo, Katherine G; LeBourgeois, Monique K

    2014-08-01

    Chronotype is a construct reflecting individual differences in diurnal preference. Although chronotype has been studied extensively in school-age children, adolescents and adults, data on young children are scarce. This study describes chronotype and its relationship to the timing of the circadian clock and sleep in 48 healthy children aged 30-36 months (33.4 ± 2.1 months; 24 males). Parents completed the Children's Chronotype Questionnaire (CCTQ) ~2 weeks before the start of the study. The CCTQ provides three measures of chronotype: midsleep time on free days, a multi-item morningness/eveningness score and a single item chronotype score. After 5 days of sleeping on their habitual schedule (assessed with actigraphy and sleep diaries), children participated in an in-home salivary dim light melatonin onset assessment. Average midsleep time on free days was 1:47 ± 0:35, and the average morningness/eveningness score was 26.8 ± 4.3. Most toddlers (58.4%) were rated as 'definitely a morning type' or 'rather morning than evening type', while none (0%) were rated as 'definitely evening type'. More morning types (midsleep time on free days and morningness/eveningness score, respectively) had earlier melatonin onset times (r = 0.45, r = 0.26), earlier habitual bedtimes (r = 0.78, r = 0.54), sleep onset times (r = 0.80, r = 0.52), sleep midpoint times (r = 0.90, r = 0.53) and wake times (r = 0.74, r = 0.34). Parent ratings using the single-item chronotype score were associated with melatonin onset (r = 0.32) and habitual bedtimes (r = 0.27), sleep onset times (r = 0.33) and sleep midpoint times (r = 0.27). Morningness may best characterize circadian preference in early childhood. Associations between chronotype and circadian physiology and sleep timing suggest adequate validity for the CCTQ in this age group. These findings have important implications for understanding the marked variability in sleep timing during the early years of life.

  3. Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption.

    Science.gov (United States)

    Touitou, Yvan; Reinberg, Alain; Touitou, David

    2017-03-15

    Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50-100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption. Shift and/or night work generally decreases the time spent sleeping, and it disrupts the circadian time structure. In the long run, this desynchronization is detrimental to health, as underscored by a large number of epidemiological studies that have uncovered elevated rates of several diseases, including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. It amounts to a public health issue in the light of the very substantial number of individuals involved. The IARC has classified shift work in group 2A of "probable carcinogens to humans" since "they involve a circadian disorganization". Countermeasures to the effects of ALAN, such as melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work. We review the evidence for the ALAN impacts on health. Furthermore, we highlight the importance of an in-depth mechanistic understanding to combat the detrimental properties of exposure to ALAN and develop strategies of prevention. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

    Institute of Scientific and Technical Information of China (English)

    Zixi Wang; Yaling Wu; Lanfen Li; Xiao-Dong Su

    2013-01-01

    CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle ARNT-like 1) are both transcription factors of the circadian core loop in mammals.Recently published mouse CLOCK-BMAL1 bHLH (basic helix-loop-helix)-PAS (period-ARNT-single-minded) complex structure sheds light on the mechanism for heterodimer formation,but the structural details of the protein-DNA recognition mechanisms remain elusive.Here we have elucidated the crystal structure of human CLOCK-BMAL1 bHLH domains bound to a canonical E-box DNA.We demonstrate that CLOCK and BMAL1 bHLH domains can be mutually selected,and that hydrogen-bonding networks mediate their E-box recognition.We identified a hydrophobic contact between BMAL1 Ile80 and a fianking thymine nucleotide,suggesting that CLOCK-BMAL1 actually reads 7-bp DNA and not the previously believed 6-bp DNA.To find potential non-canonical E-boxes that could be recognized by CLOCK-BMAL1,we constructed systematic single-nucleotide mutations on the E-box and measured their relevant affinities.We defined two non-canonical E-box patterns with high affinities,AACGTGA and CATGTGA,in which the flanking A7-T7' base pair is indispensable for recognition.These results will help us to identify functional CLOCK-BMAL1-binding sites in vivo and to search for clock-controlled genes.Furthermore,we assessed the inhibitory role of potential phosphorylation sites in bHLH regions.We found that the phospho-mimicking mutation on BMAL1 Ser78 could efficiently block DNA binding as well as abolish normal circadian oscillation in cells.We propose that BMAL1 Ser78 should be a key residue mediating input signal-regulated transcriptional inhibition for external cues to entrain the circadian clock by kinase cascade.

  5. Screening of Clock Gene Polymorphisms Demonstrates Association of a PER3 Polymorphism with Morningness–Eveningness Preference and Circadian Rhythm Sleep Disorder

    Science.gov (United States)

    Hida, Akiko; Kitamura, Shingo; Katayose, Yasuko; Kato, Mie; Ono, Hiroko; Kadotani, Hiroshi; Uchiyama, Makoto; Ebisawa, Takashi; Inoue, Yuichi; Kamei, Yuichi; Okawa, Masako; Takahashi, Kiyohisa; Mishima, Kazuo

    2014-01-01

    A system of self-sustained biological clocks controls the 24-h rhythms of behavioral and physiological processes such as the sleep–wake cycle. The circadian clock system is regulated by transcriptional and translational negative feedback loops of multiple clock genes. Polymorphisms in circadian clock genes have been associated with morningness–eveningness (diurnal) preference, familial advanced sleep phase type (ASPT), and delayed sleep phase type (DSPT). We genotyped single-nucleotide polymorphisms in circadian clock genes in 182 DSPT individuals, 67 free-running type (FRT) individuals, and 925 controls. The clock gene polymorphisms were tested for associations with diurnal preference and circadian rhythm sleep disorder (CRSD) phenotypes. The PER3 polymorphism (rs228697) was significantly associated with diurnal preference and the FRT phenotype. The minor allele of rs228697 was more prevalent in evening types than in morning types (sex-adjusted odds ratio (OR), 2.483, Bonferroni-corrected P = 0.012) and in FRT individuals compared with the controls (age- and sex-adjusted OR, 2.021, permutated P = 0.017). Our findings support the notion that PER3 polymorphisms could be a potential genetic marker for an individual's circadian and sleep phenotypes. PMID:25201053

  6. Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder.

    Science.gov (United States)

    Hida, Akiko; Kitamura, Shingo; Katayose, Yasuko; Kato, Mie; Ono, Hiroko; Kadotani, Hiroshi; Uchiyama, Makoto; Ebisawa, Takashi; Inoue, Yuichi; Kamei, Yuichi; Okawa, Masako; Takahashi, Kiyohisa; Mishima, Kazuo

    2014-09-09

    A system of self-sustained biological clocks controls the 24-h rhythms of behavioral and physiological processes such as the sleep-wake cycle. The circadian clock system is regulated by transcriptional and translational negative feedback loops of multiple clock genes. Polymorphisms in circadian clock genes have been associated with morningness-eveningness (diurnal) preference, familial advanced sleep phase type (ASPT), and delayed sleep phase type (DSPT). We genotyped single-nucleotide polymorphisms in circadian clock genes in 182 DSPT individuals, 67 free-running type (FRT) individuals, and 925 controls. The clock gene polymorphisms were tested for associations with diurnal preference and circadian rhythm sleep disorder (CRSD) phenotypes. The PER3 polymorphism (rs228697) was significantly associated with diurnal preference and the FRT phenotype. The minor allele of rs228697 was more prevalent in evening types than in morning types (sex-adjusted odds ratio (OR), 2.483, Bonferroni-corrected P = 0.012) and in FRT individuals compared with the controls (age- and sex-adjusted OR, 2.021, permutated P = 0.017). Our findings support the notion that PER3 polymorphisms could be a potential genetic marker for an individual's circadian and sleep phenotypes.

  7. The role of biological clock in glucose homeostasis 

    Directory of Open Access Journals (Sweden)

    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

  8. Molecular mechanisms underlying the Arabidopsis circadian clock.

    Science.gov (United States)

    Nakamichi, Norihito

    2011-10-01

    A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day-night cycle. This rhythm is generated by the so-called 'circadian clock'. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. This progress has provided mechanistic insights into how key clock-associated proteins are integrated, and may help in understanding the essence of the clock's molecular mechanisms.

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

    Directory of Open Access Journals (Sweden)

    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

  10. 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.

    Science.gov (United States)

    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.

  11. The association of the Clock 3111 T/C SNP with lipids and lipoproteins including small dense low-density lipoprotein: results from the Mima study.

    Science.gov (United States)

    Tsuzaki, Kokoro; Kotani, Kazuhiko; Sano, Yoshiko; Fujiwara, Shinji; Takahashi, Kaoru; Sakane, Naoki

    2010-10-21

    The clock molecule plays major roles in circadian rhythmicity and regulating lipid and glucose metabolism in peripheral organs. Disruption of the circadian rhythm can lead to cardiometabolic disorders. The existence of small dense low-density lipoprotein (sdLDL) in the circulation, an abnormality of lipid metabolism, in part associated with lifestyle, is also one of risk parameters for cardiometabolic disorders. The 3111 T/C single nucleotide polymorphism (SNP) of the Clock gene has been reported to be associated with lifestyle including morning/evening preference. We investigated whether the Clock 3111 T/C SNP may affect lipids and lipoproteins including sdLDL. In 365 community-dwelling subjects (170 men and 195 women, mean age 63 ± 14 years), the 3111 T/C SNP was genotyped using a fluorescent allele-specific DNA primer assay system. The levels of sdLDL were measured with the electrophoretic separation of lipoproteins employing the Lipoprint system. The frequency of the Clock 3111 C allele was 0.14. The area of sdLDL did not differ between the subjects with obesity and those without. In carriers of T/T homozygotes, the area of sdLDL was significantly higher compared with carriers of the C allele (T/C or C/C) (1.7 ± 3.4 vs. 0.8 ± 1.9%; p < 0.05). A multiple regression analysis showed that the area of sdLDL was significantly and negatively correlated with the Clock 3111 T/C SNP (β = -0.114, p < 0.05), independently of age, sex, body mass index, and exercise habits. Our findings indicated that the Clock 3111 T/C SNP might be associated with the existence of sdLDL.

  12. The association of the Clock 3111 T/C SNP with lipids and lipoproteins including small dense low-density lipoprotein: results from the Mima study

    Directory of Open Access Journals (Sweden)

    Takahashi Kaoru

    2010-10-01

    Full Text Available Abstract Background The clock molecule plays major roles in circadian rhythmicity and regulating lipid and glucose metabolism in peripheral organs. Disruption of the circadian rhythm can lead to cardiometabolic disorders. The existence of small dense low-density lipoprotein (sdLDL in the circulation, an abnormality of lipid metabolism, in part associated with lifestyle, is also one of risk parameters for cardiometabolic disorders. The 3111 T/C single nucleotide polymorphism (SNP of the Clock gene has been reported to be associated with lifestyle including morning/evening preference. We investigated whether the Clock 3111 T/C SNP may affect lipids and lipoproteins including sdLDL. Methods In 365 community-dwelling subjects (170 men and 195 women, mean age 63 ± 14 years, the 3111 T/C SNP was genotyped using a fluorescent allele-specific DNA primer assay system. The levels of sdLDL were measured with the electrophoretic separation of lipoproteins employing the Lipoprint system. Results The frequency of the Clock 3111 C allele was 0.14. The area of sdLDL did not differ between the subjects with obesity and those without. In carriers of T/T homozygotes, the area of sdLDL was significantly higher compared with carriers of the C allele (T/C or C/C (1.7 ± 3.4 vs. 0.8 ± 1.9%; p Clock 3111 T/C SNP (β = -0.114, p Conclusion Our findings indicated that the Clock 3111 T/C SNP might be associated with the existence of sdLDL.

  13. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm.

    Science.gov (United States)

    Dunwoodie, Sally L; Clements, Melanie; Sparrow, Duncan B; Sa, Xin; Conlon, Ronald A; Beddington, Rosa S P

    2002-04-01

    A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following gene targeting, and results in severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae and costal defects, are similar to those associated with the Dll3-dependent pudgy mutant in mouse and with spondylocostal dysplasia (MIM 277300) in humans. This study demonstrates that Dll3(neo) and Dll3(pu) are functionally equivalent alleles with respect to the skeletal dysplasia, and we suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3(neo) null allele. Our phenotypic analysis of Dll3(neo)/Dll3(neo) mutants shows that the developmental origins of the skeletal defects lie in delayed and irregular somite formation, which results in the perturbation of anteroposterior somite polarity. As the expression of Lfng, Hes1, Hes5 and Hey1 is disrupted in the presomitic mesoderm, we suggest that the somitic aberrations are founded in the disruption of the segmentation clock that intrinsically oscillates within presomitic mesoderm.

  14. Rhythmic profiles of cell cycle and circadian clock gene transcripts in mice: a possible association between two periodic systems.

    Science.gov (United States)

    Weigl, Yuval; Ashkenazi, Israel E; Peleg, Leah

    2013-06-15

    The circadian system shapes the rhythms of most biological functions. The regulation of the cell cycle by a circadian clock was suggested to operate via stages S, G2 and G2/M. This study investigated a possible time link at stages G1 and G1/S as well. The daily expression profiles of cell cycle markers (Ccnd1, Ccne1 and Pcna) and circadian clock genes (Per2 and Clock) were monitored in liver and esophagus (low and high proliferation index, respectively) of BALB/c mice. Locomotor activity displayed a 24 h rhythm, establishing the circadian organization of the suprachiasmatic nucleus. In the liver, the mRNA level of Per2 and Clock fitted the circadian rhythm with a 7.5 h shift. This temporal pattern suggests that the liver harbors a functional circadian clock. The rhythm of the analyzed cell cycle genes, however, was of low significance fitness and showed an opposite peak time between Pcna and Clock. These results indicate a weak regulatory role of the circadian clock. In the esophagus, the rhythms of Clock and Per2 mRNA had a similar peak time and non-circadian periods. These results suggest either that the esophagus does not harbor a functional circadian apparatus or that the phenotypes stem from differences in phase and amplitude of the rhythms of its various cell types. The similarity in the rhythm parameters of Clock, Ccne1 and Pcna transcripts questions the control of the circadian clock on the cell cycle along the G1 and G1/S stages. Yet the G1/S transition may play a role in modulating the local clock of proliferating tissues.

  15. Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.

    Science.gov (United States)

    Pauley, Stephen M

    2004-01-01

    The hypothesis that the suppression of melatonin (MLT) by exposure to light at night (LAN) may be one reason for the higher rates of breast and colorectal cancers in the developed world deserves more attention. The literature supports raising this subject for awareness as a growing public health issue. Evidence now exists that indirectly links exposures to LAN to human breast and colorectal cancers in shift workers. The hypothesis begs an even larger question: has medical science overlooked the suppression of MLT by LAN as a contributor to the overall incidence of cancer? The indirect linkage of breast cancer to LAN is further supported by laboratory rat experiments by David E. Blask and colleagues. Experiments involved the implanting of human MCF-7 breast cancer cell xenografts into the groins of rats and measurements were made of cancer cell growth rates, the uptake of linoleic acid (LA), and MLT levels. One group of implanted rats were placed in light-dark (12L:12D) and a second group in light-light (12L:12L) environments. Constant light suppressed MLT, increased cancer cell growth rates, and increased LA uptake into cancer cells. The opposite was seen in the light-dark group. The proposed mechanism is the suppression of nocturnal MLT by exposure to LAN and subsequent lack of protection by MLT on cancer cell receptor sites which allows the uptake of LA which in turn enhances the growth of cancer cells. MLT is a protective, oncostatic hormone and strong antioxidant having evolved in all plants and animals over the millennia. In vertebrates, MLT is normally produced by the pineal gland during the early morning hours of darkness, even in nocturnal animals, and is suppressed by exposure to LAN. Daily entrainment of the human circadian clock is important for good human health. These studies suggest that the proper use and color of indoor and outdoor lighting is important to the health of both humans and ecosystems. Lighting fixtures should be designed to minimize

  16. Clock gene modulates roles of OXTR and AVPR1b genes in prosociality.

    Directory of Open Access Journals (Sweden)

    Haipeng Ci

    Full Text Available BACKGROUND: The arginine vasopressin receptor (AVPR and oxytocin receptor (OXTR genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene. METHODOLOGY/PRINCIPAL FINDINGS: This study assessed interactions between the clock gene (rs1801260, rs6832769 and the OXTR (rs1042778, rs237887 and AVPR1b (rs28373064 genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436. The Prosocial Tendencies Measure (PTM-R was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups. CONCLUSIONS: The observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality.

  17. Circadian clock-coupled lung cellular and molecular functions in chronic airway diseases.

    Science.gov (United States)

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-09-01

    Airway diseases are associated with abnormal circadian rhythms of lung function, reflected in daily changes of airway caliber, airway resistance, respiratory symptoms, and abnormal immune-inflammatory responses. Circadian rhythms are generated at the cellular level by an autoregulatory feedback loop of interlocked transcription factors collectively referred to as clock genes. The molecular clock is altered by cigarette smoke, LPS, and bacterial and viral infections in mouse and human lungs and in patients with chronic airway diseases. Stress-mediated post-translational modification of molecular clock proteins, brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and PERIOD 2, is associated with a reduction in the activity/level of the deacetylase sirtuin 1 (SIRT1). Similarly, the levels of the nuclear receptor REV-ERBα and retinoic acid receptor-related orphan receptor α (ROR α), critical regulators of Bmal1 expression, are altered by environmental stresses. Molecular clock dysfunction is implicated in immune and inflammatory responses, DNA damage response, and cellular senescence. The molecular clock in the lung also regulates the timing of glucocorticoid sensitivity and phasic responsiveness to inflammation. Herein, we review our current understanding of clock-controlled cellular and molecular functions in the lungs, the impact of clock dysfunction in chronic airway disease, and the response of the pulmonary clock to different environmental perturbations. Furthermore, we discuss the evidence for candidate signaling pathways, such as the SIRT1-BMAL1-REV-ERBα axis, as novel targets for chronopharmacological management of chronic airway diseases.

  18. A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function

    OpenAIRE

    Aurore Woller; Hélène Duez; Bart Staels; Marc Lefranc

    2016-01-01

    To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various tem...

  19. Einstein's Clocks and Langevin's Twins

    CERN Document Server

    Weinstein, Galina

    2012-01-01

    In 1905 Einstein presented the Clock Paradox and in 1911 Paul Langevin expanded Einstein's result to human observers, the "Twin Paradox." I will explain the crucial difference between Einstein and Langevin. Einstein did not present the so-called "Twin Paradox." Later Einstein continued to speak about the clock paradox. Einstein might not have been interested in the question: what happens to the observers themselves. The reason for this could be the following; Einstein dealt with measurement procedures, clocks and measuring rods. Einstein's observers were measuring time with these clocks and measuring rods. Einstein might not have been interested in so-called biology of the observers, whether these observers were getting older, younger, or whether they have gone any other changes; these changes appeared to be out of the scope of his "Principle of relativity" or kinematics. The processes and changes occurring within observers seemed to be good for philosophical discussions. Later writers criticized Einstein's c...

  20. Molecular Mechanisms Underlying the Arabidopsis Circadian Clock

    OpenAIRE

    Nakamichi, Norihito

    2011-01-01

    A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day–night cycle. This rhythm is generated by the so-called ‘circadian clock’. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. Thi...

  1. Natural variation reveals that intracellular distribution of ELF3 protein is associated with function in the circadian clock.

    Science.gov (United States)

    Anwer, Muhammad Usman; Boikoglou, Eleni; Herrero, Eva; Hallstein, Marc; Davis, Amanda Melaragno; Velikkakam James, Geo; Nagy, Ferenc; Davis, Seth Jon

    2014-05-27

    Natural selection of variants within the Arabidopsis thaliana circadian clock can be attributed to adaptation to varying environments. To define a basis for such variation, we examined clock speed in a reporter-modified Bay-0 x Shakdara recombinant inbred line and localized heritable variation. Extensive variation led us to identify EARLY FLOWERING3 (ELF3) as a major quantitative trait locus (QTL). The causal nucleotide polymorphism caused a short-period phenotype under light and severely dampened rhythm generation in darkness, and entrainment alterations resulted. We found that ELF3-Sha protein failed to properly localize to the nucleus, and its ability to accumulate in darkness was compromised. Evidence was provided that the ELF3-Sha allele originated in Central Asia. Collectively, we showed that ELF3 protein plays a vital role in defining its light-repressor action in the circadian clock and that its functional abilities are largely dependent on its cellular localization.

  2. A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function

    Directory of Open Access Journals (Sweden)

    Aurore Woller

    2016-10-01

    Full Text Available To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet. The model reproduces the dampened clock gene expression and NAD+ rhythms reported for mice on a high-fat diet and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects and suggests a pharmacological approach to resetting the clock in obesity.

  3. A Mathematical Model of the Liver Circadian Clock Linking Feeding and Fasting Cycles to Clock Function.

    Science.gov (United States)

    Woller, Aurore; Duez, Hélène; Staels, Bart; Lefranc, Marc

    2016-10-18

    To maintain energy homeostasis despite variable energy supply and consumption along the diurnal cycle, the liver relies on a circadian clock synchronized to food timing. Perturbed feeding and fasting cycles have been associated with clock disruption and metabolic diseases; however, the mechanisms are unclear. To address this question, we have constructed a mathematical model of the mammalian circadian clock, incorporating the metabolic sensors SIRT1 and AMPK. The clock response to various temporal patterns of AMPK activation was simulated numerically, mimicking the effects of a normal diet, fasting, and a high-fat diet. The model reproduces the dampened clock gene expression and NAD(+) rhythms reported for mice on a high-fat diet and predicts that this effect may be pharmacologically rescued by timed REV-ERB agonist administration. Our model thus identifies altered AMPK signaling as a mechanism leading to clock disruption and its associated metabolic effects and suggests a pharmacological approach to resetting the clock in obesity.

  4. Genes associated with honey bee behavioral maturation affect clock-dependent and -independent aspects of daily rhythmic activity in fruit flies.

    Directory of Open Access Journals (Sweden)

    Chen Fu

    Full Text Available BACKGROUND: In the honey bee, the age-related and socially regulated transition of workers from in-hive task performance (e.g., caring for young to foraging (provisioning the hive is associated with changes in many behaviors including the 24-hour pattern of rhythmic activity. We have previously shown that the hive-bee to forager transition is associated with extensive changes in brain gene expression. In this study, we test the possible function of a subset of these genes in daily rhythmic activity pattern using neural-targeted RNA interference (RNAi of an orthologous gene set in Drosophila melanogaster. PRINCIPAL FINDINGS: Of 10 genes tested, knockdown of six affected some aspect of locomotor activity under a 12 h:h light:dark regime (LD. Inos affected anticipatory activity preceding lights-off, suggesting a possible clock-dependent function. BM-40-SPARC, U2af50 and fax affected peak activity at dawn without affecting anticipation or overall inactivity (proportion of 15-min intervals without activity, suggesting that these effects may depend on the day-night light cycle. CAH1 affected overall inactivity. The remaining gene, abl, affected peak activity levels but was not clearly time-of-day-specific. No gene tested affected length of period or strength of rhythmicity in constant dark (DD, suggesting that these genes do not act in the core clock. SIGNIFICANCE: Taking advantage of Drosophila molecular genetic tools, our study provides an important step in understanding the large set of gene expression changes that occur in the honey bee transition from hive bee to forager. We show that orthologs of many of these genes influence locomotor activity in Drosophila, possibly through both clock-dependent and -independent pathways. Our results support the importance of both circadian clock and direct environmental stimuli (apart from entrainment in shaping the bee's 24-hour pattern of activity. Our study also outlines a new approach to dissecting complex

  5. A 36 nW, 7 ppm/°C on-Chip Clock Source Platform for Near-Human-Body Temperature Applications

    Directory of Open Access Journals (Sweden)

    Divya Akella Kamakshi

    2016-05-01

    Full Text Available We propose a fully on-chip clock-source system in which an ultra-low-power diode-based temperature-uncompensated oscillator (OSCdiode serves as the main clock source and frequency locks to a higher-power temperature-compensated oscillator (OSCcmp that is disabled after each locking event to save power. The locking allows the stability of the uncompensated oscillator to stay within the stability bound of the compensated design. This paper demonstrates the functionality of a locking controller that uses a periodic (counter-based scheme implemented on-chip and a prediction (temperature-drift-based scheme. The flexible clock source platform is validated in a 130 nm CMOS technology. In the demonstrated system, it achieves an effective average temperature stability of 7 ppm/°C in the human body temperature range from 20 °C to 40 °C with a power consumption of 36 nW at 0.7 V. It achieves a frequency range of 12 kHz to 150 kHz at 0.7 V.

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

    Science.gov (United States)

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

    2017-01-01

    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. PMID:28296937

  7. 肠道菌群失调与生物钟紊乱的相关性%Relationship between intestinal dysbacteriosis and circadian clock disturbance

    Institute of Scientific and Technical Information of China (English)

    黄文雅; 陆付耳; 董慧

    2015-01-01

    The human gut harbours a certain quantity and variety of microbes called intestinal flora, which is in a state of balance under normal circumstances, and dysbacteriosis occurs when the balance of the intestinal flora is dis-turbed by the host and the changes of the external environment.Circadian clock is the biological regulation system to adapt to natural circadian rhythm, including central clock and peripheral clock.Circadian clock disturbance, particularly rotating shift-workers with irregular light-night schedules, is associated with an increased risk of immune-related diseases.The de-velopment of these diseases is closely related to intestinal dysbacteriosis.Therefore, the correlation between intestinal dys-bacteriosis and circadian clock disturbance has attracted much attention.This review aims to explore the pathophysiological basis of the development in some immune-related diseases based on the latest scientific findings about the relationship be-tween intestinal microbial flora and circadian clock.

  8. Clocks and cardiovascular function

    Science.gov (United States)

    McLoughlin, Sarah C.; Haines, Philip; FitzGerald, Garret A.

    2016-01-01

    Circadian clocks in central and peripheral tissues enable the temporal synchronization and organization of molecular and physiological processes of rhythmic animals, allowing optimum functioning of cells and organisms at the most appropriate time of day. Disruption of circadian rhythms, from external or internal forces, leads to widespread biological disruption and is postulated to underlie many human conditions, such as the incidence and timing of cardiovascular disease. Here, we describe in vivo and in vitro methodology relevant to studying the role of circadian rhythms in cardiovascular function and dysfunction PMID:25707279

  9. 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.

  10. Circadian clocks - the fall and rise of physiology

    NARCIS (Netherlands)

    Roenneberg, Till; Merrow, Martha

    2005-01-01

    Circadian clocks control the daily life of most light-sensitive organisms- from cyanobacteria to humans. Molecular processes generate cellular rhythmicity, and cellular clocks in animals coordinate rhythms through interaction ( known as coupling). This hierarchy of clocks generates a complex, simila

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Optical Clocks in Space

    CERN Document Server

    Schiller, S; Nevsky, A; Koelemeij, J C J; Wicht, A; Gill, P; Klein, H A; Margolis, H S; Mileti, G; Sterr, U; Riehle, F; Peik, E; Tamm, C; Ertmer, W; Rasel, E; Klein, V; Salomon, C; Tino, G M; Lemonde, P; Holzwarth, R; Hänsch, T W; Tamm, Chr.

    2007-01-01

    The performance of optical clocks has strongly progressed in recent years, and accuracies and instabilities of 1 part in 10^18 are expected in the near future. The operation of optical clocks in space provides new scientific and technological opportunities. In particular, an earth-orbiting satellite containing an ensemble of optical clocks would allow a precision measurement of the gravitational redshift, navigation with improved precision, mapping of the earth's gravitational potential by relativistic geodesy, and comparisons between ground clocks.

  13. Chronobiology of micturition: putative role of the circadian clock.

    Science.gov (United States)

    Negoro, Hiromitsu; Kanematsu, Akihiro; Yoshimura, Koji; Ogawa, Osamu

    2013-09-01

    Mammals urinate less frequently during the sleep period than the awake period. This is modulated by a triad of factors, including decreased arousal in the brain, a decreased urine production rate in the kidneys and increased functional bladder capacity during sleep. The circadian clock is genetic transcription-translation feedback machinery. It exists in most organs and cells, termed the peripheral clock, which is orchestrated by the central clock in the suprachiasmatic nucleus of the brain. We discuss the linkage between the day and night change in micturition frequency and the genetic rhythm maintained by the circadian clock system, focusing on the brain, kidney and bladder. We performed an inclusive review of the literature on the diurnal change in micturition frequency, urine volume, functional bladder capacity and urodynamics in humans and rodents, relating this to recent basic biological findings about the circadian clock. In humans various behavioral studies demonstrated a diurnal functional change in the kidney and bladder. Conversely, patients with nocturnal enuresis and nocturia showed impairment in this triad of factors. Rats and mice, which are nocturnal animals, also have a micturition frequency rhythm that is decreased during the day, which is the sleep phase for them. Mice with a genetically defective circadian clock system show impaired physiological rhythms in the triad of factors. The existence of the circadian clock has been proven in the brain, kidney and bladder, in which thousands of circadian oscillating genes exist. In the kidney they include genes involved in the regulation of water and major electrolytes. In the bladder they include connexin 43, a gene associated with the regulation of bladder capacity. Recent progress in molecular biology about the circadian clock provides an opportunity to investigate the genetic basis of the micturition rhythm or impairment of the rhythm in nocturnal enuresis and nocturia. If this approach is to be

  14. Exploitation of host clock gene machinery by hepatitis viruses B and C.

    Science.gov (United States)

    Vinciguerra, Manlio; Mazzoccoli, Gianluigi; Piccoli, Claudia; Tataranni, Tiziana; Andriulli, Angelo; Pazienza, Valerio

    2013-12-21

    Many aspects of cellular physiology display circadian (approximately 24-h) rhythms. Dysfunction of the circadian clock molecular circuitry is associated with human health derangements, including neurodegeneration, increased risk of cancer, cardiovascular diseases and the metabolic syndrome. Viruses triggering hepatitis depend tightly on the host cell synthesis machinery for their own replication, survival and spreading. Recent evidences support a link between the circadian clock circuitry and viruses' biological cycle within host cells. Currently, in vitro models for chronobiological studies of cells infected with viruses need to be implemented. The establishment of such in vitro models would be helpful to better understand the link between the clock gene machinery and viral replication/viral persistence in order to develop specifically targeted therapeutic regimens. Here we review the recent literature dealing with the interplay between hepatitis B and C viruses and clock genes.

  15. Circadian clock proteins and immunity.

    Science.gov (United States)

    Curtis, Anne M; Bellet, Marina M; Sassone-Corsi, Paolo; O'Neill, Luke A J

    2014-02-20

    Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. A low maintenance Sr optical lattice clock

    CERN Document Server

    Hill, Ian R; Bowden, William; Bridge, Elizabeth M; Donnellan, Sean; Curtis, E Anne; Gill, Patrick

    2016-01-01

    We describe the Sr optical lattice clock apparatus at NPL with particular emphasis on techniques used to increase reliability and minimise the human requirement in its operation. Central to this is a clock-referenced transfer cavity scheme for the stabilisation of cooling and trapping lasers. We highlight several measures to increase the reliability of the clock with a view towards the realisation of an optical time-scale. The clock contributed 502 hours of data over a 25 day period (84% uptime) in a recent measurement campaign with several uninterrupted periods of more than 48 hours. An instability of $2\\times10^{-17}$ was reached after $10^5$ s of averaging in an interleaved self-comparison of the clock.

  17. Metabolic regulation of circadian clocks.

    Science.gov (United States)

    Haydon, Michael J; Hearn, Timothy J; Bell, Laura J; Hannah, Matthew A; Webb, Alex A R

    2013-05-01

    Circadian clocks are 24-h timekeeping mechanisms, which have evolved in plants, animals, fungi and bacteria to anticipate changes in light and temperature associated with the rotation of the Earth. The current paradigm to explain how biological clocks provide timing information is based on multiple interlocking transcription-translation negative feedback loops (TTFL), which drive rhythmic gene expression and circadian behaviour of growth and physiology. Metabolism is an important circadian output, which in plants includes photosynthesis, starch metabolism, nutrient assimilation and redox homeostasis. There is increasing evidence in a range of organisms that these metabolic outputs can also contribute to circadian timing and might also comprise independent circadian oscillators. In this review, we summarise the mechanisms of circadian regulation of metabolism by TTFL and consider increasing evidence that rhythmic metabolism contributes to the circadian network. We highlight how this might be relevant to plant circadian clock function.

  18. Optimizing passive quantum clocks

    Science.gov (United States)

    Mullan, Michael; Knill, Emanuel

    2014-10-01

    We describe protocols for passive atomic clocks based on quantum interrogation of the atoms. Unlike previous techniques, our protocols are adaptive and take advantage of prior information about the clock's state. To reduce deviations from an ideal clock, each interrogation is optimized by means of a semidefinite program for atomic state preparation and measurement whose objective function depends on the prior information. Our knowledge of the clock's state is maintained according to a Bayesian model that accounts for noise and measurement results. We implement a full simulation of a running clock with power-law noise models and find significant improvements by applying our techniques.

  19. Improvement of Arabidopsis Biomass and Cold, Drought and Salinity Stress Tolerance by Modified Circadian Clock-Associated PSEUDO-RESPONSE REGULATORs.

    Science.gov (United States)

    Nakamichi, Norihito; Takao, Saori; Kudo, Toru; Kiba, Takatoshi; Wang, Yin; Kinoshita, Toshinori; Sakakibara, Hitoshi

    2016-05-01

    Plant circadian clocks control the timing of a variety of genetic, metabolic and physiological processes. Recent studies revealed a possible molecular mechanism for circadian clock regulation. Arabidopsis thaliana (Arabidopsis) PSEUDO-RESPONSE REGULATOR (PRR) genes, including TIMING OF CAB EXPRESSION 1 (TOC1), encode clock-associated transcriptional repressors that act redundantly. Disruption of multiple PRR genes results in drastic phenotypes, including increased biomass and abiotic stress tolerance, whereas PRR single mutants show subtle phenotypic differences due to genetic redundancy. In this study, we demonstrate that constitutive expression of engineered PRR5 (PRR5-VP), which functions as a transcriptional activator, can increase biomass and abiotic stress tolerance, similar to prr multiple mutants. Concomitant analyses of relative growth rate, flowering time and photosynthetic activity suggested that increased biomass of PRR5-VP plants is mostly due to late flowering, rather than to alterations in photosynthetic activity or growth rate. In addition, genome-wide gene expression profiling revealed that genes related to cold stress and water deprivation responses were up-regulated in PRR5-VP plants. PRR5-VP plants were more resistant to cold, drought and salinity stress than the wild type, whereas ft tsf and gi, well-known late flowering and increased biomass mutants, were not. These findings suggest that attenuation of PRR function by a single transformation of PRR-VP is a valuable method for increasing biomass as well as abiotic stress tolerance in Arabidopsis. Because the PRR gene family is conserved in vascular plants, PRR-VP may regulate biomass and stress responses in many plants, but especially in long-day annual plants.

  20. Optical clock networks

    Science.gov (United States)

    Riehle, Fritz

    2017-01-01

    Within the last decade, optical atomic clocks have surpassed the best cesium clocks, which are used to realize the unit of time and frequency, in terms of accuracy and stability by about two orders of magnitude. When remote optical atomic clocks are connected by links without degradation in the clock signals, an optical clock network is formed, with distinct advantages for the dissemination of time, geodesy, astronomy and basic and applied research. Different approaches for time and frequency transfer in the microwave and optical regime, via satellites and free-space links, optical fibre links, or transportable optical atomic clocks, can be used to form a hybrid clock network that may allow a future redefinition of the unit of time based on an optical reference transition.

  1. Circadian molecular clock in lung pathophysiology.

    Science.gov (United States)

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology.

  2. 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.

  3. Explaining the imperfection of the molecular clock of hominid mitochondria.

    Science.gov (United States)

    Loogväli, Eva-Liis; Kivisild, Toomas; Margus, Tõnu; Villems, Richard

    2009-12-29

    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.

  4. miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock.

    Science.gov (United States)

    Alvarez-Saavedra, Matías; Antoun, Ghadi; Yanagiya, Akiko; Oliva-Hernandez, Reynaldo; Cornejo-Palma, Daniel; Perez-Iratxeta, Carolina; Sonenberg, Nahum; Cheng, Hai-Ying M

    2011-02-15

    Mammalian circadian rhythms are synchronized to the external time by daily resetting of the suprachiasmatic nucleus (SCN) in response to light. As the master circadian pacemaker, the SCN coordinates the timing of diverse cellular oscillators in multiple tissues. Aberrant regulation of clock timing is linked to numerous human conditions, including cancer, cardiovascular disease, obesity, various neurological disorders and the hereditary disorder familial advanced sleep phase syndrome. Additionally, mechanisms that underlie clock resetting factor into the sleep and physiological disturbances experienced by night-shift workers and travelers with jet lag. The Ca(2+)/cAMP response element-binding protein-regulated microRNA, miR-132, is induced by light within the SCN and attenuates its capacity to reset, or entrain, the clock. However, the specific targets that are regulated by miR-132 and underlie its effects on clock entrainment remained elusive until now. Here, we show that genes involved in chromatin remodeling (Mecp2, Ep300, Jarid1a) and translational control (Btg2, Paip2a) are direct targets of miR-132 in the mouse SCN. Coordinated regulation of these targets underlies miR-132-dependent modulation of Period gene expression and clock entrainment: the mPer1 and mPer2 promoters are bound to and transcriptionally activated by MeCP2, whereas PAIP2A and BTG2 suppress the translation of the PERIOD proteins by enhancing mRNA decay. We propose that miR-132 is selectively enriched for chromatin- and translation-associated target genes and is an orchestrator of chromatin remodeling and protein translation within the SCN clock, thereby fine-tuning clock entrainment. These findings will further our understanding of mechanisms governing clock entrainment and its involvement in human diseases.

  5. Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rana, Sobia; Munawar, Mustafa; Shahid, Adeela; Malik, Meera; Ullah, Hafeez; Fatima, Warda; Mohsin, Shahida; Mahmood, Saqib

    2014-01-01

    Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL. Moreover, shift-work and low melatonin levels may also contribute in etiology of CLL by further perturbing of circadian clock.

  6. 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...

  7. Bovine Circadian Locomotor Output Cycles Kaput (CLOCK) and Clusterin (CLU) mRNA Quantitation in Ejaculated Crossbred Bull Spermatozoa.

    Science.gov (United States)

    Kumar, S; Deb, R; Singh, U; Ganguly, I; Mandal, D K; Tyagi, S; Kumar, M; Sengar, G; Sharma, S; Singh, R; Singh, R

    2015-06-01

    Mammalian circadian locomotor output cycles kaput (CLOCK) gene encodes a transcription factor that affects both the persistence and the period of circadian rhythms. Earlier reports suggested that CLOCK gene might be associated with male infertility in human. Present investigation, for the first time, reports that CLOCK gene expresses differentially between good and poor quality crossbred bull semen. The relative expression of CLOCK was significantly (p < 0.05) higher among good quality bull semen than motility-impaired ones. Clusterins (CLU) are series of genes associated with a variety of physiological activities including spermatogenesis, apoptosis and degenerative disease conditions. In the present context, we also investigated that the expression of CLU gene was significantly (p < 0.05) higher among motility-impaired crossbred bull semen compared to the good quality one.

  8. 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,...

  9. Messenger RNA expression of chicken CLOCK gene in the response to Campylobacter jejuni inoculation.

    Science.gov (United States)

    Liu, Xiaoyi; Liu, Liying; Zhang, Maozhi; Yang, Ning; Qi, Yukai; Sun, Yu; Li, Xianyao

    2015-09-01

    Campylobacter jejuni (C. jejuni) is a leading cause of human bacterial gastroenteritis worldwide. Previous research has shown that circadian rhythm plays a critical role in host response to C. jejuni colonization. The CLOCK gene is one of the core genes regulating circadian rhythms and shows significant expression on 7 d post-C. jejuni inoculation. The objective of this study was to investigate temporal and spatial expression of chicken CLOCK gene post-C. jejuni inoculation. Cecal and splenic RNA were isolated from 2 distinct chicken breeds and used to compare the mRNA expression of CLOCK gene between inoculated and noninoculated chickens within each breed and between breeds within each of inoculated and noninoculated groups. Our results showed that the CLOCK gene was significantly down-regulated at 20 h postinoculation (hpi) in cecum and spleen in Jiningbairi chicken. CLOCK gene was significantly down-regulated at 4 and 16 hpi and up-regulated at 8 hpi in cecum and spleen in specific pathogen free white leghorn noninoculated chicken. The findings suggested that expression of CLOCK gene was significantly changed post C. jejuin inoculation. This change was affected by genetic background, tissue, and time points postinoculation. © 2015 Poultry Science Association Inc.

  10. Evolutionary specializations of human association cortex

    NARCIS (Netherlands)

    Mars, R.B.; Passingham, R.E.; Neubert, F.X.; Verhagen, L.; Sallet, J.

    2017-01-01

    Is the human brain a big ape brain? We argue that the human association cortex is larger than would be expected for an equivalent ape brain, suggesting human association cortex is a unique adaptation. The internal organization of the human association cortex shows modifications of the ape plan in

  11. Researchers Discover Plants Biological Clock

    Institute of Scientific and Technical Information of China (English)

    王全良

    1996-01-01

    Scientists who created glow-in-the-dark plants by shooting up seedlingswith firefly DNA have identified the first biological clock gene in plants. Discovery of the timepiece gene, which controls such biological rhythmsas daily leaf movements and proe openings, flower-blooming schedules andphotosynthesis cycles, could lead to a host of applications in ornamental horti-culture, agriculture and even human health. Many researchers believe that

  12. Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Maher Hanoun

    Full Text Available Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1 is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL. Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR CD38+/immunoglobulin variable heavy chain gene (IgVH unmutated patients as compared to low-risk (LR CD38-/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL.

  13. Clocked combustor can array

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Won-Wook; McMahan, Kevin Weston; Srinivasan, Shiva Kumar

    2017-01-17

    The present application provides a clocked combustor can array for coherence reduction in a gas turbine engine. The clocked combustor can array may include a number of combustor cans positioned in a circumferential array. A first set of the combustor cans may have a first orientation and a second set of the combustor cans may have a second orientation.

  14. Clocked combustor can array

    Science.gov (United States)

    Kim, Won-Wook; McMahan, Kevin Weston; Srinivasan, Shiva Kumar

    2017-01-17

    The present application provides a clocked combustor can array for coherence reduction in a gas turbine engine. The clocked combustor can array may include a number of combustor cans positioned in a circumferential array. A first set of the combustor cans may have a first orientation and a second set of the combustor cans may have a second orientation.

  15. Active optical clock

    Institute of Scientific and Technical Information of China (English)

    CHEN JingBiao

    2009-01-01

    This article presents the principles and techniques of active optical clock, a special laser combining the laser physics of one-atom laser, bad-cavity gas laser, super-cavity stabilized laser and optical atomic clock together. As a simple example, an active optical clock based on thermal strontium atomic beam shows a quantum-limited linewidth of 0.51 Hz, which is insensitive to laser cavity-length noise, and may surpass the recorded narrowest 6.7 Hz of Hg ion optical clock and 1.5 Hz of very recent optical lattice clock. The estimated 0.1 Hz one-second instability and 0.27 Hz uncertainty are limited only by the rela-tivistic Doppler effect, and can be improved by cold atoms.

  16. Optical Lattice Clocks

    Science.gov (United States)

    Oates, Chris

    2012-06-01

    Since they were first proposed in 2003 [1], optical lattice clocks have become one of the leading technologies for the next generation of atomic clocks, which will be used for advanced timing applications and in tests of fundamental physics [2]. These clocks are based on stabilized lasers whose frequency is ultimately referenced to an ultra-narrow neutral atom transition (natural linewidths magic'' value so as to yield a vanishing net AC Stark shift for the clock transition. As a result lattice clocks have demonstrated the capability of generating high stability clock signals with small absolute uncertainties (˜ 1 part in 10^16). In this presentation I will first give an overview of the field, which now includes three different atomic species. I will then use experiments with Yb performed in our laboratory to illustrate the key features of a lattice clock. Our research has included the development of state-of-the-art optical cavities enabling ultra-high-resolution optical spectroscopy (1 Hz linewidth). Together with the large atom number in the optical lattice, we are able to achieve very low clock instability (< 0.3 Hz in 1 s) [3]. Furthermore, I will show results from some of our recent investigations of key shifts for the Yb lattice clock, including high precision measurements of ultracold atom-atom interactions in the lattice and the dc Stark effect for the Yb clock transition (necessary for the evaluation of blackbody radiation shifts). [4pt] [1] H. Katori, M. Takamoto, V. G. Pal'chikov, and V. D. Ovsiannikov, Phys. Rev. Lett. 91, 173005 (2003). [0pt] [2] Andrei Derevianko and Hidetoshi Katori, Rev. Mod. Phys. 83, 331 (2011). [0pt] [3] Y. Y. Jiang, A. D. Ludlow, N. D. Lemke, R. W. Fox, J. A. Sherman, L.-S. Ma, and C. W. Oates, Nature Photonics 5, 158 (2011).

  17. Optical Clocks and Relativity

    Science.gov (United States)

    Chou, C. W.; Hume, D. B.; Rosenband, T.; Wineland, D. J.

    2010-09-01

    Observers in relative motion or at different gravitational potentials measure disparate clock rates. These predictions of relativity have previously been observed with atomic clocks at high velocities and with large changes in elevation. We observed time dilation from relative speeds of less than 10 meters per second by comparing two optical atomic clocks connected by a 75-meter length of optical fiber. We can now also detect time dilation due to a change in height near Earth’s surface of less than 1 meter. This technique may be extended to the field of geodesy, with applications in geophysics and hydrology as well as in space-based tests of fundamental physics.

  18. Stable clocks and general relativity

    CERN Document Server

    Will, C M

    1995-01-01

    We survey the role of stable clocks in general relativity. Clock comparisons have provided important tests of the Einstein Equivalence Principle, which underlies metric gravity. These include tests of the isotropy of clock comparisons (verification of local Lorentz invariance) and tests of the homogeneity of clock comparisons (verification of local position invariance). Comparisons of atomic clocks with gravitational clocks test the Strong Equivalence Principle by bounding cosmological variations in Newton's constant. Stable clocks also play a role in the search for gravitational radiation: comparision of atomic clocks with the binary pulsar's orbital clock has verified gravitational-wave damping, and phase-sensitive detection of waves from inspiralling compact binaries using laser interferometric gravitational observatories will facilitate extraction of useful source information from the data. Stable clocks together with general relativity have found important practical applications in navigational systems s...

  19. Resetting Biological Clocks

    Science.gov (United States)

    Winfree, Arthur T.

    1975-01-01

    Reports on experiments conducted on two biological clocks, in organisms in the plant and animal kingdoms, which indicate that biological oscillation can be arrested by a single stimulus of a definite strength delivered at the proper time. (GS)

  20. Resetting Biological Clocks

    Science.gov (United States)

    Winfree, Arthur T.

    1975-01-01

    Reports on experiments conducted on two biological clocks, in organisms in the plant and animal kingdoms, which indicate that biological oscillation can be arrested by a single stimulus of a definite strength delivered at the proper time. (GS)

  1. Poorer clock draw test scores are associated with greater functional impairment in peripheral artery disease: The Walking and Leg Circulation Study II

    Science.gov (United States)

    Zimmermann, Laura J; Ferrucci, Luigi; Liu, Kiang; Tian, Lu; Guralnik, Jack M; Criqui, Michael H; Liao, Yihua; McDermott, Mary M

    2016-01-01

    We hypothesized that, in the absence of clinically recognized dementia, cognitive dysfunction measured by the clock draw test (CDT) is associated with greater functional impairment in men and women with peripheral artery disease (PAD). Participants were men and women aged 60 years and older with Mini-Mental Status Examination scores ≥ 24 with PAD (n = 335) and without PAD (n = 234). We evaluated the 6-minute walk test, 4-meter walking velocity at usual and fastest pace, the Short Physical Performance Battery (SPPB), and accelerometer-measured physical activity. CDTs were scored using the Shulman system as follows: Category 1 (worst): CDT score 0–2; Category 2: CDT score 3; Category 3 (best): CDT score 4–5. Results were adjusted for age, sex, race, education, ankle–brachial index (ABI), and comorbidities. In individuals with PAD, lower CDT scores were associated with slower 4-meter usual-paced walking velocity (Category 1: 0.78 meters/second; Category 2: 0.83 meters/second; Category 3: 0.86 meters/second; p-trend = 0.025) and lower physical activity (Category 1: 420 activity units; Category 2: 677 activity units; Category 3: 701 activity units; p-trend = 0.045). Poorer CDT scores were also associated with worse functional performance in individuals without PAD (usual and fast-paced walking velocity and SPPB, p-trend = 0.022, 0.043, and 0.031, respectively). In conclusion, cognitive impairment identified with CDT is independently associated with greater functional impairment in older, dementia-free individuals with and without PAD. Longitudinal studies are necessary to explore whether baseline CDT scores and changes in CDT scores over time can predict long-term decline in functional performance in individuals with and without PAD. PMID:21636676

  2. Clock genes and their genomic distributions in three species of salmonid fishes: Associations with genes regulating sexual maturation and cell cycling

    Directory of Open Access Journals (Sweden)

    Ferguson Moira M

    2010-07-01

    Full Text Available Abstract Background Clock family genes encode transcription factors that regulate clock-controlled genes and thus regulate many physiological mechanisms/processes in a circadian fashion. Clock1 duplicates and copies of Clock3 and NPAS2-like genes were partially characterized (genomic sequencing and mapped using family-based indels/SNPs in rainbow trout (RT(Oncorhynchus mykiss, Arctic charr (AC(Salvelinus alpinus, and Atlantic salmon (AS(Salmo salar mapping panels. Results Clock1 duplicates mapped to linkage groups RT-8/-24, AC-16/-13 and AS-2/-18. Clock3/NPAS2-like genes mapped to RT-9/-20, AC-20/-43, and AS-5. Most of these linkage group regions containing the Clock gene duplicates were derived from the most recent 4R whole genome duplication event specific to the salmonids. These linkage groups contain quantitative trait loci (QTL for life history and growth traits (i.e., reproduction and cell cycling. Comparative synteny analyses with other model teleost species reveal a high degree of conservation for genes in these chromosomal regions suggesting that functionally related or co-regulated genes are clustered in syntenic blocks. For example, anti-müllerian hormone (amh, regulating sexual maturation, and ornithine decarboxylase antizymes (oaz1 and oaz2, regulating cell cycling, are contained within these syntenic blocks. Conclusions Synteny analyses indicate that regions homologous to major life-history QTL regions in salmonids contain many candidate genes that are likely to influence reproduction and cell cycling. The order of these genes is highly conserved across the vertebrate species examined, and as such, these genes may make up a functional cluster of genes that are likely co-regulated. CLOCK, as a transcription factor, is found within this block and therefore has the potential to cis-regulate the processes influenced by these genes. Additionally, clock-controlled genes (CCGs are located in other life-history QTL regions within

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

    Science.gov (United States)

    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.

  4. Clock genes, chronotypes and diseases

    Directory of Open Access Journals (Sweden)

    Bogdan I. Voinescu

    2009-08-01

    Full Text Available Many common diseases in humans (such as cancer, heart disease, diabetes mellitus orpsychiatric disorders, such as depression seem to be linked to disruptions of circadian cycles and toclock genes variation. It is unlikely that such diseases to be caused by a genetic variation within a singlegene. They must be influenced by complex interactions among multiple genes, as well as environmentaland lifestyle factors. Therefore, it is important to understand how the resulting perturbations in ourcircadian biology could affect our physiological processes and susceptibility to disease. Associationsbetween the polymorphisms of the main components of the circadian molecular clock, circadian type(also known as diurnal preference or chronotype and diseases are presented.

  5. On clocks and clouds

    Directory of Open Access Journals (Sweden)

    M. K. Witte

    2013-09-01

    Full Text Available Cumulus clouds exhibit a life cycle that consists of: (a the growth phase (increasing size, most notably in the vertical direction; (b the mature phase (growth ceases; any precipitation that develops is strongest during this period; and (c the dissipation phase (cloud dissipates because of precipitation and/or entrainment; no more dynamical support. Although radar can track clouds over time and give some sense of the age of a cloud, most aircraft in situ measurements lack temporal context. We use large eddy simulations of trade wind cumulus cloud fields from cases during the Barbados Oceanographic and Meteorological Experiment (BOMEX and Rain In Cumulus over the Ocean (RICO campaigns to demonstrate a potential cumulus cloud "clock". We find that the volume-averaged total water mixing ratio rt is a useful cloud clock for the 12 clouds studied. A cloud's initial rt is set by the subcloud mixed-layer mean rt and decreases monotonically from the initial value due primarily to entrainment. The clock is insensitive to aerosol loading, environmental sounding and extrinsic cloud properties such as lifetime and volume. In some cases (more commonly for larger clouds, multiple pulses of buoyancy occur, which complicate the cumulus clock by replenishing rt. The clock is most effectively used to classify clouds by life phase.

  6. Explaining the Imperfection of the Molecular Clock of Hominid Mitochondria

    OpenAIRE

    Eva-Liis Loogväli; Toomas Kivisild; Tõnu Margus; Richard Villems

    2009-01-01

    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 chang...

  7. Optical atomic clocks

    CERN Document Server

    Poli, N; Gill, P; Tino, G M

    2014-01-01

    In the last ten years extraordinary results in time and frequency metrology have been demonstrated. Frequency-stabilization techniques for continuous-wave lasers and femto-second optical frequency combs have enabled a rapid development of frequency standards based on optical transitions in ultra-cold neutral atoms and trapped ions. As a result, today's best performing atomic clocks tick at an optical rate and allow scientists to perform high-resolution measurements with a precision approaching a few parts in $10^{18}$. This paper reviews the history and the state of the art in optical-clock research and addresses the implementation of optical clocks in a possible future redefinition of the SI second as well as in tests of fundamental physics.

  8. Relativistic quantum clocks

    CERN Document Server

    Lock, Maximilian P E

    2016-01-01

    The conflict between quantum theory and the theory of relativity is exemplified in their treatment of time. We examine the ways in which their conceptions differ, and describe a semiclassical clock model combining elements of both theories. The results obtained with this clock model in flat spacetime are reviewed, and the problem of generalizing the model to curved spacetime is discussed, before briefly describing an experimental setup which could be used to test of the model. Taking an operationalist view, where time is that which is measured by a clock, we discuss the conclusions that can be drawn from these results, and what clues they contain for a full quantum relativistic theory of time.

  9. The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility.

    Science.gov (United States)

    Schroder, Elizabeth A; Lefta, Mellani; Zhang, Xiping; Bartos, Daniel C; Feng, Han-Zhong; Zhao, Yihua; Patwardhan, Abhijit; Jin, Jian-Ping; Esser, Karyn A; Delisle, Brian P

    2013-05-15

    The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1(-/-) hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na(+) channel (Na(V)1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1(-/-) hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1(-/-) hearts was associated with decreased levels of Na(V)1.5 and Na(+) current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans.

  10. Turtle-associated human salmonellosis.

    NARCIS (Netherlands)

    Stam, F.; Romkens, TE; Hekker, TA; Smulders, Y.M.

    2003-01-01

    A patient who bred exotic turtles as a hobby presented with 2 episodes of severe diarrhea, the second of which was proven to be caused by turtle-associated salmonellosis that was contracted during treatment with a proton-pump inhibitor. The literature about reptile-associated salmonellosis is briefl

  11. The circadian clock goes genomic.

    Science.gov (United States)

    Staiger, Dorothee; Shin, Jieun; Johansson, Mikael; Davis, Seth J

    2013-06-24

    Large-scale biology among plant species, as well as comparative genomics of circadian clock architecture and clock-regulated output processes, have greatly advanced our understanding of the endogenous timing system in plants.

  12. SRC: Smart Reminder Clock

    Science.gov (United States)

    Kasim, Shahreen; Hafit, Hanayanti; Leong, Tan Hua; Hashim, Rathiah; Ruslai, Husni; Jahidin, Kamaruzzaman; Syafwan Arshad, Mohammad

    2016-11-01

    Nowadays, some people facing the problem to wake up in the morning. This was result to absence of the classes, meetings, and even exams. The aim of this project is to develop an android application that can force the user to wake up. The method used in this application are pedometer and Short Message Service (SMS) function. This application need the user to take their smartphone and walk about 10 steps to disable it, when the alarm clock is activated. After that, when the alarm clock was rang, this alarm application has automatically send a message to the users’ friends or parents phone to wake them up.

  13. Gravitomagnetism, clocks and geometry

    CERN Document Server

    Tartaglia, A

    2001-01-01

    New techniques to evaluate the clock effect using light are described. These are based on the flatness of the cylindrical surface containing the world lines of the rays constrained to move on circular trajectories about a spinning mass. The effect of the angular momentum of the source is manifested in the fact that inertial observers must be replaced by local non rotating observers. Starting from this an exact formula for circular trajectories is found. Numerical estimates for the Earth environment show that light would be a better probe than actual clocks to evidence the angular momentum influence. The advantages of light in connection with some principle experiments are shortly reviewed.

  14. Genetic characterization and molecular clock analyses of the Crimean-Congo hemorrhagic fever virus from human and ticks in India, 2010-2011.

    Science.gov (United States)

    Yadav, Pragya D; Cherian, Sarah S; Zawar, Divya; Kokate, Prasad; Gunjikar, Rashmi; Jadhav, Santosh; Mishra, Akhilesh C; Mourya, Devendra T

    2013-03-01

    A nosocomial outbreak of Crimean Congo hemorrhagic fever (CCHF) was reported among humans in Ahmadabad district, Gujarat, India during January, 2011. In the present study we provide the complete genomic sequences of four CCHFV isolates derived from two human patients and two pools of Hyalomma anatolicum ticks during the period of this outbreak and the complete S segment sequence of two retrospective human serum samples, positive for CCHFV in 2010. Sequence-based molecular characterization of the Indian CCHFV showed that they possessed the functional motifs known to occur in the S, M and L gene segment products as in other CCHF viruses. The S segment of the six Indian CCHF viruses showed 99.8% nucleotide identity. Notably both tick isolates shared 100% nucleotide identity with one of the Indian human isolates of 2011. Phylogenetic analysis based on the S segment demonstrated that the Indian CCHFV isolates formed a distinct cluster in the Asian-Middle East group IV of CCHF viruses. The S segment was closest to a Tajikistan strain TADJ/HU8966 of 1990 (98.5% nucleotide identity) and was of South-Asia 2 type while the M segment was of type M2. Both M and L segments were closest to an Afghanistan strain Afg09-2990 of 2009 (93% and 98% nucleotide identity, respectively). The Indian isolates were thus identified as a South-Asia 2/M2 far-east virus combination and the differing parental origin in the S and L/M segments is suggestive that it may be an intra-genotypic reassortant. Molecular clock studies further revealed that the ancestry of the viruses was not very recent and dated back to about 33years on the basis of the S segment while it was about 15years based on the M segment. Thus though the 2011 outbreak may not have resulted from a very recent introduction, considering that so far there is no evidence of multiple circulating strains in the country, the possibility of a recent re-introduction of the virus from any of the neighboring countries cannot be ruled out. The

  15. 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.

  16. 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.

  17. Cyclotomic quantum clock

    CERN Document Server

    Rosu, H C

    2003-01-01

    In the wake of our recent work on cyclotomic effects in quantum phase locking [M. Planat and H. C. Rosu, Phys. Lett. A 315, 1 (2003)], we briefly discuss here a cyclotomic extension of the Salecker and Wigner quantum clock. We also hint on a possible cyclotomic structure of time at the Planck scales

  18. Quadrivalent Human Papillomavirus recombinant vaccine associated lipoatrophy.

    Science.gov (United States)

    Ojaimi, Samar; Buttery, Jim P; Korman, Tony M

    2009-08-06

    Involutional lipoatrophy, a loss of subcutaneous fat, may be idiopathic, associated with inflammatory skin conditions, or trauma, and has also been reported following injections of medications including insulin, corticosteroids and penicillin. There have also been reports in association with Diptheria Pertussis Tetanus (DPT) vaccine. We report on two cases of lipoatrophy associated with the new Quadrivalent Human Papillomavirus (HPV) recombinant vaccine (Gardasil).

  19. 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.

  20. Relativity and Al^+ Optical Clocks

    Science.gov (United States)

    Chou, Chin-Wen; Hume, David B.; Wineland, David J.; Rosenband, Till

    2010-03-01

    We have constructed an optical clock based on quantum logic spectroscopy of an Al+ ion that has a fractional frequency inaccuracy of 8.6x10-18. The frequency of the ^1S0^3P0 clock transition is compared to that of a previously constructed Al^+ optical clock with a statistical measurement uncertainty of 7.0x10-18. The two clocks exhibit a relative stability of 2.8x10-15&-1/2circ;, and a fractional frequency difference of -1.8x10-17, consistent with the accuracy limit of the older clock. By comparing the frequencies of the clocks, we have observed relativistic effects, such as time dilation due to velocities less than 10 m/s and the gravitational red shift from a 0.33 m height change of one of the clocks.

  1. The E3 ubiquitin ligase CTRIP controls CLOCK levels and PERIOD oscillations in Drosophila.

    Science.gov (United States)

    Lamaze, Angélique; Lamouroux, Annie; Vias, Carine; Hung, Hsiu-Cheng; Weber, Frank; Rouyer, François

    2011-06-01

    In the Drosophila circadian clock, the CLOCK/CYCLE complex activates the period and timeless genes that negatively feedback on CLOCK/CYCLE activity. The 24-h pace of this cycle depends on the stability of the clock proteins. RING-domain E3 ubiquitin ligases have been shown to destabilize PERIOD or TIMELESS. Here we identify a clock function for the circadian trip (ctrip) gene, which encodes a HECT-domain E3 ubiquitin ligase. ctrip expression in the brain is mostly restricted to clock neurons and its downregulation leads to long-period activity rhythms in constant darkness. This altered behaviour is associated with high CLOCK levels and persistence of phosphorylated PERIOD during the subjective day. The control of CLOCK protein levels does not require PERIOD. Thus, CTRIP seems to regulate the pace of the oscillator by controlling the stability of both the activator and the repressor of the feedback loop.

  2. The Clock-in-the-Box, a brief cognitive screen, is associated with failure to return home in an elderly hospitalized sample

    Directory of Open Access Journals (Sweden)

    Jackson CE

    2016-11-01

    Full Text Available Colleen E Jackson,1–3 Laura J Grande,1–3 Kelly Doherty,1 Elizabeth Archambault,1 Brittany Kelly,1 Jane A Driver,1,4 William P Milberg,1,2,5 Regina McGlinchey,1,2,5 James L Rudolph6,7 1Geriatric Research, Education and Clinical Center, Department of Veterans Affairs (VA Boston Healthcare System, Boston, MA, 2Translational Research Center for TBI and Stress Disorders, Department of Veterans Affairs (VA Boston Healthcare System, Boston, MA, 3Department of Psychiatry, Boston University School of Medicine, Boston, MA, 4Department of Medicine, Harvard Medical School, Boston, MA, 5Department of Psychiatry, Harvard Medical School, Boston, MA, 6Center of Innovation in Long Term Services and Supports, Department of Veterans Affairs (VA Providence Medical Center, Providence, RI, 7Department of Medicine, Warren Alpert School of Medicine of Brown University, Providence, RI, USA Purpose: Cognitive screening upon hospital admission can provide important information about the patient’s ability to process information during the inpatient stay. The Clock-in-the-Box (CIB is a rapidly administered cognitive screening measure which has been previously validated with cognitive screening and neuropsychological assessments. The purpose of this study is to demonstrate the predictive validity of the CIB for discharge location among a sample of older medical inpatients. Patients and methods: Hospitalized Veterans (N=218, aged 55 years and older, were recruited on the day after admission after they gave their consent. These participants completed the CIB, the Montreal Cognitive Assessment, and self-report measures of daily functioning. Using logistic regression models, the bivariable and multivariable impact of the cognitive screening and functional assessments were examined for their ability to predict whether the participants did not return home after hospitalization (eg, admission to subacute rehabilitation facilities or nursing facilities. Results: The

  3. Setting the clock--by nature: circadian rhythm in the fruitfly Drosophila melanogaster.

    Science.gov (United States)

    Peschel, Nicolai; Helfrich-Förster, Charlotte

    2011-05-20

    Nowadays humans mainly rely on external, unnatural clocks such as of cell phones and alarm clocks--driven by circuit boards and electricity. Nevertheless, our body is under the control of another timer firmly anchored in our genes. This evolutionary very old biological clock drives most of our physiology and behavior. The genes that control our internal clock are conserved among most living beings. One organism that shares this ancient clock mechanism with us humans is the fruitfly Drosophila melanogaster. Since it turned out that Drosophila is an excellent model, it is no surprise that its clock is very well and intensely investigated. In the following review we want to display an overview of the current understanding of Drosophila's circadian clock. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  4. Molecular clock integration of brown adipose tissue formation and function.

    Science.gov (United States)

    Nam, Deokhwa; Yechoor, Vijay K; Ma, Ke

    2016-01-01

    The circadian clock is an essential time-keeping mechanism that entrains internal physiology to environmental cues. Despite the well-established link between the molecular clock and metabolic homeostasis, an intimate interplay between the clock machinery and the metabolically active brown adipose tissue (BAT) is only emerging. Recently, we came to appreciate that the formation and metabolic functions of BAT, a key organ for body temperature maintenance, are under an orchestrated circadian clock regulation. Two complementary studies from our group uncover that the cell-intrinsic clock machinery exerts concerted control of brown adipogenesis with consequent impacts on adaptive thermogenesis, which adds a previously unappreciated temporal dimension to the regulatory mechanisms governing BAT development and function. The essential clock transcriptional activator, Bmal1, suppresses adipocyte lineage commitment and differentiation, whereas the clock repressor, Rev-erbα, promotes these processes. This newly discovered temporal mechanism in fine-tuning BAT thermogenic capacity may enable energy utilization and body temperature regulation in accordance with external timing signals during development and functional recruitment. Given the important role of BAT in whole-body metabolic homeostasis, pharmacological interventions targeting the BAT-modulatory activities of the clock circuit may offer new avenues for the prevention and treatment of metabolic disorders, particularly those associated with circadian dysregulation.

  5. Tectonic blocks and molecular clocks

    Science.gov (United States)

    2016-01-01

    Evolutionary timescales have mainly used fossils for calibrating molecular clocks, though fossils only really provide minimum clade age constraints. In their place, phylogenetic trees can be calibrated by precisely dated geological events that have shaped biogeography. However, tectonic episodes are protracted, their role in vicariance is rarely justified, the biogeography of living clades and their antecedents may differ, and the impact of such events is contingent on ecology. Biogeographic calibrations are no panacea for the shortcomings of fossil calibrations, but their associated uncertainties can be accommodated. We provide examples of how biogeographic calibrations based on geological data can be established for the fragmentation of the Pangaean supercontinent: (i) for the uplift of the Isthmus of Panama, (ii) the separation of New Zealand from Gondwana, and (iii) for the opening of the Atlantic Ocean. Biogeographic and fossil calibrations are complementary, not competing, approaches to constraining molecular clock analyses, providing alternative constraints on the age of clades that are vital to avoiding circularity in investigating the role of biogeographic mechanisms in shaping modern biodiversity. This article is part of the themed issue ‘Dating species divergences using rocks and clocks’. PMID:27325840

  6. Round the clock librarianship

    OpenAIRE

    1995-01-01

    The concept of Round the Clock Librarianship (ROCLOLIB) is one such opportunity of terminal and critical importance to librarians, which helps people (clients) in general and reassures them about the professional commitment and devotedness of librarians. Although the concept is old, it is an exercise here to analyse its importance for the overall image and status of the practice/occupation. The chapter discusses the proposal of opening Libraries for 24 Hours. It also points out the reasons fo...

  7. Crosstalk of clock gene expression and autophagy in aging

    Science.gov (United States)

    Kalfalah, Faiza; Janke, Linda; Schiavi, Alfonso; Tigges, Julia; Ix, Alexander; Ventura, Natascia; Boege, Fritz; Reinke, Hans

    2016-01-01

    Autophagy and the circadian clock counteract tissue degeneration and support longevity in many organisms. Accumulating evidence indicates that aging compromises both the circadian clock and autophagy but the mechanisms involved are unknown. Here we show that the expression levels of transcriptional repressor components of the circadian oscillator, most prominently the human Period homologue PER2, are strongly reduced in primary dermal fibroblasts from aged humans, while raising the expression of PER2 in the same cells partially restores diminished autophagy levels. The link between clock gene expression and autophagy is corroborated by the finding that the circadian clock drives cell-autonomous, rhythmic autophagy levels in immortalized murine fibroblasts, and that siRNA-mediated downregulation of PER2 decreases autophagy levels while leaving core clock oscillations intact. Moreover, the Period homologue lin-42 regulates autophagy and life span in the nematode Caenorhabditis elegans, suggesting an evolutionarily conserved role for Period proteins in autophagy control and aging. Taken together, this study identifies circadian clock proteins as set-point regulators of autophagy and puts forward a model, in which age-related changes of clock gene expression promote declining autophagy levels. PMID:27574892

  8. A molecular clock regulates angiopoietin-like protein 2 expression.

    Science.gov (United States)

    Kadomatsu, Tsuyoshi; Uragami, Shota; Akashi, Makoto; Tsuchiya, Yoshiki; Nakajima, Hiroo; Nakashima, Yukiko; Endo, Motoyoshi; Miyata, Keishi; Terada, Kazutoyo; Todo, Takeshi; Node, Koichi; Oike, Yuichi

    2013-01-01

    Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are usually maintained by negative feedback loops of core clock genes, namely, CLOCK, BMAL, PER, and CRY. Recently, dysfunction in the circadian clock has been recognized as an important foundation for the pathophysiology of lifestyle-related diseases, such as obesity, cardiovascular disease, and some cancers. We have reported that angiopoietin-like protein 2 (ANGPTL2) contributes to the pathogenesis of these lifestyle-related diseases by inducing chronic inflammation. However, molecular mechanisms underlying regulation of ANGPTL2 expression are poorly understood. Here, we assess circadian rhythmicity of ANGPTL2 expression in various mouse tissues. We observed that ANGPTL2 rhythmicity was similar to that of the PER2 gene, which is regulated by the CLOCK/BMAL1 complex. Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression. We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells. Furthermore, Cry-deficient mice exhibited arrhythmic Angptl2 expression. Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

  9. A molecular clock regulates angiopoietin-like protein 2 expression.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Kadomatsu

    Full Text Available Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are usually maintained by negative feedback loops of core clock genes, namely, CLOCK, BMAL, PER, and CRY. Recently, dysfunction in the circadian clock has been recognized as an important foundation for the pathophysiology of lifestyle-related diseases, such as obesity, cardiovascular disease, and some cancers. We have reported that angiopoietin-like protein 2 (ANGPTL2 contributes to the pathogenesis of these lifestyle-related diseases by inducing chronic inflammation. However, molecular mechanisms underlying regulation of ANGPTL2 expression are poorly understood. Here, we assess circadian rhythmicity of ANGPTL2 expression in various mouse tissues. We observed that ANGPTL2 rhythmicity was similar to that of the PER2 gene, which is regulated by the CLOCK/BMAL1 complex. Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression. We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells. Furthermore, Cry-deficient mice exhibited arrhythmic Angptl2 expression. Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

  10. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans.

    Science.gov (United States)

    Pellegrino, Renata; Kavakli, Ibrahim Halil; Goel, Namni; Cardinale, Christopher J; Dinges, David F; Kuna, Samuel T; Maislin, Greg; Van Dongen, Hans P A; Tufik, Sergio; Hogenesch, John B; Hakonarson, Hakon; Pack, Allan I

    2014-08-01

    Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loophelix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis. Pellegrino R, Kavakli IH, Goel N, Cardinale CJ, Dinges DF, Kuna ST, Maislin G, Van Dongen HP, Tufik S, Hogenesch JB, Hakonarson H, Pack AI. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. SLEEP 2014;37(8):1327-1336.

  11. The human microbiota associated with overall health.

    Science.gov (United States)

    Xu, Xiaofei; Wang, Zhujun; Zhang, Xuewu

    2015-03-01

    Human body harbors diverse microbes, the main components include bacteria, eukaryotes and viruses. Emerging evidences show that the human microbiota is intrinsically linked with overall health. The development of next-generation sequencing provides an unprecedented opportunity to investigate the complex microbial communities that are associated with the human body. Many factors like host genetics and environmental factors have a major impact on the composition and dynamic changes of human microbiota. The purpose of this paper is to present an overview of the relationship between human health and human microbiota (skin, nasal, throat, oral, vaginal and gut microbiota), then to focus on the factors modulating the composition of the microbiota and the future challenges to manipulate the microbiota for personalized health.

  12. Transcriptional oscillation of canonical clock genes in mouse peripheral tissues

    Directory of Open Access Journals (Sweden)

    Nakahata Yasukazu

    2004-10-01

    Full Text Available Abstract Background The circadian rhythm of about 24 hours is a fundamental physiological function observed in almost all organisms from prokaryotes to humans. Identification of clock genes has allowed us to study the molecular bases for circadian behaviors and temporal physiological processes such as hormonal secretion, and has prompted the idea that molecular clocks reside not only in a central pacemaker, the suprachiasmatic nuclei (SCN of hypothalamus in mammals, but also in peripheral tissues, even in immortalized cells. Furthermore, previous molecular dissection revealed that the mechanism of circadian oscillation at a molecular level is based on transcriptional regulation of clock and clock-controlled genes. Results We systematically analyzed the mRNA expression of clock and clock-controlled genes in mouse peripheral tissues. Eight genes (mBmal1, mNpas2, mRev-erbα, mDbp, mRev-erbβ, mPer3, mPer1 and mPer2; given in the temporal order of the rhythm peak showed robust circadian expressions of mRNAs in all tissues except testis, suggesting that these genes are core molecules of the molecular biological clock. The bioinformatics analysis revealed that these genes have one or a combination of 3 transcriptional elements (RORE, DBPE, and E-box, which are conserved among human, mouse, and rat genome sequences, and indicated that these 3 elements may be responsible for the biological timing of expression of canonical clock genes. Conclusions The observation of oscillatory profiles of canonical clock genes is not only useful for physiological and pathological examination of the circadian clock in various organs but also important for systematic understanding of transcriptional regulation on a genome-wide basis. Our finding of the oscillatory expression of canonical clock genes with a temporal order provides us an interesting hypothesis, that cyclic timing of all clock and clock-controlled genes may be dependent on several transcriptional elements

  13. Time in motion: the molecular clock meets the microbiome.

    Science.gov (United States)

    Liang, Xue; Bushman, Frederic D; FitzGerald, Garret A

    2014-10-23

    Thaiss et al. report that the intestinal microbiota undergoes diurnal oscillation, which is controlled by host feeding time. Disruption of the host circadian clock induces dysbiosis, which is associated with host metabolic disorders.

  14. Circadian clock proteins in prokaryotes: hidden rhythms?

    Directory of Open Access Journals (Sweden)

    Maria eLoza-Correa

    2010-12-01

    Full Text Available Circadian clock genes are vital features of eukaryotes that have evolved such that organisms can adapt to our planet’s rotation in order to anticipate the coming day or night as well as unfavorable seasons. This circadian clock uses oscillation as a timekeeping element. However, circadian clock mechanisms exist also in prokaryotes. The circadian clock of Cyanobacteria is well studied. It is regulated by a cluster of three genes: kaiA, kaiB and kaiC. In this review, we will discuss the circadian system in cyanobacteria, and provide an overview and up-dated phylogenetic analysis of prokaryotic organisms that contain the main circadian genes. It is evident that the evolution of the kai genes has been influenced by lateral transfers but further and deeper studies are needed to get an in depth understanding of the exact evolutionary history of these genes. Interestingly, Legionella pneumophila an environmental bacterium and opportunistic human pathogen that parasitizes protozoa in fresh water environments also contains kaiB and kaiC, but their functions are not known. All of the residues described for the biochemical functions of the main pacemaker KaiC in Synechoccous elongates are also conserved in the L. pneumophila KaiC protein.

  15. Circadian Clocks in the Immune System.

    Science.gov (United States)

    Labrecque, Nathalie; Cermakian, Nicolas

    2015-08-01

    The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Microchip-Based Trapped-Atom Clocks

    CERN Document Server

    Vuletic, Vladan; Schleier-Smith, Monika H

    2011-01-01

    This is a chapter of a recently published book entitled Atom Chips, edited by Jakob Reichel and Vladan Vuletic. The contents of this chapter include: Basic Principles; Atomic-Fountain versus Trapped-Atom Clocks; Optical-Transition Clocks versus Microwave Clocks; Clocks with Magnetically Trapped Atoms--Fundamental Limits and Experimental Demonstrations; Readout in Trapped-Atom Clocks; and Spin Squeezing.

  18. Circadian clocks and breast cancer

    OpenAIRE

    Blakeman, Victoria; Jack L. Williams; Meng, Qing-Jun; Streuli, Charles H

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, an...

  19. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    OpenAIRE

    2015-01-01

    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...

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

    Directory of Open Access Journals (Sweden)

    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

  1. 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…

  2. A mixed relaxed clock model

    Science.gov (United States)

    2016-01-01

    Over recent years, several alternative relaxed clock models have been proposed in the context of Bayesian dating. These models fall in two distinct categories: uncorrelated and autocorrelated across branches. The choice between these two classes of relaxed clocks is still an open question. More fundamentally, the true process of rate variation may have both long-term trends and short-term fluctuations, suggesting that more sophisticated clock models unfolding over multiple time scales should ultimately be developed. Here, a mixed relaxed clock model is introduced, which can be mechanistically interpreted as a rate variation process undergoing short-term fluctuations on the top of Brownian long-term trends. Statistically, this mixed clock represents an alternative solution to the problem of choosing between autocorrelated and uncorrelated relaxed clocks, by proposing instead to combine their respective merits. Fitting this model on a dataset of 105 placental mammals, using both node-dating and tip-dating approaches, suggests that the two pure clocks, Brownian and white noise, are rejected in favour of a mixed model with approximately equal contributions for its uncorrelated and autocorrelated components. The tip-dating analysis is particularly sensitive to the choice of the relaxed clock model. In this context, the classical pure Brownian relaxed clock appears to be overly rigid, leading to biases in divergence time estimation. By contrast, the use of a mixed clock leads to more recent and more reasonable estimates for the crown ages of placental orders and superorders. Altogether, the mixed clock introduced here represents a first step towards empirically more adequate models of the patterns of rate variation across phylogenetic trees. This article is part of the themed issue ‘Dating species divergences using rocks and clocks’. PMID:27325829

  3. Circadian Clock Gene Plays a Key Role on Ovarian Cycle and Spontaneous Abortion

    Directory of Open Access Journals (Sweden)

    Ruiwen Li

    2015-09-01

    Full Text Available Background/Aims: Circadian locomotor output cycles protein kaput (CLOCK plays a key role in maintaining circadian rhythms and activation of downstream elements. However, its function on human female reproductive system remains unknown. Methods: To investigate the potential role of CLOCK, CLOCK-shRNAs were transfected into mouse 129 ES cells or injected into the ovaries of adult female mice. Western blotting was utilized to analyze the protein interactions and flow cytometry was used to assess apoptosis. Results: The expression of CLOCK peaked at the 6th week in the healthy fetuses. However, an abnormal expression of CLOCK was detected in fetuses from spontaneous miscarriage. To determine the effect of CLOCK on female fertility, a small hairpin RNA (shRNA strategy was used to specifically knockdown the CLOCK gene expression in vitro and in vivo. Knockdown of CLOCK induced apoptosis in mouse embryonic stem (mES cells and inhibited the proliferation in mES cells in vitro. CLOCK knockdown also led to decreased release of oocytes and smaller litter size compared with control in vivo. Conclusions: Collectively, theses findings indicate that CLOCK plays an important role in fertility and that the CLOCK knockdown leads to reduction in reproduction and increased miscarriage risk.

  4. Circadian rhythms, the molecular clock, and skeletal muscle.

    Science.gov (United States)

    Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A

    2011-01-01

    Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1(-/-) and Clock(Δ19) mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle.

  5. Diurnal oscillations of soybean circadian clock and drought responsive genes.

    Directory of Open Access Journals (Sweden)

    Juliana Marcolino-Gomes

    Full Text Available Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis-elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i drought stress affects gene expression of circadian clock components and (ii several stress responsive genes display diurnal oscillation in soybeans.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  7. Novel putative mechanisms to link circadian clocks to healthy aging.

    Science.gov (United States)

    Popa-Wagner, Aurel; Catalin, Bogdan; Buga, Ana-Maria

    2015-08-01

    The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms.

  8. Polymorphism at the Clock gene predicts phenology of long-distance migration in birds.

    Science.gov (United States)

    Saino, Nicola; Bazzi, Gaia; Gatti, Emanuele; Caprioli, Manuela; Cecere, Jacopo G; Possenti, Cristina D; Galimberti, Andrea; Orioli, Valerio; Bani, Luciano; Rubolini, Diego; Gianfranceschi, Luca; Spina, Fernando

    2015-04-01

    Dissecting phenotypic variance in life history traits into its genetic and environmental components is at the focus of evolutionary studies and of pivotal importance to identify the mechanisms and predict the consequences of human-driven environmental change. The timing of recurrent life history events (phenology) is under strong selection, but the study of the genes that control potential environmental canalization in phenological traits is at its infancy. Candidate genes for circadian behaviour entrained by photoperiod have been screened as potential controllers of phenological variation of breeding and moult in birds, with inconsistent results. Despite photoperiodic control of migration is well established, no study has reported on migration phenology in relation to polymorphism at candidate genes in birds. We analysed variation in spring migration dates within four trans-Saharan migratory species (Luscinia megarhynchos; Ficedula hypoleuca; Anthus trivialis; Saxicola rubetra) at a Mediterranean island in relation to Clock and Adcyap1 polymorphism. Individuals with larger number of glutamine residues in the poly-Q region of Clock gene migrated significantly later in one or, respectively, two species depending on sex and whether the within-individual mean length or the length of the longer Clock allele was considered. The results hinted at dominance of the longer Clock allele. No significant evidence for migration date to covary with Adcyap1 polymorphism emerged. This is the first evidence that migration phenology is associated with Clock in birds. This finding is important for evolutionary studies of migration and sheds light on the mechanisms that drive bird phenological changes and population trends in response to climate change.

  9. The timing of the human circadian clock is accurately represented by the core body temperature rhythm following phase shifts to a three-cycle light stimulus near the critical zone

    Science.gov (United States)

    Jewett, M. E.; Duffy, J. F.; Czeisler, C. A.

    2000-01-01

    A double-stimulus experiment was conducted to evaluate the phase of the underlying circadian clock following light-induced phase shifts of the human circadian system. Circadian phase was assayed by constant routine from the rhythm in core body temperature before and after a three-cycle bright-light stimulus applied near the estimated minimum of the core body temperature rhythm. An identical, consecutive three-cycle light stimulus was then applied, and phase was reassessed. Phase shifts to these consecutive stimuli were no different from those obtained in a previous study following light stimuli applied under steady-state conditions over a range of circadian phases similar to those at which the consecutive stimuli were applied. These data suggest that circadian phase shifts of the core body temperature rhythm in response to a three-cycle stimulus occur within 24 h following the end of the 3-day light stimulus and that this poststimulus temperature rhythm accurately reflects the timing of the underlying circadian clock.

  10. Colon cancer associated transcripts in human cancers.

    Science.gov (United States)

    Chen, Yincong; Xie, Haibiao; Gao, Qunjun; Zhan, Hengji; Xiao, Huizhong; Zou, Yifan; Zhang, Fuyou; Liu, Yuchen; Li, Jianfa

    2017-08-02

    Long non-coding RNAs serve as important regulators in complicated cellular activities, including cell differentiation, proliferation and death. Dysregulation of long non-coding RNAs occurs in the formation and progression of cancers. The family of colon cancer associated transcripts, long non-coding RNAs colon cancer associated transcript-1 and colon cancer associated transcript-2 are known as oncogenes involved in various cancers. Colon cancer associated transcript-1 is a novel lncRNA located in 8q24.2, and colon cancer associated transcript-2 maps to the 8q24.21 region encompassing rs6983267. Colon cancer associated transcripts have close associations with clinical characteristics, such as lymph node metastasis, high TNM stage and short overall survival. Knockdown of them can reverse the malignant phenotypes of cancer cells, including proliferation, migration, invasion and apoptosis. Moreover, they can increase the expression level of c-MYC and oncogenic microRNAs via activating a series of complex mechanisms. In brief, the family of colon cancer associated transcripts may serve as potential biomarkers or therapeutic targets for human cancers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Saffold virus infection associated with human myocarditis

    DEFF Research Database (Denmark)

    Nielsen, Trine Skov; Nielsen, Alex Yde; Banner, Jytte

    2016-01-01

    BACKGROUND: Saffold virus was described in 2007 as one of the first human viruses within the genus cardioviruses. Cardioviruses may cause severe infections of the myocardium in animals, and several studies have associated saffold virus with human disease. As a result, saffold virus has been...... isolated from different anatomical compartments, including the myocardium, but, until now, it has not been possible to demonstrate the accompanying histopathological signs of inflammation. OBJECTIVES: The aim of the study was to examine if saffold virus is capable of causing invasive infection in the human...... myocardium. STUDY DESIGN: Using real-time PCR, we retrospectively examined formalin-fixed paraffin embedded cardiac tissue specimens from 150 deceased individuals diagnosed with myocarditis at autopsy. The results were compared with histological findings. RESULTS AND CONCLUSIONS: Saffold virus was detected...

  12. Saffold virus infection associated with human myocarditis.

    Science.gov (United States)

    Nielsen, Trine Skov; Nielsen, Alex Yde; Banner, Jytte; Hansen, Jakob; Baandrup, Ulrik; Nielsen, Lars Peter

    2016-01-01

    Saffold virus was described in 2007 as one of the first human viruses within the genus cardioviruses. Cardioviruses may cause severe infections of the myocardium in animals, and several studies have associated saffold virus with human disease. As a result, saffold virus has been isolated from different anatomical compartments, including the myocardium, but, until now, it has not been possible to demonstrate the accompanying histopathological signs of inflammation. The aim of the study was to examine if saffold virus is capable of causing invasive infection in the human myocardium. Using real-time PCR, we retrospectively examined formalin-fixed paraffin embedded cardiac tissue specimens from 150 deceased individuals diagnosed with myocarditis at autopsy. The results were compared with histological findings. Saffold virus was detected in the myocardium, lung tissue and blood of one child and was accompanied by histopathological inflammation in the heart and lungs, which was supportive of a viral infection. These findings suggest that cardioviruses may be associated with myocarditis in humans. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Clocks around Sgr A*

    CERN Document Server

    Angélil, Raymond

    2014-01-01

    The S stars near the Galactic centre and any pulsars that may be on similar orbits, can be modelled in a unified way as clocks orbiting a black hole, and hence are potential probes of relativistic effects, including block-hole spin. The high eccentricities of many S stars mean that relativistic effects peak strongly around pericentre; for example, orbit precession is not a smooth effect but almost a kick at pericentre. We argue that concentration around pericentre will be an advantage when analysing redshift or pulse-arrival data to measure relativistic effects, because cumulative precession will be drowned out by Newtonian perturbations from other mass in the Galactic-centre region. Wavelet decomposition may be a way to disentangle relativistic effects from Newton perturbations. Assuming a plausible model for Newtonian perturbations on S2, relativity appears to be strongest in a two-year interval around pericentre, in wavelet modes of timescale approximately 6 months.

  14. Clock Genes in Glia Cells

    Science.gov (United States)

    Chi-Castañeda, Donají

    2016-01-01

    Circadian rhythms are periodic patterns in biological processes that allow the organisms to anticipate changes in the environment. These rhythms are driven by the suprachiasmatic nucleus (SCN), the master circadian clock in vertebrates. At a molecular level, circadian rhythms are regulated by the so-called clock genes, which oscillate in a periodic manner. The protein products of clock genes are transcription factors that control their own and other genes’ transcription, collectively known as “clock-controlled genes.” Several brain regions other than the SCN express circadian rhythms of clock genes, including the amygdala, the olfactory bulb, the retina, and the cerebellum. Glia cells in these structures are expected to participate in rhythmicity. However, only certain types of glia cells may be called “glial clocks,” since they express PER-based circadian oscillators, which depend of the SCN for their synchronization. This contribution summarizes the current information about clock genes in glia cells, their plausible role as oscillators and their medical implications. PMID:27666286

  15. Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity

    Directory of Open Access Journals (Sweden)

    Dirk van Moorsel

    2016-08-01

    Conclusions: Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.

  16. Epigenetic drift, epigenetic clocks and cancer risk.

    Science.gov (United States)

    Zheng, Shijie C; Widschwendter, Martin; Teschendorff, Andrew E

    2016-05-01

    It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as 'epigenetic drift'. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. We further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies.

  17. Simulating Future GPS Clock Scenarios with Two Composite Clock Algorithms

    Science.gov (United States)

    2010-11-01

    Alexandria, Virginia), pp. 223-242. [8] C. A. Greenhall, 2007, “A Kalman filter clock ensemble algorithm that admits measurement noise,” Metrologia ...43, S311-S321. [9] J. A. Davis, C. A. Greenhall, and P. W. Stacey, 2005, “A Kalman filter clock algorithm for use in the presence of flicker frequency modulation noise,” Metrologia , 42, 1-10.

  18. The Molecular Circadian Clock and Alcohol-Induced Liver Injury.

    Science.gov (United States)

    Udoh, Uduak S; Valcin, Jennifer A; Gamble, Karen L; Bailey, Shannon M

    2015-10-14

    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.

  19. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    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.

  20. Circadian clock components in the rat neocortex

    DEFF Research Database (Denmark)

    Rath, Martin Fredensborg; Rohde, Kristian; Fahrenkrug, Jan

    2013-01-01

    The circadian master clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the clock of the SCN is driven by a transcriptional/posttranslational autoregulatory network with clock gene products as core elements. Recent investigations...... have shown the presence of peripheral clocks in extra-hypothalamic areas of the central nervous system. However, knowledge on the clock gene network in the cerebral cortex is limited. We here show that the mammalian clock genes Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Nr1d1 and Dbp are expressed...

  1. History of early atomic clocks

    Energy Technology Data Exchange (ETDEWEB)

    Ramsey, N.F. [Harvard Univ., Cambridge, MA (United States). Lyman Lab. of Physics

    2005-06-01

    This review of the history of early atomic clocks includes early atomic beam magnetic resonance, methods of separated and successive oscillatory fields, microwave absorption, optical pumping and atomic masers. (author)

  2. A quantum network of clocks

    Science.gov (United States)

    Kómár, P.; Kessler, E. M.; Bishof, M.; Jiang, L.; Sørensen, A. S.; Ye, J.; Lukin, M. D.

    2014-08-01

    The development of precise atomic clocks plays an increasingly important role in modern society. Shared timing information constitutes a key resource for navigation with a direct correspondence between timing accuracy and precision in applications such as the Global Positioning System. By combining precision metrology and quantum networks, we propose a quantum, cooperative protocol for operating a network of geographically remote optical atomic clocks. Using nonlocal entangled states, we demonstrate an optimal utilization of global resources, and show that such a network can be operated near the fundamental precision limit set by quantum theory. Furthermore, the internal structure of the network, combined with quantum communication techniques, guarantees security both from internal and external threats. Realization of such a global quantum network of clocks may allow construction of a real-time single international time scale (world clock) with unprecedented stability and accuracy.

  3. Stochastic models for atomic clocks

    Science.gov (United States)

    Barnes, J. A.; Jones, R. H.; Tryon, P. V.; Allan, D. W.

    1983-01-01

    For the atomic clocks used in the National Bureau of Standards Time Scales, an adequate model is the superposition of white FM, random walk FM, and linear frequency drift for times longer than about one minute. The model was tested on several clocks using maximum likelihood techniques for parameter estimation and the residuals were acceptably random. Conventional diagnostics indicate that additional model elements contribute no significant improvement to the model even at the expense of the added model complexity.

  4. Insights into the regulation of the core clock component TOC1 in the green picoeukaryote Ostreococcus

    OpenAIRE

    Djouani-Tahri, El Batoul; Motta*, Jean-Paul; Bouget, François-Yves; Corellou, Florence

    2010-01-01

    Living organisms such as plants and animals have evolved endogenous clocks in order to anticipate the environmental changes associated with the earth’s rotation and to orchestrate biological processes in the course of the 24 hour daily cycle. We have recently identified clock components in the primitive green picoalga Ostreococcus tauri, a promising minimal cellular and genomic model for systems biology approaches. A homologue of the Arabidopsis core clock gene Time of CAB expression-1 (TOC1)...

  5. Human papillomavirus-associated diseases and cancers

    Institute of Scientific and Technical Information of China (English)

    Lan Yang; Jianbo Zhu Co-first author; Xiaoyue Song; Yan Qi; Xiaobin Cui; Feng Li 

    2015-01-01

    Human papilomaviruses (HPVs) have been detected in cervical cancer cels and skin papiloma cels, which have a variety of types, including low-risk and high-risk types. HPV genome replication requires the host cel’s DNA synthesis machinery, and HPVs encode proteins that maintain diferentiated epithelial cels in a replication-competent state. HPV types are tissue-specific and generaly produce diferent types of le-sions, either benign or malignant. This review examines diferent HPV types and their associated diseases and presents therapeutic options for the treatment of HPV-positive diseases.

  6. Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis.

    Science.gov (United States)

    Cheng, Bo; Anea, Ciprian B; Yao, Lin; Chen, Feng; Patel, Vijay; Merloiu, Ana; Pati, Paramita; Caldwell, R William; Fulton, David J; Rudic, R Daniel

    2011-10-11

    The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.

  7. Tonotopic organization of human auditory association cortex.

    Science.gov (United States)

    Cansino, S; Williamson, S J; Karron, D

    1994-11-07

    Neuromagnetic studies of responses in human auditory association cortex for tone burst stimuli provide evidence for a tonotopic organization. The magnetic source image for the 100 ms component evoked by the onset of a tone is qualitatively similar to that of primary cortex, with responses lying deeper beneath the scalp for progressively higher tone frequencies. However, the tonotopic sequence of association cortex in three subjects is found largely within the superior temporal sulcus, although in the right hemisphere of one subject some sources may be closer to the inferior temporal sulcus. The locus of responses for individual subjects suggests a progression across the cortical surface that is approximately proportional to the logarithm of the tone frequency, as observed previously for primary cortex, with the span of 10 mm for each decade in frequency being comparable for the two areas.

  8. Amyloid-β–Induced Changes in Molecular Clock Properties and Cellular Bioenergetics

    Science.gov (United States)

    Schmitt, Karen; Grimm, Amandine; Eckert, Anne

    2017-01-01

    Ageing is an inevitable biological process that results in a progressive structural and functional decline, as well as biochemical alterations that altogether lead to reduced ability to adapt to environmental changes. As clock oscillations and clock-controlled rhythms are not resilient to the aging process, aging of the circadian system may also increase susceptibility to age-related pathologies such as Alzheimer's disease (AD). Besides the amyloid-beta protein (Aβ)-induced metabolic decline and neuronal toxicity in AD, numerous studies have demonstrated that the disruption of sleep and circadian rhythms is one of the common and earliest signs of the disease. In this study, we addressed the questions of whether Aβ contributes to an abnormal molecular circadian clock leading to a bioenergetic imbalance. For this purpose, we used different oscillator cellular models: human skin fibroblasts, human glioma cells, as well as mouse primary cortical and hippocampal neurons. We first evaluated the circadian period length, a molecular clock property, in the presence of different Aβ species. We report here that physiologically relevant Aβ1–42 concentrations ranging from 10 to 500 nM induced an increase of the period length in human skin fibroblasts, human A172 glioma cells as well as in mouse primary neurons whereas the reverse control peptide Aβ42-1, which is devoid of toxic action, did not influence the circadian period length within the same concentration range. To better understand the underlying mechanisms that are involved in the Aβ-related alterations of the circadian clock, we examined the cellular metabolic state in the human primary skin fibroblast model. Notably, under normal conditions, ATP levels displayed circadian oscillations, which correspond to the respective circadian pattern of mitochondrial respiration. In contrast, Aβ1–42 treatment provoked a strong dampening in the metabolic oscillations of ATP levels as well as mitochondrial respiration and

  9. Evaluation of blackbody radiation shift with temperature associated fractional uncertainty at 10E-18 level for 40Ca+ ion optical clock

    CERN Document Server

    Zhang, Ping; Shu, Hua-lin; Yuan, Jin-bo; Shang, Juan-juan; Cui, Kai-feng; Chao, Si-jia; Wang, Shao-mao; Liu, Dao-xin; Huang, Xue-ren

    2016-01-01

    In this paper, blackbody radiation (BBR) temperature rise seen by the $^{40}$Ca$^+$ ion confined in a miniature Paul trap and its uncertainty have been evaluated via finite-element method (FEM) modelling. The FEM model was validated by comparing with thermal camera measurements, which were calibrated by PT1000 resistance thermometer, at several points on a dummy trap. The input modelling parameters were analyzed carefully in detail, and their contributions to the uncertainty of environment temperature were evaluated on the validated FEM model. The result shows that the temperature rise seen by $^{40}$Ca$^+$ ion is 1.72 K with an uncertainty of 0.46 K. It results in a contribution of 2.2 mHz to the systematic uncertainty of $^{40}$Ca$^+$ ion optical clock, corresponding to a fractional uncertainty 5.4$\\times$10$^{-18}$. This is much smaller than the uncertainty caused by the BBR shift coefficient, which is evaluated to be 4.8 mHz and at 10$^{-17}$ level in fractional frequency units.

  10. Evaluation of blackbody radiation shift with temperature-associated fractional uncertainty at 10-18 level for 40Ca+ ion optical clock

    Science.gov (United States)

    Zhang, Ping; Cao, Jian; Shu, Hua-lin; Yuan, Jin-bo; Shang, Jun-juan; Cui, Kai-feng; Chao, Si-jia; Wang, Shao-mao; Liu, Dao-xin; Huang, Xue-ren

    2017-01-01

    In this paper, the blackbody radiation (BBR) temperature rise experienced by a 40Ca+ ion confined in a miniature Paul trap and its uncertainty have been evaluated via finite-element method (FEM) modelling. The FEM model was validated through comparisons with thermal camera measurements at several points on a dummy trap. Before the validation, the thermal camera was calibrated by using a PT1000 resistance thermometer. The input modelling parameters were analyzed carefully, and their contributions to the uncertainty of the trap environment temperature were evaluated using the validated FEM model. The result shows that the temperature rise experienced by the 40Ca+ ion is 1.72 K with an uncertainty of 0.46 K. It results in a contribution of 2.2 mHz to the systematic uncertainty of a 40Ca+ ion optical clock, corresponding to a fractional uncertainty 5.4 × 10-18. This is much smaller than the uncertainty caused by the BBR shift coefficient, which is evaluated to be 4.8 mHz and at the 10-17 level in fractional frequency units.

  11. Entrainment of the Human Circadian Clock to the Light-Dark Cycle and its Impact on Patients in the ICU and Nursing Home Settings.

    Science.gov (United States)

    Ritchie, Hannah K; Stothard, Ellen R; Wright, Kenneth P

    2015-01-01

    A robust circadian timekeeping system is important for human health and well-being. Inappropriately timed light exposure can cause circadian and sleep disruption, which has been shown to have negative health consequences. Lighting in medical care facilities, such as the NICU, ICU, and nursing homes, is not typically controlled and may be associated with circadian disruption observed in such settings. Cycled lighting and increased exposure to sunlight in medical care facilities have been shown to have positive effects on patient recovery and well-being, and expedite hospital discharge. Additional clinical research is needed to determine the optimal light exposure timing, duration, intensity, and spectrum to best promote recovery, health and well-being in the context of medical care.

  12. Frequency Stability of Atomic Clocks Based on Coherent Population Trapping Resonance in 85Rb

    Institute of Scientific and Technical Information of China (English)

    LIU Lu; GUO Tao; DENG Ke; LIU Xin-Yuan; CHEN Xu-Zong; WANG Zhong

    2007-01-01

    An atomic clock system based on coherent population trapping (CPT) resonance in 85Rb is reported, while most past works about the CPT clock are in 87Rb. A new modulation method (full-hyperfine-frequency-splitting modulation) is presented to reduce the effect of light shift to improve the frequency stability of the CPT clock in 85Rb. The experimental results show that the short-term frequency stability of the CPT clock in 85Rb is in the order of 10-10/s and the long-term frequency stability can achieve 1.5 × 10-11 /80000s, which performs as well as 87Rb in CPT resonance. This very good frequency stability performance associated with the low-cost and low-power properties of 85Rb indicates that an atomic clock based on CPT in 85 Rb should be a promising candidate for making the chip scale atomic clock.

  13. Early nocturnal meal skipping alters the peripheral clock and increases lipogenesis in mice

    Directory of Open Access Journals (Sweden)

    Yoshida Chika

    2012-09-01

    Full Text Available Abstract Background In humans, skipping meals, especially breakfast, has been associated with obesity and other related syndromes. Recent studies in rodents suggest that fasting and feeding times are potential factors that affect the peripheral circadian clocks and metabolism. However, the link between fasting and obesity in rodents has yet to be fully demonstrated. Method We conducted early nocturnal fasting (ENF from zeitgeber time (ZT 12 to 18 for 4 consecutive days in C57B6 mice. The first set of experiments was performed under ad libitum conditions, where ENF and free-feeding (FF control groups were compared. The second set was performed under isocaloric adjustment by restricting the diet to 90% of the basal intake of ENF mice. Calorie-restricted ENF (ENF-CR mice were then compared with isocaloric controls (IC-control. Body weight, food intake, core body temperature, activity, adiposity, and clock-related gene expression levels in the liver and adipose tissues were investigated. A stable isotopic analysis was also conducted to estimate de novo lipogenesis fluxes. Results In the ad libitum condition, the ENF mice ate more during the day, increased their overall daily food intake and gained more weight than FF-control mice. The amplitude of the body core temperature rhythm in ENF mice was also lower than in the FF-controls. Under isocaloric conditions, ENF-CR attenuated the CR-induced body weight loss, compared with the IC-control. ENF-CR also altered the acrophase time of the expression of the clock genes, which is associated with time-shift of genes involved in lipid metabolism and increased lipogenesis, compared with the IC-control. Conclusions ENF in nocturnal mice disturbs the peripheral clock and increases de novo lipid synthesis and results in a predisposition to obesity.

  14. Circadian clock gene Per2 plays an important role in cell proliferation, apoptosis and cell cycle progression in human oral squamous cell carcinoma.

    Science.gov (United States)

    Wang, Qingqing; Ao, Yiran; Yang, Kai; Tang, Hong; Chen, Dan

    2016-06-01

    Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (Pcycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.

  15. The association between human papillomavirus and oropharyngeal squamous cell Carcinoma

    DEFF Research Database (Denmark)

    Walvik, Lena; Svensson, Amanda Björk; Friborg, Jeppe

    2016-01-01

    There is emerging evidence of the association between human papillomavirus and a subset of head and neck cancers. However, the role of human papillomavirus as a causal factor is still debated. This review addresses the association between human papillomavirus and oropharyngeal squamous cell...... of well-defined premalignant lesions. However, a causal relationship between human papillomavirus infection and oropharyngeal squamous cell carcinoma seems evident....

  16. MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation.

    Science.gov (United States)

    Shostak, Anton; Ruppert, Bianca; Ha, Nati; Bruns, Philipp; Toprak, Umut H; Eils, Roland; Schlesner, Matthias; Diernfellner, Axel; Brunner, Michael

    2016-06-24

    The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.

  17. Simulation of the clock framework of Gaia

    CERN Document Server

    Castaneda, J; Portell, J; García-Berro, E; Luri, X; Castaneda, Javier; Gordo, Jose P.; Portell, Jordi; Garcia-Berro, Enrique; Luri, Xavier

    2005-01-01

    Gaia will perform astrometric measurements with an unprecedented resolution. Consequently, the electronics of the Astro instrument must time tag every measurement with a precision of a few nanoseconds. Hence, it requires a high stability clock signal, for which a Rb-type spacecraft master clock has been baselined. The distribution of its signal and the generation of clock subproducts must maintain these high accuracy requirements. We have developed a software application to simulate generic clock frameworks. The most critical clock structures for Gaia have also been identified, and its master clock has been parameterised.

  18. Circadian clocks, epigenetics, and cancer

    KAUST Repository

    Masri, Selma

    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.

  19. Obesity alters the expression profile of clock genes in peripheral blood mononuclear cells

    Science.gov (United States)

    Tahira, Kazunobu; Fukuda, Noboru; Aoyama, Takahiko; Tsunemi, Akiko; Matsumoto, Siroh; Nagura, Chinami; Matsumoto, Taro; Soma, Masayoshi; Shimba, Shigeki; Matsumoto, Yoshiaki

    2011-01-01

    Introduction The aim of this study was to investigate the association between the variation in expression profile of clock genes and obesity using peripheral blood mononuclear (PMN) cells. Material and methods The subjects comprised 10 obese patients and 10 healthy volunteers. Blood was collected at different time-points during the day and levels of blood sugar, IRI, adiponectin and leptin were determined. Peripheral blood mononuclear cells were sampled, and expression levels of brain and muscle Arnt-like protein-1 (BMAL1), Period (PER)1, PER2, Cryptochrome (CRY)1, CRY2, and REV-ERBα mRNA were quantified. Results During the day, the expression levels of BMAL1, CRY1, CRY2 and PER2 genes in PMN cells of the obese group were all significantly higher compared to those in the non-obese group. In addition, expression of BMAL1, CRY1, CRY2 and PER2 genes in PMN cells increased between 12:00 and 21:00 in the obese group. In PMN cells of both groups, PER1 gene expression showed a bimodal pattern, with high expression at 9:00 and 18:00. Conclusions Differences were observed in the expression profile variation of clock genes between the obese and non-obese groups. This study reveals the differences in clock gene expression profiles between obese and non-obese subjects, with evidence for two distinct chronotypes, and suggests a contribution of these chronotypes to fat accumulation in humans. PMID:22328874

  20. Modelling the widespread effects of TOC1 signalling on the plant circadian clock and its outputs.

    Science.gov (United States)

    Pokhilko, Alexandra; Mas, Paloma; Millar, Andrew J

    2013-03-19

    24-hour biological clocks are intimately connected to the cellular signalling network, which complicates the analysis of clock mechanisms. The transcriptional regulator TOC1 (TIMING OF CAB EXPRESSION 1) is a founding component of the gene circuit in the plant circadian clock. Recent results show that TOC1 suppresses transcription of multiple target genes within the clock circuit, far beyond its previously-described regulation of the morning transcription factors LHY (LATE ELONGATED HYPOCOTYL) and CCA1 (CIRCADIAN CLOCK ASSOCIATED 1). It is unclear how this pervasive effect of TOC1 affects the dynamics of the clock and its outputs. TOC1 also appears to function in a nested feedback loop that includes signalling by the plant hormone Abscisic Acid (ABA), which is upregulated by abiotic stresses, such as drought. ABA treatments both alter TOC1 levels and affect the clock's timing behaviour. Conversely, the clock rhythmically modulates physiological processes induced by ABA, such as the closing of stomata in the leaf epidermis. In order to understand the dynamics of the clock and its outputs under changing environmental conditions, the reciprocal interactions between the clock and other signalling pathways must be integrated. We extended the mathematical model of the plant clock gene circuit by incorporating the repression of multiple clock genes by TOC1, observed experimentally. The revised model more accurately matches the data on the clock's molecular profiles and timing behaviour, explaining the clock's responses in TOC1 over-expression and toc1 mutant plants. A simplified representation of ABA signalling allowed us to investigate the interactions of ABA and circadian pathways. Increased ABA levels lengthen the free-running period of the clock, consistent with the experimental data. Adding stomatal closure to the model, as a key ABA- and clock-regulated downstream process allowed to describe TOC1 effects on the rhythmic gating of stomatal closure. The integrated

  1. Types for X10 Clocks

    Directory of Open Access Journals (Sweden)

    Francisco Martins

    2011-10-01

    Full Text Available X10 is a modern language built from the ground up to handle future parallel systems, from multicore machines to cluster configurations. We take a closer look at a pair of synchronisation mechanisms: finish and clocks. The former waits for the termination of parallel computations, the latter allow multiple concurrent activities to wait for each other at certain points in time. In order to better understand these concepts we study a type system for a stripped down version of X10. The main result assures that well typed programs do not run into the errors identified in the X10 language reference, namely the ClockUseException. The study will open, we hope, doors to a more flexible utilisation of clocks in the X10 language.

  2. Synchronous clock stopper for microprocessor

    Science.gov (United States)

    Kitchin, David A. (Inventor)

    1985-01-01

    A synchronous clock stopper circuit for inhibiting clock pulses to a microprocessor in response to a stop request signal, and for reinstating the clock pulses in response to a start request signal thereby to conserve power consumption of the microprocessor when used in an environment of limited power. The stopping and starting of the microprocessor is synchronized, by a phase tracker, with the occurrences of a predetermined phase in the instruction cycle of the microprocessor in which the I/O data and address lines of the microprocessor are of high impedance so that a shared memory connected to the I/O lines may be accessed by other peripheral devices. The starting and stopping occur when the microprocessor initiates and completes, respectively, an instruction, as well as before and after transferring data with a memory. Also, the phase tracker transmits phase information signals over a bus to other peripheral devices which signals identify the current operational phase of the microprocessor.

  3. Feeding cues and injected nutrients induce acute expression of multiple clock genes in the mouse liver.

    Directory of Open Access Journals (Sweden)

    Hideaki Oike

    Full Text Available The circadian clock is closely associated with energy metabolism. The liver clock can rapidly adapt to a new feeding cycle within a few days, whereas the lung clock is gradually entrained over one week. However, the mechanism underlying tissue-specific clock resetting is not fully understood. To characterize the rapid response to feeding cues in the liver clock, we examined the effects of a single time-delayed feeding on circadian rhythms in the liver and lungs of Per2::Luc reporter knockin mice. After adapting to a night-time restricted feeding schedule, the mice were fed according to a 4, 8, or 13 h delayed schedule on the last day. The phase of the liver clock was delayed in all groups with delayed feeding, whereas the lung clock remained unaffected. We then examined the acute response of clock and metabolism-related genes in the liver using focused DNA-microarrays. Clock mutant mice were bred under constant light to attenuate the endogenous circadian rhythm, and gene expression profiles were determined during 24 h of fasting followed by 8 h of feeding. Per2 and Dec1 were significantly increased within 1 h of feeding. Real-time RT-PCR analysis revealed a similarly acute response in hepatic clock gene expression caused by feeding wild type mice after an overnight fast. In addition to Per2 and Dec1, the expression of Per1 increased, and that of Rev-erbα decreased in the liver within 1 h of feeding after fasting, whereas none of these clock genes were affected in the lung. Moreover, an intraperitoneal injection of glucose combined with amino acids, but not either alone, reproduced a similar hepatic response. Our findings show that multiple clock genes respond to nutritional cues within 1 h in the liver but not in the lung.

  4. Identification and temporal expression of putative circadian clock transcripts in the amphipod crustacean Talitrus saltator.

    Science.gov (United States)

    O'Grady, Joseph F; Hoelters, Laura S; Swain, Martin T; Wilcockson, David C

    2016-01-01

    Talitrus saltator is an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean. T. saltator exhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species. We harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq. We identified a comprehensive suite of circadian clock gene homologues in T. saltator including the 'core' clock genes period (Talper), cryptochrome 2 (Talcry2), timeless (Taltim), clock (Talclk), and bmal1 (Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period in Talper and Talbmal1. Of the clock-related genes, casein kinase IIβ (TalckIIβ), ebony (Talebony), jetlag (Taljetlag), pigment dispensing hormone (Talpdh), protein phosphatase 1 (Talpp1), shaggy (Talshaggy), sirt1 (Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression. We report the sequences of principle genes that comprise the circadian clock of T. saltator and highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory

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

    Science.gov (United States)

    Easton, A; Arbuzova, J; Turek, F W

    2003-02-01

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

  6. Colloquium: Physics of optical lattice clocks

    CERN Document Server

    Derevianko, Andrei

    2010-01-01

    Recently invented and demonstrated, optical lattice clocks hold great promise for improving the precision of modern timekeeping. These clocks aim at the 10^-18 fractional accuracy, which translates into a clock that would neither lose or gain a fraction of a second over an estimated age of the Universe. In these clocks, millions of atoms are trapped and interrogated simultaneously, dramatically improving clock stability. Here we discuss the principles of operation of these clocks and, in particular, a novel concept of "magic" trapping of atoms in optical lattices. We also highlight recently proposed microwave lattice clocks and several applications that employ the optical lattice clocks as a platform for precision measurements and quantum information processing.

  7. A circadian clock in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Eelderink-Chen, Zheng; Mazzotta, Gabriella; Sturre, Marcel; Bosman, Jasper; Roenneberg, Till; Merrow, Martha

    2010-01-01

    Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily

  8. Single-transistor-clocked flip-flop

    Science.gov (United States)

    Zhao, Peiyi; Darwish, Tarek; Bayoumi, Magdy

    2005-08-30

    The invention provides a low power, high performance flip-flop. The flip-flop uses only one clocked transistor. The single clocked transistor is shared by the first and second branches of the device. A pulse generator produces a clock pulse to trigger the flip-flop. In one preferred embodiment the device can be made as a static explicit pulsed flip-flop which employs only two clocked transistors.

  9. Association of genetic variantions of circadian clock genes and risk of breast cancer%生物节律调控关键基因遗传变异与乳腺癌患病风险的相关性

    Institute of Scientific and Technical Information of China (English)

    王雯邈; 袁芃; 王佳玉; 马飞; 樊英; 李青; 张频; 徐兵河

    2013-01-01

    目的 研究生物节律调控关键基因Clock和Per2的遗传变异与乳腺癌发病风险的关系.方法 采用病例-对照研究,使用TaqMan荧光定量PCR法检测406例乳腺癌患者和412例健康对照者位于Clock基因(rs2070062)和Per2基因(rs2304672、rs2304669、rs934945)的4个位点的基因多态性,采用非条件Logistic回归模型分析不同基因型或等位基因与乳腺癌发病风险的关系.结果 携带rs2304669-TT基因型者发生乳腺癌的风险是携带rs2304669-CC+CT基因型者的2.33倍(P=0.001).单体型分析的结果也显示,所有含有rs2304669-T等位基因的单体型均可增加乳腺癌的发病风险.而另外3个位点未发现与乳腺癌的发病相关.结论 位于Per2基因上的rs2304669位点可能与乳腺癌的发病风险相关;生物节律调控关键基因Per2的遗传变异会增加乳腺癌的发病风险,可能可以作为乳腺癌易感性的重要分子生物标志物.%Objective To investigate the relationship between genetic variantions of circadian clock genes and risk of breast cancer.Methods A case-control study including 406 breast cancer patients and 412 controls was conducted and genes Clock (rs2070062) and Per2 (rs2304672,rs2304669,rs934945) were genotyped by TaqMan real-time PCR.Unconditional logistic regression model was used to analyze the association between the genetic polymorphisms and breast cancer.Results Individuals with the rs2304669-TT genotype showed significantly increased breast cancer risk with the OR of 2.33 when compared with the individuals with rs2304669-CC and CT genotypes (P =0.001).In addition,the three haplotypes containing the risk T allele of rs2304669 were identified to be associated with increased breast cancer risk.However,it was found that rs2304672,rs2070062 and rs934945 polymorphisms were not related with breast cancer risk.Conclusions The locus rs2304669 on Per2 gene is associated with breast cancer risk.Genetic variation of circadian clock genes may

  10. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    R Daniel Rudic

    2004-11-01

    Full Text Available Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3 and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

  11. Nucleic acid association to human prostasomes.

    Science.gov (United States)

    Olsson, I; Ronquist, G

    1990-01-01

    Human prostasomes isolated from seminal plasma were subjected to phenol extraction and then to absorbance (A) measurements at 260 nm (A260) and 280 nm (A280). The A260/A280 ratio was about 2 for prostasome extract and lower for seminal plasma extract, indicative of the presence of nucleic acid. The ratio of nucleic acid to protein in prostasomes was about 1:100, and the ratio in seminal plasma was 1:1,000. Hence nucleic acid is enriched in prostasomes (compared to seminal plasma of 10). Treatment of prostasome samples with 2% sodium dodecyl sulfate resulted in an efficient dissociation of nucleic acid from prostasomes as demonstrated by electrophoresis. The association of nucleic acids of various sizes (range; 200 to 20,000 base pairs) to prostasome membranes was most probably genuine and not the result of contamination from spermatozoa, erythrocytes, leukocytes, or bacteria. The results of experiments employing nucleic acid-degrading enzymes favored the concept that double-stranded DNA but not RNA is present at the prostasome membrane surface.

  12. Plasmoblastic lymphoma associated with human immunodeficiency virus.

    Science.gov (United States)

    Horváth, Emoke; Krenács, L; Bagdi, Eniko; Pávai, Z; Macarie, I; Nagy, Elod-Erno; Demian, Smaranda

    2008-01-01

    Plasmoblastic lymphoma (PBL) is a subtype of the diffuse large B-cell lymphoma, typically present as extranodal disease associated with human immune deficiency virus (HIV) infection. PBLs are often the initial manifestation of AIDS. Here we present a case of PBL concerning the oral cavity. A 34-year-old woman presented a tumor in the oral cavity that involved the maxilla and gingiva (confirmed by CT-scan). The gingival biopsy showed a massive infiltration by large lymphoid cells with round, vesicular nuclei, prominent nucleoli, fine chromatin and an significant amount of basophilic cytoplasm which express CD79a, CD138, cytoplasmic lambda light chain and LCA, without staining for CD20, CD38, CD3 and CTK. Serological analysis confirmed HIV positivity. PBLs lack most B-lineage markers, but many express CD79a in at least some of the cells, therefore generate difficulties in differential diagnosis. Overall assessment and correlation of the histopathological and immunohistochemical features with the clinical findings and serology investigation are the most helpful diagnostic tools and can lead to the final diagnosis.

  13. [Circadian clocks and energy metabolism: implications for health].

    Science.gov (United States)

    Kessler, K; Pivovarova, O; Pfeiffer, A F H

    2014-04-01

    On behavioural as well as physiological levels our daily life is regulated by the circadian clock - endogenous oscillators present in the hypothalamus and in peripheral tissues - which is believed to have evolved as an adaptation to Earth rotation around the Sun and its consequent 24 h dark-light cycle. Accumulative evidence suggests that the circadian clock plays a pivotal role for energy metabolism and energy homeostasis: many hormones, enzymes and transport systems involved in the regulation of energy metabolism have been shown to display circadian rhythms in their expression, secretion and/or activity patterns. The energy metabolism, in turn, can impact on the circadian clock - a process that is called entrainment. Thus, the circadian clock and energy metabolism are intimately intertwined. So far this interplay and its implications for health have not been understood very well. For health maintenance, however, it seems to be crucial to avoid any desynchronisation between the circadian clock and energy metabolism. Form a clinical point of view this might be important for the treatment of obesity and associated disorders and may lead to new life-style approaches. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Biological clocks: riding the tides.

    Science.gov (United States)

    de la Iglesia, Horacio O; Johnson, Carl Hirschie

    2013-10-21

    Animals with habitats in the intertidal zone often display biological rhythms that coordinate with both the tidal and the daily environmental cycles. Two recent studies show that the molecular components of the biological clocks mediating tidal rhythms are likely different from the phylogenetically conserved components that mediate circadian (daily) rhythms.

  15. A generalized gravitomagnetic clock effect

    CERN Document Server

    Hackmann, Eva

    2014-01-01

    In General Relativity the rotation of a gravitating body like the Earth influences the motion of orbiting test particles or satellites in a non-Newtonian way. This causes e.g. a precession of the orbital plane, known as the Lense-Thirring effect, and a precession of the spin of a gyroscope, known as the Schiff effect. Here we discuss a third effect, first introduced by Cohen and Mashhoon, called the gravitomagnetic clock effect. It describes the difference in proper time of counter revolving clocks after a revolution of $2\\pi$. For two clocks on counter rotating equatorial circular orbits around the Earth the effect is about $10^{-7}$ seconds per revolution, which is quite large. We introduce a general relativistic definition of the gravitomagnetic clock effect which is valid for arbitrary pairs of orbits. This includes rotations in the same direction and different initial conditions, which is crucial if the effect can be detected with existing satellites or with payloads on non-dedicated missions. We also de...

  16. Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis.

    Science.gov (United States)

    Kwon, Young-Ju; Park, Mi-Jeong; Kim, Sang-Gyu; Baldwin, Ian T; Park, Chung-Mo

    2014-05-19

    The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5' splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress

  17. Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock.

    Science.gov (United States)

    Sakamoto, Kensuke; Norona, Frances E; Alzate-Correa, Diego; Scarberry, Daniel; Hoyt, Kari R; Obrietan, Karl

    2013-05-22

    The CREB/CRE transcriptional pathway has been implicated in circadian clock timing and light-evoked clock resetting. To date, much of the work on CREB in circadian physiology has focused on how changes in the phosphorylation state of CREB regulate the timing processes. However, beyond changes in phosphorylation, CREB-dependent transcription can also be regulated by the CREB coactivator CRTC (CREB-regulated transcription coactivator), also known as TORC (transducer of regulated CREB). Here we profiled both the rhythmic and light-evoked regulation of CRTC1 and CRTC2 in the murine suprachiasmatic nucleus (SCN), the locus of the master mammalian clock. Immunohistochemical analysis revealed rhythmic expression of CRTC1 in the SCN. CRTC1 expression was detected throughout the dorsoventral extent of the SCN in the middle of the subjective day, with limited expression during early night, and late night expression levels intermediate between mid-day and early night levels. In contrast to CRTC1, robust expression of CRTC2 was detected during both the subjective day and night. During early and late subjective night, a brief light pulse induced strong nuclear accumulation of CRTC1 in the SCN. In contrast with CRTC1, photic stimulation did not affect the subcellular localization of CRTC2 in the SCN. Additionally, reporter gene profiling and chromatin immunoprecipitation analysis indicated that CRTC1 was associated with CREB in the 5' regulatory region of the period1 gene, and that overexpression of CRTC1 leads to a marked upregulation in period1 transcription. Together, these data raise the prospect that CRTC1 plays a role in fundamental aspects of SCN clock timing and entrainment.

  18. Unraveling the circadian clock in Arabidopsis.

    Science.gov (United States)

    Wang, Xiaoxue; Ma, Ligeng

    2013-02-01

    The circadian clock is an endogenous timing system responsible for coordinating an organism's biological processes with its environment. Interlocked transcriptional feedback loops constitute the fundamental architecture of the circadian clock. In Arabidopsis, three feedback loops, the core loop, morning loop and evening loop, comprise a network that is the basis of the circadian clock. The components of these three loops are regulated in distinct ways, including transcriptional, post-transcriptional and posttranslational mechanisms. The discovery of the DNA-binding and repressive activities of TOC1 has overturned our initial concept of its function in the circadian clock. The alternative splicing of circadian clock-related genes plays an essential role in normal functioning of the clock and enables organisms to sense environmental changes. In this review, we describe the regulatory mechanisms of the circadian clock that have been identified in Arabidopsis.

  19. Circadian clock, cell cycle and cancer

    Directory of Open Access Journals (Sweden)

    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.

  20. Reading the Molecular Clock.

    Science.gov (United States)

    McKean, Kevin

    1983-01-01

    Suggesting that the evolutionary record may be written in proteins and genes, discusses research in which species are compared by immunology, DNA, and radioimmunoassay. Molecular studies show that DNA from humans and chimps is 98 percent identical, a degree of similarity usually occurring only among animals of the same genus. (JN)

  1. Signaling to the circadian clock: plasticity by chromatin remodeling.

    Science.gov (United States)

    Nakahata, Yasukazu; Grimaldi, Benedetto; Sahar, Saurabh; Hirayama, Jun; Sassone-Corsi, Paolo

    2007-04-01

    Circadian rhythms govern several fundamental physiological functions in almost all organisms, from prokaryotes to humans. The circadian clocks are intrinsic time-tracking systems with which organisms can anticipate environmental changes and adapt to the appropriate time of day. In mammals, circadian rhythms are generated in pacemaker neurons within the suprachiasmatic nuclei (SCN), a small area of the hypothalamus, and are entrained by environmental cues, principally light. Disruption of these rhythms can profoundly influence human health, being linked to depression, insomnia, jet lag, coronary heart disease and a variety of neurodegenerative disorders. It is now well established that circadian clocks operate via transcriptional feedback autoregulatory loops that involve the products of circadian clock genes. Furthermore, peripheral tissues also contain independent clocks, whose oscillatory function is orchestrated by the SCN. The complex program of gene expression that characterizes circadian physiology involves dynamic changes in chromatin transitions. These remodeling events are therefore of great importance to ensure the proper timing and extent of circadian regulation. How signaling influences chromatin remodeling through histone modifications is therefore highly relevant in the context of circadian oscillation. Recent advances in the field have revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism.

  2. Cycles in spatial and temporal chromosomal organization driven by the circadian clock.

    Science.gov (United States)

    Aguilar-Arnal, Lorena; Hakim, Ofir; Patel, Vishal R; Baldi, Pierre; Hager, Gordon L; Sassone-Corsi, Paolo

    2013-10-01

    Dynamic transitions in the epigenome have been associated with regulated patterns of nuclear organization. The accumulating evidence that chromatin remodeling is implicated in circadian function prompted us to explore whether the clock may control nuclear architecture. We applied the chromosome conformation capture on chip technology in mouse embryonic fibroblasts (MEFs) to demonstrate the presence of circadian long-range interactions using the clock-controlled Dbp gene as bait. The circadian genomic interactions with Dbp were highly specific and were absent in MEFs whose clock was disrupted by ablation of the Bmal1 gene (also called Arntl). We establish that the Dbp circadian interactome contains a wide variety of genes and clock-related DNA elements. These findings reveal a previously unappreciated circadian and clock-dependent shaping of the nuclear landscape.

  3. A functional link between rhythmic changes in chromatin structure and the Arabidopsis biological clock.

    Science.gov (United States)

    Perales, Mariano; Más, Paloma

    2007-07-01

    Circadian clocks rhythmically coordinate biological processes in resonance with the environmental cycle. The clock function relies on negative feedback loops that generate 24-h rhythms in multiple outputs. In Arabidopsis thaliana, the clock component TIMING OF CAB EXPRESSION1 (TOC1) integrates the environmental information to coordinate circadian responses. Here, we use chromatin immunoprecipitation as well as physiological and luminescence assays to demonstrate that proper photoperiodic phase of TOC1 expression is important for clock synchronization of plant development with the environment. Our studies show that TOC1 circadian induction is accompanied by clock-controlled cycles of histone acetylation that favor transcriptionally permissive chromatin structures at the TOC1 locus. At dawn, TOC1 repression relies on the in vivo circadian binding of the clock component CIRCADIAN CLOCK ASSOCIATED1 (CCA1), while histone deacetylase activities facilitate the switch to repressive chromatin structures and contribute to the declining phase of TOC1 waveform around dusk. The use of cca1 late elongated hypocotyl double mutant and CCA1-overexpressing plants suggests a highly repressing function of CCA1, antagonizing H3 acetylation to regulate TOC1 mRNA abundance. The chromatin remodeling activities relevant at the TOC1 locus are distinctively modulated by photoperiod, suggesting a mechanism by which the clock sets the phase of physiological and developmental outputs.

  4. Entanglement of quantum clocks through gravity.

    Science.gov (United States)

    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.

  5. 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...5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES...Austrian Academy of Sciences Viktor Kaplan StraÃe 2, A-2700 Wiener Neustadt, Austria 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING

  6. Inertial Frames and Clock Rates

    CERN Document Server

    Kak, Subhash

    2012-01-01

    This article revisits the historiography of the problem of inertial frames. Specifically, the case of the twins in the clock paradox is considered to see that some resolutions implicitly assume inertiality for the non-accelerating twin. If inertial frames are explicitly identified by motion with respect to the large scale structure of the universe, it makes it possible to consider the relative inertiality of different frames.

  7. Microresonator Frequency Comb Optical Clock

    Science.gov (United States)

    2014-07-22

    Number Microresonator frequency comb optical clock Block 13: Supplementary Note © 2014 . Published in Optica , Vol. Ed. 0 1, (1) (2014), (, (1). DoD...Oscillators. http://dx.doi.org/10.1364/ OPTICA .1.000010 1. INTRODUCTION Optical frequency combs enable extraordinary measurement precision and accuracy...1, No. 1 / July 2014 / Optica 10 deviation for 1 s averaging is completely dominated by the Rb reference, and the microcomb contribution is only ɚ

  8. 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.

  9. The Increase in Signaling by Kisspeptin Neurons in the Preoptic Area and Associated Changes in Clock Gene Expression That Trigger the LH Surge in Female Rats Are Dependent on the Facilitatory Action of a Noradrenaline Input.

    Science.gov (United States)

    Kalil, Bruna; Ribeiro, Aline B; Leite, Cristiane M; Uchôa, Ernane T; Carolino, Ruither O; Cardoso, Thais S R; Elias, Lucila L K; Rodrigues, José A; Plant, Tony M; Poletini, Maristela O; Anselmo-Franci, Janete A

    2016-01-01

    In rodents, kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) of the preoptic area are considered to provide a major stimulatory input to the GnRH neuronal network that is responsible for triggering the preovulatory LH surge. Noradrenaline (NA) is one of the main modulators of GnRH release, and NA fibers are found in close apposition to kisspeptin neurons in the RP3V. Our objective was to interrogate the role of NA signaling in the kisspeptin control of GnRH secretion during the estradiol induced LH surge in ovariectomized rats, using prazosin, an α1-adrenergic receptor antagonist. In control rats, the estradiol-induced LH surge at 17 hours was associated with a significant increase in GnRH and kisspeptin content in the median eminence with the increase in kisspeptin preceding that of GnRH and LH. Prazosin, administered 5 and 3 hours prior to the predicted time of the LH surge truncated the LH surge and abolished the rise in GnRH and kisspeptin in the median eminence. In the preoptic area, prazosin blocked the increases in Kiss1 gene expression and kisspeptin content in association with a disruption in the expression of the clock genes, Per1 and Bmal1. Together these findings demonstrate for the first time that NA modulates kisspeptin synthesis in the RP3V through the activation of α1-adrenergic receptors prior to the initiation of the LH surge and indicate a potential role of α1-adrenergic signaling in the circadian-controlled pathway timing of the preovulatory LH surge.

  10. Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition

    Directory of Open Access Journals (Sweden)

    Ramkumar Menon

    2017-08-01

    Full Text Available Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species—indicative of different phylogenetic clocks and alarms—but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen-activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system.

  11. Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition.

    Science.gov (United States)

    Menon, Ramkumar; Mesiano, Sam; Taylor, Robert N

    2017-01-01

    Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species-indicative of different phylogenetic clocks and alarms-but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen-activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers) that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system.

  12. Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition

    Science.gov (United States)

    Menon, Ramkumar; Mesiano, Sam; Taylor, Robert N.

    2017-01-01

    Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species—indicative of different phylogenetic clocks and alarms—but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen-activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers) that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system. PMID:28861041

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

    Directory of Open Access Journals (Sweden)

    Aleix Ribas-Latre

    2016-03-01

    Major conclusions: Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors. Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.

  14. Diabetes and cardiovascular disease: related disorders created by disturbances in the endogenous clock.

    Science.gov (United States)

    Scott, Eleanor M; Carter, A M; Grant, Peter J

    2008-11-01

    The factors underpinning the development of type 2 diabetes mirror closely the presentation of atherothrombotic risk factors that enhance risk of macrovascular disease. It has been postulated that this relationship is so tight as to indicate that diabetes and cardiovascular disease are the same condition with common genetic and environmental antecedents ('the common soil hypothesis'). The huge Increase in prevalence of type 2 diabetes in the Asia-Pacific region in recent years has raised serious concerns regarding the cardiovascular consequences for these populations. For example, in the UK, subjects of S. Asian origin have a higher prevalence of type 2 diabetes with a relative risk of macrovascular disease of -1.5 compared to the Indigenous population. Current opinion favours the view that the development of obesity is associated with an insulin resistant phenotype that promotes vascular risk. Our endogenous clock is regulated centrally in the hypothalamus by light exposure and in peripheral tissues to place our metabolic needs in time with day length and the seasons. Evidence from animal and cellular studies with early data from human studies indicates that disruption of the endogenous clock as can occur with obesity, is associated with a metabolic syndrome phenotype. The adaption of western lifestyles by S Asian subjects may promote disruption of circadian rhythms with associated increases in both diabetes and cardiovascular disease.

  15. Globicatella sanguinis Meningitis Associated with Human Carriage▿

    Science.gov (United States)

    Héry-Arnaud, Geneviève; Doloy, Alexandra; Ansart, Séverine; Le Lay, Geneviève; Le Flèche-Matéos, Anne; Seizeur, Romuald; Garré, Michel; Payan, Christopher; Bouvet, Anne

    2010-01-01

    Globicatella sanguinis is a rare cause of acute meningitis. We demonstrated human carriage of Globicatella by identifying cefotaxime-resistant strains in groin and rectal specimens 9 months after invasive infection. The pathogenic strain isolated from the cerebrospinal fluid and the carriage strains were accurately identified by sodA gene sequence analysis. PMID:20147641

  16. The Implementation of E1 Clock Recovery

    Directory of Open Access Journals (Sweden)

    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.

  17. The circadian clock coordinates ribosome biogenesis.

    Directory of Open Access Journals (Sweden)

    Céline Jouffe

    Full Text Available Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.

  18. Association of human immunodeficiency virus-induced immunosuppression with human papillomavirus infection and cervical intraepithelial neoplasia.

    Science.gov (United States)

    Henry, M J; Stanley, M W; Cruikshank, S; Carson, L

    1989-02-01

    Human papillomavirus infection plays an important causal role in cervical intraepithelial neoplasia and carcinoma. The rate of infection with human papillomavirus as well as the incidence of cervical intraepithelial neoplasia and carcinoma are increased in immunosuppressed patients. We report a possible association between infection with human immunodeficiency virus and cervical intraepithelial neoplasia with human papillomavirus infection.

  19. Optical to microwave clock frequency ratios with a nearly continuous strontium optical lattice clock

    CERN Document Server

    Lodewyck, Jérôme; Bookjans, Eva; Robyr, Jean-Luc; Shi, Chunyan; Vallet, Grégoire; Targat, Rodolphe Le; Nicolodi, Daniele; Coq, Yann Le; Guéna, Jocelyne; Abgrall, Michel; Rosenbusch, Peter; Bize, Sébastien

    2016-01-01

    Optical lattice clocks are at the forefront of frequency metrology. Both the instability and systematic uncertainty of these clocks have been reported to be two orders of magnitude smaller than the best microwave clocks. For this reason, a redefinition of the SI second based on optical clocks seems possible in the near future. However, the operation of optical lattice clocks has not yet reached the reliability that microwave clocks have achieved so far. In this paper, we report on the operation of a strontium optical lattice clock that spans several weeks, with more than 80% uptime. We make use of this long integration time to demonstrate a reproducible measurement of frequency ratios between the strontium clock transition and microwave Cs primary and Rb secondary frequency standards.

  20. Collisionally induced atomic clock shifts and correlations

    Energy Technology Data Exchange (ETDEWEB)

    Band, Y. B.; Osherov, I. [Departments of Chemistry and Electro-Optics and the Ilse Katz Center for Nano-Science, Ben-Gurion University, Beer-Sheva 84105 (Israel)

    2011-07-15

    We develop a formalism to incorporate exchange symmetry considerations into the calculation of collisional frequency shifts for atomic clocks using a density-matrix formalism. The formalism is developed for both fermionic and bosonic atomic clocks. Numerical results for a finite-temperature {sup 87}Sr {sup 1}S{sub 0} (F=9/2) atomic clock in a magic wavelength optical lattice are presented.

  1. 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…

  2. Distinction between Clock and Time, and a Suggested Experiment with Different Types of Clocks in GPS

    Science.gov (United States)

    Smarandache, Florentin

    2013-03-01

    The clock is an instrument for measuring the time, instrument that may not run perfectly (accurately) under certain conditions (like, say, in strong electromagnetic field, in strong gravitational field, in extremely high or low temperature, pressure, etc.), but this does not mean that time itself runs slower or faster as Einstein's Theory of Relativity asserts. We are referring to an absolute time, i.e. time measured not with respect to ether or non-ether, but with respect to an absolute mathematical reference frame. Several types of clocks could run at a more slowly rate in a moving frame of reference than other types of clocks; it depends on the construction material and functioning principle of each type of clock. Relativists say that ``gravity slows time''. This is incorrect, since actually gravity slows today's types of clocks. And one type of clock is slowed more or less than another type of clock. Not only gravity but other (electric, magnetic, etc.) fields or various medium composition elements or structures may slow or accelerate clocks that are in that medium. The clocks used today in the satellites for the GPS necessitate a correction with respect to the Earth clocks. But in the future, when new types of clocks will be built based on different construction material and functioning principle, the correction of the GPS clocks would be different. In order to make the distinction between ``clock'' and ``time'', we suggest a Experiment # 1 with different types of clocks for the GPS clocks, in order to prove that the resulted dilation and contraction factors are different from those obtained with today's cesium atomic clock.

  3. Song I-Yeong's Armillary Clock

    Science.gov (United States)

    Kim, Sang Hyuk; Lee, Yong Sam

    In 1669 (the 10th year of the reign of King Hyeonjong), Song I-Yeong (宋以穎, 1619-1692), who was a professor of astronomy at Gwansanggam (Bureau of Astronomy), developed the armillary clock which uses the weight power system of an alarm clock. The armillary clock is a unique astronomical clock that combines the traditional armillary sphere of Joseon and the principle of a Western alarm clock. Song I-Yeong's armillary clock was repaired in 1687-1688 according to the records, and since then not much is known about the history of the armillary clock. After many years, in the early 1930s which was the Japanese colonial era, Inchon (仁村) Kim Seong-Su (金性洙, 1891-1955) purchased the armillary clock at the Insa-dong antique street and donated to the Korea University Museum of the present time (designated as National Treasure No. 230 in 1985). Currently, the armillary clock is not in operation because some of the parts are damaged or lost.

  4. Clock Genes Explain a Large Proportion of Phenotypic Variance in Systolic Blood Pressure and This Control Is Not Modified by Environmental Temperature.

    Science.gov (United States)

    Dashti, Hassan S; Aslibekyan, Stella; Scheer, Frank A J L; Smith, Caren E; Lamon-Fava, Stefania; Jacques, Paul; Lai, Chao-Qiang; Tucker, Katherine L; Arnett, Donna K; Ordovás, José M

    2016-01-01

    Diurnal variation in blood pressure (BP) is regulated, in part, by an endogenous circadian clock; however, few human studies have identified associations between clock genes and BP. Accounting for environmental temperature may be necessary to correct for seasonal bias. We examined whether environmental temperature on the day of participants' assessment was associated with BP, using adjusted linear regression models in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) (n = 819) and the Boston Puerto Rican Health Study (BPRHS) (n = 1,248) cohorts. We estimated phenotypic variance in BP by 18 clock genes and examined individual single-nucleotide polymorphism (SNP) associations with BP using an additive genetic model, with further consideration of environmental temperature. In GOLDN, each additional 1 °C increase in environmental temperature was associated with 0.18 mm Hg lower systolic BP [SBP; β ± SE = -0.18 ± 0.05 mm Hg; P = 0.0001] and 0.10mm Hg lower diastolic BP [DBP; -0.10 ± 0.03 mm Hg; P = 0.001]. Similar results were seen in the BPRHS for SBP only. Clock genes explained a statistically significant proportion of the variance in SBP [V G/V P ± SE = 0.071 ± 0.03; P = 0.001] in GOLDN, but not in the BPRHS, and we did not observe associations between individual SNPs and BP. Environmental temperature did not influence the identified genetic associations. We identified clock genes that explained a statistically significant proportion of the phenotypic variance in SBP, supporting the importance of the circadian pathway underlying cardiac physiology. Although temperature was associated with BP, it did not affect results with genetic markers in either study. Therefore, it does not appear that temperature measures are necessary for interpreting associations between clock genes and BP. Trials related to this study were registered at clinicaltrials.gov as NCT00083369 (Genetic and Environmental Determinants of Triglycerides) and NCT01231958 (Boston Puerto

  5. Recent progress in engineering human-associated microbiomes.

    Science.gov (United States)

    Yaung, Stephanie J; Church, George M; Wang, Harris H

    2014-01-01

    Recent progress in molecular biology and genetics opens up the possibility of engineering a variety of biological systems, from single-cellular to multicellular organisms. The consortia of microbes that reside on the human body, the human-associated microbiota, are particularly interesting as targets for forward engineering and manipulation due to their relevance in health and disease. New technologies in analysis and perturbation of the human microbiota will lead to better diagnostic and therapeutic strategies against diseases of microbial origin or pathogenesis. Here, we discuss recent advances that are bringing us closer to realizing the true potential of an engineered human-associated microbial community.

  6. Clock-controlled mir-142-3p can target its activator, Bmal1

    Directory of Open Access Journals (Sweden)

    Tan Xiaochao

    2012-09-01

    Full Text Available Abstract Background microRNAs (miRNAs are shown to be involved in the regulation of circadian clock. However, it remains largely unknown whether miRNAs can regulate the core clock genes (Clock and Bmal1. Results In this study, we found that mir-142-3p directly targeted the 3’UTR of human BMAL1 and mouse Bmal1. The over-expression (in 293ET and NIH3T3 cells and knockdown (in U87MG cells of mir-142-3p reduced and up-regulated the Bmal1/BMAL1 mRNA and protein levels, respectively. Moreover, the expression level of mir-142-3p oscillated in serum-shocked NIH3T3 cells and the results of ChIP and luciferase reporter assays suggested that the expression of mir-142-3p was directly controlled by CLOCK/BMAL1 heterodimers in NIH3T3 cells. Conclusions Our study demonstrates that mir-142-3p can directly target the 3’UTR of Bmal1. In addition, the expression of mir-142-3p is controlled by CLOCK/BMAL1 heterodimers, suggesting a potential negative feedback loop consisting of the miRNAs and the core clock genes. These findings open new perspective for studying the molecular mechanism of circadian clock.

  7. Circadian neurons in the lateral habenula: Clocking motivated behaviors.

    Science.gov (United States)

    Mendoza, Jorge

    2017-06-28

    The main circadian clock in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN), however, central timing mechanisms are also present in other brain structures beyond the SCN. The lateral habenula (LHb), known for its important role in the regulation of the monoaminergic system, contains such a circadian clock whose molecular and cellular mechanisms as well as functional role are not well known. However, since monoaminergic systems show circadian activity, it is possible that the LHb-clock's role is to modulate the rhythmic activity of the dopamine, serotonin and norephinephrine systems, and associated behaviors. Moreover, the LHb is involved in different pathological states such as depression, addiction and schizophrenia, states in which sleep and circadian alterations have been reported. Thus, perturbations of circadian activity in the LHb might, in part, be a cause of these rhythmic alterations in psychiatric ailments. In this review the current state of the LHb clock and its possible implications in the control of monoaminergic systems rhythms, motivated behaviors (e.g., feeding, drug intake) and depression (with circadian disruptions and altered motivation) will be discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. A molecular clock for autoionization decay

    Science.gov (United States)

    Medišauskas, Lukas; Bello, Roger Y.; Palacios, Alicia; González-Castrillo, Alberto; Morales, Felipe; Plimak, Lev; Smirnova, Olga; Martín, Fernando; Ivanov, Misha Yu

    2017-07-01

    The ultrafast decay of highly excited electronic states is resolved with a molecular clock technique, using the vibrational motion associated to the ionic bound states as a time-reference. We demonstrate the validity of the method in the context of autoionization of the hydrogen molecule, where nearly exact full dimensional ab-initio calculations are available. The vibrationally resolved photoionization spectrum provides a time-energy mapping of the autoionization process into the bound states that is used to fully reconstruct the decay in time. A resolution of a fraction of the vibrational period is achieved. Since no assumptions are made on the underlying coupled electron-nuclear dynamics, the reconstruction procedure can be applied to describe the general problem of the decay of highly excited states in other molecular targets.

  9. High accuracy correction of blackbody radiation shift in an optical lattice clock

    CERN Document Server

    Middelmann, Thomas; Lisdat, Christian; Sterr, Uwe

    2012-01-01

    We have determined the frequency shift that blackbody radiation is inducing on the $5s^2$ $^1$S$_0$ -- $5s5p$ $^3$P$_0$ clock transition in strontium. Previously its uncertainty limited the uncertainty of strontium lattice clocks to $1\\times10^{-16}$. Now the uncertainty associated to the black body radiation shift correction translates to $5\\times 10^{-18}$ relative frequency uncertainty at room temperature. Our evaluation is based on a measurement of the differential dc-polarizability of the two clock states and on a modeling of the dynamic contribution using this value and experimental data for other atomic properties.

  10. Uncertainty principle in larmor clock

    Institute of Scientific and Technical Information of China (English)

    QIAO Chuan; REN Zhong-Zhou

    2011-01-01

    It is well known that the spin operators of a quantum particle must obey uncertainty relations.We use the uncertainty principle to study the Larmor clock.To avoid breaking the uncertainty principle,Larmor time can be defined as the ratio of the phase difference between a spin-up particle and a spin-down particle to the corresponding Larmor frequency.The connection between the dwell time and the Larmor time has also been confirmed.Moreover,the results show that the behavior of the Larmor time depends on the height and width of the barrier.

  11. Gigabit Ethernet Asynchronous Clock Compensation FIFO

    Science.gov (United States)

    Duhachek, Jeff

    2012-01-01

    Clock compensation for Gigabit Ethernet is necessary because the clock recovered from the 1.25 Gb/s serial data stream has the potential to be 200 ppm slower or faster than the system clock. The serial data is converted to 10-bit parallel data at a 125 MHz rate on a clock recovered from the serial data stream. This recovered data needs to be processed by a system clock that is also running at a nominal rate of 125 MHz, but not synchronous to the recovered clock. To cross clock domains, an asynchronous FIFO (first-in-first-out) is used, with the write pointer (wprt) in the recovered clock domain and the read pointer (rptr) in the system clock domain. Because the clocks are generated from separate sources, there is potential for FIFO overflow or underflow. Clock compensation in Gigabit Ethernet is possible by taking advantage of the protocol data stream features. There are two distinct data streams that occur in Gigabit Ethernet where identical data is transmitted for a period of time. The first is configuration, which happens during auto-negotiation. The second is idle, which occurs at the end of auto-negotiation and between every packet. The identical data in the FIFO can be repeated by decrementing the read pointer, thus compensating for a FIFO that is draining too fast. The identical data in the FIFO can also be skipped by incrementing the read pointer, which compensates for a FIFO draining too slowly. The unique and novel features of this FIFO are that it works in both the idle stream and the configuration streams. The increment or decrement of the read pointer is different in the idle and compensation streams to preserve disparity. Another unique feature is that the read pointer to write pointer difference range changes between compensation and idle to minimize FIFO latency during packet transmission.

  12. Timing of molt of barn swallows is delayed in a rare Clock genotype

    Directory of Open Access Journals (Sweden)

    Nicola Saino

    2013-02-01

    Full Text Available Photoperiodic responses are major factors entraining circannual life-cycles, functioning to adaptively synchronize annual routines to seasonal fluctuations in ecological conditions. Photoperiodism in physiology and behaviour is enforced by genes, including the vertebrate Clock orthologues, which are associated, for example, with phenology of migration in fish and breeding in birds. However, the role of Clock in photoperiodic plumage molt processes is unknown. We analyzed variation in molt schedules in relation to Clock genotype, using the long-distance migratory barn swallow (Hirundo rustica as a model and by identifying males and females using molecular sexing techniques. Consistently with previous studies, we found one very common (Q7 and two rare (Q6, Q8 variants of a functionally significant Clock polyglutamine repeat. Molt schedules of primary wing feathers of swallows during their wintering period in Nigeria differed among Clock genotypes: rare (1.1% Q7/Q8 heterozygotes had significantly delayed molt compared to the other genotypes. Molt schedules did not differ between males and females, and no differential association between molt and Clock in relation to sex emerged. The same rare Clock genotype that exhibited delayed breeding in Europe was here found to delay molt in Africa. Though based on a limited number of Q7/Q8 individuals from an otherwise very large sample, these novel results suggest that Clock is involved in the photoperiodic control of both molt and breeding, potentially also via reciprocal carry-over effects. If confirmed in species with higher Clock polymorphism, present results may have far-reaching consequences for the study of photoperiodic control of molt and expression of annual routines.

  13. Arabidopsis circadian clock and photoperiodism: time to think about location

    OpenAIRE

    Imaizumi, Takato

    2009-01-01

    Plants possess a circadian clock that enables them to coordinate internal biological events with external daily changes. Recent studies in Arabidopsis revealed that tissue specific clock components exist and that the clock network architecture also varies within different organs. These findings indicate that the makeup of circadian clock(s) within a plant is quite variable. Plants utilize the circadian clock to measure day-length changes for regulating seasonal responses, such as flowering. T...

  14. Human Health Effects Associated with Exposure to Toxic Cyanobacteria

    Science.gov (United States)

    Reports of toxic cyanobacteria blooms are increasing worldwide. Warming and eutrophic surface water systems support the development of blooms. We examine the evidence for adverse human health effects associated with exposure to toxic blooms in drinking water, recreational water a...

  15. Human Health Effects Associated with Exposure to Toxic Cyanobacteria

    Science.gov (United States)

    Reports of toxic cyanobacteria blooms are increasing worldwide. Warming and eutrophic surface water systems support the development of blooms. We examine the evidence for adverse human health effects associated with exposure to toxic blooms in drinking water, recreational water a...

  16. Noradrenergic enhancement of associative fear memory in humans

    NARCIS (Netherlands)

    Soeter, M.; Kindt, M.

    2011-01-01

    Ample evidence in animals and humans supports the noradrenergic modulation in the formation of emotional memory. However, in humans the effects of stress on emotional memory are traditionally investigated by declarative memory tests (e.g., recall, recognition) for non-associative emotional stimuli (

  17. 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.

  18. 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).

  19. 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...

  20. Internal Clock Drift Estimation in Computer Clusters

    Directory of Open Access Journals (Sweden)

    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.

  1. Temperature influences in receiver clock modelling

    Science.gov (United States)

    Wang, Kan; Meindl, Michael; Rothacher, Markus; Schoenemann, Erik; Enderle, Werner

    2016-04-01

    In Precise Point Positioning (PPP), hardware delays at the receiver site (receiver, cables, antenna, …) are always difficult to be separated from the estimated receiver clock parameters. As a result, they are partially or fully contained in the estimated "apparent" clocks and will influence the deterministic and stochastic modelling of the receiver clock behaviour. In this contribution, using three years of data, the receiver clock corrections of a set of high-precision Hydrogen Masers (H-Masers) connected to stations of the ESA/ESOC network and the International GNSS Service (IGS) are firstly characterized concerning clock offsets, drifts, modified Allan deviations and stochastic parameters. In a second step, the apparent behaviour of the clocks is modelled with the help of a low-order polynomial and a known temperature coefficient (Weinbach, 2013). The correlations between the temperature and the hardware delays generated by different types of antennae are then analysed looking at daily, 3-day and weekly time intervals. The outcome of these analyses is crucial, if we intend to model the receiver clocks in the ground station network to improve the estimation of station-related parameters like coordinates, troposphere zenith delays and ambiguities. References: Weinbach, U. (2013) Feasibility and impact of receiver clock modeling in precise GPS data analysis. Dissertation, Leibniz Universität Hannover, Germany.

  2. Atomic clocks with suppressed blackbody radiation shift

    CERN Document Server

    Yudin, V I; Okhapkin, M V; Bagayev, S N; Tamm, Chr; Peik, E; Huntemann, N; Mehlstaubler, T E; Riehle, F

    2011-01-01

    We develop a nonstandard concept of atomic clocks where the blackbody radiation shift (BBRS) and its temperature fluctuations can be dramatically suppressed (by one to three orders of magnitude) independent of the environmental temperature. The suppression is based on the fact that in a system with two accessible clock transitions (with frequencies $\

  3. A circadian clock in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Eelderink-Chen, Zheng; Mazzotta, Gabriella; Sturre, Marcel; Bosman, Jasper; Roenneberg, Till; Merrow, Martha

    2010-01-01

    Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily cha

  4. 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

  5. "Molecular Clock" Analogs: A Relative Rates Exercise

    Science.gov (United States)

    Wares, John P.

    2008-01-01

    Although molecular clock theory is a commonly discussed facet of evolutionary biology, undergraduates are rarely presented with the underlying information of how this theory is examined relative to empirical data. Here a simple contextual exercise is presented that not only provides insight into molecular clocks, but is also a useful exercise for…

  6. Progress of the ~(87)Rb Fountain Clock

    Institute of Scientific and Technical Information of China (English)

    ZHOU Zi-Chao; WEI Rong; SHI Chun-Yan; LV De-Sheng; LI Tang; WANG Yu-Zhu

    2009-01-01

    A fountain atomic clock based on cold ~(87)Rb atoms has been in operation in our laboratory for several months.We therefore report the design of the rubidium fountain clock including its physical package,optical system and daily operation.Ramsey fringes have been attained with the signal to noise ratio of about 100.

  7. Single electron relativistic clock interferometer

    Science.gov (United States)

    Bushev, P. A.; Cole, J. H.; Sholokhov, D.; Kukharchyk, N.; Zych, M.

    2016-09-01

    Although time is one of the fundamental notions in physics, it does not have a unique description. In quantum theory time is a parameter ordering the succession of the probability amplitudes of a quantum system, while according to relativity theory each system experiences in general a different proper time, depending on the system's world line, due to time dilation. It is therefore of fundamental interest to test the notion of time in the regime where both quantum and relativistic effects play a role, for example, when different amplitudes of a single quantum clock experience different magnitudes of time dilation. Here we propose a realization of such an experiment with a single electron in a Penning trap. The clock can be implemented in the electronic spin precession and its time dilation then depends on the radial (cyclotron) state of the electron. We show that coherent manipulation and detection of the electron can be achieved already with present day technology. A single electron in a Penning trap is a technologically ready platform where the notion of time can be probed in a hitherto untested regime, where it requires a relativistic as well as quantum description.

  8. CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock.

    Directory of Open Access Journals (Sweden)

    Brigitte Grima

    Full Text Available Eukaryotic circadian clocks rely on transcriptional feedback loops. In Drosophila, the PERIOD (PER and TIMELESS (TIM proteins accumulate during the night, inhibit the activity of the CLOCK (CLK/CYCLE (CYC transcriptional complex, and are degraded in the early morning. The control of PER and TIM oscillations largely depends on post-translational mechanisms. They involve both light-dependent and light-independent pathways that rely on the phosphorylation, ubiquitination, and proteasomal degradation of the clock proteins. SLMB, which is part of a CULLIN-1-based E3 ubiquitin ligase complex, is required for the circadian degradation of phosphorylated PER. We show here that CULLIN-3 (CUL-3 is required for the circadian control of PER and TIM oscillations. Expression of either Cul-3 RNAi or dominant negative forms of CUL-3 in the clock neurons alters locomotor behavior and dampens PER and TIM oscillations in light-dark cycles. In constant conditions, CUL-3 deregulation induces behavioral arrhythmicity and rapidly abolishes TIM cycling, with slower effects on PER. CUL-3 affects TIM accumulation more strongly in the absence of PER and forms protein complexes with hypo-phosphorylated TIM. In contrast, SLMB affects TIM more strongly in the presence of PER and preferentially associates with phosphorylated TIM. CUL-3 and SLMB show additive effects on TIM and PER, suggesting different roles for the two ubiquitination complexes on PER and TIM cycling. This work thus shows that CUL-3 is a new component of the Drosophila clock, which plays an important role in the control of TIM oscillations.

  9. Human-associated fungi in deep subseafloor sediment?

    Science.gov (United States)

    Fulfer, V. M.; Kirkpatrick, J. B.; D'Hondt, S.

    2015-12-01

    Recent studies have reported fungi in marine sediment samples from depths as great as 1740 meters below seafloor (mbsf) (Rédou et al., 2014). Such studies have utilized a variety of techniques to identify fungi, including cultivation of isolates, amplicon sequencing, and metagenomics. Six recent studies of marine sediment collectively identify nearly 100 fungal taxa at the genus and species levels (Damare et al., 2006; Lai et al., 2007; Edgcomb et al., 2010; Singh et al., 2010; Orsi et al., 2013; Rédou et al., 2014). Known marine taxa are rarely identified by these studies. For individual studies with more than two taxa, between 16% and 57% of the fungal taxa are human microflora or associated with human environments (e.g., human skin or indoor air). For example, three of the six studies identified Malassezia species that are common skin inhabitants of humans and dogs. Although human-associated taxa have been identified in both shallow and deep sediment, they pose a particularly acute problem for deep subseafloor samples, where claims of a eukaryotic deep biosphere are most striking; depending on the study, 25% to 38% of species identified in sediment taken at depths greater than 40 meters are human-associated. Only one to three species have been reported from each of the four samples taken at depths greater than one km (eight species total; Rédou et al., 2014). Of these eight species, three are human-associated. This ubiquity of human-associated microflora is very problematic for interpretations of an indigenous deep subseafloor fungal community; either human-associated taxa comprise a large fraction of marine sedimentary fungi, or sample and analytical contamination is so widespread that the extent and ubiquity of a deep subseafloor fungal community remains uncertain. This highlights the need for stringent quality control measures throughout coring, sampling, and recovery of marine sediment, and when cultivating, extracting, and/or sequencing fungi from

  10. Laser controlled atom source for optical clocks

    Science.gov (United States)

    Kock, Ole; He, Wei; Świerad, Dariusz; Smith, Lyndsie; Hughes, Joshua; Bongs, Kai; Singh, Yeshpal

    2016-11-01

    Precision timekeeping has been a driving force in innovation, from defining agricultural seasons to atomic clocks enabling satellite navigation, broadband communication and high-speed trading. We are on the verge of a revolution in atomic timekeeping, where optical clocks promise an over thousand-fold improvement in stability and accuracy. However, complex setups and sensitivity to thermal radiation pose limitations to progress. Here we report on an atom source for a strontium optical lattice clock which circumvents these limitations. We demonstrate fast (sub 100 ms), cold and controlled emission of strontium atomic vapours from bulk strontium oxide irradiated by a simple low power diode laser. Our results demonstrate that millions of strontium atoms from the vapour can be captured in a magneto-optical trap (MOT). Our method enables over an order of magnitude reduction in scale of the apparatus. Future applications range from satellite clocks testing general relativity to portable clocks for inertial navigation systems and relativistic geodesy.

  11. Cost and Precision of Brownian Clocks

    CERN Document Server

    Barato, Andre C

    2016-01-01

    Brownian clocks are biomolecular networks that can count time. A paradigmatic example are proteins that go through a cycle thus regulating some oscillatory behaviour in a living system. Typically, such a cycle requires free energy often provided by ATP hydrolysis. We investigate the relation between the precision of such a clock and its thermodynamic costs. For clocks driven by a constant thermodynamic force, a given precision requires a minimal cost that diverges as the uncertainty of the clock vanishes. In marked contrast, we show that a clock driven by a periodic variation of an external protocol can achieve arbitrary precision at arbitrarily low cost. This result constitutes a fundamental difference between processes driven by a fixed thermodynamic force and those driven periodically. As a main technical tool, we map a periodically driven system with a deterministic protocol to one subject to an external protocol that changes in stochastic time intervals, which simplifies calculations significantly. In th...

  12. Studying risk factors associated with Human Leptospirosis

    Directory of Open Access Journals (Sweden)

    Ramachandra Kamath

    2014-01-01

    Full Text Available Background: Leptospirosis is one of the most under diagnosed and underreported disease in both developed and developing countries including India. It is established that environmental conditions and occupational habit of the individuals put them at risk of acquiring disease, which varies from community to community. Various seroprevalence studies across the world have documented emerging situation of this neglected tropical disease, but limited have probed to identify the risk factors, especially in India. Objectives: The objective of this study was to identify the environmental and occupational risk factors associated with the disease in Udupi District. Materials and Methods: This population-based case-control study was carried out in Udupi, a District in Southern India from April 2012 until August 2012. Udupi is considered to be endemic for Leptospirosis and reported 116 confirmed cases in the year 2011. Seventy of 116 laboratory confirmed cases and 140 sex matched neighborhood healthy controls participated in the study. A predesigned, semi-structured and validated questionnaire was used for data collection through house to house visit and observations were noted about environmental conditions. Univariate analysis followed by multivariate analysis (back ward conditional logistic regression was performed by using STATA version 9.2 (StataCorp, College Station, TX, USA to identify potential risk factors. Results: Occupational factors such as outdoor activities (matched odds ratio [OR] of 3.95, 95% confidence interval [CI]: 1.19-13.0, presence of cut or wound at body parts during work (matched OR: 4.88, CI: 1.83-13.02 and environmental factors such as contact with rodents through using the food materials ate by rat (matched OR: 4.29, CI: 1.45-12.73 and contact with soil or water contaminated with urine of rat (matched OR: 4.58, CI: 1.43-14.67 were the risk factors identified to be associated with disease. Conclusion: Leptospirosis is still

  13. [Machina Machinarum. The clock as a concept and metaphor between 1450 and 1750].

    Science.gov (United States)

    Neumann, Hanns-Peter

    2010-01-01

    The changing use of the clock metaphor serves as a helpful contrast medium to highlight the different concepts of the body-soul-system between 1450 and 1750. This article first relates to the social, political and philosophical functions of the horologium. Then it outlines the different fields of discourse, in which the clock metaphor was mainly invoked. Finally, it examines the writings of a number of significant authors (Cusanus, Ficino, Descartes, Leibniz, Wolff, La Mettrie) with an eye to the evolution of the clock metaphor in various theological, metaphysical and physiological contexts. Surprisingly enough, the clock (or watch) initially represented the life-giving soul and human consciousness, before turning into the well-known symbol for the body-machine, and in particular for its neurophysiological operations.

  14. Expression of core clock genes in colorectal tumour cells compared with normal mucosa

    DEFF Research Database (Denmark)

    Fonnes, S; Donatsky, A M; Gögenur, I

    2015-01-01

    AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its correlat......AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its...... correlation to clinicopathological features and survival. METHOD: A systematic review was conducted without meta-analysis according to the PRISMA guidelines on 24 March 2014 using PubMed and EMBASE. Eligibility criteria were: study design, original research article, English language, human subjects and gene...

  15. Low Variation in the Polymorphic Clock Gene Poly-Q Region Despite Population Genetic Structure across Barn Swallow (Hirundo rustica) Populations

    Science.gov (United States)

    Dor, Roi; Lovette, Irby J.; Safran, Rebecca J.; Billerman, Shawn M.; Huber, Gernot H.; Vortman, Yoni; Lotem, Arnon; McGowan, Andrew; Evans, Matthew R.; Cooper, Caren B.; Winkler, David W.

    2011-01-01

    Recent studies of several species have reported a latitudinal cline in the circadian clock gene, Clock, which influences rhythms in both physiology and behavior. Latitudinal variation in this gene may hence reflect local adaptation to seasonal variation. In some bird populations, there is also an among-individual association between Clock poly-Q genotype and clutch initiation date and incubation period. We examined Clock poly-Q allele variation in the Barn Swallow (Hirundo rustica), a species with a cosmopolitan geographic distribution and considerable variation in life-history traits that may be influenced by the circadian clock. We genotyped Barn Swallows from five populations (from three subspecies) and compared variation at the Clock locus to that at microsatellite loci and mitochondrial DNA (mtDNA). We found very low variation in the Clock poly-Q region, as >96% of individuals were homozygous, and the two other alleles at this locus were globally rare. Genetic differentiation based on the Clock poly-Q locus was not correlated with genetic differentiation based on either microsatellite loci or mtDNA sequences. Our results show that high diversity in Clock poly-Q is not general across avian species. The low Clock variation in the background of heterogeneity in microsatellite and mtDNA loci in Barn Swallows may be an outcome of stabilizing selection on the Clock locus. PMID:22216124

  16. Low variation in the polymorphic Clock gene poly-Q region despite population genetic structure across barn swallow (Hirundo rustica populations.

    Directory of Open Access Journals (Sweden)

    Roi Dor

    Full Text Available Recent studies of several species have reported a latitudinal cline in the circadian clock gene, Clock, which influences rhythms in both physiology and behavior. Latitudinal variation in this gene may hence reflect local adaptation to seasonal variation. In some bird populations, there is also an among-individual association between Clock poly-Q genotype and clutch initiation date and incubation period. We examined Clock poly-Q allele variation in the Barn Swallow (Hirundo rustica, a species with a cosmopolitan geographic distribution and considerable variation in life-history traits that may be influenced by the circadian clock. We genotyped Barn Swallows from five populations (from three subspecies and compared variation at the Clock locus to that at microsatellite loci and mitochondrial DNA (mtDNA. We found very low variation in the Clock poly-Q region, as >96% of individuals were homozygous, and the two other alleles at this locus were globally rare. Genetic differentiation based on the Clock poly-Q locus was not correlated with genetic differentiation based on either microsatellite loci or mtDNA sequences. Our results show that high diversity in Clock poly-Q is not general across avian species. The low Clock variation in the background of heterogeneity in microsatellite and mtDNA loci in Barn Swallows may be an outcome of stabilizing selection on the Clock locus.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    2010-01-01

    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. PMID:20433765

  19. Phylogenetic footprint of the plant clock system in angiosperms: evolutionary processes of pseudo-response regulators.

    Science.gov (United States)

    Takata, Naoki; Saito, Shigeru; Saito, Claire Tanaka; Uemura, Matsuo

    2010-05-01

    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. 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. 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.

  20. Does the core circadian clock in the moss Physcomitrella patens (Bryophyta) comprise a single loop?

    Science.gov (United States)

    Holm, Karl; Källman, Thomas; Gyllenstrand, Niclas; Hedman, Harald; Lagercrantz, Ulf

    2010-06-15

    The endogenous circadian clock allows the organism to synchronize processes both to daily and seasonal changes. In plants, many metabolic processes such as photosynthesis, as well as photoperiodic responses, are under the control of a circadian clock. Comparative studies with the moss Physcomitrella patens provide the opportunity to study many aspects of land plant evolution. Here we present a comparative overview of clock-associated components and the circadian network in the moss P. patens. The moss P. patens has a set of conserved circadian core components that share genetic relationship and gene expression patterns with clock genes of vascular plants. These genes include Myb-like transcription factors PpCCA1a and PpCCA1b, pseudo-response regulators PpPRR1-4, and regulatory elements PpELF3, PpLUX and possibly PpELF4. However, the moss lacks homologs of AtTOC1, AtGI and the AtZTL-family of genes, which can be found in all vascular plants studied here. These three genes constitute essential components of two of the three integrated feed-back loops in the current model of the Arabidopsis circadian clock mechanism. Consequently, our results suggest instead a single loop circadian clock in the moss. Possibly as a result of this, temperature compensation of core clock gene expression appears to be decreased in P. patens. This study is the first comparative overview of the circadian clock mechanism in a basal land plant, the moss P. patens. Our results indicate that the moss clock mechanism may represent an ancestral state in contrast to the more complex and partly duplicated structure of subsequent land plants. These findings may provide insights into the understanding of the evolution of circadian network topology.

  1. Role of circadian gene Clock during differentiation of mouse pluripotent stem cells

    Directory of Open Access Journals (Sweden)

    Chao Lu

    2016-09-01

    Full Text Available Abstract Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs. However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs. These studies indicated that the development of biological rhythms in ESCs might be closely associated with the maintenance and differentiation of ESCs. The core circadian gene Clock is essential for regulation of biological rhythms. Its role in the development of biological rhythms of ESCs is totally unknown. Here, we used CRISPR/CAS9-mediated genetic editing techniques, to completely knock out the Clock expression in mouse ESCs. By AP, teratoma formation, quantitative real-time PCR and Immunofluorescent staining, we did not find any difference between Clock knockout mESCs and wild type mESCs in morphology and pluripotent capability under the pluripotent state. In brief, these data indicated Clock did not influence the maintaining of pluripotent state. However, they exhibited decreased proliferation and increased apoptosis. Furthermore, the biological rhythms failed to develop in Clock knockout mESCs after spontaneous differentiation, which indicated that there was no compensational factor in most peripheral tissues as described in mice models before (DeBruyne et al., 2007b. After spontaneous differentiation, loss of CLOCK protein due to Clock gene silencing induced spontaneous differentiation of mESCs, indicating an exit from the pluripotent state, or its differentiating ability. Our findings indicate that the core circadian gene Clock may be essential during normal mESCs differentiation by regulating mESCs proliferation, apoptosis and activity.

  2. Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock.

    Science.gov (United States)

    Ohdo, Shigehiro; Koyanagi, Satoru; Matsunaga, Naoya

    2010-07-31

    In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24h cycles. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes and cancer. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. On the other hand, the change of the drug pharmacodynamic and pharmacokinetic (PK/PD) parameters are influenced by not only inter-individual variability but also intra-individual variabilities of medications. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from viewpoint of clock genes. On the other hand, several drugs have an effect on molecular clock. Thus, the knowledge of intra- and inter-individual variability of molecular clock should be applied for the clinical practice. Therefore, we introduce the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes.

  3. Positive temporal dependence of the biological clock implies hyperbolic discounting

    Directory of Open Access Journals (Sweden)

    Debajyoti eRay

    2011-01-01

    Full Text Available Temporal preferences of animals and humans often exhibit inconsistencies, whereby an earlier, smaller reward may be preferred when it occurs immediately but not when it is delayed. Such choices reflect hyperbolic discounting of future rewards, rather than the exponential discounting required for temporal consistency. Simultaneously, however, evidence has emerged that suggests that animals and humans have an internal representation of time that often differs from the calendar time used in detection of temporal inconsistencies. Here, we prove that temporal inconsistencies emerge if fixed durations in calendar time are experienced as positively related (positive quadrant dependent. Hence, what are time-consistent choices within the time framework of the decision maker appear as time-inconsistent to an outsider who analyzes choices in calendar time. As the biological clock becomes more variable, the fit of the hyperbolic discounting model improves. A recent alternative explanation for temporal choice inconsistencies builds on persistent under-estimation of the length of distant time intervals. By increasing the expected speed of our stochastic biological clock for time farther into the future, we can emulate this explanation. Ours is therefore an encompassing theoretical framework that predicts context-dependent degrees of intertemporal choice inconsistencies, to the extent that context can generate changes in autocorrelation, variability, and expected speed of the biological clock. Our finding should lead to novel experiments that will clarify the role of time perception in impulsivity, with critical implications for, among others, our understanding of aging, drug abuse and pathological gambling.

  4. The Pentose Phosphate Pathway Regulates the Circadian Clock.

    Science.gov (United States)

    Rey, Guillaume; Valekunja, Utham K; Feeney, Kevin A; Wulund, Lisa; Milev, Nikolay B; Stangherlin, Alessandra; Ansel-Bollepalli, Laura; Velagapudi, Vidya; O'Neill, John S; Reddy, Akhilesh B

    2016-09-13

    The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.

  5. Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer's Disease?

    Directory of Open Access Journals (Sweden)

    Brianne Alyssia Kent

    2014-09-01

    Full Text Available Alzheimer’s disease (AD is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behaviour and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.

  6. SCA1+ Cells from the Heart Possess a Molecular Circadian Clock and Display Circadian Oscillations in Cellular Functions

    Directory of Open Access Journals (Sweden)

    Bastiaan C. Du Pré

    2017-09-01

    Full Text Available Stem cell antigen 1-positive (SCA1+ cells (SPCs have been investigated in cell-based cardiac repair and pharmacological research, although improved cardiac function after injection has been variable and the mode of action remains unclear. Circadian (24-hr rhythms are biorhythms regulated by molecular clocks that play an important role in (pathophysiology. Here, we describe (1 the presence of a molecular circadian clock in SPCs and (2 circadian rhythmicity in SPC function. We isolated SPCs from human fetal heart and found that these cells possess a molecular clock based on typical oscillations in core clock components BMAL1 and CRY1. Functional analyses revealed that circadian rhythmicity also governs SPC proliferation, stress tolerance, and growth factor release, with large differences between peaks and troughs. We conclude that SPCs contain a circadian molecular clock that controls crucial cellular functions. Taking circadian rhythms into account may improve reproducibility and outcome of research and therapies using SPCs.

  7. Circadian clocks are designed optimally

    CERN Document Server

    Hasegawa, Yoshihiko

    2014-01-01

    Circadian rhythms are acquired through evolution to increase the chances for survival by synchronizing to the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. Since both properties have been tuned through natural selection, their adaptation can be formalized in the framework of mathematical optimization. By using a succinct model, we found that simultaneous optimization of regularity and entrainability entails inherent features of the circadian mechanism irrespective of model details. At the behavioral level we discovered the existence of a dead zone, a time during which light pulses neither advance nor delay the clock. At the molecular level we demonstrate the role-sharing of two light inputs, phase advance and delay, as is well observed in mammals. We also reproduce the results of phase-controlling experiments and predict molecular elements responsible for the clockwork...

  8. Half Swing Clocking Scheme at 45nm

    Directory of Open Access Journals (Sweden)

    Sakshi Verma,

    2014-01-01

    Full Text Available Achievement of high processor speed with low power consumption is an elemental factor in processor technology, especially for hand-held devices. The need for low power has caused a major paradigm shift where power dissipation has become a important consideration as performance and area. In CMOS circuits, dynamic power consumption is proportional to the transition frequency, capacitance, and square of supply voltage. Consequentially, lowering supply voltage delivers significant power savings compromising the speed of processor. Large portion of the total power is consumed in the clocking circuitry in embedded processor technology. So clock power can be reduced using half swing of clock scheme which will cut down the power dissipation and minimum speed degradation. In Digital circuits by using double-edge triggered flip flops (DETFFs, the clock frequency can be significantly reduced ideally, in half while preserving the rate of data processing. Using lower clock frequency may translate into considerable power savings for the clocked portions of a circuit, including the clock distribution network and flip-flops. The designing is based on 45nm process technology.

  9. The molecular clock as a metabolic rheostat.

    Science.gov (United States)

    Perelis, M; Ramsey, K M; Bass, J

    2015-09-01

    Circadian clocks are biologic oscillators present in all photosensitive species that produce 24-h cycles in the transcription of rate-limiting metabolic enzymes in anticipation of the light-dark cycle. In mammals, the clock drives energetic cycles to maintain physiologic constancy during the daily switch in behavioural (sleep/wake) and nutritional (fasting/feeding) states. A molecular connection between circadian clocks and tissue metabolism was first established with the discovery that 24-h transcriptional rhythms are cell-autonomous and self-sustained in most tissues and comprise a robust temporal network throughout the body. A major window in understanding how the clock is coupled to metabolism was opened with discovery of metabolic syndrome pathologies in multi-tissue circadian mutant mice including susceptibility to diet-induced obesity and diabetes. Using conditional transgenesis and dynamic metabolic testing, we have pinpointed tissue-specific roles of the clock in energy and glucose homeostasis, with our most detailed understanding of this process in endocrine pancreas. Here, we review evidence for dynamic regulation of insulin secretion and oxidative metabolic functions by the clock transcription pathway to regulate homeostatic responses to feeding and fasting. These studies indicate that clock transcription is a determinant of tissue function and provide a reference for understanding molecular pathologies linking circadian desynchrony to metabolic disease.

  10. Variations in Phase and Amplitude of Rhythmic Clock Gene Expression across Prefrontal Cortex, Hippocampus, Amygdala, and Hypothalamic Paraventricular and Suprachiasmatic Nuclei of Male and Female Rats.

    Science.gov (United States)

    Chun, Lauren E; Woodruff, Elizabeth R; Morton, Sarah; Hinds, Laura R; Spencer, Robert L

    2015-10-01

    The molecular circadian clock is a self-regulating transcription/translation cycle of positive (Bmal1, Clock/Npas2) and negative (Per1,2,3, Cry1,2) regulatory components. While the molecular clock has been well characterized in the body's master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), only a few studies have examined both the positive and negative clock components in extra-SCN brain tissue. Furthermore, there has yet to be a direct comparison of male and female clock gene expression in the brain. This comparison is warranted, as there are sex differences in circadian functioning and disorders associated with disrupted clock gene expression. This study examined basal clock gene expression (Per1, Per2, Bmal1 mRNA) in the SCN, prefrontal cortex (PFC), rostral agranular insula, hypothalamic paraventricular nucleus (PVN), amygdala, and hippocampus of male and female rats at 4-h intervals throughout a 12:12 h light:dark cycle. There was a significant rhythm of Per1, Per2, and Bmal1 in the SCN, PFC, insula, PVN, subregions of the hippocampus, and amygdala with a 24-h period, suggesting the importance of an oscillating molecular clock in extra-SCN brain regions. There were 3 distinct clock gene expression profiles across the brain regions, indicative of diversity among brain clocks. Although, generally, the clock gene expression profiles were similar between male and female rats, there were some sex differences in the robustness of clock gene expression (e.g., females had fewer robust rhythms in the medial PFC, more robust rhythms in the hippocampus, and a greater mesor in the medial amygdala). Furthermore, females with a regular estrous cycle had attenuated aggregate rhythms in clock gene expression in the PFC compared with noncycling females. This suggests that gonadal hormones may modulate the expression of the molecular clock.

  11. Cross-talk between the circadian clock and the cell cycle in cancer.

    Science.gov (United States)

    Soták, Matúš; Sumová, Alena; Pácha, Jiří

    2014-06-01

    The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.

  12. Iterative quantum algorithm for distributed clock synchronization

    Institute of Scientific and Technical Information of China (English)

    Wang Hong-Fu; Zhang Shou

    2012-01-01

    Clock synchronization is a well-studied problem with many practical and scientific applications.We propose an arbitrary accuracy iterative quantum algorithm for distributed clock synchronization using only three qubits.The n bits of the time difference △ between two spatially separated clocks can be deterministically extracted by communicating only O(n) messages and executing the quantum iteration process n times based on the classical feedback and measurement operations.Finally,we also give the algorithm using only two qubits and discuss the success probability of the algorithm.

  13. Using Atomic Clocks to Detect Gravitational Waves

    CERN Document Server

    Loeb, Abraham

    2015-01-01

    Atomic clocks have recently reached a fractional timing precision of $<10^{-18}$. We point out that an array of atomic clocks, distributed along the Earth's orbit around the Sun, will have the sensitivity needed to detect the time dilation effect of mHz gravitational waves (GWs), such as those emitted by supermassive black hole binaries at cosmological distances. Simultaneous measurement of clock-rates at different phases of a passing GW provides an attractive alternative to the interferometric detection of temporal variations in distance between test masses separated by less than a GW wavelength, currently envisioned for the eLISA mission.

  14. CMOS Law-jitter Clock Driver Design

    OpenAIRE

    2012-01-01

    [ANGLÈS] Design of a low-jitter, low-phase noise clock driver in 40 nm CMOS technology. The work is in the field of analog integrated circuit (IC) design in nanometer CMOS technologies. [CASTELLÀ] Diseño de un circuito integrado "clock driver" de bajo jitter y bajo ruido de fase en tecnología CMOS 40 nm. El trabajo se contextualiza en el campo del diseño de circuitos integrados analógicos en tecnologías CMOS nanométricas. [CATALÀ] Disseny d'un circuit "clock driver" de baix jitter i bai...

  15. Light clocks in strong gravitational fields

    CERN Document Server

    Punzi, Raffaele; Wohlfarth, Mattias N R

    2009-01-01

    We argue that the time measured by a light clock operating with photons rather than classical light requires a refinement of the standard clock postulate in general relativity. In the presence of a gravitational field, already the one-loop quantum corrections to classical Maxwell theory affect light propagation and the construction of observers' frames of reference. Carefully taking into account these kinematic effects, a concise geometric expression for the time shown by a light clock is obtained. This result has far-reaching implications for physics in strong gravitational fields.

  16. Sleep: the sound of a local alarm clock.

    Science.gov (United States)

    Adamantidis, Antoine R

    2015-01-05

    Besides the master clock located in the suprachiasmatic nucleus (SCN) of the brain, additional clocks are distributed across the central nervous system and the body. The role of these 'secondary' clocks remains unclear. A new study shows that the lack of an internal clock in histamine neurons profoundly perturbs sleep. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. 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 pe

  18. The dynamic Allan Variance IV: characterization of atomic clock anomalies.

    Science.gov (United States)

    Galleani, Lorenzo; Tavella, Patrizia

    2015-05-01

    The number of applications where precise clocks play a key role is steadily increasing, satellite navigation being the main example. Precise clock anomalies are hence critical events, and their characterization is a fundamental problem. When an anomaly occurs, the clock stability changes with time, and this variation can be characterized with the dynamic Allan variance (DAVAR). We obtain the DAVAR for a series of common clock anomalies, namely, a sinusoidal term, a phase jump, a frequency jump, and a sudden change in the clock noise variance. These anomalies are particularly common in space clocks. Our analytic results clarify how the clock stability changes during these anomalies.

  19. Curli fimbria: an Escherichia coli adhesin associated with human cystitis

    Directory of Open Access Journals (Sweden)

    Melina Aparecida Cordeiro

    2016-06-01

    Full Text Available Abstract Escherichia coli is the major causative agent of human cystitis. In this study, a preliminary molecular analysis carried out by PCR (polymerase chain reaction demonstrated that 100% of 31 E. coli strains isolated from patients with recurrent UTIs (urinary tract infections showed the presence of the curli fimbria gene (csgA. Curli fimbria is known to be associated with bacterial biofilm formation but not with the adhesion of human cystitis-associated E. coli. Therefore, this work aimed to study how curli fimbria is associated with uropathogenic E. coli (UPEC as an adhesion factor. For this purpose, the csgA gene was deleted from strain UPEC-4, which carries three adhesion factor genes (csgA, fimH and ompA. The wild-type UPEC-4 strain and its mutant (ΔcsgA were analyzed for their adhesion ability over HTB-9 (human bladder carcinoma, Vero (kidney cells of African green monkey and HUVEC (human umbilical vein cells in the presence of α-D-mannose. All the wild-type UPEC strains tested (100% were able to adhere to all three cell types, while the UPEC-4 ΔcsgA mutant lost its adherence to HTB-9 but continued to adhere to the HUVEC and Vero cells. The results suggest that curli fimbria has an important role in the adhesion processes associated with human UPEC-induced cystitis.

  20. The human urine virome in association with urinary tract infections

    Directory of Open Access Journals (Sweden)

    Tasha M Santiago-Rodriguez

    2015-01-01

    Full Text Available While once believed to represent a sterile environment, the human urinary tract harbors a unique cellular microbiota. We sought to determine whether the human urinary tract also is home to viral communities whose membership might reflect urinary tract health status. We recruited and sampled urine from 20 subjects, 10 subjects with urinary tract infections (UTIs and 10 without UTIs, and found viral communities in the urine of each subject group. Most of the identifiable viruses were bacteriophage, but eukaryotic viruses also were identified in all subjects. We found reads from human papillomaviruses (HPVs in 95% of the subjects studied, but none were found to be high-risk genotypes that are associated with cervical and rectal cancers. We verified the presence of some HPV genotypes by quantitative PCR. Some of the HPV genotypes identified were homologous to relatively novel and uncharacterized viruses that previously have been detected on skin in association with cancerous lesions, while others may be associated with anal and genital warts. On a community level, there was no association between the membership or diversity of viral communities based on urinary tract health status. While more data are still needed, detection of HPVs as members of the human urinary virome using viral metagenomics represents a non-invasive technique that could augment current screening techniques to detect low-risk HPVs in the genitourinary tracts of humans.

  1. The human urine virome in association with urinary tract infections

    Science.gov (United States)

    Santiago-Rodriguez, Tasha M.; Ly, Melissa; Bonilla, Natasha; Pride, David T.

    2014-01-01

    While once believed to represent a sterile environment, the human urinary tract harbors a unique cellular microbiota. We sought to determine whether the human urinary tract also is home to viral communities whose membership might reflect urinary tract health status. We recruited and sampled urine from 20 subjects, 10 subjects with urinary tract infections (UTIs) and 10 without UTIs, and found viral communities in the urine of each subject group. Most of the identifiable viruses were bacteriophage, but eukaryotic viruses also were identified in all subjects. We found reads from human papillomaviruses (HPVs) in 95% of the subjects studied, but none were found to be high-risk genotypes that are associated with cervical and rectal cancers. We verified the presence of some HPV genotypes by quantitative PCR. Some of the HPV genotypes identified were homologous to relatively novel and uncharacterized viruses that previously have been detected on skin in association with cancerous lesions, while others may be associated with anal and genital warts. On a community level, there was no association between the membership or diversity of viral communities based on urinary tract health status. While more data are still needed, detection of HPVs as members of the human urinary virome using viral metagenomics represents a non-invasive technique that could augment current screening techniques to detect low-risk HPVs in the genitourinary tracts of humans. PMID:25667584

  2. Curli fimbria: an Escherichia coli adhesin associated with human cystitis.

    Science.gov (United States)

    Cordeiro, Melina Aparecida; Werle, Catierine Hirsch; Milanez, Guilherme Paier; Yano, Tomomasa

    2016-01-01

    Escherichia coli is the major causative agent of human cystitis. In this study, a preliminary molecular analysis carried out by PCR (polymerase chain reaction) demonstrated that 100% of 31 E. coli strains isolated from patients with recurrent UTIs (urinary tract infections) showed the presence of the curli fimbria gene (csgA). Curli fimbria is known to be associated with bacterial biofilm formation but not with the adhesion of human cystitis-associated E. coli. Therefore, this work aimed to study how curli fimbria is associated with uropathogenic E. coli (UPEC) as an adhesion factor. For this purpose, the csgA gene was deleted from strain UPEC-4, which carries three adhesion factor genes (csgA, fimH and ompA). The wild-type UPEC-4 strain and its mutant (ΔcsgA) were analyzed for their adhesion ability over HTB-9 (human bladder carcinoma), Vero (kidney cells of African green monkey) and HUVEC (human umbilical vein) cells in the presence of α-d-mannose. All the wild-type UPEC strains tested (100%) were able to adhere to all three cell types, while the UPEC-4 ΔcsgA mutant lost its adherence to HTB-9 but continued to adhere to the HUVEC and Vero cells. The results suggest that curli fimbria has an important role in the adhesion processes associated with human UPEC-induced cystitis.

  3. Biological clocks and regulation of seasonal reproduction and migration in birds.

    Science.gov (United States)

    Kumar, Vinod; Wingfield, John C; Dawson, Alistair; Ramenofsky, Marilyn; Rani, Sangeeta; Bartell, Paul

    2010-01-01

    Timekeeping is important at two levels: to time changes in physiology and behavior within each day and within each year. For the former, birds have a system of at least three independent circadian clocks present in the retina of the eyes, the pineal gland, and the hypothalamus. This differs from the situation in mammals in which the input, pacemaker, and output are localized in different structures. Each bird clock interacts with at least one other clock, and together, they appear to form a centralized clock system that keeps daily time. These clocks have a powerful endogenous component, and the daily light-dark cycle entrains them to 24 h. The timing and duration of life history stages that make up annual cycle of an individual must also be controlled by some form of timekeeping. However, evidence for the existence of an equivalent endogenous circannual clock is less clear. Environmental cues, particularly photoperiod, appear to have a more direct role than simply entraining the clock to calendar time. For example, the timing of migration is probably greatly influenced by photoperiod, but its manifestation each day, as Zugunruhe, appears to be under circadian control. Migration involves marked changes in physiology to cope with the energetic demands. There is still much that we do not know about how organisms' timekeeping systems respond to their natural environment, particularly how salient signals from the environment are perceived and then transduced into appropriately timed biological functions. However, given that changes in environmental input affects the clock, increasing human disturbance of the environment is likely to adversely affect these systems.

  4. Circadian and Circalunar Clock Interactions in a Marine Annelid

    Directory of Open Access Journals (Sweden)

    Juliane Zantke

    2013-10-01

    Full Text Available Life is controlled by multiple rhythms. Although the interaction of the daily (circadian clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1δ/ε. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function.

  5. Non-molecular-clock-like evolution following viral origins in homo sapiens.

    Science.gov (United States)

    Mok, Wendy; Seto, Kelly; Stone, Jon

    2007-09-26

    Researchers routinely adopt molecular clock assumptions in conducting sequence analyses to estimate dates for viral origins in humans. We used computational methods to examine the extent to which this practice can result in inaccurate 'retrodiction.' Failing to account for dynamic molecular evolution can affect greatly estimating index case dates, resulting in an overestimated age for the SARS-CoV-human infection, for instance.

  6. Contribution of daily and seasonal biorhythms to obesity in humans

    Science.gov (United States)

    Kanikowska, Dominika; Sato, Maki; Witowski, Janusz

    2015-04-01

    While the significance of obesity as a serious health problem is well recognized, little is known about whether and how biometerological factors and biorhythms causally contribute to obesity. Obesity is often associated with altered seasonal and daily rhythmicity in food intake, metabolism and adipose tissue function. Environmental stimuli affect both seasonal and daily rhythms, and the latter are under additional control of internal molecular oscillators, or body clocks. Modifications of clock genes in animals and changes to normal daily rhythms in humans (as in shift work and sleep deprivation) result in metabolic dysregulation that favours weight gain. Here, we briefly review the potential links between biorhythms and obesity in humans.

  7. A New Design of Clock Synchronization Algorithm

    Directory of Open Access Journals (Sweden)

    Jingmeng Liu

    2014-05-01

    Full Text Available The introduction of Ethernet makes the distributed network system more flexible and efficient, but it also makes nodes which are far apart from each other unable to work in the same time basis due to the long distance. This is not allowed for the high performance requirements of the system synchronization, such as high-precision multiaxis machining system. This paper presents a high-precision network clock synchronization algorithm, namely, optimal PI clock servo, which imposes a PI controller in order to compensate for the clock drift of each network node. Then a simulation platform established by the toolbox TrueTime is used to verify the stability of the algorithm and compare it with the clock synchronization algorithm of EtherCAT. The results show that the new synchronization algorithm has higher synchronization precision and faster convergence rate.

  8. 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.

  9. 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.

  10. Draper Clock-Synchronization Protocol in SAL

    Data.gov (United States)

    National Aeronautics and Space Administration — In 1973, Daly, Hpokins, and McKenna (from Draper Lab.) presented a fault-tolerant digital clocking system at the FTCS conference. This is probably one of the first...

  11. Turning Back the Aging Clock -- in Mice

    Science.gov (United States)

    ... 164250.html Turning Back the Aging Clock -- in Mice Elderly rodents treated with cellular therapy regained lost fur, became ... 2017 THURSDAY, March 23, 2017 (HealthDay News) -- Aging mice became more youthful following a new cellular therapy ...

  12. Circadian clock circuitry in colorectal cancer.

    Science.gov (United States)

    Mazzoccoli, Gianluigi; Vinciguerra, Manlio; Papa, Gennaro; Piepoli, Ada

    2014-04-21

    Colorectal cancer is the most prevalent among digestive system cancers. Carcinogenesis relies on disrupted control of cellular processes, such as metabolism, proliferation, DNA damage recognition and repair, and apoptosis. Cell, tissue, organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery. Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis, and altered expression of clock genes has been found in cancer patients. Epidemiological studies have shown that circadian disruption, that is, alteration of bodily temporal organization, is a cancer risk factor, and an increased incidence of colorectal neoplastic disease is reported in shift workers. In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer.

  13. Micro Mercury Ion Clock (MMIC) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Demonstrate micro clock based on trapped Hg ions with more than 10x size reduction and power; Fractional frequency stability at parts per 1014 level, adequate for...

  14. Modeling circadian clocks: From equations to oscillations

    National Research Council Canada - National Science Library

    Gonze, Didier

    2011-01-01

    ... (such as light and temperature) is greatly helped by mathematical modeling. In the present paper we review some mathematical models for circadian clocks, ranging from abstract, phenomenological models to the most detailed molecular models...

  15. Human microbiota-associated swine: current progress and future opportunities.

    Science.gov (United States)

    Wang, Mei; Donovan, Sharon M

    2015-01-01

    Gnotobiotic (GN) rodent models have provided insight into the contributions of the gut microbiota to host health and preventing disease. However, rodent models are limited by several important physiological and metabolic differences from humans, and many rodent models do not dependably replicate the clinical manifestations of human diseases. Due to the high degree of similarity in anatomy, physiology, immunology and brain growth, the domestic pig (Sus scrofa) is considered a clinically relevant model to study factors influencing human gastrointestinal, immune, and brain development. Gnotobiotic piglet models have been developed and shown to recapitulate key aspects of GN rodent models. Human microbiota-associated (HMA) piglets have been established using inocula from infants, children, and adults. The gut microbiota of recipient HMA piglets was more similar to that of the human donor than that of conventionally reared piglets harboring a pig microbiota. Moreover, Bifidobacterium and Bacteroides, two predominant bacterial groups of infant gut, were successfully established in the HMA piglets. Thus, the HMA pig model has the potential to be a valuable model for investigating how the gut microbiota composition changes in response to environmental factors, such as age, diet, vaccination, antibiotic use and infection. The HMA also represents a robust model for screening the efficacy of pre- and probiotic interventions. Lastly, HMA piglets can be an ideal model with which to elucidate microbe-host interactions in human health and disease due to the similarities to humans in anatomy, physiology, developmental maturity at birth, and the pathophysiology of many human diseases.

  16. PTTI 2030 - System Applications of Advanced Clocks

    Science.gov (United States)

    2010-11-01

    while you enjoy the freedom of hands-free driving. 42 nd Annual Precise Time and Time Interval (PTTI) Meeting 587 PLATE TECTONICS ...MONITORING Ultra-stable clocks have been recognized for some time as great tools to calibrate plate movement on the earth’s crust. In combination...position after a seismic event. The addition of multiple clocks to a worldwide monitoring system has allowed improved accuracy of these measurements

  17. Magic Wavelengths for Terahertz Clock Transitions

    OpenAIRE

    Zhou, Xiaoji; Xu, Xia; Chen, Xuzong; Chen, Jingbiao

    2010-01-01

    Magic wavelengths for laser trapping of boson isotopes of alkaline-earth Sr, Ca and Mg atoms are investigated while considering terahertz clock transitions between the $^{3}P_{0}, ^{3}P_{1}, ^{3}P_{2}$ metastable triplet states. Our calculation shows that magic wavelengths of trapping laser do exist. This result is important because those metastable states have already been used to realize accurate clocks in the terahertz frequency domain. Detailed discussions for magic wavelength for teraher...

  18. 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.

  19. Cesium Atomic Fountain Clocks at NMIJ

    Science.gov (United States)

    2010-11-01

    Wynands and S. Weyers, 2005, “Atomic fountain clocks,” Metrologia , 42, S64-S79. [2] M. Takamoto, F. L. Hong, R. Higashi, et al., 2005, “An optical...beam of laser-cooled cesium atoms,” Physical Review, A 60, R4241-R4244. [13] V. Gerginov, N. Nemitz, S. Weyers, et al., 2010, “Uncertainty evaluation of the caesium fountain clock PTB-CSF2,” Metrologia , 47, 65-79.

  20. Zebrafish circadian clocks: cells that see light.

    Science.gov (United States)

    Tamai, T K; Carr, A J; Whitmore, D

    2005-11-01

    In the classical view of circadian clock organization, the daily rhythms of most organisms were thought to be regulated by a central, 'master' pacemaker, usually located within neural structures of the animal. However, with the results of experiments performed in zebrafish, mammalian cell lines and, more recently, mammalian tissues, this view has changed to one where clock organization is now seen as being highly decentralized. It is clear that clocks exist in the peripheral tissues of animals as diverse as Drosophila, zebrafish and mammals. In the case of Drosophila and zebrafish, these tissues are also directly light-responsive. This light sensitivity and direct clock entrainability is also true for zebrafish cell lines and early-stage embryos. Using luminescent reporter cell lines containing clock gene promoters driving the expression of luciferase and single-cell imaging techniques, we have been able to show how each cell responds rapidly to a single light pulse by being shifted to a common phase, equivalent to the early day. This direct light sensitivity might be related to the requirement for light in these cells to activate the transcription of genes involved in DNA repair. It is also clear that the circadian clock in zebrafish regulates the timing of the cell cycle, demonstrating the wide impact that this light sensitivity and daily rhythmicity has on the biology of zebrafish.

  1. Adipose Clocks: Burning the Midnight Oil.

    Science.gov (United States)

    Henriksson, Emma; Lamia, Katja A

    2015-10-01

    Circadian clocks optimize the timing of physiological processes in synchrony with daily recurring and therefore predictable changes in the environment. Until the late 1990s, circadian clocks were thought to exist only in the central nervous systems of animals; elegant studies in cultured fibroblasts and using genetically encoded reporters in Drosophila melanogaster and in mice showed that clocks are ubiquitous and cell autonomous. These findings inspired investigations of the advantages construed by enabling each organ to independently adjust its function to the time of day. Studies of rhythmic gene expression in several organs suggested that peripheral organ clocks might play an important role in optimizing metabolic physiology by synchronizing tissue-intrinsic metabolic processes to cycles of nutrient availability and energy requirements. The effects of clock disruption in liver, pancreas, muscle, and adipose tissues support that hypothesis. Adipose tissues coordinate energy storage and utilization and modulate behavior and the physiology of other organs by secreting hormones known as "adipokines." Due to behavior- and environment-driven diurnal variations in supply and demand for chemical and thermal energy, adipose tissues might represent an important peripheral location for coordinating circadian energy balance (intake, storage, and utilization) over the whole organism. Given the complexity of adipose cell types and depots, the sensitivity of adipose tissue biology to age and diet composition, and the plethora of known and yet-to-be-discovered adipokines and lipokines, we have just begun to scratch the surface of understanding the role of circadian clocks in adipose tissues.

  2. Short-term GNSS satellite clock stability

    Science.gov (United States)

    Griggs, E.; Kursinski, E. R.; Akos, D.

    2015-08-01

    Global Navigation Satellite System (GNSS) clock stability is characterized via the modified Allan deviation using active hydrogen masers as the receiver frequency reference. The high stability of the maser reference allows the GNSS clock contribution to the GNSS carrier phase variance to be determined quite accurately. Satellite clock stability for four different GNSS constellations are presented, highlighting the similarities and differences between the constellations as well as satellite blocks and clock types. Impact on high-rate applications, such as GNSS radio occultation (RO), is assessed through the calculation of the maximum carrier phase error due to clock instability. White phase noise appears to dominate at subsecond time scales. However, while we derived the theoretical contribution of white phase modulation to the modified Allan deviation, our analysis of the GNSS satellite clocks was limited to 1-200 s time scales because of inconsistencies between the subsecond results from the commercial and software-defined receivers. The rubidium frequency standards on board the Global Positioning System (GPS) Block IIF, BeiDou, and Galileo satellites show improved stability results in comparison to previous GPS blocks for time scales relevant to RO. The Globalnaya Navigatsionnaya Sputnikovaya Sistema (GLONASS) satellites are the least stable of the GNSS constellations in the short term and will need high-rate corrections to produce RO results comparable to those from the other GNSS constellations.

  3. Optical lattice clocks and frequency comparison

    Energy Technology Data Exchange (ETDEWEB)

    Katori, Hidetoshi; Takano, Tetsushi; Takamoto, Masao, E-mail: katori@amo.t.u-tokyo.ac.jp [Department of Applied Physics, University of Tokyo, Tokyo (Japan); CREST, Japan Science and Technology Agency, Saitama (Japan)

    2011-01-10

    We consider designs of optical lattice clocks in view of the quantum statistics, relevant atomic spins, and atom-lattice interactions. The first two issues lead to two optimal constructions for the clock: a one-dimensional (1D) optical lattice loaded with spin-polarized fermions and a 3D optical lattice loaded with bosons. By taking atomic multipolar interactions with the lattice fields into account, an 'atomic motion insensitive' wavelength is proposed to provide a precise definition of the 'magic wavelength'. We then present a frequency comparison of these two optical lattice clocks: spin-polarized fermionic {sup 87}Sr and bosonic {sup 88}Sr prepared in 1D and 3D optical lattices, respectively. Synchronous interrogations of these two optical lattice clocks by the same probe laser allowed canceling out its frequency noise as a common mode noise to achieve a relative stability of 3x10{sup -17} for an averaging time of {tau} = 350 s. The scheme, therefore, provides us with a powerful means to investigate intrinsic uncertainty of the clocks regardless of the probe laser stability. We discuss prospects of the synchronous operation of the clocks on the measurement of the geoid height difference and on the search of constancy of fundamental constants.

  4. Cryptochrome is present in the compound eyes and a subset of Drosophila's clock neurons.

    Science.gov (United States)

    Yoshii, Taishi; Todo, Takeshi; Wülbeck, Corinna; Stanewsky, Ralf; Helfrich-Förster, Charlotte

    2008-06-20

    Cryptochrome (CRY) is intimately associated with the circadian clock of many organisms. In the fruit fly Drosophila melanogaster, CRY seems to be involved in photoreception as well as in the core clockwork. In spite of the critical role of CRY for the clock of Drosophila, it was not quite clear whether CRY is expressed in every clock cell. With the help of a new antibody and a mutant that lacks CRY, we show here that CRY is expressed in specific subsets of Drosophila's pacemaker neurons and in the photoreceptor cells of the compound eyes. In the pacemaker neurons, CRY levels and kinetics under light-dark cycles are quite different from each other. High-amplitude oscillations are observed in only three groups of clock neurons, suggesting that these three groups are strongly receptive to light. The different CRY kinetics may account for phase differences in oscillations of the clock proteins observed in these three groups in earlier studies. The molecular clock of the neurons that contain lower CRY levels or are completely CRY negative can still be synchronized by light, probably via intercellular communication with the CRY-positive neurons as well as via external photoreceptors.

  5. Expression of Clock genes in the pineal glands of newborn rats with hypoxic-ischemic encephalopathy

    Institute of Scientific and Technical Information of China (English)

    Bin Sun; Xing Feng; Xin Ding; Li Bao; Yongfu Li; Jun He; Meifang Jin

    2012-01-01

    Clock genes are involved in circadian rhythm regulation,and surviving newborns with hypoxic-ischemic encephalopathy may present with sleep-wake cycle reversal.This study aimed to determine the expression of the clock genes Clock and Bmall,in the pineal gland of rats with hypoxic-ischemic brain damage.Results showed that levels of Clock mRNA were not significantly changed within 48 hours after cerebral hypoxia and ischemia.Expression levels of CLOCK and BMAL1 protein were significantly higher after 48 hours.The levels of Bmall mRNA reached a peak at 36 hours,but were significantly reduced at 48 hours.Experimental findings indicate that Clock and Bmall genes were indeed expressed in the pineal glands of neonatal rats.At the initial stage (within 36 hours) of hypoxic-ischemic brain damage,only slight changes in the expression levels of these two genes were detected,followed by significant changes at 36 48 hours.These changes may be associated with circadian rhythm disorder induced by hypoxic-ischemic brain damage.

  6. Temporal Expression of the Clock Genes in the Water Flea Daphnia pulex (Crustacea: Cladocera).

    Science.gov (United States)

    Bernatowicz, Piotr P; Kotwica-Rolinska, Joanna; Joachimiak, Ewa; Sikora, Anna; Polanska, Marta A; Pijanowska, Joanna; Bębas, Piotr

    2016-04-01

    The timekeeping mechanisms that operate at the core of circadian clocks (oscillators) are based on interacting molecular feedback loops consisting of clock and clock-associated genes. However, there is a lack of comprehensive studies on the expression of clock genes (particularly those forming its core) in single crustacean species at the mRNA and protein levels, and these studies could serve as a basis for constructing a model of the crustacean molecular oscillator. Studies on Daphnia pulex are well suited to fill this gap because this species is the only representative crustacean whose genome has been sequenced. We analyzed the abundance of 20 gene transcripts throughout the day in the whole bodies of D. pulex (single clone); we found that 15 of these genes were transcriptionally active, and most had daily expression level changes. According to the functional classification of their homologues in insects, these genes may represent elements of the Daphnia molecular oscillator core and its input and output pathways. Studies of PERIOD (PER) protein, one of the main clock components, revealed its rhythmic expression pattern in the epidermis, gut, and ovaries. Finally, the cycling levels of many of these clock components observed in animals reared in continuous light led to the conclusion that the Daphnia oscillator, even if it is structurally similar to the oscillators of other arthropods, can be considered a particularly important adaptive mechanism for living in environments with extreme photoperiods. © 2016 Wiley Periodicals, Inc.

  7. Expression of the Circadian Clock Genes Pert, Per2 in Sporadic, Familial Breast Tumors

    Directory of Open Access Journals (Sweden)

    Sherry L. Winter

    2007-10-01

    Full Text Available There is a growing body of evidence implicating aberrant circadian clock expression in the development of cancer. Based on our initial experiments identifying a putative interaction between BRCA1, the clock proteins Per1, Per2, as well as the reported involvement of the circadian clock in the development of cancer, we have performed an expression analysis of the circadian clock genes Per1, Per2 in both sporadic, familial primary breast tumors, normal breast tissues using real-time polymerase chain reaction. Significantly decreased levels of Per1 were observed between sporadic tumors, normal samples (P < .00001, as well as a further significant decrease between familial, sporadic breast tumors for both Per1 (P < .00001, Per2 (P < .00001. Decreased Per1 was also associated with estrogen receptor negativity (53% vs 15%, P = .04. These results suggest a role for both Perl, Per2 in normal breast function, show for the first time that deregulation of the circadian clock may be an important factor in the development of familial breast cancer. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle, on the ability of cells to undergo apoptosis, potentially promoting carcinogenesis.

  8. Alternative Splicing Mediates Responses of the Arabidopsis Circadian Clock to Temperature Changes[W

    Science.gov (United States)

    James, Allan B.; Syed, Naeem Hasan; Bordage, Simon; Marshall, Jacqueline; Nimmo, Gillian A.; Jenkins, Gareth I.; Herzyk, Pawel; Brown, John W.S.; Nimmo, Hugh G.

    2012-01-01

    Alternative splicing plays crucial roles by influencing the diversity of the transcriptome and proteome and regulating protein structure/function and gene expression. It is widespread in plants, and alteration of the levels of splicing factors leads to a wide variety of growth and developmental phenotypes. The circadian clock is a complex piece of cellular machinery that can regulate physiology and behavior to anticipate predictable environmental changes on a revolving planet. We have performed a system-wide analysis of alternative splicing in clock components in Arabidopsis thaliana plants acclimated to different steady state temperatures or undergoing temperature transitions. This revealed extensive alternative splicing in clock genes and dynamic changes in alternatively spliced transcripts. Several of these changes, notably those affecting the circadian clock genes LATE ELONGATED HYPOCOTYL (LHY) and PSEUDO RESPONSE REGULATOR7, are temperature-dependent and contribute markedly to functionally important changes in clock gene expression in temperature transitions by producing nonfunctional transcripts and/or inducing nonsense-mediated decay. Temperature effects on alternative splicing contribute to a decline in LHY transcript abundance on cooling, but LHY promoter strength is not affected. We propose that temperature-associated alternative splicing is an additional mechanism involved in the operation and regulation of the plant circadian clock. PMID:22408072

  9. The clock gene circuit in Arabidopsis includes a repressilator with additional feedback loops.

    Science.gov (United States)

    Pokhilko, Alexandra; Fernández, Aurora Piñas; Edwards, Kieron D; Southern, Megan M; Halliday, Karen J; Millar, Andrew J

    2012-03-06

    Circadian clocks synchronise biological processes with the day/night cycle, using molecular mechanisms that include interlocked, transcriptional feedback loops. Recent experiments identified the evening complex (EC) as a repressor that can be essential for gene expression rhythms in plants. Integrating the EC components in this role significantly alters our mechanistic, mathematical model of the clock gene circuit. Negative autoregulation of the EC genes constitutes the clock's evening loop, replacing the hypothetical component Y. The EC explains our earlier conjecture that the morning gene Pseudo-Response Regulator 9 was repressed by an evening gene, previously identified with Timing Of CAB Expression1 (TOC1). Our computational analysis suggests that TOC1 is a repressor of the morning genes Late Elongated Hypocotyl and Circadian Clock Associated1 rather than an activator as first conceived. This removes the necessity for the unknown component X (or TOC1mod) from previous clock models. As well as matching timeseries and phase-response data, the model provides a new conceptual framework for the plant clock that includes a three-component repressilator circuit in its complex structure.

  10. The REVEILLE clock genes inhibit growth of juvenile and adult plants by control of cell size.

    Science.gov (United States)

    Gray, Jennifer A; Shalit-Kaneh, Akiva; Chu, Dalena Nhu; Hsu, Polly Yingshan; Harmer, Stacey

    2017-03-02

    The circadian clock is a complex regulatory network that enhances plant growth and fitness in a constantly changing environment. In Arabidopsis thaliana, the clock is comprised of numerous regulatory feedback loops in which REVEILLE8 (RVE8) and its homologs RVE4 and RVE6 act in a partially redundant manner to promote clock pace. Here, we report that the remaining members of the RVE8 clade, RVE3 and RVE5, play only minor roles in regulation of clock function. However, we find that RVE8 clade proteins have unexpected functions in modulation of light input to the clock and control of plant growth at multiple stages of development. In seedlings, these proteins repress hypocotyl elongation in a day-length and sucrose dependent manner. Strikingly, adult rve4 6 8 and rve3 4 5 6 8 mutants are much larger than wild type, with both increased leaf area and biomass. This size phenotype is associated with a faster growth rate and larger cell size and is not simply due to a delay in the transition to flowering. Gene expression and epistasis analysis reveal that the growth phenotypes of rve mutants are due to misregulation of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 expression. Our results shows that even small changes in PIF gene expression caused by perturbation of clock gene function can have large effects on the growth of adult plants.

  11. Estradiol differently affects melanin synthesis of malignant and normal melanocytes: a relationship with clock and clock-controlled genes.

    Science.gov (United States)

    Poletini, Maristela Oliveira; de Assis, Leonardo Vinicius Monteiro; Moraes, Maria Nathalia; Castrucci, Ana Maria de Lauro

    2016-10-01

    Melanin production within melanocytes is regulated, among others, by estradiol, whose effects on melanogenesis are still not completely elucidated. Here we show that although 10(-7) M 17β-estradiol (E2) increased tyrosinase mRNA levels in B16-F10 malignant melanocytes, there was a transient decrease and abolishment of the temporal variation of melanin content. Both parameters were much higher in the malignant than in normal Melan-a cells. Considering that silencing clock machinery in human melanocytes increases melanogenesis, we investigated clock gene expression in those cell lines. Except for Melan-a Bmal1 and B16-F10 Per2 expression of control cells, Per1, Per2, and Bmal1 expression increased independently of cell type or E2 treatment after 24 h. However, melanoma cells showed a marked increase in Per1 and Bma11 expression in response to E2 at the same time points, what may rule out E2 as a synchronizer agent since the expression of those genes were not in antiphase. Next, we investigated the expression of Xpa, a clock-controlled gene, which in Melan-a cells, peaked at 18 h, and E2 treatment shifted this peak to 24 h, whereas B16-F10 Xpa expression peaked at 24 h in both control and E2 group, and it was higher compared to Melan-a cells in both groups. Therefore, malignant and normal melanocytes display profound differences on core elements of the local clock, and how they respond to E2, what is most probably determinant of the differences seen on melanin synthesis and Tyrosinase and Xpa expression. Understanding these processes at the molecular level could bring new strategies to treat melanoma.

  12. The evolution of distributed association networks in the human brain.

    Science.gov (United States)

    Buckner, Randy L; Krienen, Fenna M

    2013-12-01

    The human cerebral cortex is vastly expanded relative to other primates and disproportionately occupied by distributed association regions. Here we offer a hypothesis about how association networks evolved their prominence and came to possess circuit properties vital to human cognition. The rapid expansion of the cortical mantle may have untethered large portions of the cortex from strong constraints of molecular gradients and early activity cascades that lead to sensory hierarchies. What fill the gaps between these hierarchies are densely interconnected networks that widely span the cortex and mature late into development. Limitations of the tethering hypothesis are discussed as well as its broad implications for understanding critical features of the human brain as a byproduct of size scaling. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Addressing the human factors issues associated with control room modifications

    Energy Technology Data Exchange (ETDEWEB)

    O`Hara, J.; Stubler, W. [Brookhaven National Lab., Upton, NY (United States). Dept. of Advanced Technology; Kramer, J. [Nuclear Regulatory Commission, Washington, DC (United States). Office of Nuclear Regulatory Research

    1998-03-01

    Advanced human-system interface (HSI) technology is being integrated into existing nuclear plants as part of plant modifications and upgrades. The result of this trend is that hybrid HSIs are created, i.e., HSIs containing a mixture of conventional (analog) and advanced (digital) technology. The purpose of the present research is to define the potential effects of hybrid HSIs on personnel performance and plant safety and to develop human factors guidance for safety reviews of them where necessary. In support of this objective, human factors issues associated with hybrid HSIs were identified. The issues were evaluated for their potential significance to plant safety, i.e., their human performance concerns have the potential to compromise plant safety. The issues were then prioritized and a subset was selected for design review guidance development.

  14. Human Microbiome and its Association With Health and Diseases.

    Science.gov (United States)

    Althani, Asmaa A; Marei, Hany E; Hamdi, Wedad S; Nasrallah, Gheyath K; El Zowalaty, Mohamed E; Al Khodor, Souhaila; Al-Asmakh, Maha; Abdel-Aziz, Hassan; Cenciarelli, Carlo

    2016-08-01

    Human microbiota are distinct communities of microorganisms that resides at different body niches. Exploration of the human microbiome has become a reality due to the availability of powerful metagenomics and metatranscriptomic analysis technologies. Recent advances in sequencing and bioinformatics over the past decade help provide a deep insight into the nature of the host-microbial interactions and identification of potential deriver genes and pathways associated with human health, well-being, and predisposition to different diseases. In the present review, we outline recent studies devoted to elucidate the possible link between the microbiota and various type of diseases. The present review also highlights the potential utilization of microbiota as a potential therapeutic option to treat a wide array of human diseases. J. Cell. Physiol. 231: 1688-1694, 2016. © 2015 Wiley Periodicals, Inc.

  15. Keeping the right time in space:importance of circadian clock and sleep for physiology and performance of astronauts

    Institute of Scientific and Technical Information of China (English)

    Jin-Hu Guo; Wei-Min Qu; Shan-Guang Chen; Xiao-Ping Chen; Ke Lv; Zhi-Li Huang; Yi-Lan Wu

    2014-01-01

    The circadian clock and sleep are essential for human physiology and behavior; deregulation of circadian rhythms impairs health and performance. Circadian clocks and sleep evolved to adapt to Earth’s environment, which is characterized by a 24-hour light–dark cycle. Changes in gravity load, lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, in turn jeopardizing the mood, cognition and performance of orbiting astronauts. In this review, we summarize our understanding of both the influence of the space environment on the circadian timing system and sleep and the impact of these changes on astronaut physiology and performance.

  16. An Upper Palaeolithic engraved human bone associated with ritualistic cannibalism.

    Science.gov (United States)

    Bello, Silvia M; Wallduck, Rosalind; Parfitt, Simon A; Stringer, Chris B

    2017-01-01

    Cut-marked and broken human bones are a recurrent feature of Magdalenian (~17-12,000 years BP, uncalibrated dates) European sites. Human remains at Gough's Cave (UK) have been modified as part of a Magdalenian mortuary ritual that combined the intensive processing of entire corpses to extract edible tissues and the modification of skulls to produce skull-cups. A human radius from Gough's Cave shows evidence of cut marks, percussion damage and human tooth marks, indicative of cannibalism, as well as a set of unusual zig-zagging incisions on the lateral side of the diaphysis. These latter incisions cannot be unambiguously associated with filleting of muscles. We compared the macro- and micro-morphological characteristics of these marks to over 300 filleting marks on human and non-human remains and to approximately 120 engraved incisions observed on two artefacts from Gough's Cave. The new macro- and micro-morphometric analyses of the marks, as well as further comparisons with French Middle Magdalenian engraved artefacts, suggest that these modifications are the result of intentional engraving. The engraved motif comfortably fits within a Magdalenian pattern of design; what is exceptional in this case, however, is the choice of raw material (human bone) and the cannibalistic context in which it was produced. The sequence of the manipulations suggests that the engraving was a purposeful component of the cannibalistic practice, implying a complex ritualistic funerary behaviour that has never before been recognized for the Palaeolithic period.

  17. Ubiquity and diversity of human-associated Demodex mites.

    Directory of Open Access Journals (Sweden)

    Megan S Thoemmes

    Full Text Available Demodex mites are a group of hair follicle and sebaceous gland-dwelling species. The species of these mites found on humans are arguably the animals with which we have the most intimate interactions. Yet, their prevalence and diversity have been poorly explored. Here we use a new molecular method to assess the occurrence of Demodex mites on humans. In addition, we use the 18S rRNA gene (18S rDNA to assess the genetic diversity and evolutionary history of Demodex lineages. Within our samples, 100% of people over 18 years of age appear to host at least one Demodex species, suggesting that Demodex mites may be universal associates of adult humans. A phylogenetic analysis of 18S rDNA reveals intraspecific structure within one of the two named human-associated Demodex species, D. brevis. The D. brevis clade is geographically structured, suggesting that new lineages are likely to be discovered as humans from additional geographic regions are sampled.

  18. Ubiquity and diversity of human-associated Demodex mites.

    Science.gov (United States)

    Thoemmes, Megan S; Fergus, Daniel J; Urban, Julie; Trautwein, Michelle; Dunn, Robert R

    2014-01-01

    Demodex mites are a group of hair follicle and sebaceous gland-dwelling species. The species of these mites found on humans are arguably the animals with which we have the most intimate interactions. Yet, their prevalence and diversity have been poorly explored. Here we use a new molecular method to assess the occurrence of Demodex mites on humans. In addition, we use the 18S rRNA gene (18S rDNA) to assess the genetic diversity and evolutionary history of Demodex lineages. Within our samples, 100% of people over 18 years of age appear to host at least one Demodex species, suggesting that Demodex mites may be universal associates of adult humans. A phylogenetic analysis of 18S rDNA reveals intraspecific structure within one of the two named human-associated Demodex species, D. brevis. The D. brevis clade is geographically structured, suggesting that new lineages are likely to be discovered as humans from additional geographic regions are sampled.

  19. A hypothetical neurological association between dehumanization and human rights abuses.

    Science.gov (United States)

    Murrow, Gail B; Murrow, Richard

    2015-07-01

    Dehumanization is anecdotally and historically associated with reduced empathy for the pain of dehumanized individuals and groups and with psychological and legal denial of their human rights and extreme violence against them. We hypothesize that 'empathy' for the pain and suffering of dehumanized social groups is automatically reduced because, as the research we review suggests, an individual's neural mechanisms of pain empathy best respond to (or produce empathy for) the pain of people whom the individual automatically or implicitly associates with her or his own species. This theory has implications for the philosophical conception of 'human' and of 'legal personhood' in human rights jurisprudence. It further has implications for First Amendment free speech jurisprudence, including the doctrine of 'corporate personhood' and consideration of the potential harm caused by dehumanizing hate speech. We suggest that the new, social neuroscience of empathy provides evidence that both the vagaries of the legal definition or legal fiction of 'personhood' and hate speech that explicitly and implicitly dehumanizes may (in their respective capacities to artificially humanize or dehumanize) manipulate the neural mechanisms of pain empathy in ways that could pose more of a true threat to human rights and rights-based democracy than previously appreciated.

  20. Gated Clock Implementation of Arithmetic Logic Unit (ALU

    Directory of Open Access Journals (Sweden)

    Dr. Neelam R. Prakash

    2013-05-01

    Full Text Available Low power design has emerged as one of the challenging area in today’s ASIC (Application specific integrated circuit design. With continuous decrease in transistor size, power density is increasing and there is an urgent need for reduction in total power consumption. Clock gating is one most effective technique for low power synchronous circuit design. Clock gating technique in low power design is used to reduce the dynamic power consumption. Clock signal in a synchronous circuit is used for synchronization only and hence does not carry any important information. Since clock is applied to each block of a synchronous circuit, and clock switches for every cycle, clock power is the major part of dynamic power consumption in synchronous circuits. Clock gating is a well known technique to reduce clock power. In clock gating clock to an idle block is disabled. Thus significant amount of power consumption is reduced by employing clock gating. In this paper an ALU design is proposed employing Gated clock for its operation. Design simulation has been performed on Xilinx ISE design suite, and power calculation is done by Xilinx Xpower analyzer. Results show that approximately 17% of total clock power consumption is reduced by gated clock implementation.

  1. Common Kibra alleles are associated with human memory performance.

    Science.gov (United States)

    Papassotiropoulos, Andreas; Stephan, Dietrich A; Huentelman, Matthew J; Hoerndli, Frederic J; Craig, David W; Pearson, John V; Huynh, Kim-Dung; Brunner, Fabienne; Corneveaux, Jason; Osborne, David; Wollmer, M Axel; Aerni, Amanda; Coluccia, Daniel; Hänggi, Jürgen; Mondadori, Christian R A; Buchmann, Andreas; Reiman, Eric M; Caselli, Richard J; Henke, Katharina; de Quervain, Dominique J-F

    2006-10-20

    Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

  2. Hormonal and pharmacological manipulation of the circadian clock: recent developments and future strategies.

    Science.gov (United States)

    Richardson, G; Tate, B

    2000-05-01

    contrast to jet lag, shiftwork produces chronic sleep disruption lasting for the duration of shiftwork exposure. For while individual differences in the ability to adjust to a nocturnal work schedule clearly exist, recent studies suggest that few if any night workers regularly experience restful and restorative day sleep equivalent to that considered normal at night. This chronic sleep limitation is associated with significant increases in a number of consequent problems including sleepiness-related accidents, social disruption, and psychiatric disturbances. In addition, chronic exposure to shiftwork has now been shown to be an independent risk factor for the development of both cardiovascular and gastrointestinal diseases. While these epidemiological studies have not identified the specific aspect of shiftwork that is associated with increased risk of these disorders, the chronic limitation and disruption is foremost among plausible factors. The most important aspect of human circadian physiology that limits adaptation to the extreme schedules inherent in shiftwork and jet travel is the primacy of light among entraining signals, or zeitgebers. Exposure to sunlight for night shiftworkers, or for jet travelers at their destination, results in maintenance (or resetting) of the clock to environmental time. This response can be prevented or overridden with extraordinary avoidance of sunlight or with provision of artificial light of sufficient duration and intensity to negate the sunlight signal, an approach shown to be effective in the treatment of shiftwork sleep disruption. Practical issues sharply limit the application of artificial lighting to all shiftwork settings, however, and the role for a pharmacological chronobiotic agent capable of accomplishing the same end is potentially very large (Copinschi et al., 1995; Jamieson et al., 1998). For example, the effects of zolpidem vs. placebo on sleep, daytime alertness, and fatigue in travelers who complain of jet lag was co

  3. DESIGN OF TWO-PHASE SINUSOIDAL POWER CLOCK AND CLOCKED TRANSMISSION GATE ADIABATIC LOGIC CIRCUIT

    Institute of Scientific and Technical Information of China (English)

    Wang Pengjun; Yu Junjun

    2007-01-01

    First the research is conducted on the design of the two-phase sinusoidal power clock generator in this paper. Then the design of the new adiabatic logic circuit adopting the two-phase sinusoidal power clocks-Clocked Transmission Gate Adiabatic Logic (CTGAL) circuit is presented. This circuit makes use of the clocked transmission gates to sample the input signals, then the output loads are charged and discharged in a fully adiabatic manner by using bootstrapped N-Channel Metal Oxide Semiconductor (NMOS) and Complementary Metal Oxide Semiconductor (CMOS) latch structure.Finally, with the parameters of Taiwan Semiconductor Manufacturing Company (TSMC) 0.25 μm CMOS device, the transient energy consumption of CTGAL, Bootstrap Charge-Recovery Logic (BCRL)and Pass-transistor Adiabatic Logic (PAL) including their clock generators is simulated. The simulation result indicates that CTGAL circuit has the characteristic of remarkably low energy consumption.

  4. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis.

    Science.gov (United States)

    Ramsey, Kathryn Moynihan; Yoshino, Jun; Brace, Cynthia S; Abrassart, Dana; Kobayashi, Yumiko; Marcheva, Biliana; Hong, Hee-Kyung; Chong, Jason L; Buhr, Ethan D; Lee, Choogon; Takahashi, Joseph S; Imai, Shin-Ichiro; Bass, Joseph

    2009-05-01

    The circadian clock is encoded by a transcription-translation feedback loop that synchronizes behavior and metabolism with the light-dark cycle. Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1.

  5. Large-scale appearance of ultraconserved elements in tetrapod genomes and slowdown of the molecular clock.

    Science.gov (United States)

    Stephen, Stuart; Pheasant, Michael; Makunin, Igor V; Mattick, John S

    2008-02-01

    Mammalian genomes contain millions of highly conserved noncoding sequences, many of which are regulatory. The most extreme examples are the 481 ultraconserved elements (UCEs) that are identical over at least 200 bp in human, mouse, and rat and show 96% identity with chicken, which diverged approximately 310 MYA. If the substitution rate in UCEs remained constant, these elements should also be present with a high level of identity in fish (approximately 450 Myr), but this is not the case, suggesting that many appeared in the amniotes or tetrapods or that the molecular clock has slowed down in these lineages, or both. Taking advantage of the availability of multiple genomes, we identified 13,736 UCEs in the human genome that are identical over at least 100 bp in at least 3 of 5 placental mammals, including 2,189 sequences over at least 200 bp, thereby greatly expanding the repertoire of known UCEs, and investigated the evolution of these sequences in opossum, chicken, frog, and fish. We conclude that there was a massive genome-wide acquisition and expansion of UCEs during tetrapod and then amniote evolution, accompanied by a slowdown of the molecular clock, particularly in the amniotes, a process consistent with their functional exaptation in these lineages. The majority of tetrapod-specific UCEs are noncoding and associated with genes involved in regulation of transcription and development. In contrast, fish genomes contain relatively few UCEs, the majority of which are common to all bony vertebrates. These elements are different from other conserved noncoding elements and appear to be important regulatory innovations that became fixed following the emergence of vertebrates from the sea to the land.

  6. A human-specific de novo protein-coding gene associated with human brain functions.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2010-03-01

    Full Text Available To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203. Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.

  7. A human-specific de novo protein-coding gene associated with human brain functions.

    Directory of Open Access Journals (Sweden)

    Chuan-Yun Li

    2010-03-01

    Full Text Available To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203. Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions.

  8. Understanding the Association of Human Rhinovirus with Asthma.

    Science.gov (United States)

    Stone, Cosby A; Miller, E Kathryn

    2015-09-16

    Human rhinoviruses are ubiquitous seasonal pathogens. They have known associations with first onset of wheezing illnesses in children and with asthma exacerbations in patients of all ages. It is not yet certain whether human rhinoviruses play a direct role in the pathogenesis of asthma by activating deleterious inflammatory responses or if they only serve as a catalyst to accelerate the disease in genetically predisposed individuals. There have been previously demonstrated reductions in the development of the asthmatic phenotype with passive immunization against respiratory syncytial virus; however, in the case of rhinovirus, there are barriers to effective vaccine development, such as the lack of a common antigenic target due to alterations of surface markers among subtypes. It remains to be determined whether certain subtypes of human rhinovirus are more asthmagenic and therefore worthy of greater attention as vaccine candidates, but several studies have suggested that RV-C and certain RV-A strains may be more strongly linked with asthma.

  9. Orbitography for next generation space clocks

    CERN Document Server

    Duchayne, Loïc; Wolf, Peter

    2007-01-01

    Over the last decade of the 20th century and the first few years of the 21st, the uncertainty of atomic clocks has decreased by about two orders of magnitude, passing from the low 10^-14 to below 10^-16, in relative frequency . Space applications in fundamental physics, geodesy, time/frequency metrology, navigation etc... are among the most promising for this new generation of clocks. Onboard terrestrial or solar system satellites, their exceptional frequency stability and accuracy makes them a prime tool to test the fundamental laws of nature, and to study gravitational potentials and their evolution. In this paper, we study in more detail the requirements on orbitography compatible with operation of next generation space clocks at the required uncertainty based on a completely relativistic model. Using the ACES (Atomic Clock Ensemble in Space) mission as an example, we show that the required accuracy goal can be reached with relatively modest constraints on the orbitography of the space clock, much less str...

  10. Feasibility of an optical fiber clock

    Science.gov (United States)

    Ilinova, Ekaterina; Babb, James F.; Derevianko, Andrei

    2017-09-01

    We explore the feasibility of a fiber clock, i.e., a compact, high-precision, optical lattice atomic clock based on atoms trapped inside a hollow-core optical fiber. Such a setup offers an intriguing potential both for a substantially increased number of interrogated atoms (and thereby an improved clock stability) and for miniaturization. We evaluate the sensitivity of the 1S0-3P0 clock transition in Hg and other divalent atoms to the fiber inner core surface at nonzero temperatures. The Casimir-Polder interaction induced 1S0-3P0 transition frequency shift is calculated for the atom inside the hollow capillary as a function of atomic position, capillary material, and geometric parameters. For Hg atoms on the axis of a silica capillary with inner radius ≥15 μ m and optimally chosen thickness d ˜1 μ m , the atom-surface interaction induced 1S0-3P0 clock transition frequency shift can be kept on the level δ ν /νHg˜10-19 . We also estimate the atom loss and heating due to collisions with the buffer gas, lattice intensity noise induced heating, spontaneous photon scattering heating, and residual birefringence induced frequency shifts.

  11. Body weight, metabolism and clock genes

    Directory of Open Access Journals (Sweden)

    Zanquetta Melissa M

    2010-08-01

    Full Text Available Abstract Biological rhythms are present in the lives of almost all organisms ranging from plants to more evolved creatures. These oscillations allow the anticipation of many physiological and behavioral mechanisms thus enabling coordination of rhythms in a timely manner, adaption to environmental changes and more efficient organization of the cellular processes responsible for survival of both the individual and the species. Many components of energy homeostasis exhibit circadian rhythms, which are regulated by central (suprachiasmatic nucleus and peripheral (located in other tissues circadian clocks. Adipocyte plays an important role in the regulation of energy homeostasis, the signaling of satiety and cellular differentiation and proliferation. Also, the adipocyte circadian clock is probably involved in the control of many of these functions. Thus, circadian clocks are implicated in the control of energy balance, feeding behavior and consequently in the regulation of body weight. In this regard, alterations in clock genes and rhythms can interfere with the complex mechanism of metabolic and hormonal anticipation, contributing to multifactorial diseases such as obesity and diabetes. The aim of this review was to define circadian clocks by describing their functioning and role in the whole body and in adipocyte metabolism, as well as their influence on body weight control and the development of obesity.

  12. Direct laser cooling Al+ ions optical clocks

    CERN Document Server

    Zhang, J; Luo, J; Lu, Z H

    2016-01-01

    Al$^+$ ions optical clock is a very promising optical frequency standard candidate due to its extremely small blackbody radiation shift. It has been successfully demonstrated with indirect cooled, quantum-logic-based spectroscopy technique. Its accuracy is limited by second-order Doppler shift, and its stability is limited by the number of ions that can be probed in quantum logic processing. We propose a direct laser cooling scheme of Al$^+$ ions optical clocks where both the stability and accuracy of the clocks are greatly improved. In the proposed scheme, two Al$^+$ ions traps are utilized. The first trap is used to trap a large number of Al$^+$ ions to improve the stability of the clock laser, while the second trap is used to trap a single Al$^+$ ions to provide the ultimate accuracy. Both traps are cooled with a continuous wave 167 nm laser. The expected clock laser stability can reach $9.0\\times10^{-17}/\\sqrt{\\tau}$. For the second trap, in addition to 167 nm laser Doppler cooling, a second stage pulsed ...

  13. Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder.

    Science.gov (United States)

    Bunney, B G; Li, J Z; Walsh, D M; Stein, R; Vawter, M P; Cartagena, P; Barchas, J D; Schatzberg, A F; Myers, R M; Watson, S J; Akil, H; Bunney, W E

    2015-02-01

    Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small

  14. Dynamic association of NUP98 with the human genome.

    Directory of Open Access Journals (Sweden)

    Yun Liang

    Full Text Available Faithful execution of developmental gene expression programs occurs at multiple levels and involves many different components such as transcription factors, histone-modification enzymes, and mRNA processing proteins. Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Overexpression of a dominant negative fragment of NUP98 levels decreases expression levels of NUP98-bound genes. In addition, we identify two modes of developmental gene regulation by NUP98 that are differentiated by the spatial localization of NUP98 target genes. Genes in the initial stage of developmental induction can associate with NUP98 that is embedded in the nuclear pores at the nuclear periphery. Alternatively, genes that are highly induced can interact with NUP98 in the nuclear interior, away from the nuclear pores. This work demonstrates for the first time that NUP98 dynamically associates with the human genome during differentiation, revealing a role of a nuclear pore protein in regulating developmental gene expression programs.

  15. Glutamatergic metabolites are associated with visual plasticity in humans.

    Science.gov (United States)

    Wijtenburg, S Andrea; West, Jeffrey; Korenic, Stephanie A; Kuhney, Franchesca; Gaston, Frank E; Chen, Hongji; Roberts, Meredith; Kochunov, Peter; Hong, L Elliot; Rowland, Laura M

    2017-02-10

    Long-term potentiation (LTP) is a basic cellular mechanism underlying learning and memory. LTP-like plasticity in the visual cortex can be induced by high frequency visual stimulation in rodents and humans. Since glutamate plays a fundamental role in LTP, this study investigated if visual cortical glutamate and glutamine levels, measured by proton magnetic resonance spectroscopy (MRS), relate to visual plasticity in humans. Since plasticity requires a delicate excitation and inhibition balance, GABA was also explored. Eighteen healthy participants completed MRS and a visual fMRI paradigm. Results revealed enhanced fMRI activations after high frequency visual stimulation, suggesting visual plasticity occurred. Higher activations were associated with higher resting glutamine levels after family wise error-correction. Exploratory analyses revealed that higher resting glutamate and GABA levels were associated with visual plasticity, suggesting there may be a critical excitation-inhibition balance necessary for experience dependent plasticity. This is the first empirical evidence that resting glutamine levels and potentially glutamate and GABA levels are associated with visual plasticity in humans.

  16. Evolutionary links between circadian clocks and photoperiodic diapause in insects.

    Science.gov (United States)

    Meuti, Megan E; Denlinger, David L

    2013-07-01

    In this article, we explore links between circadian clocks and the clock involved in photoperiodic regulation of diapause in insects. Classical resonance (Nanda-Hamner) and night interruption (Bünsow) experiments suggest a circadian basis for the diapause response in nearly all insects that have been studied. Neuroanatomical studies reveal physical connections between circadian clock cells and centers controlling the photoperiodic diapause response, and both mutations and knockdown of clock genes with RNA interference (RNAi) point to a connection between the clock genes and photoperiodic induction of diapause. We discuss the challenges of determining whether the clock, as a functioning module, or individual clock genes acting pleiotropically are responsible for the photoperiodic regulation of diapause, and how a stable, central circadian clock could be linked to plastic photoperiodic responses without compromising the clock's essential functions. Although we still lack an understanding of the exact mechanisms whereby insects measure day/night length, continued classical and neuroanatomical approaches, as well as forward and reverse genetic experiments, are highly complementary and should enable us to decipher the diverse ways in which circadian clocks have been involved in the evolution of photoperiodic induction of diapause in insects. The components of circadian clocks vary among insect species, and diapause appears to have evolved independently numerous times, thus, we anticipate that not all photoperiodic clocks of insects will interact with circadian clocks in the same fashion.

  17. Susceptibility of Redundant Versus Singular Clock Domains Implemented in SRAM-Based FPGA TMR Designs

    Science.gov (United States)

    Berg, Melanie D.; LaBel, Kenneth A.; Pellish, Jonathan

    2016-01-01

    We present the challenges that arise when using redundant clock domains due to their clock-skew. Radiation data show that a singular clock domain (DTMR) provides an improved TMR methodology for SRAM-based FPGAs over redundant clocks.

  18. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age

    Energy Technology Data Exchange (ETDEWEB)

    Keith, Dove; Finlay, Liam; Butler, Judy [Linus Pauling Institute, Oregon State University (United States); Gómez, Luis; Smith, Eric [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States); Moreau, Régis [Linus Pauling Institute, Oregon State University (United States); Hagen, Tory, E-mail: Tory.Hagen@oregonstate.edu [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States)

    2014-07-18

    Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.

  19. Sugars, the clock and transition to flowering

    Directory of Open Access Journals (Sweden)

    Mohammad Reza eBolouri Moghaddam

    2013-02-01

    Full Text Available Sugars do not only act as source of energy, but they also act as signals in plants. This mini review summarizes the emerging links between sucrose-mediated signaling and the cellular networks involved in flowering time control and defense. Cross-talks with gibberellin (GA and jasmonate (JA signaling pathways are highlighted. The circadian clock fulfills a crucial role at the heart of cellular networks and the bilateral relation between sugar signaling and the clock is discussed. It is proposed that important factors controlling plant growth (DELLAs, PIFs, invertases and trehalose- 6-phosphate or T6P might fulfill central roles in the transition to flowering as well. The emerging concept of ‘sweet immunity’, modulated by the clock, might at least partly rely on a sucrose-specific signaling pathway that needs further exploration.

  20. Quantum clock: A critical discussion on spacetime

    CERN Document Server

    Burderi, Luciano; Iaria, Rosario

    2016-01-01

    We critically discuss the measure of very short time intervals. By means of a Gedankenexperiment, we describe an ideal clock based on the occurrence of completely random events. Many previous thought experiments have suggested fundamental Planck-scale limits on measurements of distance and time. Here we present a new type of thought experiment, based on a different type of clock, that provide further support for the existence of such limits. We show that the minimum time interval $\\Delta t$ that this clock can measure scales as the inverse of its size $\\Delta r$. This implies an uncertainty relation between space and time: $\\Delta r$ $\\Delta t$ $> G \\hbar / c^4$; where G, $\\hbar$ and c are the gravitational constant, the reduced Planck constant, and the speed of light, respectively. We outline and briefly discuss the implications of this uncertainty conjecture.

  1. Models of the Primordial Standard Clock

    CERN Document Server

    Chen, Xingang; Wang, Yi

    2014-01-01

    Oscillating massive fields in the primordial universe can be used as Standard Clocks. The ticks of these oscillations induce features in the density perturbations, which directly record the time evolution of the scale factor of the primordial universe, thus if detected, provide a direct evidence for the inflation scenario or the alternatives. In this paper, we construct a full inflationary model of primordial Standard Clock and study its predictions on the density perturbations. This model provides a full realization of several key features proposed previously. We compare the theoretical predictions from inflation and alternative scenarios with the Planck 2013 temperature data on Cosmic Microwave Background (CMB), and identify a statistically marginal but interesting candidate. We discuss how future CMB temperature and polarization data, non-Gaussianity analysis and Large Scale Structure data may be used to further test or constrain the Standard Clock signals.

  2. Biogeographic calibrations for the molecular clock.

    Science.gov (United States)

    Ho, Simon Y W; Tong, K Jun; Foster, Charles S P; Ritchie, Andrew M; Lo, Nathan; Crisp, Michael D

    2015-09-01

    Molecular estimates of evolutionary timescales have an important role in a range of biological studies. Such estimates can be made using methods based on molecular clocks, including models that are able to account for rate variation across lineages. All clock models share a dependence on calibrations, which enable estimates to be given in absolute time units. There are many available methods for incorporating fossil calibrations, but geological and climatic data can also provide useful calibrations for molecular clocks. However, a number of strong assumptions need to be made when using these biogeographic calibrations, leading to wide variation in their reliability and precision. In this review, we describe the nature of biogeographic calibrations and the assumptions that they involve. We present an overview of the different geological and climatic events that can provide informative calibrations, and explain how such temporal information can be incorporated into dating analyses.

  3. Achieving shift work excellence: maximizing health, safety and operating efficiency in round-the-clock operations

    Energy Technology Data Exchange (ETDEWEB)

    Sirois, W. G. (circadian Technologies Ltd., Cambridge, MA (United States))

    1999-01-01

    Alertness Assurance techniques, Lifestyle Training and Shift Scheduling practices are described as weapons in the fight against the consequences of sleep deprivation and fatigue, higher operating risks , the adverse health, safety and quality of life effects on workers. Fatigue is a fundamental problem for all round-the-clock industries. The central message of this paper is that by making appropriate interventions and taking counter-measures to fatigue, the risks and liabilities of human error can be dramatically minimized through increased employee alertness, vigilance and cognitive reasoning skills around-the-clock. 12 refs., 1 fig.

  4. Behavioral responses associated with a human-mediated predator shelter.

    Directory of Open Access Journals (Sweden)

    Graeme Shannon

    Full Text Available Human activities in protected areas can affect wildlife populations in a similar manner to predation risk, causing increases in movement and vigilance, shifts in habitat use and changes in group size. Nevertheless, recent evidence indicates that in certain situations ungulate species may actually utilize areas associated with higher levels of human presence as a potential refuge from disturbance-sensitive predators. We now use four-years of behavioral activity budget data collected from pronghorn (Antilocapra americana and elk (Cervus elephus in Grand Teton National Park, USA to test whether predictable patterns of human presence can provide a shelter from predatory risk. Daily behavioral scans were conducted along two parallel sections of road that differed in traffic volume--with the main Teton Park Road experiencing vehicle use that was approximately thirty-fold greater than the River Road. At the busier Teton Park Road, both species of ungulate engaged in higher levels of feeding (27% increase in the proportion of pronghorn feeding and 21% increase for elk, lower levels of alert behavior (18% decrease for pronghorn and 9% decrease for elk and formed smaller groups. These responses are commonly associated with reduced predatory threat. Pronghorn also exhibited a 30% increase in the proportion of individuals moving at the River Road as would be expected under greater exposure to predation risk. Our findings concur with the 'predator shelter hypothesis', suggesting that ungulates in GTNP use human presence as a potential refuge from predation risk, adjusting their behavior accordingly. Human activity has the potential to alter predator-prey interactions and drive trophic-mediated effects that could ultimately impact ecosystem function and biodiversity.

  5. Timing of multiple overlapping intervals : How many clocks do we have?

    NARCIS (Netherlands)

    van Rijn, Hedderik; Taatgen, Niels A.

    2008-01-01

    Humans perceive and reproduce short intervals of time (e.g. 1-60 s) relatively accurately, and are capable of timing multiple overlapping intervals if these intervals are presented in different modalities [e.g., Rousseau, L., & Rousseau, RL (1996). Stop-reaction time and the internal clock. Percepti

  6. Sample-Clock Phase-Control Feedback

    Science.gov (United States)

    Quirk, Kevin J.; Gin, Jonathan W.; Nguyen, Danh H.; Nguyen, Huy

    2012-01-01

    To demodulate a communication signal, a receiver must recover and synchronize to the symbol timing of a received waveform. In a system that utilizes digital sampling, the fidelity of synchronization is limited by the time between the symbol boundary and closest sample time location. To reduce this error, one typically uses a sample clock in excess of the symbol rate in order to provide multiple samples per symbol, thereby lowering the error limit to a fraction of a symbol time. For systems with a large modulation bandwidth, the required sample clock rate is prohibitive due to current technological barriers and processing complexity. With precise control of the phase of the sample clock, one can sample the received signal at times arbitrarily close to the symbol boundary, thus obviating the need, from a synchronization perspective, for multiple samples per symbol. Sample-clock phase-control feedback was developed for use in the demodulation of an optical communication signal, where multi-GHz modulation bandwidths would require prohibitively large sample clock frequencies for rates in excess of the symbol rate. A custom mixedsignal (RF/digital) offset phase-locked loop circuit was developed to control the phase of the 6.4-GHz clock that samples the photon-counting detector output. The offset phase-locked loop is driven by a feedback mechanism that continuously corrects for variation in the symbol time due to motion between the transmitter and receiver as well as oscillator instability. This innovation will allow significant improvements in receiver throughput; for example, the throughput of a pulse-position modulation (PPM) with 16 slots can increase from 188 Mb/s to 1.5 Gb/s.

  7. Predicting human brain activity associated with the meanings of nouns.

    Science.gov (United States)

    Mitchell, Tom M; Shinkareva, Svetlana V; Carlson, Andrew; Chang, Kai-Min; Malave, Vicente L; Mason, Robert A; Just, Marcel Adam

    2008-05-30

    The question of how the human brain represents conceptual knowledge has been debated in many scientific fields. Brain imaging studies have shown that different spatial patterns of neural activation are associated with thinking about different semantic categories of pictures and words (for example, tools, buildings, and animals). We present a computational model that predicts the functional magnetic resonance imaging (fMRI) neural activation associated with words for which fMRI data are not yet available. This model is trained with a combination of data from a trillion-word text corpus and observed fMRI data associated with viewing several dozen concrete nouns. Once trained, the model predicts fMRI activation for thousands of other concrete nouns in the text corpus, with highly significant accuracies over the 60 nouns for which we currently have fMRI data.

  8. Education of dietitian's in Brazil: Minimum clock hours of instruction for a bachelor's degree in nutrition

    Directory of Open Access Journals (Sweden)

    Maria Angélica Tavares de Medeiros

    2013-10-01

    Full Text Available This essay aims to debate the minimum clock hours of instruction necessary for obtaining a bachelor's degree in nutrition considering the challenges to educate health professionals. Official documents on the minimum clock hours of instruction required by undergraduate nutrition programs were analyzed to investigate compliance with the curriculum guidelines for the area, the law that regulates the profession of dietitian, and the necessary education for the Sistema Único de Saúde (Unified Health Care System. Compared with other health programs, nutrition presented the smallest increase in the minimum clock hours of instruction required for the degree. The changes that occurred in the epidemiological, demographic, and nutritional profile of the population and scientific advances require specific nutrition actions. Since Sistema Único de Saúde focuses on comprehensiveness in the three levels of care, on humanization, and on health care, the theoretical and methodological concepts given in undergraduate programs need to be improved for the dietitians education to meet the Sistema Único de Saúde needs. Incorporation of the knowledge needed for working with food and nutritional phenomena, including its social and cultural dimensions, management of public policies, quantity cooking, and food and nutritional surveillance requires a higher minimum clock hours of instruction. In conclusion, dietitians need a minimum clock hours of instruction of 4,000 to acquire a proper education, integrate into the university life, and coordinate interdisciplinary experiences of the triad teaching/research/extension.

  9. Remodeling the clock: coactivators and signal transduction in the circadian clockworks

    Science.gov (United States)

    Weber, Frank

    2009-03-01

    Most organisms on earth such as cyanobacteria, fungi, plants, insects, animals, and humans synchronize their physiological and behavioral activities with the environmental cycles of day and night. Significant progress has been made in unraveling the genetic components that constitute a molecular circadian clock, which facilitates the temporal control of physiology and behavior. Clock genes assemble interlocked transcriptional/translational feedback loops that underlie the circadian oscillations. Recent investigations revealed that posttranslational regulation of clock proteins is crucial for functioning of the molecular oscillator and for precise temporal control of circadian transcription. This review provides an overview of the homologous clockworks in Drosophila and mammals, with a special focus on recent insights in the posttranslational regulation of clock proteins as well as the role of coactivators, repressors, and signal transduction for circadian controlled genome-wide transcription. The emerging mechanisms of clock gene regulation provide an understanding of the temporal control of transcription in general and the circadian orchestration of physiology and behavior in particular.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Hayashi, Akane; Matsunaga, Naoya; Okazaki, Hiroyuki; Kakimoto, Keisuke; Kimura, Yoshinori; Azuma, Hiroki; Ikeda, Eriko; Shiba, Takeshi; Yamato, Mayumi; Yamada, Ken-Ichi; Koyanagi, Satoru; Ohdo, Shigehiro

    2013-06-01

    Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum. Although the motor symptoms are still regarded as the main problem, non-motor symptoms in PD also markedly impair the quality of life. Several non-motor symptoms, such as sleep disturbances and depression, are suggested to be implicated in the alteration in circadian clock function. In this study, we investigated circadian disruption and the mechanism in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-treated mice exhibited altered 24-h rhythms in body temperature and locomotor activity. In addition, MPTP treatment also affected the circadian clock system at the genetic level. The exposure of human neuroblastoma cells (SH-SY5Y) to 1-metyl-4-phenylpyridinium (MPP(+)) increased or decreased the mRNA levels of several clock genes in a dose-dependent manner. MPP(+)-induced changes in clock genes expression were reversed by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Most importantly, addition of ATP to the drinking water of MPTP-treated mice attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK activation and prevented circadian disruption. The present findings suggest that the activation of AMPK caused circadian dysfunction, and ATP may be a novel therapeutic strategy based on the molecular clock in PD.

  12. Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth

    Directory of Open Access Journals (Sweden)

    Celine eFeillet

    2015-05-01

    Full Text Available Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumour growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.

  13. Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth.

    Science.gov (United States)

    Feillet, Celine; van der Horst, Gijsbertus T J; Levi, Francis; Rand, David A; Delaunay, Franck

    2015-01-01

    Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.

  14. Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

    Science.gov (United States)

    He, Lan; Hamm, J Austin; Reddy, Alex; Sams, David; Peliciari-Garcia, Rodrigo A; McGinnis, Graham R; Bailey, Shannon M; Chow, Chi-Wing; Rowe, Glenn C; Chatham, John C; Young, Martin E

    2016-06-01

    Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.

  15. Secure and self-stabilizing clock synchronization in sensor networks

    NARCIS (Netherlands)

    Hoepman, J.H.; Larsson, A.; Schiller, E.M.; Tsigas, P.

    2007-01-01

    In sensor networks, correct clocks have arbitrary starting offsets and nondeterministic fluctuating skews. We consider an adversary that aims at tampering with the clock synchronization by intercepting messages, replaying intercepted messages (after the adversary's choice of delay), and capturing no

  16. Analysis of the performance of hydrogen maser clocks at the ...

    African Journals Online (AJOL)

    Cilence

    clock characteristics have a direct influence on precision and accuracy of the ..... Generation Atomic Fountain Clock at NIST', Proceedings of the 2004 IEEE International ... Plag H-P, Altamimi Z, Bettadpur S, Beutler G, Beyerle G, Cazenve A, ...

  17. Unusual Maths clock or Reverse Traveling Salesman Problem

    Directory of Open Access Journals (Sweden)

    Valerij F. Ochkov

    2014-01-01

    Full Text Available The article discusses some of the mathematical problem, attached to the clock. We show how to use the clock in the classroom for mathematics to illustrate some mathematical problems 

  18. Genome-Wide Association Studies of the Human Gut Microbiota.

    Directory of Open Access Journals (Sweden)

    Emily R Davenport

    Full Text Available The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both. These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%. For example, we identified an association between a taxon known to affect obesity (genus Akkermansia and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7. Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut.

  19. Clocking Scheme for Switched-Capacitor Circuits

    DEFF Research Database (Denmark)

    Steensgaard-Madsen, Jesper

    1998-01-01

    A novel clocking scheme for switched-capacitor (SC) circuits is presented. It can enhance the understanding of SC circuits and the errors caused by MOSFET (MOS) switches. Charge errors, and techniques to make SC circuits less sensitive to them are discussed.......A novel clocking scheme for switched-capacitor (SC) circuits is presented. It can enhance the understanding of SC circuits and the errors caused by MOSFET (MOS) switches. Charge errors, and techniques to make SC circuits less sensitive to them are discussed....

  20. The Large Water-Clock of Amphiaraeion

    Science.gov (United States)

    Theodossiou, E.; Manimanis, V. N.; Katsiotis, M.; Mantarakis, P.

    2010-07-01

    A very well preserved ancient water-clock exists at the Amphiaraeion, in Oropos, Greece. The Amphiaraeion, sanctuary of the mythical oracle and deified healer Amphiaraus, was active from the pre-classic period until the 5th Century A.D. In such a place the measurement of time, both day and night, was a necessity. Therefore, time was kept with both a conical sundial and a water-clock in the shape of a fountain, which, according to the archaeologists, dates to the 4th Century B.C.

  1. Mutations in inhibin and activin genes associated with human disease.

    Science.gov (United States)

    Shelling, Andrew N

    2012-08-15

    Inhibins and activins are members of the transforming growth factor (TGFβ) superfamily, that includes the TGFβs, inhibins and activins, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). The family members are expressed throughout the human body, and are involved in the regulation of a range of important functions. The precise regulation of the TGFβ pathways is critical, and mutations of individual molecules or even minor alterations of signalling will have a significant affect on function, that may lead to development of disease or predisposition to the development of disease. The inhibins and activins regulate aspects of the male and female reproductive system, therefore, it is not surprising that most of the diseases associated with abnormalities of the inhibin and activin genes are focused on reproductive disorders and reproductive cancers. In this review, I highlight the role of genetic variants in the development of conditions such as premature ovarian failure, pre-eclampsia, and various reproductive cancers. Given the recent advances in human genetic research, such as genome wide association studies and next generation sequencing, it is likely that inhibins and activins will be shown to play more important roles in a range of human genetic diseases in the future.

  2. Immunometabolism: Is it under the eye of the clock?

    OpenAIRE

    Early, James O.; Curtis, Anne M.

    2016-01-01

    Molecular clocks allow an organism to track time of day, providing the means to anticipate and respond to the daily changes within the environment. In mammals the molecular clock consists of a network of proteins that form auto-regulatory feedback loops that drive rhythms in physiology and behavior. In recent times the extent to which the molecular clock controls key metabolic and immune pathways has begun to emerge. For example, the main clock protein BMAL1 has been linked to mitochondrial m...

  3. Overview of Emerging Contaminants and Associated Human Health Effects

    Directory of Open Access Journals (Sweden)

    Meng Lei

    2015-01-01

    Full Text Available In recent decades, because of significant progress in the analysis and detection of trace pollutants, emerging contaminants have been discovered and quantified in living beings and diverse environmental substances; however, the adverse effects of environmental exposure on the general population are largely unknown. This review summarizes the conclusions of the comprehensive epidemic literature and representative case reports relevant to emerging contaminants and the human body to address concerns about potential harmful health effects in the general population. The most prevalent emerging contaminants include perfluorinated compounds, water disinfection byproducts, gasoline additives, manufactured nanomaterials, human and veterinary pharmaceuticals, and UV-filters. Rare but statistically meaningful connections have been reported for a number of contaminants and cancer and reproductive risks. Because of contradictions in the outcomes of some investigations and the limited number of articles, no significant conclusions regarding the relationship between adverse effects on humans and extents of exposure can be drawn at this time. Here, we report that the current evidence is not conclusive and comprehensive and suggest prospective cohort studies in the future to evaluate the associations between human health outcomes and emerging environmental contaminants.

  4. Overview of Emerging Contaminants and Associated Human Health Effects.

    Science.gov (United States)

    Lei, Meng; Zhang, Lun; Lei, Jianjun; Zong, Liang; Li, Jiahui; Wu, Zheng; Wang, Zheng

    2015-01-01

    In recent decades, because of significant progress in the analysis and detection of trace pollutants, emerging contaminants have been discovered and quantified in living beings and diverse environmental substances; however, the adverse effects of environmental exposure on the general population are largely unknown. This review summarizes the conclusions of the comprehensive epidemic literature and representative case reports relevant to emerging contaminants and the human body to address concerns about potential harmful health effects in the general population. The most prevalent emerging contaminants include perfluorinated compounds, water disinfection byproducts, gasoline additives, manufactured nanomaterials, human and veterinary pharmaceuticals, and UV-filters. Rare but statistically meaningful connections have been reported for a number of contaminants and cancer and reproductive risks. Because of contradictions in the outcomes of some investigations and the limited number of articles, no significant conclusions regarding the relationship between adverse effects on humans and extents of exposure can be drawn at this time. Here, we report that the current evidence is not conclusive and comprehensive and suggest prospective cohort studies in the future to evaluate the associations between human health outcomes and emerging environmental contaminants.

  5. Association between living environment and human oral viral ecology.

    Science.gov (United States)

    Robles-Sikisaka, Refugio; Ly, Melissa; Boehm, Tobias; Naidu, Mayuri; Salzman, Julia; Pride, David T

    2013-09-01

    The human oral cavity has an indigenous microbiota known to include a robust community of viruses. Very little is known about how oral viruses are spread throughout the environment or to which viruses individuals are exposed. We sought to determine whether shared living environment is associated with the composition of human oral viral communities by examining the saliva of 21 human subjects; 11 subjects from different households and 10 unrelated subjects comprising 4 separate households. Although there were many viral homologues shared among all subjects studied, there were significant patterns of shared homologues in three of the four households that suggest shared living environment affects viral community composition. We also examined CRISPR (clustered regularly interspaced short palindromic repeat) loci, which are involved in acquired bacterial and archaeal resistance against invading viruses by acquiring short viral sequences. We analyzed 2 065 246 CRISPR spacers from 5 separate repeat motifs found in oral bacterial species of Gemella, Veillonella, Leptotrichia and Streptococcus to determine whether individuals from shared living environments may have been exposed to similar viruses. A significant proportion of CRISPR spacers were shared within subjects from the same households, suggesting either shared ancestry of their oral microbiota or similar viral exposures. Many CRISPR spacers matched virome sequences from different subjects, but no pattern specific to any household was found. Our data on viromes and CRISPR content indicate that shared living environment may have a significant role in determining the ecology of human oral viruses.

  6. Brain expression genome-wide association study (eGWAS identifies human disease-associated variants.

    Directory of Open Access Journals (Sweden)

    Fanggeng Zou

    Full Text Available Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202 and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197. We conducted an expression genome-wide association study (eGWAS using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5-1.67 × 10(-82. Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5-1.70 × 10(-141. The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6. We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6 of significant cisSNPs with suggestive AD-risk association (p<10(-3 in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings

  7. Association between osteopontin and human abdominal aortic aneurysm.

    Science.gov (United States)

    Golledge, Jonathan; Muller, Juanita; Shephard, Neil; Clancy, Paula; Smallwood, Linda; Moran, Corey; Dear, Anthony E; Palmer, Lyle J; Norman, Paul E

    2007-03-01

    In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated. OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P=0.004) for the population cohort and 4.08 (1.67 to 10.00, P=0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P=0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion. Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth.

  8. Epigenetic changes in virus-associated human cancers

    Institute of Scientific and Technical Information of China (English)

    Hsin Pai LI; Yu Wei LEU; Yu Sun CHANG

    2005-01-01

    Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding of specific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is a prevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increased activity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players in regulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing and the signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus 40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection of epigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigenetic changes should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection,prognosis, and therapy of cancer.

  9. Oral lesions associated with human immunodeficiency virus disease.

    Science.gov (United States)

    Patton, Lauren L

    2013-10-01

    Human immunodeficiency virus (HIV)-associated oral disease among people living with HIV infection includes oral candidiasis, oral hairy leukoplakia, Kaposi sarcoma, oral warts, herpes simplex virus ulcers, major aphthous ulcers or ulcers not otherwise specified, HIV salivary gland disease, and atypical gingival and periodontal diseases. Diagnosis of some oral lesions is based on clinical appearance and behavior, whereas others require biopsy, culture, or imaging for definitive diagnosis. Management strategies including pharmacologic and nonpharmacologic approaches are discussed in this article. Dentists also need to be cognizant of the potential oral side effects of HIV antiretroviral medications.

  10. Porokeratoma: A Possible Association with Human Papillomavirus Infection

    Directory of Open Access Journals (Sweden)

    Patricia Caseiro Silverio

    2015-04-01

    Full Text Available Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe the case of a 52-year-old male patient who presented with four well-defined, verrucous and hyperkeratotic lesions. Microscopically, one of the lesions showed acanthopapillomatosis overlying compact orthokeratosis. Prominent broad and confluent cornoid lamellae were present, with no granular layer and some dyskeratotic keratinocytes. PCR sequencing and in situ hybridization revealed the presence of human papillomavirus (HPV type 16 in the lesion. The association of porokeratoma and HPV infection has not previously been reported.

  11. Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal.

    Science.gov (United States)

    Putker, Marrit; O'Neill, John Stuart

    2016-01-01

    Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redox-sensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian time-keeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological time-keeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.

  12. Autonomous Quantum Clocks: Does Thermodynamics Limit Our Ability to Measure Time?

    Science.gov (United States)

    Erker, Paul; Mitchison, Mark T.; Silva, Ralph; Woods, Mischa P.; Brunner, Nicolas; Huber, Marcus

    2017-07-01

    Time remains one of the least well-understood concepts in physics, most notably in quantum mechanics. A central goal is to find the fundamental limits of measuring time. One of the main obstacles is the fact that time is not an observable and thus has to be measured indirectly. Here, we explore these questions by introducing a model of time measurements that is complete and autonomous. Specifically, our autonomous quantum clock consists of a system out of thermal equilibrium—a prerequisite for any system to function as a clock—powered by minimal resources, namely, two thermal baths at different temperatures. Through a detailed analysis of this specific clock model, we find that the laws of thermodynamics dictate a trade-off between the amount of dissipated heat and the clock's performance in terms of its accuracy and resolution. Our results furthermore imply that a fundamental entropy production is associated with the operation of any autonomous quantum clock, assuming that quantum machines cannot achieve perfect efficiency at finite power. More generally, autonomous clocks provide a natural framework for the exploration of fundamental questions about time in quantum theory and beyond.

  13. 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.

  14. LUX ARRHYTHMO encodes a nighttime repressor of circadian gene expression in the Arabidopsis core clock.

    Science.gov (United States)

    Helfer, Anne; Nusinow, Dmitri A; Chow, Brenda Y; Gehrke, Andrew R; Bulyk, Martha L; Kay, Steve A

    2011-01-25

    Circadian clocks provide an adaptive advantage by allowing organisms to anticipate daily and seasonal environmental changes [1, 2]. Eukaryotic oscillators rely on complex hierarchical networks composed of transcriptional and posttranslational regulatory circuits [3]. In Arabidopsis, current representations of the circadian clock consist of three or four interlocked transcriptional feedback loops [3, 4]. Although molecular components contributing to different domains of these circuits have been described, how the loops are connected at the molecular level is not fully understood. Genetic screens previously identified LUX ARRHYTHMO (LUX) [5], also known as PHYTOCLOCK1 (PCL1) [6], an evening-expressed putative transcription factor essential for circadian rhythmicity. We determined the in vitro DNA-binding specificity for LUX by using universal protein binding microarrays; we then demonstrated that LUX directly regulates the expression of PSEUDO RESPONSE REGULATOR9 (PRR9), a major component of the morning transcriptional feedback circuit, through association with the newly discovered DNA binding site. We also show that LUX binds to its own promoter, defining a new negative autoregulatory feedback loop within the core clock. These novel connections between the archetypal loops of the Arabidopsis clock represent a significant advance toward defining the molecular dynamics underlying the circadian network in plants and provide the first mechanistic insight into the molecular function of the previously orphan clock factor LUX.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    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.

  16. Conserved function of core clock proteins in the gymnosperm Norway spruce (Picea abies L. Karst).

    Science.gov (United States)

    Karlgren, Anna; Gyllenstrand, Niclas; Källman, Thomas; Lagercrantz, Ulf

    2013-01-01

    From studies of the circadian clock in the plant model species Arabidopsis (Arabidopsis thaliana), a number of important properties and components have emerged. These include the genes CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), GIGANTEA (GI), ZEITLUPE (ZTL) and TIMING OF CAB EXPRESSION 1 (TOC1 also known as PSEUDO-RESPONSE REGULATOR 1 (PRR1)) that via gene expression feedback loops participate in the circadian clock. Here, we present results from ectopic expression of four Norway spruce (Picea abies) putative homologs (PaCCA1, PaGI, PaZTL and PaPRR1) in Arabidopsis, their flowering time, circadian period length, red light response phenotypes and their effect on endogenous clock genes were assessed. For PaCCA1-ox and PaZTL-ox the results were consistent with Arabidopsis lines overexpressing the corresponding Arabidopsis genes. For PaGI consistent results were obtained when expressed in the gi2 mutant, while PaGI and PaPRR1 expressed in wild type did not display the expected phenotypes. These results suggest that protein function of PaCCA1, PaGI and PaZTL are at least partly conserved compared to Arabidopsis homologs, however further studies are needed to reveal the protein function of PaPRR1. Our data suggest that components of the three-loop network typical of the circadian clock in angiosperms were present before the split of gymnosperms and angiosperms.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Zhu, Zhu; Hua, Bingxuan; Shang, Zhanxian; Yuan, Gongsheng; Xu, Lirong; Li, Ermin; Li, Xiaobo; Sun, Ning; Yan, Zuoqin; Qian, Ruizhe; Lu, Chao

    2016-01-01

    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.

  19. Synchrony of plant cellular circadian clocks with heterogeneous properties under light/dark cycles.

    Science.gov (United States)

    Okada, Masaaki; Muranaka, Tomoaki; Ito, Shogo; Oyama, Tokitaka

    2017-03-22

    Individual cells in a plant can work independently as circadian clocks, and their properties are the basis of various circadian phenomena. The behaviour of individual cellular clocks in Lemna gibba was orderly under 24-h light/dark cycles despite their heterogeneous free-running periods (FRPs). Here, we reveal the entrainment habits of heterogeneous cellular clocks using non-24-h light/dark cycles (T-cycles). The cellular rhythms of AtCCA1::LUC under T = 16 h cycles showed heterogeneous entrainment that was associated with their heterogeneous FRPs. Under T = 12 h cycles, most cells showed rhythms having ~24-h periods. This suggested that the lower limit of entrainment to the light/dark cycles of heterogeneous cellular circadian clocks is set to a period longer than 12 h, which enables them to be synchronous under ~24-h daily cycles without being perturbed by short light/dark cycles. The entrainment habits of individual cellular clocks are likely to be the basis of the circadian behaviour of plant under the natural day-night cycle with noisy environmental fluctuations. We further suggest that modifications of EARLY FLOWERING3 (ELF3) in individual cells deviate the entrainability to shorter T-cycles possibly by altering both the FRPs and light responsiveness.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. Disrupted Ultradian Activity Rhythms and Differential Expression of Several Clock Genes in Interleukin-6-Deficient Mice

    Science.gov (United States)

    Monje, Francisco J.; Cicvaric, Ana; Acevedo Aguilar, Juan Pablo; Elbau, Immanuel; Horvath, Orsolya; Diao, Weifei; Glat, Micaela; Pollak, Daniela D.

    2017-01-01

    The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer’s disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders.

  2. The salient features of the clock

    DEFF Research Database (Denmark)

    Ebbesen, Toke Riis

    2005-01-01

    of functional semiotics is explained in short terms and then further demonstrated in the analysis of a basic mechanical alarm clock. On this ground, the digital watch and digital design products in general are characterised and three possible avenues for the interpretation of the interactive possibilities...

  3. Circadian clocks: Omnes viae Romam ducunt.

    Science.gov (United States)

    Roenneberg, T; Merrow, M

    2000-10-19

    The circadian clock in all organisms is so intimately linked to light reception that it appears as if evolution has simply wired a timer into the mechanism that processes photic information. Several recent studies have provided new insights into the role of light input pathways in the circadian system of Arabidopsis.

  4. The mammalian retina as a clock

    Science.gov (United States)

    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.

  5. Radium single-ion optical clock

    NARCIS (Netherlands)

    Versolato, O. O.; Wansbeek, L. W.; Jungmann, K.; Timmermans, R. G. E.; Willmann, L.; Wilschut, H. W.

    2011-01-01

    We explore the potential of the electric quadrupole transitions $7s\\,^2S_{1/2}$ - $6d\\,^2D_{3/2}$, $6d\\,^2D_{5/2}$ in radium isotopes as single-ion optical frequency standards. The frequency shifts of the clock transitions due to external fields and the corresponding uncertainties are calculated.

  6. Biochemical basis for the biological clock

    Science.gov (United States)

    Morre, D. James; Chueh, Pin-Ju; Pletcher, Jake; Tang, Xiaoyu; Wu, Lian-Ying; Morre, Dorothy M.

    2002-01-01

    NADH oxidases at the external surface of plant and animal cells (ECTO-NOX proteins) exhibit stable and recurring patterns of oscillations with potentially clock-related, entrainable, and temperature-compensated period lengths of 24 min. To determine if ECTO-NOX proteins might represent the ultradian time keepers (pacemakers) of the biological clock, COS cells were transfected with cDNAs encoding tNOX proteins having a period length of 22 min or with C575A or C558A cysteine to alanine replacements having period lengths of 36 or 42 min. Here we demonstrate that such transfectants exhibited 22, 36, or 40 to 42 h circadian patterns in the activity of glyceraldehyde-3-phosphate dehydrogenase, a common clock-regulated protein, in addition to the endogenous 24 h circadian period length. The fact that the expression of a single oscillatory ECTO-NOX protein determines the period length of a circadian biochemical marker (60 X the ECTO-NOX period length) provides compelling evidence that ECTO-NOX proteins are the biochemical ultradian drivers of the cellular biological clock.

  7. Internal clock formulation of quantum mechanics

    Science.gov (United States)

    Małkiewicz, Przemysław; Miroszewski, Artur

    2017-08-01

    The basic tenet of the present work is the assumption of the lack of external and fixed time in the Universe. This assumption is best embodied by general relativity, which replaces the fixed space-time structure with the gravitational field, which is subject to dynamics. The lack of time does not imply the lack of evolution but rather brings to the forefront the role of internal clocks which are some largely arbitrary internal degrees of freedom with respect to which the evolution of timeless systems can be described. We take this idea seriously and try to understand what it implies for quantum mechanics when the fixed external time is replaced by an arbitrary internal clock. We put the issue in a solid, mathematically rigorous framework. We find that the dynamical interpretation of a quantum state of a timeless system depends on the employed internal clock. In particular, we find that the continuous spectra of well-known dynamical observables like the position of a free particle on the real line may turn discrete if measured in unusual clocks. We discuss the meaning of our result for attempts at quantization of global gravitational degrees of freedom.

  8. Circadian clocks - from genes to complex behaviour

    NARCIS (Netherlands)

    Roenneberg, Till; Merrow, Martha

    1999-01-01

    Circadian clocks control temporal structure in practically all organisms and on all levels of biology, from gene expression to complex behaviour and cognition. Over the last decades, research has begun to unravel the physiological and, more recently, molecular mechanisms that underlie this endogenou

  9. The Rubidium Atomic Clock and Basic Research

    Science.gov (United States)

    2007-12-10

    photodetector . (Chip-scale clock image from ref. 14.) 38 November 2007 Physics Today www.physicstoday.org an all-optical fashion:13 The laser field is...spectroscopy, laser chemistry, atmospheric propagation and beam control, LIDAR /LADAR remote sensing; solar cell and array testing and evaluation, battery

  10. Using circadian entrainment to find cryptic clocks

    NARCIS (Netherlands)

    Eelderink-Chen, Zheng; Olmedo, Maria; Bosman, Jasper; Merrow, Martha

    2015-01-01

    Three properties are most often attributed to the circadian clock: a ca. 24-h free-running rhythm, temperature compensation of the circadian rhythm, and its entrainment to zeitgeber cycles. Relatively few experiments, however, are performed under entrainment conditions. Rather, most chronobiology pr

  11. Current Status of the Molecular Clock Hypothesis

    Science.gov (United States)

    Hermann, Gilbert

    2003-01-01

    Molecular genetics is a rapidly changing field with new developments almost from day to day. One interesting hypothesis that has come from everyone's ability to sequence proteins and/or genes is that of the molecular clock. This hypothesis postulates that homologous sequences of DNA and thus macro molecules evolve at a constant and invariable rate…

  12. Clock Synchronization for Multihop Wireless Sensor Networks

    Science.gov (United States)

    Solis Robles, Roberto

    2009-01-01

    In wireless sensor networks, more so generally than in other types of distributed systems, clock synchronization is crucial since by having this service available, several applications such as media access protocols, object tracking, or data fusion, would improve their performance. In this dissertation, we propose a set of algorithms to achieve…

  13. Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock".

    NARCIS (Netherlands)

    Wu, Y.-H.; Fischer, D.F.; Kalsbeek, A.; Garidou-Boof, M.-L.; Vliet, J. van der; Heijningen, C. van; Liu, R.-Y.; Zhou, J.-N.; Swaab, D.F.

    2006-01-01

    The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD

  14. Clock measurements to improve the geopotential determination

    Science.gov (United States)

    Lion, Guillaume; Panet, Isabelle; Delva, Pacôme; Wolf, Peter; Bize, Sébastien; Guerlin, Christine

    2017-04-01

    Comparisons between optical clocks with an accuracy and stability approaching the 10-18 in term of relative frequency shift are opening new perspectives for the direct determination of geopotential at a centimeter-level accuracy in geoid height. However, so far detailed quantitative estimates of the possible improvement in geoid determination when adding such clock measurements to existing data are lacking. In this context, the present work aims at evaluating the contribution of this new kind of direct measurements in determining the geopotential at high spatial resolution (10 km). We consider the Massif Central area, marked by smooth, moderate altitude mountains and volcanic plateaus leading to variations of the gravitational field over a range of spatial scales. In such type of region, the scarcity of gravity data is an important limitation in deriving accurate high resolution geopotential models. We summarize our methodology to assess the contribution of clock data in the geopotential recovery, in combination with ground gravity measurements. We sample synthetic gravity and disturbing potential data from a spherical harmonics geopotential model, and a topography model, up to 10 km resolution; we also build a potential control grid. From the synthetic data, we estimate the disturbing potential by least-squares collocation. Finally, we assess the quality of the reconstructed potential by comparing it to that of the control grid. We show that adding only a few clock data reduces the reconstruction bias significantly and improves the standard deviation by a factor 3. We discuss the role of different parameters, such as the effect of the data coverage and data quality on these results, the trade-off between the measurement noise level and the number of data, and the optimization of the clock data network.

  15. Maximum likelihood molecular clock comb: analytic solutions.

    Science.gov (United States)

    Chor, Benny; Khetan, Amit; Snir, Sagi

    2006-04-01

    Maximum likelihood (ML) is increasingly used as an optimality criterion for selecting evolutionary trees, but finding the global optimum is a hard computational task. Because no general analytic solution is known, numeric techniques such as hill climbing or expectation maximization (EM), are used in order to find optimal parameters for a given tree. So far, analytic solutions were derived only for the simplest model--three taxa, two state characters, under a molecular clock. Four taxa rooted trees have two topologies--the fork (two subtrees with two leaves each) and the comb (one subtree with three leaves, the other with a single leaf). In a previous work, we devised a closed form analytic solution for the ML molecular clock fork. In this work, we extend the state of the art in the area of analytic solutions ML trees to the family of all four taxa trees under the molecular clock assumption. The change from the fork topology to the comb incurs a major increase in the complexity of the underlying algebraic system and requires novel techniques and approaches. We combine the ultrametric properties of molecular clock trees with the Hadamard conjugation to derive a number of topology dependent identities. Employing these identities, we substantially simplify the system of polynomial equations. We finally use tools from algebraic geometry (e.g., Gröbner bases, ideal saturation, resultants) and employ symbolic algebra software to obtain analytic solutions for the comb. We show that in contrast to the fork, the comb has no closed form solutions (expressed by radicals in the input data). In general, four taxa trees can have multiple ML points. In contrast, we can now prove that under the molecular clock assumption, the comb has a unique (local and global) ML point. (Such uniqueness was previously shown for the fork.).

  16. Non-Human Primates Harbor Diverse Mammalian and Avian Astroviruses Including Those Associated with Human Infections.

    Directory of Open Access Journals (Sweden)

    Erik A Karlsson

    Full Text Available Astroviruses (AstVs are positive sense, single-stranded RNA viruses transmitted to a wide range of hosts via the fecal-oral route. The number of AstV-infected animal hosts has rapidly expanded in recent years with many more likely to be discovered because of the advances in viral surveillance and next generation sequencing. Yet no study to date has identified human AstV genotypes in animals, although diverse AstV genotypes similar to animal-origin viruses have been found in children with diarrhea and in one instance of encephalitis. Here we provide important new evidence that non-human primates (NHP can harbor a wide variety of mammalian and avian AstV genotypes, including those only associated with human infection. Serological analyses confirmed that >25% of the NHP tested had antibodies to human AstVs. Further, we identified a recombinant AstV with parental relationships to known human AstVs. Phylogenetic analysis suggests AstVs in NHP are on average evolutionarily much closer to AstVs from other animals than are AstVs from bats, a frequently proposed reservoir. Our studies not only demonstrate that human astroviruses can be detected in NHP but also suggest that NHP are unique in their ability to support diverse AstV genotypes, further challenging the paradigm that astrovirus infection is species-specific.

  17. Survival of human-associated bacteria in SLS

    Science.gov (United States)

    Fu, Yuming; Tikhomirov, Alexander A.; Nickolay Manukovsky, D..; Khizhnyak, Sergey; Kovalev, Vladimir

    2016-07-01

    Management of microbial communities to minimize the potential for risk to the crew and to the plants to be used for supporting the crew is an essential component of successful bioregenerative life support systems (BLSS). Previously it was shown that soil-like substrate (SLS), obtained as a result of bioconversion of non-edible plant biomass in the higher plants based BLSS, demonstrates strong anti-fungal activity against soil-borne plant pathogens (Nesterenko et al., 2009). The present study is devoted to the estimation of anti-bacterial activity of SLS against gram-negative (presented with Escherichia coli) and gram-positive (presented with Staphylococcus aureus) human-associated bacteria, both of which belong to the group of opportunistic pathogen. In vitro effects of different types of SLS on E. coli and S. aureus and in situ survival curves of the bacteria with corresponding math models are presented. Additionally we have examined the influence of community richness (the indigenous community of SLS) on the ability of introduced human-associated bacteria to persist within SLS. The work was carried out within the frames of the state task on the subject No 56.1.4 of the Basic Research Program (Section VI) of Russian State Academies for 2013-2020.

  18. Suppression of Clock Shifts at Magnetic-Field-Insensitive Transitions

    Science.gov (United States)

    Arnold, K. J.; Barrett, M. D.

    2016-10-01

    We show that it is possible to significantly reduce rank 2 tensor shifts of a clock transition by operating at a judiciously chosen magnetic-field-insensitive point. In some cases shifts are almost completely eliminated making the transition an effective J =0 to J =0 candidate. This significantly improves the feasibility of a recent proposal for clock operation with large ion crystals. For such multi-ion clocks, geometric constraints and selection rules naturally divide clock operation into two categories based on the orientation of the magnetic field. We discuss the limitations imposed on each type and how calibrations might be carried out for clock operation.

  19. Suppression of clock shifts at field-insensitive transitions

    CERN Document Server

    Arnold, Kyle J

    2016-01-01

    We show that it is possible to significantly reduce quadrupole and tensor polarizability shifts of a clock transition by operating at a judiciously chosen field-insensitive point. In some cases shifts are almost completely eliminated making the transition an effective J = 0 to J = 0 candidate. This significantly improves the feasibility of a recent proposal for clock operation with large ion crystals. For such multi-ion clocks, geometric constraints and selection rules naturally divide clock operation into two categories based on the orientation of the magnetic field. We discuss the limitations imposed on each type and how calibrations might be carried out for clock operation.

  20. Prevalence of lipodystrophy associated with human recombinant insulin

    Directory of Open Access Journals (Sweden)

    S. Akbarzadeh

    2008-01-01

    Full Text Available AbstractBackground and Purpose: Lipodystrophy is potentially a clinical adverse effect, associated with insulin therapy and is believed that usage of human recombinant insulin’s is associated with decreasing prevalence of Lipodystrophy. The objective of this study was to determine the prevalence of insulin induced Lipodystrophy, among diabetic out-patients referred to Imam Khomeini Hospital, in Sari during 2007.Materials and Methods: In this cross sectional descriptive study, 220 diabetic patients referred to the Diabetes Center at Imam Khomeini Hospital, in Sari, who under treatment by insulin at least three months prior to referral was evaluated.First, the demographic and clinical characteristics of the patients were recorded in a questionnaire; then all patients were examined clinically to evaluate lipodystrophy. In all subjects, glycated hemoglobin (HbA1C was measured to assess the range of blood glucose level control. Recorded data were analyzed by statistical methods, such as descriptive T-test and X².Results: Of 220 diabetic patients studied, thirty-five (15.9% showed clinical evidences of insulin induced Lipodystrophy; 32 out of 35 cases of Lipodystrophic patients (14.5% had Lipohypertrophy, while 3 cases (1.4% had Lipoatrophy.The factors included Age, Sex, Education, BMI (Body mass index, type of Diabetes, The duration of insulin consumption and injection site had statistically significant effects on development of insulin induced Lipodystrophy (P<0.05.Conclusion: The results of this study demonstrated that despite using human recombinant insulin’s, the prevalence of insulin induced lipodystrophy, especially Lipohypertrophy, has remained high up to present. Therefore, regular examination of patients for this side effect is necessary, especially in subjects without good control of blood glucose level.Prevalence of lipodystrophy associated with human recombinant insulinZ. Kashi, M.D. + Z. Hajheydari, M.D.* O. Akha, M.D. * S

  1. A methyl transferase links the circadian clock to the regulation of alternative splicing.

    Science.gov (United States)

    Sanchez, Sabrina E; Petrillo, Ezequiel; Beckwith, Esteban J; Zhang, Xu; Rugnone, Matias L; Hernando, C Esteban; Cuevas, Juan C; Godoy Herz, Micaela A; Depetris-Chauvin, Ana; Simpson, Craig G; Brown, John W S; Cerdán, Pablo D; Borevitz, Justin O; Mas, Paloma; Ceriani, M Fernanda; Kornblihtt, Alberto R; Yanovsky, Marcelo J

    2010-11-04

    Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day-night cycle. Post-transcriptional regulation is emerging as an important component of circadian networks, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones and Sm spliceosomal proteins, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5'-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions.

  2. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  3. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  4. Small Sample Kernel Association Tests for Human Genetic and Microbiome Association Studies.

    Science.gov (United States)

    Chen, Jun; Chen, Wenan; Zhao, Ni; Wu, Michael C; Schaid, Daniel J

    2016-01-01

    Kernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant- and microbiome-based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method. © 2015 WILEY PERIODICALS, INC.

  5. Molecular-clock methods for estimating evolutionary rates and timescales.

    Science.gov (United States)

    Ho, Simon Y W; Duchêne, Sebastián

    2014-12-01

    The molecular clock presents a means of estimating evolutionary rates and timescales using genetic data. These estimates can lead to important insights into evolutionary processes and mechanisms, as well as providing a framework for further biological analyses. To deal with rate variation among genes and among lineages, a diverse range of molecular-clock methods have been developed. These methods have been implemented in various software packages and differ in their statistical properties, ability to handle different models of rate variation, capacity to incorporate various forms of calibrating information and tractability for analysing large data sets. Choosing a suitable molecular-clock model can be a challenging exercise, but a number of model-selection techniques are available. In this review, we describe the different forms of evolutionary rate heterogeneity and explain how they can be accommodated in molecular-clock analyses. We provide an outline of the various clock methods and models that are available, including the strict clock, local clocks, discrete clocks and relaxed clocks. Techniques for calibration and clock-model selection are also described, along with methods for handling multilocus data sets. We conclude our review with some comments about the future of molecular clocks.

  6. Critical Role of the Circadian Clock in Memory Formation: Lessons from Aplysia

    Directory of Open Access Journals (Sweden)

    Lisa Carlson Lyons

    2011-12-01

    Full Text Available Unraveling the complexities of learning and the formation of memory requires identification of the cellular and molecular processes through which neural plasticity arises as well as recognition of the conditions or factors through which those processes are modulated. With its relatively simple nervous system, the marine mollusk Aplysia californica has proven an outstanding model system for studies of memory formation and identification of the molecular mechanisms underlying learned behaviors, including classical and operant associative learning paradigms and non-associative behaviors. In vivo behavioral studies in Aplysia have significantly furthered our understanding of how the endogenous circadian clock modulates memory formation. Sensitization of the tail-siphon withdrawal reflex represents a defensive non-associative learned behavior for which the circadian clock strongly modulates intermediate and long-term memory formation. Likewise, Aplysia exhibit circadian rhythms in long-term memory, but not short-term memory, for an operant associative learning paradigm. This review focuses on circadian modulation of intermediate and long-term memory and the putative mechanisms through which this modulation occurs. Additionally, potential functions and the adaptive advantages of time of day pressure on memory formation are considered. The influence of the circadian clock on learning and memory crosses distant phylogeny highlighting the evolutionary importance of the circadian clock on metabolic, physiological and behavioral processes. Thus, studies in a simple invertebrate model system have and will continue to provide critical mechanistic insights to complementary processes in higher organisms.

  7. Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans.

    Directory of Open Access Journals (Sweden)

    Barbora de Courten

    Full Text Available Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists.Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography, % body fat (bioimpedance, abdominal subcutaneous and visceral adiposity (magnetic resonance imaging, insulin sensitivity (euglycaemic hyperinsulinemic clamp, resting energy expenditure (REE, indirect calorimetry, free-living ambulatory physical activity (accelerometers and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04 and subcutaneous (r = 0.38, p = 0.02 but not visceral fat (r = 0.17, p = 0.33. Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008, REE (r = -0.58, p<0.001 and HDL-cholesterol levels (r = -0.34, p = 0.048. Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity.Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.

  8. Entangling the lattice clock: Towards Heisenberg-limited timekeeping

    CERN Document Server

    Weinstein, Jonathan D; Derevianko, Andrei

    2009-01-01

    We present a scheme for entangling the atoms of an optical lattice to reduce the quantum projection noise of a clock measurement. The divalent clock atoms are held in a lattice at a ``magic'' wavelength that does not perturb the clock frequency -- to maintain clock accuracy -- while an open-shell J=1/2 ``head'' atom is coherently transported between lattice sites via the lattice polarization. This polarization-dependent ``Archimedes' screw'' transport at magic wavelength takes advantage of the vanishing vector polarizability of the scalar, J=0, clock states of bosonic isotopes of divalent atoms. The on-site interactions between the clock atoms and the head atom are used to engineer entanglement and for clock readout.

  9. Satellite virtual atomic clock with pseudorange difference function

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Satellite atomic clocks are the basis of GPS for the control of time and frequency of navigation signals. In the Chinese Area Positioning System (CAPS), a satellite navigation system without the satellite atomic clocks onboard is successfully developed. Thus, the method of time synchronization based on satellite atomic clocks in GPS is not suitable. Satellite virtual atomic clocks are used to implement satellite navigation. With the satellite virtual atomic clocks, the time at which the signals are transmitted from the ground can be delayed into the time that the signals are transmitted from the satellites and the pseudorange measuring can be fulfilled as in GPS. Satellite virtual atomic clocks can implement the navigation, make a pseudorange difference, remove the ephemeris error, and improve the accuracy of navigation positioning. They not only provide a navigation system without satellite clocks, but also a navigation system with pseudorange difference.

  10. Arabidopsis circadian clock and photoperiodism: time to think about location.

    Science.gov (United States)

    Imaizumi, Takato

    2010-02-01

    Plants possess a circadian clock that enables them to coordinate internal biological events with external daily changes. Recent studies in Arabidopsis revealed that tissue-specific clock components exist and that the clock network architecture also varies within different organs. These findings indicate that the makeup of circadian clock(s) within a plant is quite variable. Plants utilize the circadian clock to measure day-length changes for regulating seasonal responses, such as flowering. To ensure that flowering occurs under optimum conditions, the clock regulates diurnal CONSTANS (CO) expression. Subsequently, CO protein induces FLOWERING LOCUS T (FT) expression which leads to flowering. It is emerging that both CO and FT expression are intricately controlled by groups of transcription factors with overlapping functions. Copyright 2009 Elsevier Ltd. All rights reserved.

  11. The Jumonji C domain-containing protein JMJ30 regulates period length in the Arabidopsis circadian clock.

    Science.gov (United States)

    Lu, Sheen X; Knowles, Stephen M; Webb, Candace J; Celaya, R Brandon; Cha, Chuah; Siu, Jonathan P; Tobin, Elaine M

    2011-02-01

    Histone methylation plays an essential role in regulating chromatin structure and gene expression. Jumonji C (JmjC) domain-containing proteins are generally known as histone demethylases. Circadian clocks regulate a large number of biological processes, and recent studies suggest that chromatin remodeling has evolved as an important mechanism for regulating both plant and mammalian circadian systems. Here, we analyzed a subgroup of JmjC domain-containing proteins and identified Arabidopsis (Arabidopsis thaliana) JMJ30 as a novel clock component involved in controlling the circadian period. Analysis of loss- and gain-of-function mutants of JMJ30 indicates that this evening-expressed gene is a genetic regulator of period length in the Arabidopsis circadian clock. Furthermore, two key components of the central oscillator of plants, transcription factors CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL, bind directly to the JMJ30 promoter to repress its expression, suggesting that JMJ30 regulates the pace of the circadian clock in close association with the central oscillator. JMJ30 represents, to our knowledge, the first JmjC domain-containing protein involved in circadian function, and we envision that this provides a possible molecular connection between chromatin remodeling and the circadian clock.

  12. Mapping gene associations in human mitochondria using clinical disease phenotypes.

    Directory of Open Access Journals (Sweden)

    Curt Scharfe

    2009-04-01

    Full Text Available Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects

  13. [Discrimination and homophobia associated to the human immunodeficiency virus epidemic].

    Science.gov (United States)

    Orozco-Núñez, Emanuel; Alcalde-Rabanal, Jacqueline Elizabeth; Ruiz-Larios, José Arturo; Sucilla-Pérez, Héctor; García-Cerde, Rodrigo

    2015-01-01

    To describe a political mapping on discrimination and homophobia associated to human immunodeficiency virus (HIV) in the context of public institutions in Mexico. The political mapping was conducted in six Mexican states. Stakeholders who were involved in HIV actions from public and private sectors were included. Semistructured interviews were applied to explore homophobia and discrimination associated with HIV. Information was systematized using the Policy Maker software, which is a good support for analyzing health policies. Discriminatory and homophobic practices in the public domain occurred, damaging people´s integrity via insults, derision and hate crimes. Most stakeholders expressed a supportive position to prevent discrimination and homophobia and some of them had great influence on policy-making decisions. It was found that state policy frameworks are less specific in addressing these issues. Homophobia and discrimination associated to HIV are still considered problematic in Mexico. Homophobia is a very sensitive issue that requires further attention. Also, an actual execution of governmental authority requires greater enforcement of laws against discrimination and homophobia.

  14. 78 FR 27993 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2013-05-13

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... has corrected an inventory of human remains and associated funerary objects published in a Notice of... control of these human remains and associated funerary objects should submit a written request to the...

  15. 78 FR 27994 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2013-05-13

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... has corrected an inventory of human remains and associated funerary objects published in a Notice of... transfer of control of these human remains and associated funerary objects should submit a written request...

  16. 78 FR 25470 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2013-05-01

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... Parkway has corrected an inventory of human remains and associated funerary objects, published in a Notice... human remains and associated funerary objects under the control of the U.S. Department of the Interior...

  17. 78 FR 27995 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2013-05-13

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... these human remains and associated funerary objects should submit a written request to the U.S. Army... human remains and associated funerary objects to the lineal descendants, Indian tribes, or Native...

  18. 78 FR 27992 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2013-05-13

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... has corrected an inventory of human remains and associated funerary objects published in a Notice of... control of these human remains and associated funerary objects should submit a written request to the...

  19. Network news: prime time for systems biology of the plant circadian clock truncated form of the title: Plant circadian clocks

    Science.gov (United States)

    McClung, C. Robertson; Gutiérrez, Rodrigo A.

    2011-01-01

    Summary Whole-transcriptome analyses have established that the plant circadian clock regulates virtually every plant biological process and most prominently hormonal and stress response pathways. Systems biology efforts have successfully modeled the plant central clock machinery and an iterative process of model refinement and experimental validation has contributed significantly to the current view of the central clock machinery. The challenge now is to connect this central clock to the output pathways for understanding how the plant circadian clock contributes to plant growth and fitness in a changing environment. Undoubtedly, systems approaches will be needed to integrate and model the vastly increased volume of experimental data in order to extract meaningful biological information. Thus, we have entered an era of systems modeling, experimental testing, and refinement. This approach, coupled with advances from the genetic and biochemical analyses of clock function, is accelerating our progress towards a comprehensive understanding of the plant circadian clock network. PMID:20889330

  20. The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK).

    Science.gov (United States)

    Matsumura, Ritsuko; Tsuchiya, Yoshiki; Tokuda, Isao; Matsuo, Takahiro; Sato, Miho; Node, Koichi; Nishida, Eisuke; Akashi, Makoto

    2014-11-14

    The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system.

  1. Characterization and modeling of intermittent locomotor dynamics in clock gene-deficient mice.

    Directory of Open Access Journals (Sweden)

    Toru Nakamura

    Full Text Available The scale-invariant and intermittent dynamics of animal behavior are attracting scientific interest. Recent findings concerning the statistical laws of behavioral organization shared between healthy humans and wild-type mice (WT and their alterations in human depression patients and circadian clock gene (Period 2; Per2 mutant mice indicate that clock genes play functional roles in intermittent, ultradian locomotor dynamics. They also claim the clinical and biological importance of the laws as objective biobehavioral measures or endophenotypes for psychiatric disorders. In this study, to elucidate the roles of breakdown of the broader circadian regulatory circuit in intermittent behavioral dynamics, we studied the statistical properties and rhythmicity of locomotor activity in Per2 mutants and mice deficient in other clock genes (Bmal1, Clock. We performed wavelet analysis to examine circadian and ultradian rhythms and estimated the cumulative distributions of resting period durations during which locomotor activity levels are continuously lower than a predefined threshold value. The wavelet analysis revealed significant amplification of ultradian rhythms in the BMAL1-deficient mice, and instability in the Per2 mutants. The resting period distributions followed a power-law form in all mice. While the distributions for the BMAL1-deficient and Clock mutant mice were almost identical to those for the WT mice, with no significant differences in their parameter (power-law scaling exponent, only the Per2 mutant mice showed consistently and significantly lower values of the scaling exponent, indicating the increased intermittency in ultradian locomotor dynamics. Furthermore, based on a stochastic priority queuing model, we explained the power-law nature of resting period distributions, as well as its alterations shared with human depressive patients and Per2 mutant mice. Our findings lead to the development of a novel mathematical model for abnormal

  2. Human anthrax outbreak associated with livestock exposure: Georgia, 2012.

    Science.gov (United States)

    Navdarashvili, A; Doker, T J; Geleishvili, M; Haberling, D L; Kharod, G A; Rush, T H; Maes, E; Zakhashvili, K; Imnadze, P; Bower, W A; Walke, H T; Shadomy, S V

    2016-01-01

    Human anthrax cases reported in the country of Georgia increased 75% from 2011 (n = 81) to 2012 (n = 142). This increase prompted a case-control investigation using 67 culture- or PCR-confirmed cases and 134 controls matched by residence and gender to investigate risk factor(s) for infection during the month before case onset. Independent predictors most strongly associated with disease in the multivariable modelling were slaughtering animals [odds ratio (OR) 7·3, 95% confidence interval (CI) 2·9-18·1, P 1 km; 15 (12%) of 125 had sick livestock; and 11 (9%) of 128 respondents reported finding dead livestock. We recommend joint public health and veterinary anthrax case investigations to identify areas of increased risk for livestock anthrax outbreaks, annual anthrax vaccination of livestock in those areas, and public awareness education.

  3. Cardiac Disease Associated with Human Immunodeficiency Virus Infection.

    Science.gov (United States)

    Bloomfield, Gerald S; Leung, Claudia

    2017-02-01

    Over the last 2 decades human immunodeficiency virus (HIV) infection has become a chronic disease requiring long-term management. Aging, antiretroviral therapy, chronic inflammation, and several other factors contribute to the increased risk of cardiovascular disease in patients infected with HIV. In low-income and middle-income countries where antiretroviral therapy access is limited, cardiac disease is most commonly related to opportunistic infections and end-stage manifestations of HIV/acquired immunodeficiency syndrome, including HIV-associated cardiomyopathy, pericarditis, and pulmonary arterial hypertension. Cardiovascular screening, prevention, and risk factor management are important factors in the management of patients infected with HIV worldwide. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Cytokine profile associated with human chronic schistosomiasis mansoni

    Directory of Open Access Journals (Sweden)

    Andréa Magalhães

    2004-08-01

    Full Text Available This study objective was to evaluate the cytokines associated with early events of hepatic fibrosis in schistosomiasis mansoni. Hepatic fibrosis was classified by ultrasonography in 94 patients. Immunological evaluation was performed by measurement of secreted cytokines (interleukin IL-5, IL-10, IL-13, interferon-gamma, tumor necrosis factor-alpha and transforming growth factors-beta in peripherl blood mononuclear cells stimulated by Schistosoma mansoni antigens. Significantly, higher levels of IL-5, IL-10 and IL-13 were found in supernatants of SEA-stimulated PBMC from subjects with degree III hepatic fibrosis as compared to patients with degree I or II fibrosis, Significant increases in IL-5 and IL-13 levels were also observed in some of the subjects who remained untreated for one year following initial assessment and developed more serious fibrosis during this period. The data suggests a role for type 2 cytokines in early stages of hepatic fibrosis in human schistosomiasis mansoni.

  5. Gene expression analysis in human breast cancer associated blood vessels.

    Directory of Open Access Journals (Sweden)

    Dylan T Jones

    Full Text Available Angiogenesis is essential for solid tumour growth, whilst the molecular profiles of tumour blood vessels have been reported to be different between cancer types. Although presently available anti-angiogenic strategies are providing some promise for the treatment of some cancers it is perhaps not surprisingly that, none of the anti-angiogenic agents available work on all tumours. Thus, the discovery of novel anti-angiogenic targets, relevant to individual cancer types, is required. Using Affymetrix microarray analysis of laser-captured, CD31-positive blood vessels we have identified 63 genes that are upregulated significantly (5-72 fold in angiogenic blood vessels associated with human invasive ductal carcinoma (IDC of the breast as compared with blood vessels in normal human breast. We tested the angiogenic capacity of a subset of these genes. Genes were selected based on either their known cellular functions, their enriched expression in endothelial cells and/or their sensitivity to anti-VEGF treatment; all features implicating their involvement in angiogenesis. For example, RRM2, a ribonucleotide reductase involved in DNA synthesis, was upregulated 32-fold in IDC-associated blood vessels; ATF1, a nuclear activating transcription factor involved in cellular growth and survival was upregulated 23-fold in IDC-associated blood vessels and HEX-B, a hexosaminidase involved in the breakdown of GM2 gangliosides, was upregulated 8-fold in IDC-associated blood vessels. Furthermore, in silico analysis confirmed that AFT1 and HEX-B also were enriched in endothelial cells when compared with non-endothelial cells. None of these genes have been reported previously to be involved in neovascularisation. However, our data establish that siRNA depletion of Rrm2, Atf1 or Hex-B had significant anti-angiogenic effects in VEGF-stimulated ex vivo mouse aortic ring assays. Overall, our results provide proof-of-principle that our approach can identify a cohort of

  6. Microbial dysbiosis is associated with human breast cancer.

    Directory of Open Access Journals (Sweden)

    Caiyun Xuan

    Full Text Available Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, we investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, we found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, we observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. Our findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications.

  7. Reorganized PKA-AKAP associations in the failing human heart.

    Science.gov (United States)

    Aye, Thin-Thin; Soni, Siddarth; van Veen, Toon A B; van der Heyden, Marcel A G; Cappadona, Salvatore; Varro, Andras; de Weger, Roel A; de Jonge, Nicolaas; Vos, Marc A; Heck, Albert J R; Scholten, Arjen

    2012-02-01

    Here we reveal that the characterization of large-scale re-arrangements of signaling scaffolds induced by heart failure can serve as a novel concept to identify more specific therapeutic targets. In the mammalian heart, the cAMP pathway, with the cAMP-dependent protein kinase (PKA) in a central role, acts directly downstream of adrenergic receptors to mediate cardiac contractility and rhythm. Heart failure, characterized by severe alterations in adrenergic stimulation is, amongst other interventions, often treated with β-blockers. Contrasting results, however, have shown both beneficial and detrimental effects of decreased cAMP levels in failing hearts. We hypothesize that the origin of this behavior lies in the complex spatiotemporal organization of the regulatory subunit of PKA (PKA-R), which associates tightly with various A-kinase anchoring proteins (AKAPs) to specifically localize PKA's activity. Using chemical proteomics directly applied to human patient and control heart tissue we demonstrate that the association profile of PKA-R with several AKAPs is severely altered in the failing heart, for instance effecting the interaction between PKA and the novel AKAP SPHKAP was 6-fold upregulated upon failing heart conditions. Also a significant increase in captured cGMP-dependent protein kinase (PKG) and phosphodiesterase 2 (PDE2) was observed. The observed altered profiles can already explain many aspects of the aberrant cAMP-response in the failing human heart, validating that this dataset may provide a resource for several novel, more specific, treatment options. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

  8. Electrophysiological CNS-processes related to associative learning in humans.

    Science.gov (United States)

    Christoffersen, Gert R J; Schachtman, Todd R

    2016-01-01

    The neurophysiology of human associative memory has been studied with electroencephalographic techniques since the 1930s. This research has revealed that different types of electrophysiological processes in the human brain can be modified by conditioning: sensory evoked potentials, sensory induced gamma-band activity, periods of frequency-specific waves (alpha and beta waves, the sensorimotor rhythm and the mu-rhythm) and slow cortical potentials. Conditioning of these processes has been studied in experiments that either use operant conditioning or repeated contingent pairings of conditioned and unconditioned stimuli (classical conditioning). In operant conditioning, the appearance of a specific brain process is paired with an external stimulus (neurofeedback) and the feedback enables subjects to obtain varying degrees of control of the CNS-process. Such acquired self-regulation of brain activity has found practical uses for instance in the amelioration of epileptic seizures, Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). It has also provided communicative means of assistance for tetraplegic patients through the use of brain computer interfaces. Both extra and intracortically recorded signals have been coupled with contingent external feedback. It is the aim for this review to summarize essential results on all types of electromagnetic brain processes that have been modified by classical or operant conditioning. The results are organized according to type of conditioned EEG-process, type of conditioning, and sensory modalities of the conditioning stimuli.

  9. Circadian clock proteins control adaptation to novel environment and memory formation

    Science.gov (United States)

    A.Kondratova, Anna; V.Dubrovsky, Yuliya; Antoch, Marina P.; Kondratov, Roman V.

    2010-01-01

    Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning. PMID:20519775

  10. Development of a compact cold-atom atomic clock based on coherent population trapping

    Science.gov (United States)

    Blanshan, Eric M.

    Field-grade atomic clocks capable of primary standard performance in compact physics packages would be of significant value in a variety of applications ranging from network synchronization and secure communications to GPS hold-over and inertial navigation. A cold-atom coherent population trapping (CACPT) clock featuring laser-cooled atoms and pulsed Ramsey interrogation is a strong candidate for this technology if the principal frequency shifts can be controlled and the performance degradation associated with miniaturization can be overcome. In this thesis, research focused on the development of this type of compact atomic clock is presented. To address the low atom numbers obtained in small cold-atom sources, experiments were performed in which an atomic beam was decelerated with bichromatic stimulated laser forces and loaded into a mm-scale magneto-optical trap, increasing the atom number by a factor of 12.5. A CACPT clock using the high-contrast lin||lin optical interrogation technique was developed and achieved a stability of 7 x 10-13 after one hour of integration. Doppler shifts in the clock are explained using a simple kinematic model and canceled by interrogating the atoms with a counter-propagating CPT configuration. Finally, a thorough characterization of the AC-stark effect in lin||lin CPT was performed. Observed shifts are explained in terms of contributions from coherent CPT-generating couplings and population transfer effects caused by optical pumping from incoherent light. Measurements are compared with existing and new theoretical treatments, and a laser configuration is identified that reduces clock drift from light shifts to less than 10-14 for the current system.

  11. Monitoring cell-autonomous circadian clock rhythms of gene expression using luciferase bioluminescence reporters.

    Science.gov (United States)

    Ramanathan, Chidambaram; Khan, Sanjoy K; Kathale, Nimish D; Xu, Haiyan; Liu, Andrew C

    2012-09-27

    genome of both dividing and non-dividing cells. Once a reporter cell line is established, the dynamics of clock function can be examined through bioluminescence recording. We first describe the generation of P(Per2)-dLuc reporter lines, and then present data from this and other circadian reporters. In these assays, 3T3 mouse fibroblasts and U2OS human osteosarcoma cells are used as cellular models. We also discuss various ways of using these clock models in circadian studies. Methods described here can be applied to a great variety of cell types to study the cellular and molecular basis of circadian clocks, and may prove useful in tackling problems in other biological systems.

  12. Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders.

    Science.gov (United States)

    Nador, Roland G; Chadburn, Amy; Gundappa, Girija; Cesarman, Ethel; Said, Jonathan W; Knowles, Daniel M

    2003-03-01

    The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition. During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain

  13. Optimal Implementations for Reliable Circadian Clocks

    Science.gov (United States)

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-09-01

    Circadian rhythms are acquired through evolution to increase the chances for survival through synchronizing with the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. We find by using a phase model with multiple inputs that achieving the maximal limit of regularity and entrainability entails many inherent features of the circadian mechanism. At the molecular level, we demonstrate the role sharing of two light inputs, phase advance and delay, as is well observed in mammals. At the behavioral level, the optimal phase-response curve inevitably contains a dead zone, a time during which light pulses neither advance nor delay the clock. We reproduce the results of phase-controlling experiments entrained by two types of periodic light pulses. Our results indicate that circadian clocks are designed optimally for reliable clockwork through evolution.

  14. The Large Built Water Clock Of Amphiaraeion.

    Science.gov (United States)

    Theodossiou, E.; Katsiotis, M.; Manimanis, V. N.; Mantarakis, P.

    A very well preserved ancient water clock was discovered during excavations at the Amphiaraeion, in Oropos, Greece. The Amphiaraeion, a famous religious and oracle center of the deified healer Amphiaraus, was active from the pre-classic period until the replacement of the ancient religion by Christianity in the 5th Century A.D.. The foretelling was supposedly done through dreams sent by the god to the believers sleeping in a special gallery. In these dreams the god suggesting to them the therapy for their illness or the solution to their problems. The patients, then threw coins into a spring of the sanctuary. In such a place, the measurement of time was a necessity. Therefore, time was kept with both a conical sundial and a water clock in the form of a fountain. According to archeologists, the large built structure that measured the time for the sanctuary dates from the 4th Century B.C.

  15. Sagnac interferometry with a single atomic clock

    CERN Document Server

    Stevenson, R; Bishop, T; Lesanovsky, I; Fernholz, T

    2015-01-01

    We theoretically discuss an implementation of a Sagnac interferometer with cold atoms. In contrast to currently existing schemes our protocol does not rely on any free propagation of atoms. Instead it is based on superpositions of fully confined atoms and state-dependent transport along a closed path. Using Ramsey sequences for an atomic clock, the accumulated Sagnac phase is encoded in the resulting population imbalance between two internal (clock) states. Using minimal models for the above protocol we analytically quantify limitations arising from atomic dynamics and finite temperature. We discuss an actual implementation of the interferometer with adiabatic radio-frequency potentials that is inherently robust against common mode noise as well as phase noise from the reference oscillator.

  16. Molecular clock on a neutral network.

    Science.gov (United States)

    Raval, Alpan

    2007-09-28

    The number of fixed mutations accumulated in an evolving population often displays a variance that is significantly larger than the mean (the overdispersed molecular clock). By examining a generic evolutionary process on a neutral network of high-fitness genotypes, we establish a formalism for computing all cumulants of the full probability distribution of accumulated mutations in terms of graph properties of the neutral network, and use the formalism to prove overdispersion of the molecular clock. We further show that significant overdispersion arises naturally in evolution when the neutral network is highly sparse, exhibits large global fluctuations in neutrality, and small local fluctuations in neutrality. The results are also relevant for elucidating aspects of neutral network topology from empirical measurements of the substitution process.

  17. Regulated DNA Methylation and the Circadian Clock: Implications in Cancer

    Directory of Open Access Journals (Sweden)

    Tammy M. Joska

    2014-09-01

    Full Text Available Since the cloning and discovery of DNA methyltransferases (DNMT, there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has become evident that dynamic DNA methylation accompanies the circadian clock and is found at clock genes in Neurospora, mice and cancer cells. The relationship among the circadian clock, cancer and DNA methylation at clock genes suggests a correlative indication that improper DNA methylation may influence clock gene expression, contributing to the etiology of cancer. The molecular mechanism underlying DNA methylation at clock loci is best studied in the filamentous fungi, Neurospora crassa, and recent data indicate a mechanism analogous to the RNA-dependent DNA methylation (RdDM or RNAi-mediated facultative heterochromatin. Although it is still unclear, DNA methylation at clock genes may function as a terminal modification that serves to prevent the regulated removal of histone modifications. In this capacity, aberrant DNA methylation may serve as a readout of misregulated clock genes and not as the causative agent. This review explores the implications of DNA methylation at clock loci and describes what is currently known regarding the molecular mechanism underlying DNA methylation at circadian clock genes.

  18. Photoperiodic plasticity in circadian clock neurons in insects

    Directory of Open Access Journals (Sweden)

    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.

  19. Geopotential measurements with synchronously linked optical lattice clocks

    Science.gov (United States)

    Takano, Tetsushi; Takamoto, Masao; Ushijima, Ichiro; Ohmae, Noriaki; Akatsuka, Tomoya; Yamaguchi, Atsushi; Kuroishi, Yuki; Munekane, Hiroshi; Miyahara, Basara; Katori, Hidetoshi

    2016-10-01

    According to Einstein's theory of relativity, the passage of time changes in a gravitational field. On Earth, raising a clock by 1 cm increases its apparent tick rate by 1.1 parts in 1018, allowing chronometric levelling through comparison of optical clocks. Here, we demonstrate such geopotential measurements by determining the height difference of master and slave clocks separated by 15 km with an uncertainty of 5 cm. A subharmonic of the master clock laser is delivered through a telecom fibre to synchronously operate the distant clocks. Clocks operated under such phase coherence reject clock laser noise and facilitate proposals for linking clocks and interferometers. Taken over half a year, 11 measurements determine the fractional frequency difference between the two clocks to be 1,652.9(5.9) × 10-18, consistent with an independent measurement by levelling and gravimetry. Our system demonstrates a building block for an internet of clocks, which may constitute ‘quantum benchmarks’, serving as height references with dynamic responses.

  20. Incremental Placement-Based Clock Network Minimization Methodology

    Institute of Scientific and Technical Information of China (English)

    ZHOU Oiang; CAI Yici; HUANG Liang; HONG Xianlong

    2008-01-01

    Power is the major challenge threatening the progress of very large scale integration (VLSI) tech-nology development. In ultra-deep submicron VLSI designs, clock network size must be minimized to re-duce power consumption, power supply noise, and the number of clock buffers which are vulnerable to process variations. Traditional design methodologies usually let the clock router independently undertake the clock network minimization. Since clock routing is based on register locations, register placement actu-ally strongly influences the clock network size. This paper describes a clock network design methodology that optimizes register placement. For a given cell placement result, incremental modifications are per-formed based on the clock skew specifications by moving registers toward preferred locations that may re-duce the clock network size. At the same time, the side-effects to logic cell placement, such as signal net wirelength and critical path delay, are controlled. Test results on benchmark circuits show that the methodol-ogy can considerably reduce clock network size with limited impact on signal net wirelength and critical path delay.

  1. A compact model for the complex plant circadian clock

    Directory of Open Access Journals (Sweden)

    Didier eGonze

    2016-02-01

    Full Text Available The circadian clock is an endogenous timekeeper that allows organisms to anticipate and adapt to the daily variations of their environment. The plant clock is an intricate network of interlocked feedback loops, in which transcription factors regulate each other to generate oscillations with expression peaks at specific times of the day. Over the last decade, mathematical modeling approaches have been used to understand the inner workings of the clock in the model plant Arabidopsis thaliana. Those efforts have produced a number of models of ever increasing complexity. Here, we present an alternative model that combines a low number of equations and parameters, similar to the very earliest models, with the complex network structure found in more recent ones. This simple model describes the temporal evolution of the abundance of eight clock genes and captures key features of the clock on a qualitative level, namely the entrained and free-running behaviors of the wild type clock, as well as the defects found in knockout mutants (such as altered free-running periods, lack of entrainment, or changes in the expression of other clock genes. Additionally, our model produces complex responses to various light cues, such as extreme photoperiods and non-24h environmental cycles, and can describe the control of hypocotyl growth by the clock. Our model constitutes a useful tool to probe dynamical properties of the clock as well as model more clock-dependent processes.

  2. Interstitial lung disease associated with human papillomavirus vaccination

    Directory of Open Access Journals (Sweden)

    Yasushi Yamamoto

    2015-01-01

    Full Text Available Vaccinations against the human papillomavirus (HPV have been recommended for the prevention of cervical cancer. HPV-16/18 AS04-adjuvanted vaccines (Cervarix are said to have favourable safety profiles. Interstitial lung diseases (ILDs can occur following exposure to a drug or a biological agent. We report a case of ILD associated with a Cervarix vaccination. A woman in her 40's, with a history of conisation, received three inoculations of Cervarix. Three months later, she presented with a cough and shortness of breath. Findings from a computed tomography of the chest and a transbronchial lung biopsy were consistent with non-specific interstitial pneumonia. Workup eliminated all other causes of the ILD, except for the vaccination. Over the 11 months of the follow-up period, her symptoms resolved without steroid therapy. The onset and spontaneous resolution of the ILD showed a chronological association with the HPV vaccination. The semi-quantitative algorithm revealed that the likelihood of an adverse drug reaction to Cervarix was “Probable”. The outcome was relatively good, but more attention should be paid to a potential risk for HPV vaccinations to cause ILDs. Wherever possible, chest radiographic examinations should be performed in order not to overlook any ILDs.

  3. Is Human Papillomavirus Associated with Prostate Cancer Survival?

    Directory of Open Access Journals (Sweden)

    Mariarosa Pascale

    2013-01-01

    Full Text Available The role of human papillomavirus (HPV in prostate carcinogenesis is highly controversial: some studies suggest a positive association between HPV infection and an increased risk of prostate cancer (PCa, whereas others do not reveal any correlation. In this study, we investigated the prognostic impact of HPV infection on survival in 150 primary PCa patients. One hundred twelve (74.67% patients had positive expression of HPV E7 protein, which was evaluated in tumour tissue by immunohistochemistry. DNA analysis on a subset of cases confirmed HPV infection and revealed the presence of genotype 16. In Kaplan-Meier analysis, HPV-positive cancer patients showed worse overall survival (OS (median 4.59 years compared to HPV-negative (median 8.24 years, P=0.0381. In multivariate analysis age (P<0.001, Gleason score (P<0.001, nuclear grading (P=0.002, and HPV status (P=0.034 were independent prognostic factors for OS. In our cohort, we observed high prevalence of HPV nuclear E7 oncoprotein and an association between HPV infection and PCa survival. In the debate about the oncogenic activity of HPV in PCa, our results further confirm the need for additional studies to clarify the possible role of HPV in prostate carcinogenesis.

  4. The Circadian Clock, Reward, and Memory

    OpenAIRE

    Urs eAlbrecht

    2011-01-01

    During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance, and reward may be related to one another. This review will summarize data that describe the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes.

  5. The circadian clock, reward and memory

    Directory of Open Access Journals (Sweden)

    Urs eAlbrecht

    2011-11-01

    Full Text Available During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance and reward may be related to one another. This review will summarize data that describes the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes.

  6. Molecular clock in neutral protein evolution

    Directory of Open Access Journals (Sweden)

    Wilke Claus O

    2004-08-01

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

  7. Radium single-ion optical clock

    CERN Document Server

    Versolato, O O; Jungmann, K; Timmermans, R G E; Willmann, L; Wilschut, H W

    2011-01-01

    We explore the potential of the electric quadrupole transitions $7s\\,^2S_{1/2}$ - $6d\\,^2D_{3/2}$, $6d\\,^2D_{5/2}$ in radium isotopes as single-ion optical frequency standards. The frequency shifts of the clock transitions due to external fields and the corresponding uncertainties are calculated. Several competitive $^A$Ra$^+$ candidates with $A=$ 223 - 229 are identified. In particular, we show that the transition $7s\\,^2S_{1/2}\\,(F=2,m_F=0)$ - $6d\\,^2D_{3/2}\\,(F=0,m_F=0)$ at 828 nm in $^{223}$Ra$^+$, with no linear Zeeman and electric quadrupole shifts, stands out as a relatively simple case, which could be exploited as a compact, robust, and low-cost atomic clock operating at a fractional frequency uncertainty of $10^{-17}$. With more experimental effort, the $^{223,225,226}$Ra$^+$ clocks could be pushed to a projected performance reaching the $10^{-18}$ level.

  8. Clock drawing performance in cognitively normal elderly.

    Science.gov (United States)

    Hubbard, Emily J; Santini, Veronica; Blankevoort, Christiaan G; Volkers, Karin M; Barrup, Melissa S; Byerly, Laura; Chaisson, Christine; Jefferson, Angela L; Kaplan, Edith; Green, Robert C; Stern, Robert A

    2008-05-01

    The Clock Drawing Test (CDT) is a common neuropsychological measure sensitive to cognitive changes and functional skills (e.g., driving test performance) among older adults. However, normative data have not been adequately developed. We report the distribution of CDT scores using three common scoring systems [Mendez, M. F., Ala, T., & Underwood, K. L. (1992). Development of scoring criteria for the Clock Drawing Task in Alzheimer's Disease. Journal of the American Geriatrics Society, 40, 1095-1099; Cahn, D. A., Salmon, D. P., Monsch, A. U., Butters, N., Wiederholt, W. C., & Corey-Bloom, J. (1996). Screening for dementia of the Alzheimer type in the community: The utility of the Clock Drawing Test. Archives of Clinical Neuropsychology, 11(6), 529-539], among 207 cognitively normal elderly. The systems were well correlated, took little time to use, and had high inter-rater reliability. We found statistically significant differences in CDT scores based on age and WRAT-3 Reading score, a marker of education quality. We present means, standard deviations, and t- and z-scores based on these subgroups. We found that "normal" CDT performance includes a wider distribution of scores than previously reported. Our results may serve as useful comparisons for clinicians wishing to know whether their patients perform in the general range of cognitively normal elderly.

  9. A microresonator frequency comb optical clock

    CERN Document Server

    Papp, Scott B; DelHaye, Pascal; Quinlan, Franklyn; Lee, Hansuek; Vahala, Kerry J; Diddams, Scott A

    2013-01-01

    Optical-frequency combs enable measurement precision at the 20th digit, and accuracy entirely commensurate with their reference oscillator. A new direction in experiments is the creation of ultracompact frequency combs by way of nonlinear parametric optics in microresonators. We refer to these as microcombs, and here we report a silicon-chip-based microcomb optical clock that phase-coherently converts an optical-frequency reference to a microwave signal. A low-noise comb spectrum with 25 THz span is generated with a 2 mm diameter silica disk and broadening in nonlinear fiber. This spectrum is stabilized to rubidium frequency references separated by 3.5 THz by controlling two teeth 108 modes apart. The optical clocks output is the electronically countable 33 GHz microcomb line spacing, which features an absolute stability better than the rubidium transitions by the expected factor of 108. Our work demonstrates the comprehensive set of tools needed for interfacing microcombs to state-of-the-art optical clocks.

  10. Chromatin remodelling and the Arabidopsis biological clock.

    Science.gov (United States)

    Más, Paloma

    2008-02-01

    Plants, as sessile organisms, rely on accurate time measurement to synchronize their physiology and development to the most favourable time-of-day or time-of-year. The biological clock is the endogenous mechanism responsible for the integration of the photoperiodic information thus coordinating metabolism in resonance with the environmental cycle. Despite the importance of circadian clock function in plant reproduction and survival, we are still far from understanding the specific molecular mechanisms governing the rhythmic expression of clock components. Recently, we have described a new mechanism of circadian regulation that involves changes in chromatin structure at the TOC1 (TIMING OF CAB EXPRESSION 1) locus. The mechanism is defined by activators and repressors that are precisely coordinated to favor a hyper- or hypo-acetylated state of histones that leads to TOC1 transcriptional activation or repression, respectively. The clockcontrolled rhythms in histone acetylation/deacetylation at the TOC1 promoter are differentially modulated by day-length or photoperiod suggesting a mechanism by which plants ensure the phase of entrainment in physiological and developmental outputs.

  11. 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

  12. 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 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.

  13. Telomere shortening may be associated with human keloids

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    Wilson Robert R

    2009-10-01

    Full Text Available Abstract Background Keloids are benign skin tumors that are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are inherited with an autosomal dominant mode with incomplete clinical penetrance and variable expression. Keloids are characterized by formation of excess scar tissue beyond the boundaries of the wound. The exact etiology is still unknown and there is currently no appropriate treatment for keloid disease. Methods We analyzed sample tissues were obtained from 20 patients with keloid skin lesions and normal skin was obtained from 20 healthy donors. The telomeres were measured by Terminal Restriction Fragment (TRF analysis and Real-Time PCR assay. Quantitative Real-Time RT-PCR analysis of hTERT gene expression was performed and intracellular ROS generation was measured. Results In this study, we determined whether telomeric shortening and the expression of human telomerase reverse transcriptase (hTERT occurs in keloid patients. Using Terminal Restriction Fragment (TRF analysis and Real-Time PCR assay, we detected a significant telomere shortening of 30% in keloid specimens compared to normal skin. Using quantitative Real-Time RT-PCR, telomerase activity was found absent in the keloid tissues. Moreover, an increase in ROS generation was detected in fibroblasts cell cultures from keloid specimens as more time elapsed compared to fibroblasts from normal skin. Conclusion Telomere shortening has been reported in several metabolic and cardiovascular diseases. We found that telomere shortening can also be associated with human keloids. Chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases. Here we found increased ROS generation in fibroblasts from keloid fibroblasts cell cultures when compared to normal skin fibroblasts. Hence we conclude that oxidative stress might be an important modulator of telomere loss in keloid because of the absence of active

  14. BENIGN EPITHELIAL NEOPLASIA ASSOCIATED WITH BETA-HUMAN PAPILLOMA VIRUS

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    V. A. Molochkov

    2014-01-01

    Full Text Available Aim: To study an association between acrochordon and human papilloma virus (HPV using quantitative analysis of viral desoxyribonucleic acid (DNA; to detect different phenotypes of beta-HPV. Materials and methods: We examined 52  patients (22 immuno-suppressed patients and 30 immunocompetent subjects in the Dermatovenereology and Dermato-Oncology Department and Chronic Dialysis and Kidney Transplantation Department of the Moscow Regional Research and Clinical Institute (MONIKI. Control group included 49 healthy donors. Burr biopsy samples (micro-samples of acrochordon and intact skin (apper arm were collected in sterile conditions. After sample procession and DNA isolation using DNK-sorb-C kit (Central Research Institute for Epidemiology – CRIE, polymerase chain reaction for HPV was performed with real-time fluorescent hybridization detection. For DNA amplification and detection we used RotorGene 3000 analyzer (Corbett Research, Australia. In the beta-HPV assay, recombinant plasmids were used as positive controls and control human beta-globin gene fragments (CRIE. 4 oligo-nucleotide systems (group-specific primers and probes were used for the detection of beta-HPV DNA. Results: Preliminary data indicated that acrochordons of open and covered skin regions were common in renal transplant recipients. Beta-HPV DNA was more frequent in acrochordons and intact skin (64% and 54% of renal transplant recipients compared to healthy donors (47%. 57% of renal transplant recipients demonstrated mixed infection in acrochordons. Conclusion: HPV DNA was frequently detected in acrochordons and intact skin of renal transplant recipients. In immunocompetent patients prevalence of HPV DNA in acrochordons was significantly higher compared to intact skin.

  15. Casein kinase 1 proteomics reveal prohibitin 2 function in molecular clock.

    Directory of Open Access Journals (Sweden)

    Lorna S Kategaya

    Full Text Available Throughout the day, clock proteins synchronize changes in animal physiology (e.g., wakefulness and appetite with external cues (e.g., daylight and food. In vertebrates, both casein kinase 1 delta and epsilon (CK1δ and CK1ε regulate these circadian changes by phosphorylating other core clock proteins. In addition, CK1 can regulate circadian-dependent transcription in a non-catalytic manner, however, the mechanism is unknown. Furthermore, the extent of functional redundancy between these closely related kinases is debated. To further advance knowledge about CK1δ and CK1ε mechanisms of action in the biological clock, we first carried out proteomic analysis of both kinases in human cells. Next, we tested interesting candidates in a cell-based circadian readout which resulted in the discovery of PROHIBITIN 2 (PHB2 as a modulator of period length. Decreasing the expression of PHB2 increases circadian-driven transcription, thus revealing PHB2 acts as an inhibitor in the molecular clock. While stable binding of PHB2 to either kinase was not detected, knocking down CK1ε expression increases PHB2 protein levels and, unexpectedly, knocking down CK1δ decreases PHB2 transcript levels. Thus, isolating CK1 protein complexes led to the identification of PHB2 as an inhibitor of circadian transcription. Furthermore, we show that CK1δ and CK1ε differentially regulate the expression of PHB2.

  16. Casein kinase 1 proteomics reveal prohibitin 2 function in molecular clock.

    Science.gov (United States)

    Kategaya, Lorna S; Hilliard, Aisha; Zhang, Louying; Asara, John M; Ptáček, Louis J; Fu, Ying-Hui

    2012-01-01

    Throughout the day, clock proteins synchronize changes in animal physiology (e.g., wakefulness and appetite) with external cues (e.g., daylight and food). In vertebrates, both casein kinase 1 delta and epsilon (CK1δ and CK1ε) regulate these circadian changes by phosphorylating other core clock proteins. In addition, CK1 can regulate circadian-dependent transcription in a non-catalytic manner, however, the mechanism is unknown. Furthermore, the extent of functional redundancy between these closely related kinases is debated. To further advance knowledge about CK1δ and CK1ε mechanisms of action in the biological clock, we first carried out proteomic analysis of both kinases in human cells. Next, we tested interesting candidates in a cell-based circadian readout which resulted in the discovery of PROHIBITIN 2 (PHB2) as a modulator of period length. Decreasing the expression of PHB2 increases circadian-driven transcription, thus revealing PHB2 acts as an inhibitor in the molecular clock. While stable binding of PHB2 to either kinase was not detected, knocking down CK1ε expression increases PHB2 protein levels and, unexpectedly, knocking down CK1δ decreases PHB2 transcript levels. Thus, isolating CK1 protein complexes led to the identification of PHB2 as an inhibitor of circadian transcription. Furthermore, we show that CK1δ and CK1ε differentially regulate the expression of PHB2.

  17. Self-Adaptive Clock Synchronization for Computational Grid

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ying(赵英); ZHOU WanLei(周万雷); HUANG JiuMei(黄九梅); YU Shui(余水); E.J.Lanham

    2003-01-01

    This paper presents an innovative method to synchronize physical clocks for a computational grid, in particular for a computational grid linked through the asynchronous Intranet or Internet environments. The method discussed is an asynchronous self-adaptive clock synchronization mechanism. Two strategies for clock synchronisation are introduced. (1) Use continuous time intervals to calculate the precision of clocks, which can reduce the effect of network delay efficiently. (2) Every node synchronizes its clock with its leader actively. In addition, a node self-adaptive model is presented, and the relationship between the clock precision and synchronization time is induced, hence a node can predict when it should begin the synchronization process.Detailed simulation and extension of this issue are provided at the end of the paper. The presented model is both practical and feasible.

  18. Immunometabolism: Is it under the eye of the clock?

    Science.gov (United States)

    Early, James O; Curtis, Anne M

    2016-10-01

    Molecular clocks allow an organism to track time of day, providing the means to anticipate and respond to the daily changes within the environment. In mammals the molecular clock consists of a network of proteins that form auto-regulatory feedback loops that drive rhythms in physiology and behavior. In recent times the extent to which the molecular clock controls key metabolic and immune pathways has begun to emerge. For example, the main clock protein BMAL1 has been linked to mitochondrial metabolism, mitochondrial dynamics and various host defense pathways. The molecular clock may function to integrate daily metabolic changes driven by feeding-fasting to immune function and output. Understanding how the clock intersects with metabolic pathways within immune cells to affect immune phenotypes will have broad implications for the management of metabolic, inflammatory and infectious diseases.

  19. Realization of a time-scale with an optical clock

    CERN Document Server

    Grebing, C; Dörscher, S; Häfner, S; Gerginov, V; Weyers, S; Lipphardt, B; Riehle, F; Sterr, U; Lisdat, C

    2015-01-01

    Optical clocks are not only powerful tools for prime fundamental research, but are also deemed for the re-definition of the SI base unit second as they surpass the performance of caesium atomic clocks in both accuracy and stability by more than an order of magnitude. However, an important obstacle in this transition has so far been the limited reliability of the optical clocks that made a continuous realization of a time-scale impractical. In this paper, we demonstrate how this dilemma can be resolved and that a time-scale based on an optical clock can be established that is superior to one based on even the best caesium fountain clocks. The paper also gives further proof of the international consistency of strontium lattice clocks on the $10^{-16}$ accuracy level, which is another prerequisite for a change in the definition of the second.

  20. A clock network for geodesy and fundamental science

    CERN Document Server

    Lisdat, C; 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; Coq, Y Le; Santarelli, G; Amy-Klein, A; Targat, R Le; Lodewyck, J; Lopez, O; Pottie, P -E

    2015-01-01

    Leveraging the unrivaled performance of optical clocks in applications in fundamental physics beyond the standard model, in geo-sciences, and in astronomy requires comparing the frequency of distant optical clocks truthfully. Meeting this requirement, we report on the first comparison and agreement of fully independent optical clocks separated by 700 km being only limited by the uncertainties of the clocks themselves. This is achieved by a phase-coherent optical frequency transfer via a 1415 km long telecom fiber link that enables substantially better precision than classical means of frequency transfer. The fractional precision in comparing the optical clocks of three parts in $10^{17}$ was reached after only 1000 s averaging time, which is already 10 times better and more than four orders of magnitude faster than with any other existing frequency transfer method. The capability of performing high resolution international clock comparisons paves the way for a redefinition of the unit of time and an all-optic...

  1. Clock genes in hypertension: novel insights from rodent models.

    Science.gov (United States)

    Richards, Jacob; Diaz, Alexander N; Gumz, Michelle L

    2014-10-01

    The circadian clock plays an integral role in the regulation of physiological processes, including the regulation of blood pressure. However, deregulation of the clock can lead to pathophysiological states including hypertension. Recent work has implicated the circadian clock genes in the regulation of processes in the heart, kidney, vasculature, and the metabolic organs, which are all critical in the regulation of the blood pressure. The goal of this review is to provide an introduction and general overview into the role of circadian clock genes in the regulation of blood pressure with a focus on their deregulation in the etiology of hypertension. This review will focus on the core circadian clock genes CLOCK, BMAL1, Per, and Cry.

  2. Dynamic Power Reduction of Digital Circuits by ClockGating

    Directory of Open Access Journals (Sweden)

    Varsha Dewre

    2017-04-01

    Full Text Available In this paper we have presented clock gating process for low power VLSI (very large scale integration circuit design. Clock gating is one of the most quite often used systems in RTL to shrink dynamic power consumption without affecting the performance of the design. One process involves inserting gating requisites in the RTL, which the synthesis tool translates to clock gating cells in the clock-path of a register bank. This helps to diminish the switching activity on the clock network, thereby decreasing dynamic power consumption within the design. Due to the fact the translation accomplished via the synthesis tool is solely combinational; it is referred to as combinational clock gating. This transformation does not alter the behavior of the register being gated

  3. Synthetic Spin-Orbit Coupling in an Optical Lattice Clock

    Science.gov (United States)

    Wall, Michael L.; Koller, Andrew P.; Li, Shuming; Zhang, Xibo; Cooper, Nigel R.; Ye, Jun; Rey, Ana Maria

    2016-01-01

    We propose the use of optical lattice clocks operated with fermionic alkaline-earth atoms to study spin-orbit coupling (SOC) in interacting many-body systems. The SOC emerges naturally during the clock interrogation, when atoms are allowed to tunnel and accumulate a phase set by the ratio of the "magic" lattice wavelength to the clock transition wavelength. We demonstrate how standard protocols such as Rabi and Ramsey spectroscopy that take advantage of the sub-Hertz resolution of state-of-the-art clock lasers can perform momentum-resolved band tomography and determine SOC-induced s -wave collisions in nuclear-spin-polarized fermions. With the use of a second counterpropagating clock beam, we propose a method for engineering controlled atomic transport and study how it is modified by p - and s -wave interactions. The proposed spectroscopic probes provide clean and well-resolved signatures at current clock operating temperatures.

  4. Caveolin-1 associated adenovirus entry into human corneal cells.

    Directory of Open Access Journals (Sweden)

    Mohammad A Yousuf

    Full Text Available The cellular entry of viruses represents a critical area of study, not only for viral tropism, but also because viral entry dictates the nature of the immune response elicited upon infection. Epidemic keratoconjunctivitis (EKC, caused by viruses within human adenovirus species D (HAdV-D, is a severe, ocular surface infection associated with corneal inflammation. Clathrin-mediated endocytosis has previously been shown to play a critical role in entry of other HAdV species into many host cell types. However, HAdV-D endocytosis into corneal cells has not been extensively studied. Herein, we show an essential role for cholesterol rich, lipid raft microdomains and caveolin-1, in the entry of HAdV-D37 into primary human corneal fibroblasts. Cholesterol depletion using methyl-β-cyclodextrin (MβCD profoundly reduced viral infection. When replenished with soluble cholesterol, the effect of MβCD was reversed, allowing productive viral infection. HAdV-D37 DNA was identified in caveolin-1 rich endosomal fractions after infection. Src kinase activity was also increased in caveolin-1 rich endosomal fractions after infection, and Src phosphorylation and CXCL1 induction were both decreased in caveolin-1-/- mice corneas compared to wild type mice. siRNA knock down of caveolin-1 in corneal cells reduced chemokine induction upon viral infection, and caveolin-1-/- mouse corneas showed reduced cellular entry of HAdV-D37. As a control, HAdV-C2, a non-corneal pathogen, appeared to utilize the caveolar pathway for entry into A549 cells, but failed to infect corneal cells entirely, indicating virus and cell specific tropism. Immuno-electron microscopy confirmed the presence of caveolin-1 in HAdV-D37-containing vesicles during the earliest stages of viral entry. Collectively, these experiments indicate for the first time that HAdV-D37 uses a lipid raft mediated caveolin-1 associated pathway for entry into corneal cells, and connects the processes of viral entry with

  5. Atomic fountains and optical clocks at SYRTE: status and perspectives

    CERN Document Server

    Abgrall, M; De Sarlo, L; Guéna, J; Laurent, Ph; Coq, Y Le; Targat, R Le; Lodewyck, J; Lours, M; Rosenbusch, P; Rovera, D; Bize, S

    2015-01-01

    In this article, we report on the work done with the LNE-SYRTE atomic clock ensemble during the last 10 years. We cover progress made in atomic fountains and in their application to timekeeping. We also cover the development of optical lattice clocks based on strontium and on mercury. We report on tests of fundamental physical laws made with these highly accurate atomic clocks. We also report on work relevant to a future possible redefinition of the SI second.

  6. System-wide power management control via clock distribution network

    Energy Technology Data Exchange (ETDEWEB)

    Coteus, Paul W.; Gara, Alan; Gooding, Thomas M.; Haring, Rudolf A.; Kopcsay, Gerard V.; Liebsch, Thomas A.; Reed, Don D.

    2015-05-19

    An apparatus, method and computer program product for automatically controlling power dissipation of a parallel computing system that includes a plurality of processors. A computing device issues a command to the parallel computing system. A clock pulse-width modulator encodes the command in a system clock signal to be distributed to the plurality of processors. The plurality of processors in the parallel computing system receive the system clock signal including the encoded command, and adjusts power dissipation according to the encoded command.

  7. Transcriptional repressor PRR5 directly regulates clock-output pathways

    OpenAIRE

    Nakamichi, Norihito; Kiba, Takatoshi; Kamioka, Mari; Suzuki, Takamasa; Yamashino, Takafumi; Higashiyama, Tetsuya; Sakakibara, Hitoshi; Mizuno, Takeshi

    2012-01-01

    The circadian clock is an endogenous time-keeping mechanism that enables organisms to adapt to external daily cycles. The clock coordinates biological activities with these cycles, mainly through genome-wide gene expression. However, the exact mechanism underlying regulation of circadian gene expression is poorly understood. Here we demonstrated that an Arabidopsis PSEUDO-RESPONSE REGULATOR 5 (PRR5), which acts in the clock genetic circuit, directly regulates expression timing of key transcri...

  8. The Rock Island Clock Tower, From Ordnance to Engineers

    Science.gov (United States)

    1977-05-01

    11.) The Clock Tower shows no influence of two other architectural styles which were rapidly becoming popular in 1863: the Victor ian and gothic ...the hoist and to the clock on the fifth and sixth floors. The outside of the building, however, shows more attention to architectural design than...called for on the original plans. A comparison of the Columbus plans with the Rock Island Clock Tower shows an interesting architectural shift

  9. Circadian clocks and cell division: What's the pacemaker?

    OpenAIRE

    Johnson, Carl Hirschie

    2010-01-01

    Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to...

  10. Chronobiology of micturition: putative role of the circadian clock.

    OpenAIRE

    Negoro, Hiromitsu; Kanematsu, Akihiro; Yoshimura, Koji; Ogawa, Osamu

    2013-01-01

    [Purpose]Mammals urinate less frequently during the sleep period than the awake period. This is modulated by a triad of factors, including decreased arousal in the brain, a decreased urine production rate in the kidneys and increased functional bladder capacity during sleep. The circadian clock is genetic transcription-translation feedback machinery. It exists in most organs and cells, termed the peripheral clock, which is orchestrated by the central clock in the suprachiasmatic nucleus of th...

  11. HIV-1 production is specifically associated with human NMT1 long form in human NMT isozymes.

    Science.gov (United States)

    Takamune, Nobutoki; Gota, Kayoko; Misumi, Shogo; Tanaka, Kenzo; Okinaka, Shigetaka; Shoji, Shozo

    2008-02-01

    The N-myristoylation of the N-terminal of human immunodeficiency virus type-1 (HIV-1) Pr55(gag) by human N-myristoyltransferase (hNMT) is a prerequisite modification for HIV-1 production. hNMT consists of multiple isozymes encoded by hNMT1 and hNMT2. The hNMT1 isozyme consists of long, medium, and short forms. Here, we investigated which isozyme is crucial for HIV-1 production. Human embryonic kidney (HEK) 293 cells transfected with infectious HIV-1 vectors were used as models of HIV-1-infected cells in this study. The significant reduction in HIV-1 production and the failure of the specific localization of Pr55(gag) in a detergent-resistant membrane fraction were dependent on the knockdown of the different forms of the hNMT1 isozyme but not of the hNMT2 isozyme. Additionally, the coexpression of an inactive mutant hNMT1 isozyme, namely the hNMT1 long form (hNMT1(L)), but not that of other hNMT mutants resulted in a significant reduction in HIV-1 production. These results strongly suggest that HIV-1 production is specifically associated with hNMT1, particularly hNMT1(L), but not with hNMT2 in vivo, contributing to the understanding of a step in HIV-1 replication.

  12. 76 FR 795 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2011-01-06

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... Act (NAGPRA), 25 U.S.C. 3003, of the completion of an inventory of human remains and associated... Trace Parkway, Tupelo, MS. The human remains and cultural items were removed from Claiborne County, MS...

  13. 77 FR 11583 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2012-02-27

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... completion of an inventory of human remains and associated funerary objects in the possession of San Diego State University, San Diego, CA. The human remains and cultural items were removed from the vicinity of...

  14. 77 FR 59659 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2012-09-28

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated....S.C. 3003, of the completion of an inventory of human remains and associated funerary objects in the control of San Francisco State University, San Francisco, CA. The ] human remains were removed from...

  15. 77 FR 68825 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2012-11-16

    ... Inventory Completion for Native American Human Remains and Associated Funerary Objects in the Control of... of human remains and associated funerary objects in the possession of the U.S. Department of the Interior, National Park Service, Casa Grande Ruins National Monument, Coolidge, AZ. The human remains and...

  16. 76 FR 58037 - Notice of Inventory Completion for Native American Human Remains and Associated Funerary Objects...

    Science.gov (United States)

    2011-09-19

    ... National Park Service Notice of Inventory Completion for Native American Human Remains and Associated... Society (History Colorado) completed an inventory of human remains and associated funerary objects, and... cultural affiliation with the human remains should contact the Colorado Historical Society at the address...

  17. [Factors associated with job satisfaction of human resources in healthcare].

    Science.gov (United States)

    Вежновець, Тетяна А; Парій, Валентин Д; Вишнивецький, Іван І; Москаленко, Максим В

    Healthcare employee satisfaction is an important criterion for the efficiency of human resource management and prognostic impact factor for high turnover of staff. Furthermore, job satisfaction positively affects patient satisfaction, which is an important indicator for quality of care. The goal of our study was to identify factors associated with job satisfaction in healthcare organizations in Ukraine. We conducted sociological and psychological survey of 190 healthcare professionals (81% response rate) in Kherson City Hospital. Job satisfaction and organizational climate was assessed through developed questionnaire, "Test Motype" method of Gerchikov (motivational profile designing) and "Diagnosis Syndrome emotional burnout" method of Boyko. Spearman rank correlation was used for analysis. Job satisfaction positively correlated with personnel age and time record, career prospects, professional development, superior-subordinate, peer-to-peer and patient communications (psatisfaction did not correlate with responsibility of executives, factors for satisfaction of job description, working conditions and range of wages (all p> 0.05). Based on findings we developed dual job satisfaction-dissatisfaction approach specific for healthcare employee in Ukraine. This model includes internal factors such as work experience, career prospects, professional motivation; external factors such as leadership, governance, work environment, customer satisfaction and preventive factors such as staff role, job description, company policies, salary and benefits.

  18. Composition of the HLA-DR-associated human thymus peptidome.

    Science.gov (United States)

    Collado, Javier A; Alvarez, Iñaki; Ciudad, M Teresa; Espinosa, Gabriel; Canals, Francesc; Pujol-Borrell, Ricardo; Carrascal, Montserrat; Abian, Joaquín; Jaraquemada, Dolores

    2013-09-01

    Major histocompatibility complex class II (MHC-II) molecules bind to and display antigenic peptides on the surface of antigen-presenting cells (APCs). In the absence of infection, MHC-II molecules on APCs present self-peptides and interact with CD4(+) T cells to maintain tolerance and homeostasis. In the thymus, self-peptides bind to MHC-II molecules expressed by defined populations of APCs specialised for the different steps of T-cell selection. Cortical epithelial cells present peptides for positive selection, whereas medullary epithelial cells and dendritic cells are responsible for peptide presentation for negative selection. However, few data are available on the peptides presented by MHC molecules in the thymus. Here, we apply mass spectrometry to analyse and identify MHC-II-associated peptides from five fresh human thymus samples. The data show a diverse self-peptide repertoire, mostly consisting of predicted MHC-II high binders. Despite technical limitations preventing single cell population analyses of peptides, these data constitute the first direct assessment of the HLA-II-bound peptidome and provide insight into how this peptidome is generated and how it drives T-cell repertoire formation.

  19. The Possible Association between Constitutive Heterochromatin Polymorphism and Human Leukemias

    Directory of Open Access Journals (Sweden)

    Abolfazl Movafagh

    2007-01-01

    Full Text Available Objective: Polymorphism of the size of heterochromatin region of chromosomes has been well documented in human genome and it consists of DNA sequences that are not transcribed. The prime aim of the present study was to evaluate the heterochromatin polymorphism associated with chromosomes in leukemic patients.Materials and Methods: The study was conducted on 35 consecutive leukemic patients and 34 healthy individuals in Modaress and Taleghani hospitals, Tehran, Iran between 2004-2006. By applying Barium Hydroxide saline Giemsa (BSC method with certain alterations, the variant heterochromatin polymorphism of chromosomes 1, 9 and 16 on bone marrow and peripheral blood lymphocyte cultures were evaluated. Chi-square and Fisher’s exact tests were used for statistical analysis with SPSS software.Results: Constitutive heterochromatin polymorphism of chromosomes 1 and 9 in leukemic patients revealed statistical significant differences when compared with chromosomes of healthy controls (p=0.0005 and (p=0.006 respectively. The differences were not significant for chromosome 16, it was 11.4% in leukemic patients and 0% in the control group (p=0.05. The frequency of partial and complete inversions did not show any significant differences between the leukemic patients and the control group.Conclusion: The constitutive heterochromatin polymorphism blocks may provide an opportunity to serve as a marker for the detection and characterization of the chromosomes in leukemic patients.

  20. 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.