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Sample records for bayesian molecular clock

  1. Comparison of different strategies for using fossil calibrations to generate the time prior in Bayesian molecular clock dating.

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    Barba-Montoya, Jose; Dos Reis, Mario; Yang, Ziheng

    2017-09-01

    Fossil calibrations are the utmost source of information for resolving the distances between molecular sequences into estimates of absolute times and absolute rates in molecular clock dating analysis. The quality of calibrations is thus expected to have a major impact on divergence time estimates even if a huge amount of molecular data is available. In Bayesian molecular clock dating, fossil calibration information is incorporated in the analysis through the prior on divergence times (the time prior). Here, we evaluate three strategies for converting fossil calibrations (in the form of minimum- and maximum-age bounds) into the prior on times, which differ according to whether they borrow information from the maximum age of ancestral nodes and minimum age of descendent nodes to form constraints for any given node on the phylogeny. We study a simple example that is analytically tractable, and analyze two real datasets (one of 10 primate species and another of 48 seed plant species) using three Bayesian dating programs: MCMCTree, MrBayes and BEAST2. We examine how different calibration strategies, the birth-death process, and automatic truncation (to enforce the constraint that ancestral nodes are older than descendent nodes) interact to determine the time prior. In general, truncation has a great impact on calibrations so that the effective priors on the calibration node ages after the truncation can be very different from the user-specified calibration densities. The different strategies for generating the effective prior also had considerable impact, leading to very different marginal effective priors. Arbitrary parameters used to implement minimum-bound calibrations were found to have a strong impact upon the prior and posterior of the divergence times. Our results highlight the importance of inspecting the joint time prior used by the dating program before any Bayesian dating analysis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. The relative ages of ectomycorrhizal mushrooms and their plant hosts estimated using Bayesian relaxed molecular clock analyses

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    Hibbett, David S; Matheny, P Brandon

    2009-01-01

    Background Ectomycorrhizae (ECM) are symbioses formed by polyphyletic assemblages of fungi (mostly Agaricomycetes) and plants (mostly Pinaceae and angiosperms in the rosid clade). Efforts to reconstruct the evolution of the ECM habit in Agaricomycetes have yielded vastly different results, ranging from scenarios with many relatively recent origins of the symbiosis and no reversals to the free-living condition; a single ancient origin of ECM and many subsequent transitions to the free-living condition; or multiple gains and losses of the association. To test the plausibility of these scenarios, we performed Bayesian relaxed molecular clock analyses including fungi, plants, and other eukaryotes, based on the principle that a symbiosis cannot evolve prior to the origin of both partners. As we were primarily interested in the relative ages of the plants and fungi, we did not attempt to calibrate the molecular clock using the very limited fossil record of Agaricomycetes. Results Topologically constrained and unconstrained analyses suggest that the root node of the Agaricomycetes is much older than either the rosids or Pinaceae. The Agaricomycetidae, a large clade containing the Agaricales and Boletales (collectively representing 70% of Agaricomycetes), is also significantly older than the rosids. The relative age of Agaricomycetidae and Pinaceae, however, is sensitive to tree topology, and the inclusion or exclusion of the gnetophyte Welwitschia mirabilis. Conclusion The ancestor of the Agaricomycetes could not have been an ECM species because it existed long before any of its potential hosts. Within more derived clades of Agaricomycetes, there have been at least eight independent origins of ECM associations involving angiosperms, and at least six to eight origins of associations with gymnosperms. The first ECM symbioses may have involved Pinaceae, which are older than rosids, but several major clades of Agaricomycetes, such as the Boletales and Russulales, are young

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

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    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…

  4. Circadian molecular clock in lung pathophysiology

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    Sundar, Isaac K.; Yao, Hongwei; Sellix, Michael T.

    2015-01-01

    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. PMID:26361874

  5. Testing the molecular clock using mechanistic models of fossil preservation and molecular evolution.

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    Warnock, Rachel C M; Yang, Ziheng; Donoghue, Philip C J

    2017-06-28

    Molecular sequence data provide information about relative times only, and fossil-based age constraints are the ultimate source of information about absolute times in molecular clock dating analyses. Thus, fossil calibrations are critical to molecular clock dating, but competing methods are difficult to evaluate empirically because the true evolutionary time scale is never known. Here, we combine mechanistic models of fossil preservation and sequence evolution in simulations to evaluate different approaches to constructing fossil calibrations and their impact on Bayesian molecular clock dating, and the relative impact of fossil versus molecular sampling. We show that divergence time estimation is impacted by the model of fossil preservation, sampling intensity and tree shape. The addition of sequence data may improve molecular clock estimates, but accuracy and precision is dominated by the quality of the fossil calibrations. Posterior means and medians are poor representatives of true divergence times; posterior intervals provide a much more accurate estimate of divergence times, though they may be wide and often do not have high coverage probability. Our results highlight the importance of increased fossil sampling and improved statistical approaches to generating calibrations, which should incorporate the non-uniform nature of ecological and temporal fossil species distributions. © 2017 The Authors.

  6. Molecular clock in neutral protein evolution

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    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. Bayesian molecular dating: opening up the black box.

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    Bromham, Lindell; Duchêne, Sebastián; Hua, Xia; Ritchie, Andrew M; Duchêne, David A; Ho, Simon Y W

    2018-05-01

    Molecular dating analyses allow evolutionary timescales to be estimated from genetic data, offering an unprecedented capacity for investigating the evolutionary past of all species. These methods require us to make assumptions about the relationship between genetic change and evolutionary time, often referred to as a 'molecular clock'. Although initially regarded with scepticism, molecular dating has now been adopted in many areas of biology. This broad uptake has been due partly to the development of Bayesian methods that allow complex aspects of molecular evolution, such as variation in rates of change across lineages, to be taken into account. But in order to do this, Bayesian dating methods rely on a range of assumptions about the evolutionary process, which vary in their degree of biological realism and empirical support. These assumptions can have substantial impacts on the estimates produced by molecular dating analyses. The aim of this review is to open the 'black box' of Bayesian molecular dating and have a look at the machinery inside. We explain the components of these dating methods, the important decisions that researchers must make in their analyses, and the factors that need to be considered when interpreting results. We illustrate the effects that the choices of different models and priors can have on the outcome of the analysis, and suggest ways to explore these impacts. We describe some major research directions that may improve the reliability of Bayesian dating. The goal of our review is to help researchers to make informed choices when using Bayesian phylogenetic methods to estimate evolutionary rates and timescales. © 2017 Cambridge Philosophical Society.

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

    OpenAIRE

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

    2015-01-01

    Abstract 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 circ...

  9. Molecular components of the mammalian circadian clock

    OpenAIRE

    Buhr, Ethan D.; Takahashi, Joseph S.

    2013-01-01

    Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissu...

  10. Finding Clocks in Genes: A Bayesian Approach to Estimate Periodicity

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    Yan Ren

    2016-01-01

    Full Text Available Identification of rhythmic gene expression from metabolic cycles to circadian rhythms is crucial for understanding the gene regulatory networks and functions of these biological processes. Recently, two algorithms, JTK_CYCLE and ARSER, have been developed to estimate periodicity of rhythmic gene expression. JTK_CYCLE performs well for long or less noisy time series, while ARSER performs well for detecting a single rhythmic category. However, observing gene expression at high temporal resolution is not always feasible, and many scientists are interested in exploring both ultradian and circadian rhythmic categories simultaneously. In this paper, a new algorithm, named autoregressive Bayesian spectral regression (ABSR, is proposed. It estimates the period of time-course experimental data and classifies gene expression profiles into multiple rhythmic categories simultaneously. Through the simulation studies, it is shown that ABSR substantially improves the accuracy of periodicity estimation and clustering of rhythmic categories as compared to JTK_CYCLE and ARSER for the data with low temporal resolution. Moreover, ABSR is insensitive to rhythmic patterns. This new scheme is applied to existing time-course mouse liver data to estimate period of rhythms and classify the genes into ultradian, circadian, and arrhythmic categories. It is observed that 49.2% of the circadian profiles detected by JTK_CYCLE with 1-hour resolution are also detected by ABSR with only 4-hour resolution.

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

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    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.

  12. Redox regulation of circadian molecular clock in chronic airway diseases.

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

    2017-10-31

    At the cellular level, circadian timing is maintained by the molecular clock, a family of interacting clock gene transcription factors, nuclear receptors and kinases called clock genes. Daily rhythms in pulmonary function are dictated by the circadian timing system, including rhythmic susceptibility to the harmful effects of airborne pollutants, exacerbations in patients with chronic airway disease and the immune-inflammatory response to infection. Further, evidence strongly suggests that the circadian molecular clock has a robust reciprocal interaction with redox signaling and plays a considerable role in the response to oxidative/carbonyl stress. Disruption of the circadian timing system, particularly in airway cells, impairs pulmonary rhythms and lung function, enhances oxidative stress due to airway inhaled pollutants like cigarette smoke and airborne particulate matter and leads to enhanced inflammosenescence, inflammasome activation, DNA damage and fibrosis. Herein, we briefly review recent evidence supporting the role of the lung molecular clock and redox signaling in regulating inflammation, oxidative stress, and DNA damage responses in lung diseases and their exacerbations. We further describe the potential for clock genes as novel biomarkers and therapeutic targets for the treatment of chronic lung diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Circadian molecular clocks tick along ontogenesis

    Czech Academy of Sciences Publication Activity Database

    Sumová, Alena; Bendová, Zdeňka; Sládek, Martin; El-Hennamy, Rehab; Matějů, Kristýna; Polidarová, Lenka; Sosniyenko, Serhiy; Illnerová, Helena

    2008-01-01

    Roč. 57, Suppl.3 (2008), S139-S148 ISSN 0862-8408 R&D Projects: GA ČR GA309/08/0503; GA AV ČR(CZ) IAA500110605; GA MŠk(CZ) LC554 Grant - others:EC(XE) LSH-2004-115-4-018741 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * ontogenesis * suprachiasmatic nucleus Subject RIV: FH - Neurology Impact factor: 1.653, year: 2008

  14. Major radiations in the evolution of Caviid rodents: reconciling fossils, ghost lineages, and relaxed molecular clocks.

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    Pérez, María Encarnación; Pol, Diego

    2012-01-01

    Caviidae is a diverse group of caviomorph rodents that is broadly distributed in South America and is divided into three highly divergent extant lineages: Caviinae (cavies), Dolichotinae (maras), and Hydrochoerinae (capybaras). The fossil record of Caviidae is only abundant and diverse since the late Miocene. Caviids belongs to Cavioidea sensu stricto (Cavioidea s.s.) that also includes a diverse assemblage of extinct taxa recorded from the late Oligocene to the middle Miocene of South America ("eocardiids"). A phylogenetic analysis combining morphological and molecular data is presented here, evaluating the time of diversification of selected nodes based on the calibration of phylogenetic trees with fossil taxa and the use of relaxed molecular clocks. This analysis reveals three major phases of diversification in the evolutionary history of Cavioidea s.s. The first two phases involve two successive radiations of extinct lineages that occurred during the late Oligocene and the early Miocene. The third phase consists of the diversification of Caviidae. The initial split of caviids is dated as middle Miocene by the fossil record. This date falls within the 95% higher probability distribution estimated by the relaxed Bayesian molecular clock, although the mean age estimate ages are 3.5 to 7 Myr older. The initial split of caviids is followed by an obscure period of poor fossil record (referred here as the Mayoan gap) and then by the appearance of highly differentiated modern lineages of caviids, which evidentially occurred at the late Miocene as indicated by both the fossil record and molecular clock estimates. The integrated approach used here allowed us identifying the agreements and discrepancies of the fossil record and molecular clock estimates on the timing of the major events in cavioid evolution, revealing evolutionary patterns that would not have been possible to gather using only molecular or paleontological data alone.

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

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    Uduak S. Udoh

    2015-10-01

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

  16. Testing the molecular clock: molecular and paleontological estimates of divergence times in the Echinoidea (Echinodermata).

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    Smith, Andrew B; Pisani, Davide; Mackenzie-Dodds, Jacqueline A; Stockley, Bruce; Webster, Bonnie L; Littlewood, D Timothy J

    2006-10-01

    The phylogenetic relationships of 46 echinoids, with representatives from 13 of the 14 ordinal-level clades and about 70% of extant families commonly recognized, have been established from 3 genes (3,226 alignable bases) and 119 morphological characters. Morphological and molecular estimates are similar enough to be considered suboptimal estimates of one another, and the combined data provide a tree that, when calibrated against the fossil record, provides paleontological estimates of divergence times and completeness of their fossil record. The order of branching on the cladogram largely agrees with the stratigraphic order of first occurrences and implies that their fossil record is more than 85% complete at family level and at a resolution of 5-Myr time intervals. Molecular estimates of divergence times derived from applying both molecular clock and relaxed molecular clock models are concordant with estimates based on the fossil record in up to 70% of cases, with most concordant results obtained using Sanderson's semiparametric penalized likelihood method and a logarithmic-penalty function. There are 3 regions of the tree where molecular and fossil estimates of divergence time consistently disagree. Comparison with results obtained when molecular divergence dates are estimated from the combined (morphology + gene) tree suggests that errors in phylogenetic reconstruction explain only one of these. In another region the error most likely lies with the paleontological estimates because taxa in this region are demonstrated to have a very poor fossil record. In the third case, morphological and paleontological evidence is much stronger, and the topology for this part of the molecular tree differs from that derived from the combined data. Here the cause of the mismatch is unclear but could be methodological, arising from marked inequality of molecular rates. Overall, the level of agreement reached between these different data and methodological approaches leads us to

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

    Indian Academy of Sciences (India)

    2009-10-30

    Oct 30, 2009 ... This paper presents a brief review of recent advances in the classification of mammals at higher levels using fossils and molecular clocks. It also discusses latest fossil discoveries from the Cretaceous – Eocene (66–55 m.y.) rocks of India and their relevance to our current understanding of placental ...

  18. Using more than the oldest fossils: dating osmundaceae with three Bayesian clock approaches.

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    Grimm, Guido W; Kapli, Paschalia; Bomfleur, Benjamin; McLoughlin, Stephen; Renner, Susanne S

    2015-05-01

    A major concern in molecular clock dating is how to use information from the fossil record to calibrate genetic distances from DNA sequences. Here we apply three Bayesian dating methods that differ in how calibration is achieved-"node dating" (ND) in BEAST, "total evidence" (TE) dating in MrBayes, and the "fossilized birth-death" (FBD) in FDPPDiv-to infer divergence times in the royal ferns. Osmundaceae have 16-17 species in four genera, two mainly in the Northern Hemisphere and two in South Africa and Australasia; they are the sister clade to the remaining leptosporangiate ferns. Their fossil record consists of at least 150 species in ∼17 genera. For ND, we used the five oldest fossils, whereas for TE and FBD dating, which do not require forcing fossils to nodes and thus can use more fossils, we included up to 36 rhizomes and frond compression/impression fossils, which for TE dating were scored for 33 morphological characters. We also subsampled 10%, 25%, and 50% of the 36 fossils to assess model sensitivity. FBD-derived divergence ages were generally greater than those inferred from ND; two of seven TE-derived ages agreed with FBD-obtained ages, the others were much younger or much older than ND or FBD ages. We prefer the FBD-derived ages because they best fit the Osmundales fossil record (including Triassic fossils not used in our study). Under the preferred model, the clade encompassing extant Osmundaceae (and many fossils) dates to the latest Paleozoic to Early Triassic; divergences of the extant species occurred during the Neogene. Under the assumption of constant speciation and extinction rates, the FBD approach yielded speciation and extinction rates that overlapped those obtained from just neontological data. However, FBD estimates of speciation and extinction are sensitive to violations in the assumption of continuous fossil sampling; therefore, these estimates should be treated with caution. © The Author(s) 2014. Published by Oxford University Press

  19. On the age of eukaryotes: evaluating evidence from fossils and molecular clocks.

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    Eme, Laura; Sharpe, Susan C; Brown, Matthew W; Roger, Andrew J

    2014-08-01

    Our understanding of the phylogenetic relationships among eukaryotic lineages has improved dramatically over the few past decades thanks to the development of sophisticated phylogenetic methods and models of evolution, in combination with the increasing availability of sequence data for a variety of eukaryotic lineages. Concurrently, efforts have been made to infer the age of major evolutionary events along the tree of eukaryotes using fossil-calibrated molecular clock-based methods. Here, we review the progress and pitfalls in estimating the age of the last eukaryotic common ancestor (LECA) and major lineages. After reviewing previous attempts to date deep eukaryote divergences, we present the results of a Bayesian relaxed-molecular clock analysis of a large dataset (159 proteins, 85 taxa) using 19 fossil calibrations. We show that for major eukaryote groups estimated dates of divergence, as well as their credible intervals, are heavily influenced by the relaxed molecular clock models and methods used, and by the nature and treatment of fossil calibrations. Whereas the estimated age of LECA varied widely, ranging from 1007 (943-1102) Ma to 1898 (1655-2094) Ma, all analyses suggested that the eukaryotic supergroups subsequently diverged rapidly (i.e., within 300 Ma of LECA). The extreme variability of these and previously published analyses preclude definitive conclusions regarding the age of major eukaryote clades at this time. As more reliable fossil data on eukaryotes from the Proterozoic become available and improvements are made in relaxed molecular clock modeling, we may be able to date the age of extant eukaryotes more precisely. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

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

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    Loeza-Quintana, Tzitziki; Adamowicz, Sarah J

    2018-02-01

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

  1. Using fossils to break long branches in molecular dating: a comparison of relaxed clocks applied to the origin of angiosperms.

    Science.gov (United States)

    Magallón, Susana

    2010-07-01

    Long branches are potentially problematic in molecular dating because they can encompass a vast number of combinations of substitution rate and time. A long branch is suspected to have biased molecular clock estimates of the age of flowering plants (angiosperms) to be much older than their earliest fossils. This study explores the effect of the long branch subtending angiosperms in molecular dating and how different relaxed clocks react to it. Fossil angiosperm relatives, identified through a combined morphological and molecular phylogenetic analysis for living and fossil seed plants, were used to break the long angiosperm stem branch. Nucleotide sequences of angiosperm fossil relatives were simulated using a phylogeny and model parameters from living taxa and incorporated in molecular dating. Three relaxed clocks, which implement among-lineage rate heterogeneity differently, were used: penalized likelihood (using 2 different rate smoothing optimization criteria), a Bayesian rate-autocorrelated method, and a Bayesian uncorrelated method. Different clocks provided highly correlated ages across the tree. Breaking the angiosperm stem branch did not result in major age differences, except for a few sensitive nodes. Breaking the angiosperm stem branch resulted in a substantially younger age for crown angiosperms only with 1 of the 4 methods, but, nevertheless, the obtained age is considerably older than the oldest angiosperm fossils. The origin of crown angiosperms is estimated between the Upper Triassic and the early Permian. The difficulty in estimating crown angiosperm age probably lies in a combination of intrinsic and extrinsic complicating factors, including substantial molecular rate heterogeneity among lineages and through time. A more adequate molecular dating approach might combine moderate background rate heterogeneity with large changes in rate at particular points in the tree.

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

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    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. Fossil butterflies, calibration points and the molecular clock (Lepidoptera: Papilionoidea).

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    Jong, Rienk DE

    2017-05-25

    Fossil butterflies are extremely rare. Yet, they are the only direct evidence of the first appearance of particular characters and as such, they are crucial for calibrating a molecular clock, from which divergence ages are estimated. In turn, these estimates, in combination with paleogeographic information, are most important in paleobiogeographic considerations. The key issue here is the correct allocation of fossils on the phylogenetic tree from which the molecular clock is calibrated.The allocation of a fossil on a tree should be based on an apomorphic character found in a tree based on extant species, similar to the allocation of a new extant species. In practice, the latter is not done, at least not explicitly, on the basis of apomorphy, but rather on overall similarity or on a phylogenetic analysis, which is not possible for most butterfly fossils since they usually are very fragmentary. Characters most often preserved are in the venation of the wings. Therefore, special attention is given to possible apomorphies in venational characters in extant butterflies. For estimation of divergence times, not only the correct allocation of the fossil on the tree is important, but also the tree itself influences the outcome as well as the correct determination of the age of the fossil. These three aspects are discussed.        All known butterfly fossils, consisting of 49 taxa, are critically reviewed and their relationship to extant taxa is discussed as an aid for correctly calibrating a molecular clock for papilionoid Lepidoptera. In this context some aspects of age estimation and biogeographic conclusions are briefly mentioned in review. Specific information has been summarized in four appendices.

  4. Using Higher-Order Dynamic Bayesian Networks to Model Periodic Data from the Circadian Clock of Arabidopsis Thaliana

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    Daly, Rónán; Edwards, Kieron D.; O'Neill, John S.; Aitken, Stuart; Millar, Andrew J.; Girolami, Mark

    Modelling gene regulatory networks in organisms is an important task that has recently become possible due to large scale assays using technologies such as microarrays. In this paper, the circadian clock of Arabidopsis thaliana is modelled by fitting dynamic Bayesian networks to luminescence data gathered from experiments. This work differs from previous modelling attempts by using higher-order dynamic Bayesian networks to explicitly model the time lag between the various genes being expressed. In order to achieve this goal, new techniques in preprocessing the data and in evaluating a learned model are proposed. It is shown that it is possible, to some extent, to model these time delays using a higher-order dynamic Bayesian network.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    The central circadian clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the circadian clockwork of the SCN constitutes a self-sustained autoregulatory feedback mechanism reflected by the rhythmic expression of clock genes. However......, recent studies have shown the presence of extrahypothalamic oscillators in other areas of the brain including the cerebellum. In the present study, the authors unravel the cerebellar molecular clock by analyzing clock gene expression in the cerebellum of the rat by use of radiochemical in situ...... hybridization and quantitative real-time polymerase chain reaction. The authors here show that all core clock genes, i.e., Per1, Per2, Per3, Cry1, Cry2, Clock, Arntl, and Nr1d1, as well as the clock-controlled gene Dbp, are expressed in the granular and Purkinje cell layers of the cerebellar cortex. Among...

  6. Pacemaker-neuron–dependent disturbance of the molecular clockwork by a Drosophila CLOCK mutant homologous to the mouse Clock mutation

    Science.gov (United States)

    Lee, Euna; Cho, Eunjoo; Kang, Doo Hyun; Jeong, Eun Hee; Chen, Zheng; Yoo, Seung-Hee; Kim, Eun Young

    2016-01-01

    Circadian clocks are composed of transcriptional/translational feedback loops (TTFLs) at the cellular level. In Drosophila TTFLs, the transcription factor dCLOCK (dCLK)/CYCLE (CYC) activates clock target gene expression, which is repressed by the physical interaction with PERIOD (PER). Here, we show that amino acids (AA) 657–707 of dCLK, a region that is homologous to the mouse Clock exon 19-encoded region, is crucial for PER binding and E-box–dependent transactivation in S2 cells. Consistently, in transgenic flies expressing dCLK with an AA657–707 deletion in the Clock (Clkout) genetic background (p{dClk-Δ};Clkout), oscillation of core clock genes’ mRNAs displayed diminished amplitude compared with control flies, and the highly abundant dCLKΔ657–707 showed significantly decreased binding to PER. Behaviorally, the p{dClk-Δ};Clkout flies exhibited arrhythmic locomotor behavior in the photic entrainment condition but showed anticipatory activities of temperature transition and improved free-running rhythms in the temperature entrainment condition. Surprisingly, p{dClk-Δ};Clkout flies showed pacemaker-neuron–dependent alterations in molecular rhythms; the abundance of dCLK target clock proteins was reduced in ventral lateral neurons (LNvs) but not in dorsal neurons (DNs) in both entrainment conditions. In p{dClk-Δ};Clkout flies, however, strong but delayed molecular oscillations in temperature cycle-sensitive pacemaker neurons, such as DN1s and DN2s, were correlated with delayed anticipatory activities of temperature transition. Taken together, our study reveals that the LNv molecular clockwork is more sensitive than the clockwork of DNs to dysregulation of dCLK by AA657–707 deletion. Therefore, we propose that the dCLK/CYC-controlled TTFL operates differently in subsets of pacemaker neurons, which may contribute to their specific functions. PMID:27489346

  7. Ultracold Molecules in Optical Lattices: Efficient Production and Application to Molecular Clocks

    Science.gov (United States)

    2015-05-03

    Martin, M. M. Boyd, and J. Ye. Rabi spectroscopy and excitation inhomogeneity in a one-dimensional optical lattice clock. Phys. Rev. A, 80:052703, 2009...can fully control the molecules’ internal and external quantum states, as in state-of-the-art atomic lattice clocks. Using the quantized molecular...spectra in an optical lattice , we devised a new lattice thermometry method that is advantageous for many lattice experiments, including clocks and

  8. Improving the accuracy of demographic and molecular clock model comparison while accommodating phylogenetic uncertainty.

    Science.gov (United States)

    Baele, Guy; Lemey, Philippe; Bedford, Trevor; Rambaut, Andrew; Suchard, Marc A; Alekseyenko, Alexander V

    2012-09-01

    Recent developments in marginal likelihood estimation for model selection in the field of Bayesian phylogenetics and molecular evolution have emphasized the poor performance of the harmonic mean estimator (HME). Although these studies have shown the merits of new approaches applied to standard normally distributed examples and small real-world data sets, not much is currently known concerning the performance and computational issues of these methods when fitting complex evolutionary and population genetic models to empirical real-world data sets. Further, these approaches have not yet seen widespread application in the field due to the lack of implementations of these computationally demanding techniques in commonly used phylogenetic packages. We here investigate the performance of some of these new marginal likelihood estimators, specifically, path sampling (PS) and stepping-stone (SS) sampling for comparing models of demographic change and relaxed molecular clocks, using synthetic data and real-world examples for which unexpected inferences were made using the HME. Given the drastically increased computational demands of PS and SS sampling, we also investigate a posterior simulation-based analogue of Akaike's information criterion (AIC) through Markov chain Monte Carlo (MCMC), a model comparison approach that shares with the HME the appealing feature of having a low computational overhead over the original MCMC analysis. We confirm that the HME systematically overestimates the marginal likelihood and fails to yield reliable model classification and show that the AICM performs better and may be a useful initial evaluation of model choice but that it is also, to a lesser degree, unreliable. We show that PS and SS sampling substantially outperform these estimators and adjust the conclusions made concerning previous analyses for the three real-world data sets that we reanalyzed. The methods used in this article are now available in BEAST, a powerful user

  9. Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

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    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.

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

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    Mitsunori Miyazaki

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

  11. New Evo-SETI results about civilizations and molecular clock

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    Maccone, Claudio

    2017-01-01

    In two recent papers (Maccone 2013, 2014) as well as in the book (Maccone 2012), this author described the Evolution of life on Earth over the last 3.5 billion years as a lognormal stochastic process in the increasing number of living Species. In (Maccone 2012, 2013), the process used was `Geometric Brownian Motion' (GBM), largely used in Financial Mathematics (Black-Sholes models). The GBM mean value, also called `the trend', always is an exponential in time and this fact corresponds to the so-called `Malthusian growth' typical of population genetics. In (Maccone 2014), the author made an important generalization of his theory by extending it to lognormal stochastic processes having an arbitrary trend m L (t), rather than just a simple exponential trend as the GBM have. The author named `Evo-SETI' (Evolution and SETI) his theory inasmuch as it may be used not only to describe the full evolution of life on Earth from RNA to modern human societies, but also the possible evolution of life on exoplanets, thus leading to SETI, the current Search for ExtraTerrestrial Intelligence. In the Evo-SETI Theory, the life of a living being (let it be a cell or an animal or a human or a Civilization of humans or even an ET Civilization) is represented by a b-lognormal, i.e. a lognormal probability density function starting at a precise instant b (`birth') then increasing up to a peak-time p, then decreasing to a senility-time s (the descending inflexion point) and then continuing as a straight line down to the death-time d (`finite b-lognormal'). (1) Having so said, the present paper describes the further mathematical advances made by this author in 2014-2015, and is divided in two halves: Part One, devoted to new mathematical results about the History of Civilizations as b-lognormals, and (2) Part Two, about the applications of the Evo-SETI Theory to the Molecular Clock, well known to evolutionary geneticists since 50 years: the idea is that our EvoEntropy grows linearly in time

  12. The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus.

    Science.gov (United States)

    Kudo, Takashi; Block, Gene D; Colwell, Christopher S

    2015-01-01

    The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca(2+)]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca(2+)]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca(2+)]i-activated channel is one of the targets. © The Author(s) 2015.

  13. 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.

  14. Origin of the Eumetazoa: testing ecological predictions of molecular clocks against the Proterozoic fossil record

    Science.gov (United States)

    Peterson, Kevin J.; Butterfield, Nicholas J.

    2005-01-01

    Molecular clocks have the potential to shed light on the timing of early metazoan divergences, but differing algorithms and calibration points yield conspicuously discordant results. We argue here that competing molecular clock hypotheses should be testable in the fossil record, on the principle that fundamentally new grades of animal organization will have ecosystem-wide impacts. Using a set of seven nuclear-encoded protein sequences, we demonstrate the paraphyly of Porifera and calculate sponge/eumetazoan and cnidarian/bilaterian divergence times by using both distance [minimum evolution (ME)] and maximum likelihood (ML) molecular clocks; ME brackets the appearance of Eumetazoa between 634 and 604 Ma, whereas ML suggests it was between 867 and 748 Ma. Significantly, the ME, but not the ML, estimate is coincident with a major regime change in the Proterozoic acritarch record, including: (i) disappearance of low-diversity, evolutionarily static, pre-Ediacaran acanthomorphs; (ii) radiation of the high-diversity, short-lived Doushantuo-Pertatataka microbiota; and (iii) an order-of-magnitude increase in evolutionary turnover rate. We interpret this turnover as a consequence of the novel ecological challenges accompanying the evolution of the eumetazoan nervous system and gut. Thus, the more readily preserved microfossil record provides positive evidence for the absence of pre-Ediacaran eumetazoans and strongly supports the veracity, and therefore more general application, of the ME molecular clock.

  15. Influence of Tertiary paleoenvironmental changes on the diversification of South American mammals: a relaxed molecular clock study within xenarthrans

    Directory of Open Access Journals (Sweden)

    Vizcaíno Sergio F

    2004-04-01

    Full Text Available Abstract Background Comparative genomic data among organisms allow the reconstruction of their phylogenies and evolutionary time scales. Molecular timings have been recently used to suggest that environmental global change have shaped the evolutionary history of diverse terrestrial organisms. Living xenarthrans (armadillos, anteaters and sloths constitute an ideal model for studying the influence of past environmental changes on species diversification. Indeed, extant xenarthran species are relicts from an evolutionary radiation enhanced by their isolation in South America during the Tertiary era, a period for which major climate variations and tectonic events are relatively well documented. Results We applied a Bayesian approach to three nuclear genes in order to relax the molecular clock assumption while accounting for differences in evolutionary dynamics among genes and incorporating paleontological uncertainties. We obtained a molecular time scale for the evolution of extant xenarthrans and other placental mammals. Divergence time estimates provide substantial evidence for contemporaneous diversification events among independent xenarthran lineages. This correlated pattern of diversification might possibly relate to major environmental changes that occurred in South America during the Cenozoic. Conclusions The observed synchronicity between planetary and biological events suggests that global change played a crucial role in shaping the evolutionary history of extant xenarthrans. Our findings open ways to test this hypothesis further in other South American mammalian endemics like hystricognath rodents, platyrrhine primates, and didelphid marsupials.

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

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    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.

  17. Ultracold photodissociation and progress towards a molecular lattice clock with 88 Sr

    Science.gov (United States)

    Lee, Chih-Hsi; McGuyer, Bart; McDonald, Mickey; Apfelback, Florian; Grier, Andrew; Zelevinsky, Tanya

    2016-05-01

    Techniques originally developed for the construction of atomic clocks can be adapted to the study of ultracold molecules, with applications ranging from studies of ultracold chemistry to searches for new physics. We present recent experimental results involving studies of fully quantum state-resolved photodissociation of 88 Sr2 molecules, as well as progress toward building a molecular clock. First, our system has allowed for precise, quantum state-resolved photodissociation studies, revealing not only excellent control over quantum states but also a more accurate way to describe the photodissociation of diatomic molecules and access ultracold chemistry. Second, the molecular clock will allow us to search for a possible time variation of the proton-electron mass ratio. The ``oscillator'' of such a molecular clock would consist of the frequency difference between two lasers driving a two-photon Raman transition between deeply and intermediately-bound rovibrational levels in the electronic ground state. Accomplishing this task requires exploring several research directions, including the precision spectroscopy of bound states and developing tools for the control and minimization of differential lattice light shifts.

  18. Testing the Molecular Clock Using the Best Fossil Record: Case Studies from the Planktic Foraminifera

    Science.gov (United States)

    Steel, B. A.; Kucera, M.; Darling, K.

    2004-12-01

    Criticism of molecular clock studies often centres on inadequate calibration and a perceived lack of correlation between reproductive isolation and recognisable morphological evolution. Since many major groups (e.g. birds, mammals, reptiles) have a poor fossil record, it is often difficult to test and refute these limitations. Planktic foraminifera represent an exception to this rule. Deep-sea sediments are super-abundant in foraminifera, and large numbers of specimens and occurrences are easily garnered from Ocean Drilling Programme cores. Planktic foraminifera therefore represent an ideal model group with which to test and refine molecular clock studies. Since the 1990AƒAøAøâ_sA¬Aøâ_zAøs, genetic sequences (principally 18S r-RNA) have been extracted from living planktic foraminifera, and a large genetic library has developed. Our study attempts to contextualise and test molecular data, particularly AƒAøAøâ_sA¬Asmall amount of morphological evolution observed within the plexus. We have used morphometric methods on a large (over 2000 pooled specimens) dataset in an effort to independently test the molecular clock, using SEM-based measurement of pore metrics (for Gl. siphonifera) and a multivariate analysis of whole-test characteristics (for Gs. ruber). Comparison of results for the two species suggests interesting patterns; whilst the two cryptic sub-types of Gl. siphonifera seemingly can be traced through time and seem to respond to external oceanographic forcing, the sub-types of Gs. ruber appear to be truly cryptic, and cannot be distinguished in the fossil record beyond 0.7 Ma. This raises two important points; firstly, the molecular clock (at least for foraminifera) bears considerable scrutiny, appears to be relatively robust to substitution bias and is seemingly broadly in accordance with morphological data; and secondly, the relationship between form and function in planktic foraminifera appears to be ill-defined, raising important questions for

  19. The molecular clock of neutral evolution can be accelerated or slowed by asymmetric spatial structure.

    Directory of Open Access Journals (Sweden)

    Benjamin Allen

    2015-02-01

    Full Text Available Over time, a population acquires neutral genetic substitutions as a consequence of random drift. A famous result in population genetics asserts that the rate, K, at which these substitutions accumulate in the population coincides with the mutation rate, u, at which they arise in individuals: K = u. This identity enables genetic sequence data to be used as a "molecular clock" to estimate the timing of evolutionary events. While the molecular clock is known to be perturbed by selection, it is thought that K = u holds very generally for neutral evolution. Here we show that asymmetric spatial population structure can alter the molecular clock rate for neutral mutations, leading to either Ku. Our results apply to a general class of haploid, asexually reproducing, spatially structured populations. Deviations from K = u occur because mutations arise unequally at different sites and have different probabilities of fixation depending on where they arise. If birth rates are uniform across sites, then K ≤ u. In general, K can take any value between 0 and Nu. Our model can be applied to a variety of population structures. In one example, we investigate the accumulation of genetic mutations in the small intestine. In another application, we analyze over 900 Twitter networks to study the effect of network topology on the fixation of neutral innovations in social evolution.

  20. WNT Takes Two to Tango: Molecular Links between the Circadian Clock and the Cell Cycle in Adult Stem Cells.

    Science.gov (United States)

    Matsu-Ura, Toru; Moore, Sean R; Hong, Christian I

    2018-02-01

    Like two dancers, the circadian clock and cell cycle are biological oscillators engaged in bidirectional communication, resulting in circadian clock-gated cell division cycles in species ranging from cyanobacteria to mammals. The identified mechanisms for this phenomenon have expanded beyond intracellular molecular coupling components to include intercellular connections. However, detailed molecular mechanisms, dynamics, and physiological functions of the circadian clock and cell cycle as coupled oscillators remain largely unknown. In this review, we discuss current understanding of this connection in light of recent findings that have uncovered intercellular coupling between the circadian clock in Paneth cells and the cell cycle in intestinal stem cells via WNT signaling. This extends the impact of circadian rhythms regulating the timing of cell divisions beyond the intracellular domain of homogenous cell populations into dynamic, multicellular systems. In-depth understanding of the molecular links and dynamics of these two oscillators will identify potential targets and temporal regimens for effective chronotherapy.

  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. © 2015 John Wiley & Sons Ltd.

  2. Identification of the molecular components of a Tigriopus californicus (Crustacea, Copepoda) circadian clock.

    Science.gov (United States)

    Nesbit, Katherine T; Christie, Andrew E

    2014-12-01

    Copepods of the genus Tigriopus have been proposed as marine models for investigations of environmental perturbation. One rapidly increasing anthropogenic stressor for intertidal organisms is light pollution. Given the sensitivity of circadian rhythms to exogenous light, the genes/proteins of a Tigriopus circadian pacemaker represent a potential system for investigating the influences of artificial light sources on circadian behavior in an intertidal species. Here, the molecular components of a putative Tigriopus californicus circadian clock were identified using publicly accessible transcriptome data; the recently deduced circadian proteins of the copepod Calanus finmarchicus were used as a reference. Transcripts encoding homologs of all commonly recognized ancestral arthropod core clock proteins were identified (i.e. CLOCK, CRYPTOCHROME 2, CYCLE, PERIOD and TIMELESS), as were ones encoding proteins likely to modulate the core clock (i.e. CASEIN KINASE II, CLOCKWORK ORANGE, DOUBLETIME, PROTEIN PHOSPHATASE 1, PROTEIN PHOSPHATASE 2A, SHAGGY, SUPERNUMERARY LIMBS and VRILLE) or to act as inputs to it (i.e. CRYPTOCHROME 1). PAR DOMAIN PROTEIN 1 was the only circadian-associated protein not identified in Tigriopus; it appears absent in Calanus too. These data represent just the third full set of molecular components for a crustacean circadian pacemaker (Daphnia pulex and C. finmarchicus previously), and only the second obtained from transcribed sequences (C. finmarchicus previously). Given Tigriopus' proposed status as a model for investigating the influences of anthropogenic stressors in the marine environment, these data provide the first suite of gene/protein targets for understanding how light pollution may influence circadian physiology and behavior in an intertidal organism. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Ochman Howard

    2009-09-01

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

  4. Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process

    Science.gov (United States)

    Iijima, Leo; Suzuki, Shingo; Hashimoto, Tomomi; Oyake, Ayana; Kobayashi, Hisaka; Someya, Yuki; Narisawa, Dai; Yomo, Tetsuya

    2015-01-01

    The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution. PMID:26177190

  5. The origin of animals: Can molecular clocks and the fossil record be reconciled?

    Science.gov (United States)

    Cunningham, John A; Liu, Alexander G; Bengtson, Stefan; Donoghue, Philip C J

    2017-01-01

    The evolutionary emergence of animals is one of the most significant episodes in the history of life, but its timing remains poorly constrained. Molecular clocks estimate that animals originated and began diversifying over 100 million years before the first definitive metazoan fossil evidence in the Cambrian. However, closer inspection reveals that clock estimates and the fossil record are less divergent than is often claimed. Modern clock analyses do not predict the presence of the crown-representatives of most animal phyla in the Neoproterozoic. Furthermore, despite challenges provided by incomplete preservation, a paucity of phylogenetically informative characters, and uncertain expectations of the anatomy of early animals, a number of Neoproterozoic fossils can reasonably be interpreted as metazoans. A considerable discrepancy remains, but much of this can be explained by the limited preservation potential of early metazoans and the difficulties associated with their identification in the fossil record. Critical assessment of both records may permit better resolution of the tempo and mode of early animal evolution. © 2016 The Authors BioEssays Published by WILEY Periodicals, Inc.

  6. A new African fossil caprin and a combined molecular and morphological Bayesian phylogenetic analysis of caprini (Mammalia: Bovidae).

    Science.gov (United States)

    Bibi, F; Vrba, E; Fack, F

    2012-09-01

    Given that most species that have ever existed on Earth are extinct, no evolutionary history can ever be complete without the inclusion of fossil taxa. Bovids (antelopes and relatives) are one of the most diverse clades of large mammals alive today, with over a hundred living species and hundreds of documented fossil species. With the advent of molecular phylogenetics, major advances have been made in the phylogeny of this clade; however, there has been little attempt to integrate the fossil record into the developing phylogenetic picture. We here describe a new large fossil caprin species from ca. 1.9-Ma deposits from the Middle Awash, Ethiopia. To place the new species phylogenetically, we perform a Bayesian analysis of a combined molecular (cytochrome b) and morphological (osteological) character supermatrix. We include all living species of Caprini, the new fossil species, a fossil takin from the Pliocene of Ethiopia (Budorcas churcheri), and the insular subfossil Myotragus balearicus. The combined analysis demonstrates successful incorporation of both living and fossil species within a single phylogeny based on both molecular and morphological evidence. Analysis of the combined supermatrix produces superior resolution than with either the molecular or morphological data sets considered alone. Parsimony and Bayesian analyses of the data set are also compared and shown to produce similar results. The combined phylogenetic analysis indicates that the new fossil species is nested within Capra, making it one of the earliest representatives of this clade, with implications for molecular clock calibration. Geographical optimization indicates no less than four independent dispersals into Africa by caprins since the Pliocene. © 2012 The Authors. Journal of Evolutionary Biology © 2012 European Society For Evolutionary Biology.

  7. Deleting the Arntl clock gene in the granular layer of the mouse cerebellum: impact on the molecular circadian clockwork.

    Science.gov (United States)

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

    2017-07-14

    The suprachiasmatic nucleus houses the central circadian clock and is characterized by the timely regulated expression of clock genes. However, neurons of the cerebellar cortex also contain a circadian oscillator with circadian expression of clock genes being controlled by the suprachiasmatic nucleus. It has been suggested that the cerebellar circadian oscillator is involved in food anticipation, but direct molecular evidence of the role of the circadian oscillator of the cerebellar cortex is currently unavailable. To investigate the hypothesis that the circadian oscillator of the cerebellum is involved in circadian physiology and food anticipation, we therefore by use of Cre-LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located in this cell type. We here report that deletion of Arntl heavily influences the molecular clock of the cerebellar cortex with significantly altered and arrhythmic expression of other central clock and clock-controlled genes. On the other hand, daily expression of clock genes in the suprachiasmatic nucleus was unaffected. Telemetric registrations in different light regimes did not detect significant differences in circadian rhythms of running activity and body temperature between Arntl conditional knockout mice and controls. Furthermore, food anticipatory behavior did not differ between genotypes. These data suggest that Arntl is an essential part of the cerebellar oscillator; however, the oscillator of the granular layer of the cerebellar cortex does not control traditional circadian parameters or food anticipation. © 2017 International Society for Neurochemistry.

  8. Beyond fossil calibrations: Realities of molecular clock practices in evolutionary biology

    Directory of Open Access Journals (Sweden)

    Christy Anna Hipsley

    2014-05-01

    Full Text Available Molecular-based divergence dating methods, or molecular clocks, are the primary neontological tool for estimating the temporal origins of clades. While the appropriate use of vertebrate fossils as external clock calibrations has stimulated heated discussions in the paleontological community, less attention has been given to the quality and implementation of other calibration types. In lieu of appropriate fossils, many studies rely on alternative sources of age constraints based on geological events, substitution rates and heterochronous sampling, as well as dates secondarily derived from previous analyses. To illustrate the breadth and frequency of calibration types currently employed, we conducted a literature survey of over 600 articles published from 2007 to 2013. Over half of all analyses implemented one or more fossil dates as constraints, followed by geological events and secondary calibrations (15% each. Vertebrate taxa were subjects of nearly half of all studies, while invertebrates and plants together accounted for 43%, followed by viruses, protists and fungi (3% each. Current patterns in calibration practices were disproportionate to the number of discussions on their proper use, particularly regarding plants and secondarily derived dates, which are both relatively neglected. Based on our survey, we provide a comprehensive overview of the latest approaches in clock calibration, and outline strengths and weaknesses associated with each. This critique should serve as a call to action for researchers across multiple communities, particularly those working on clades for which fossil records are poor, to develop their own guidelines regarding selection and implementation of alternative calibration types. This issue is particularly relevant now, as time-calibrated phylogenies are used for more than dating evolutionary origins, but often serve as the backbone of investigations into biogeography, diversity dynamics and rates of phenotypic

  9. Beyond fossil calibrations: realities of molecular clock practices in evolutionary biology.

    Science.gov (United States)

    Hipsley, Christy A; Müller, Johannes

    2014-01-01

    Molecular-based divergence dating methods, or molecular clocks, are the primary neontological tool for estimating the temporal origins of clades. While the appropriate use of vertebrate fossils as external clock calibrations has stimulated heated discussions in the paleontological community, less attention has been given to the quality and implementation of other calibration types. In lieu of appropriate fossils, many studies rely on alternative sources of age constraints based on geological events, substitution rates and heterochronous sampling, as well as dates secondarily derived from previous analyses. To illustrate the breadth and frequency of calibration types currently employed, we conducted a literature survey of over 600 articles published from 2007 to 2013. Over half of all analyses implemented one or more fossil dates as constraints, followed by geological events and secondary calibrations (15% each). Vertebrate taxa were subjects in nearly half of all studies, while invertebrates and plants together accounted for 43%, followed by viruses, protists and fungi (3% each). Current patterns in calibration practices were disproportionate to the number of discussions on their proper use, particularly regarding plants and secondarily derived dates, which are both relatively neglected in methodological evaluations. Based on our survey, we provide a comprehensive overview of the latest approaches in clock calibration, and outline strengths and weaknesses associated with each. This critique should serve as a call to action for researchers across multiple communities, particularly those working on clades for which fossil records are poor, to develop their own guidelines regarding selection and implementation of alternative calibration types. This issue is particularly relevant now, as time-calibrated phylogenies are used for more than dating evolutionary origins, but often serve as the backbone of investigations into biogeography, diversity dynamics and rates of

  10. Nuclear rDNA-based molecular clock of the evolution of triatominae (Hemiptera: Reduviidae, vectors of Chagas disease

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    Bargues MD

    2000-01-01

    Full Text Available The evolutionary history and times of divergence of triatomine bug lineages are estimated from molecular clocks inferred from nucleotide sequences of the small subunit SSU (18S and the second internal transcribed spacer (ITS-2 of the nuclear ribosomal DNA of these reduviids. The 18S rDNA molecular clock rate in Triatominae, and Prosorrhynchan Hemiptera in general, appears to be of 1.8% per 100 million years (my. The ITS-2 molecular clock rate in Triatominae is estimated to be around 0.4-1% per 1 my, indicating that ITS-2 evolves 23-55 times faster than 18S rDNA. Inferred chronological data about the evolution of Triatominae fit well with current hypotheses on their evolutionary histories, but suggest reconsideration of the current taxonomy of North American species complexes.

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

    NARCIS (Netherlands)

    Oosterman, J.E.

    2017-01-01

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

  12. Dating the Time of Origin of Major Clades: Molecular Clocks and the Fossil Record

    Science.gov (United States)

    Smith, Andrew B.; Peterson, Kevin J.

    Molecular and paleontological data provide independent means of estimating when groups of organisms evolved in the geological past, but neither approach can be considered straightforward. The single most fundamental obstacle to developing an accurate estimate of times of origination from gene sequence data is variation in rates of molecular evolution, both through time and among lineages. Although various techniques have been proposed to circumvent this problem, none unambiguously allow the components of time and rate to be separated. Furthermore, problems of establishing accurate calibration points, correctly rooted phylogenies, and accurate estimates of branch length remain formidable. Conversely, paleontological dates fix only the latest possible time of divergence, and so probabilistic methods are required to set a lower boundary on origination dates. Realistic confidence intervals that take preservational biases into account are only just becoming available. Although molecular and paleontological approaches to dating often agree reasonably well, there are two notable areas of disagreement; when mammal and bird orders originated and when the major phyla originated. The discrepancy in dating bird/mammal ordinal origins probably reflects a global rock-record bias. Paleontological sampling in the Late Cretaceous is still too restricted geographically to draw any firm conclusions about the existence of a pre-Tertiary record for modern orders of bird or mammal from anywhere other than North America. Dating the time of origin of phyla is more complicated, and is confounded by both preservational biases and problems of molecular clock estimation.

  13. Relaxed molecular clock provides evidence for long-distance dispersal of Nothofagus (southern beech.

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    Michael Knapp

    2005-01-01

    Full Text Available Nothofagus (southern beech, with an 80-million-year-old fossil record, has become iconic as a plant genus whose ancient Gondwanan relationships reach back into the Cretaceous era. Closely associated with Wegener's theory of "Kontinentaldrift", Nothofagus has been regarded as the "key genus in plant biogeography". This paradigm has the New Zealand species as passengers on a Moa's Ark that rafted away from other landmasses following the breakup of Gondwana. An alternative explanation for the current transoceanic distribution of species seems almost inconceivable given that Nothofagus seeds are generally thought to be poorly suited for dispersal across large distances or oceans. Here we test the Moa's Ark hypothesis using relaxed molecular clock methods in the analysis of a 7.2-kb fragment of the chloroplast genome. Our analyses provide the first unequivocal molecular clock evidence that, whilst some Nothofagus transoceanic distributions are consistent with vicariance, trans-Tasman Sea distributions can only be explained by long-distance dispersal. Thus, our analyses support the interpretation of an absence of Lophozonia and Fuscospora pollen types in the New Zealand Cretaceous fossil record as evidence for Tertiary dispersals of Nothofagus to New Zealand. Our findings contradict those from recent cladistic analyses of biogeographic data that have concluded transoceanic Nothofagus distributions can only be explained by vicariance events and subsequent extinction. They indicate that the biogeographic history of Nothofagus is more complex than envisaged under opposing polarised views expressed in the ongoing controversy over the relevance of dispersal and vicariance for explaining plant biodiversity. They provide motivation and justification for developing more complex hypotheses that seek to explain the origins of Southern Hemisphere biota.

  14. Divergence time estimates of mammals from molecular clocks and fossils: relevance of new fossil finds from India.

    Science.gov (United States)

    Prasad, G V R

    2009-11-01

    This paper presents a brief review of recent advances in the classification of mammals at higher levels using fossils and molecular clocks. It also discusses latest fossil discoveries from the Cretaceous - Eocene (66-55 m.y.) rocks of India and their relevance to our current understanding of placental mammal origins and diversifications.

  15. Evolutionary history of genus Macrobrachium inferred from mitochondrial markers: a molecular clock approach.

    Science.gov (United States)

    Jose, Deepak; Harikrishnan, Mahadevan

    2018-04-17

    Caridea, an infraorder of shrimps coming under Pleocyemata was first reported from the oceans before 417 million years followed by their radiation recorded during the Permian period. Hitherto, about 3877 extant caridean species were accounted within which one quarter constitute freshwater species. Freshwater prawns of genus Macrobrachium (Infraorder Caridea; Family Palaemonidae), with more than 240 species are inhabitants of diverse aquatic habitats like coastal lagoons, lakes, tropical streams, ponds and rivers. Previous studies on Macrobrachium relied on the highly variable morphological characters which were insufficient for accurate diagnosis of natural species groups. Present study focuses on the utility of molecular markers (viz. COI and 16S rRNA) for resolving the evolutionary history of genus Macrobrachium using a combination of phylogeny and timescale components. It is for the first time a molecular clock approach had been carried out towards genus Macrobrachium in a broad aspect with the incorporation of congeners inhabiting diverse geographical realms including endemic species M. striatum from South West coast of India. Molecular results obtained revealed the phylogenetic relationships between congeners of genus Macrobrachium at intra/inter-continental level along with the corresponding evolutionary time estimates.

  16. The circadian oscillator of the cerebral cortex: molecular, biochemical and behavioral effects of deleting the Arntl clock gene in cortical neurons

    DEFF Research Database (Denmark)

    Bering, Tenna; Carstensen, Mikkel Bloss; Wörtwein, Gitta

    2018-01-01

    A molecular circadian oscillator resides in neurons of the cerebral cortex, but its role is unknown. Using the Cre-LoxP method, we have here abolished the core clock gene Arntl in those neurons. This mouse represents the first model carrying a deletion of a circadian clock component specifically...

  17. Molecular clock evidence for survival of Antarctic cyanobacteria (Oscillatoriales, Phormidium autumnale) from Paleozoic times.

    Science.gov (United States)

    Strunecký, Otakar; Elster, Josef; Komárek, Jiří

    2012-11-01

    Cyanobacteria are well adapted to freezing and desiccation; they have been proposed as possible survivors of comprehensive Antarctic glaciations. Filamentous types from the order Oscillatoriales, especially the species Phormidium autumnale Kützing ex Gomont 1892, have widely diverse morphotypes that dominate in Antarctic aquatic microbial mats, seepages, and wet soils. Currently little is known about the dispersion of cyanobacteria in Antarctica and of their population history. We tested the hypothesis that cyanobacteria survived Antarctic glaciations directly on site after the Gondwana breakup by using the relaxed and strict molecular clock in the analysis of the 16S rRNA gene. We estimated that the biogeographic history of Antarctic cyanobacteria belonging to P. autumnale lineages has ancient origins. The oldest go further back in time than the breakup of Gondwana and originated somewhere on the supercontinent between 442 and 297 Ma. Enhanced speciation rate was found around the time of the opening of the Drake Passage (c. 31-45 Ma) with beginning of glaciations (c. 43 Ma). Our results, based primarily on the strains collected in maritime Antarctica, mostly around James Ross Island, support the hypothesis that long-term survival took place in glacial refuges. The high morphological diversification of P. autumnale suggested the coevolution of lineages and formation of complex associations with different morphologies, resulting in a specific endemic Antarctic cyanobacterial flora. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  18. The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit

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    Pascale Bouchard-Cannon

    2013-11-01

    Full Text Available The subgranular zone (SGZ of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

  19. Strategies for Partitioning Clock Models in Phylogenomic Dating: Application to the Angiosperm Evolutionary Timescale.

    Science.gov (United States)

    Foster, Charles S P; Ho, Simon Y W

    2017-10-01

    Evolutionary timescales can be inferred from molecular sequence data using a Bayesian phylogenetic approach. In these methods, the molecular clock is often calibrated using fossil data. The uncertainty in these fossil calibrations is important because it determines the limiting posterior distribution for divergence-time estimates as the sequence length tends to infinity. Here, we investigate how the accuracy and precision of Bayesian divergence-time estimates improve with the increased clock-partitioning of genome-scale data into clock-subsets. We focus on a data set comprising plastome-scale sequences of 52 angiosperm taxa. There was little difference among the Bayesian date estimates whether we chose clock-subsets based on patterns of among-lineage rate heterogeneity or relative rates across genes, or by random assignment. Increasing the degree of clock-partitioning usually led to an improvement in the precision of divergence-time estimates, but this increase was asymptotic to a limit presumably imposed by fossil calibrations. Our clock-partitioning approaches yielded highly precise age estimates for several key nodes in the angiosperm phylogeny. For example, when partitioning the data into 20 clock-subsets based on patterns of among-lineage rate heterogeneity, we inferred crown angiosperms to have arisen 198-178 Ma. This demonstrates that judicious clock-partitioning can improve the precision of molecular dating based on phylogenomic data, but the meaning of this increased precision should be considered critically. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  20. A comparison of machine learning and Bayesian modelling for molecular serotyping.

    Science.gov (United States)

    Newton, Richard; Wernisch, Lorenz

    2017-08-11

    Streptococcus pneumoniae is a human pathogen that is a major cause of infant mortality. Identifying the pneumococcal serotype is an important step in monitoring the impact of vaccines used to protect against disease. Genomic microarrays provide an effective method for molecular serotyping. Previously we developed an empirical Bayesian model for the classification of serotypes from a molecular serotyping array. With only few samples available, a model driven approach was the only option. In the meanwhile, several thousand samples have been made available to us, providing an opportunity to investigate serotype classification by machine learning methods, which could complement the Bayesian model. We compare the performance of the original Bayesian model with two machine learning algorithms: Gradient Boosting Machines and Random Forests. We present our results as an example of a generic strategy whereby a preliminary probabilistic model is complemented or replaced by a machine learning classifier once enough data are available. Despite the availability of thousands of serotyping arrays, a problem encountered when applying machine learning methods is the lack of training data containing mixtures of serotypes; due to the large number of possible combinations. Most of the available training data comprises samples with only a single serotype. To overcome the lack of training data we implemented an iterative analysis, creating artificial training data of serotype mixtures by combining raw data from single serotype arrays. With the enhanced training set the machine learning algorithms out perform the original Bayesian model. However, for serotypes currently lacking sufficient training data the best performing implementation was a combination of the results of the Bayesian Model and the Gradient Boosting Machine. As well as being an effective method for classifying biological data, machine learning can also be used as an efficient method for revealing subtle biological

  1. Subfemtosecond electron dynamics of H{sub 2} in strong fields or the quest for the molecular clock

    Energy Technology Data Exchange (ETDEWEB)

    Staudte, A.

    2005-07-01

    In this work we have studied experimentally and theoretically hydrogen and deuterium molecules in strong laser fields. We wanted to demonstrate that control of dynamical processes on the time scale below a single laser cycle (2.7 fs) can be achieved even without using attosecond pulses just by employing the advanced experimental technique COLTRIMS. In order to do this, we have pursued two goals: 1. To examine, whether laser steered electron wavepackets can be used for laser induced electron diffraction (LIED) on molecules. 2. To demonstrate, that the double ionization of H{sub 2} can be followed with sub laser cycle temporal resolution (the molecular clock). Laser induced electron diffraction needs linearly polarized light since its mechanism relies on rescattering of the ionized electron in the molecular potential. With rescattering occurring within a few hundred attoseconds, LIED is really a process of attosecond physics. In principle, two extreme scattering geometries are possible for a homonuclear diatomic molecule like H{sub 2}: the perpendicular geometry, which corresponds to the classical double slit experiment where the electron microbunch is steered transversely to the molecular axis, and the tangential geometry with the electron moving parallel to the molecular axis. Experimental restrictions prevented us to investigate the perpendicular geometry. The molecular clock, on the other hand, employs circularly polarized light to map the absolute phase of the laser electric field onto the spatial direction of the electron momentum. Thereby, a full laser cycle is mapped onto 360 in momentum space. Thus, different electron ejection angles in the laboratory frame correspond to different ejection times. Together with the correlated kinetic energy release of the Coulomb exploding molecules an unambiguous clock running from 0-8 fs with a few 100 as resolution can be envisioned. In direct relation to this experiment, we studied the influence of the long range

  2. Molecular Approach to the Nyctinastic Movement of the Plant Controlled by a Biological Clock

    Directory of Open Access Journals (Sweden)

    Shosuke Yamamura

    2001-10-01

    Full Text Available Most leguminous plants close their leaves in the evening, as if to sleep, and open them early in the morning. This circadian rhythm is known to be controlled by the biological clock of such plants. Extensive studies on other nyctinastic plants led to the isolation of a variety of leaf-closing and leaf-opening substances. And, we found that the circadian rhythmic leaf-movement of these plants is controlled by a biological clock that regulates the balance of concentration between leaf-opening and -closing substances.

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

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    Pengcheng Song

    2017-01-01

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

  4. RelTime Rates Collapse to a Strict Clock When Estimating the Timeline of Animal Diversification.

    Science.gov (United States)

    Lozano-Fernandez, Jesus; Dos Reis, Mario; Donoghue, Philip C J; Pisani, Davide

    2017-05-01

    Establishing an accurate timescale for the history of life is crucial to understand evolutionary processes. For this purpose, relaxed molecular clock models implemented in a Bayesian MCMC framework are generally used. However, these methods are time consuming. RelTime, a non-Bayesian method implementing a fast, ad hoc, algorithm for relative dating, was developed to overcome the computational inefficiencies of Bayesian software. RelTime was recently used to investigate the timing of origin of animals, yielding results consistent with early strict clock studies from the 1980s and 1990s, estimating metazoans to have a Mesoproterozoic origin-over a billion years ago. RelTime results are unexpected and disagree with the largest majority of modern, relaxed, Bayesian molecular clock analyses, which suggest animals originated in the Tonian-Cryogenian (less that 850 million years ago). Here, we demonstrate that RelTime-inferred divergence times for the origin of animals are spurious, a consequence of the inability of RelTime to relax the clock along the internal branches of the animal phylogeny. RelTime-inferred divergence times are comparable to strict-clock estimates because they are essentially inferred under a strict clock. Our results warn us of the danger of using ad hoc algorithms making implicit assumptions about rate changes along a tree. Our study roundly rejects a Mesoproterozoic origin of animals; metazoans emerged in the Tonian-Cryogenian, and diversified in the Ediacaran, in the immediate prelude to the routine fossilization of animals in the Cambrian associated with the emergence of readily preserved skeletons. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  5. “The Environment is Everything That Isn't Me”: Molecular Mechanisms and Evolutionary Dynamics of Insect Clocks in Variable Surroundings

    Science.gov (United States)

    Rivas, Gustavo B. S.; Bauzer, Luiz G. S. da R.; Meireles-Filho, Antonio C. A.

    2016-01-01

    Circadian rhythms are oscillations in behavior, metabolism and physiology that have a period close to 24 h. These rhythms are controlled by an internal pacemaker that evolved under strong selective pressures imposed by environmental cyclical changes, mainly of light and temperature. The molecular nature of the circadian pacemaker was extensively studied in a number of organisms under controlled laboratory conditions. But although these studies were fundamental to our understanding of the circadian clock, most of the environmental conditions used resembled rather crudely the relatively constant situation at lower latitudes. At higher latitudes light-dark and temperature cycles vary considerably across different seasons, with summers having long and hot days and winters short and cold ones. Considering these differences and other external cues, such as moonlight, recent studies in more natural and semi-natural situations revealed unexpected features at both molecular and behavioral levels, highlighting the dramatic influence of multiple environmental variables in the molecular clockwork. This emphasizes the importance of studying the circadian clock in the wild, where seasonal environmental changes fine-tune the underlying circadian mechanism, affecting population dynamics and impacting the geographical variation in clock genes. Indeed, latitudinal clines in clock gene frequencies suggest that natural selection and demography shape the circadian clock over wide geographical ranges. In this review we will discuss the recent advances in understanding the molecular underpinnings of the circadian clock, how it resonates with the surrounding variables (both in the laboratory and in semi-natural conditions) and its impact on population dynamics and evolution. In addition, we will elaborate on how next-generation sequencing technologies will complement classical reductionist approaches by identifying causal variants in natural populations that will link genetic variation to

  6. A survey of nuclear ribosomal internal transcribed spacer substitution rates across angiosperms: an approximate molecular clock with life history effects

    Science.gov (United States)

    Kay, Kathleen M; Whittall, Justen B; Hodges, Scott A

    2006-01-01

    Background A full understanding of the patterns and processes of biological diversification requires the dating of evolutionary events, yet the fossil record is inadequate for most lineages under study. Alternatively, a molecular clock approach, in which DNA or amino acid substitution rates are calibrated with fossils or geological/climatic events, can provide indirect estimates of clade ages and diversification rates. The utility of this approach depends on the rate constancy of molecular evolution at a genetic locus across time and across lineages. Although the nuclear ribosomal internal transcribed spacer region (nrITS) is increasingly being used to infer clade ages in plants, little is known about the sources or magnitude of variation in its substitution rate. Here, we systematically review the literature to assess substitution rate variation in nrITS among angiosperms, and we evaluate possible correlates of the variation. Results We summarize 28 independently calibrated nrITS substitution rates ranging from 0.38 × 10-9 to 8.34 × 10-9 substitutions/site/yr. We find that herbaceous lineages have substitution rates almost twice as high as woody plants, on average. We do not find any among-lineage phylogenetic constraint to the rates, or any effect of the type of calibration used. Within life history categories, both the magnitude of the rates and the variance among rates tend to decrease with calibration age. Conclusion Angiosperm nrITS substitution rates vary by approximately an order of magnitude, and some of this variation can be attributed to life history categories. We make cautious recommendations for the use of nrITS as an approximate plant molecular clock, including an outline of more appropriate phylogenetic methodology and caveats against over interpretation of results. We also suggest that for lineages with independent calibrations, much of the variation in nrITS substitution rates may come from uncertainty in calibration date estimates, highlighting

  7. Bayesian refinement of protein structures and ensembles against SAXS data using molecular dynamics.

    Science.gov (United States)

    Shevchuk, Roman; Hub, Jochen S

    2017-10-01

    Small-angle X-ray scattering is an increasingly popular technique used to detect protein structures and ensembles in solution. However, the refinement of structures and ensembles against SAXS data is often ambiguous due to the low information content of SAXS data, unknown systematic errors, and unknown scattering contributions from the solvent. We offer a solution to such problems by combining Bayesian inference with all-atom molecular dynamics simulations and explicit-solvent SAXS calculations. The Bayesian formulation correctly weights the SAXS data versus prior physical knowledge, it quantifies the precision or ambiguity of fitted structures and ensembles, and it accounts for unknown systematic errors due to poor buffer matching. The method further provides a probabilistic criterion for identifying the number of states required to explain the SAXS data. The method is validated by refining ensembles of a periplasmic binding protein against calculated SAXS curves. Subsequently, we derive the solution ensembles of the eukaryotic chaperone heat shock protein 90 (Hsp90) against experimental SAXS data. We find that the SAXS data of the apo state of Hsp90 is compatible with a single wide-open conformation, whereas the SAXS data of Hsp90 bound to ATP or to an ATP-analogue strongly suggest heterogenous ensembles of a closed and a wide-open state.

  8. Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness.

    Science.gov (United States)

    Goldsmith, Charles S; Kim, Sam Moon; Karunarathna, Nirmala; Neuendorff, Nichole; Gerard Toussaint, L; Earnest, David J; Bell-Pedersen, Deborah

    2018-01-10

    The circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body. MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system. Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use. Here, we test if timed application of the specific p38 MAPK inhibitor VX-745 reduces glioma cell invasive properties in vitro. The levels and rhythmic accumulation of active phosphorylated p38 MAPK in different cell lines were determined by western blots. Rhythmic luciferase activity from clock gene luciferase reporter cells lines was used to test the effect of p38 MAPK inhibition on clock properties as determined using the damped sine fit and Levenberg-Marquardt algorithm. Nonlinear regression and Akaike's information criteria were used to establish rhythmicity. Boyden chamber assays were used to measure glioma cell invasiveness following time-of-day-specific treatment with VX-745. Significant differences were established using t-tests. We demonstrate the activity of p38 MAPK cycles under control of the clock in mouse fibroblast and SCN cell lines. The levels of phosphorylated p38 MAPK were significantly reduced in clock-deficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Inhibition of p38 MAPK activity with VX-745 led to cell-type-specific period changes in the molecular clock. In addition, phosphorylated p38 MAPK levels were rhythmic in HA glial cells, and high and arrhythmic in invasive IM3 glioma cells. We show that inhibition of

  9. Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus.

    Directory of Open Access Journals (Sweden)

    Ashley N Filiano

    Full Text Available Chronic ethanol consumption disrupts several metabolic pathways including β-oxidation and lipid biosynthesis, facilitating the development of alcoholic fatty liver disease. Many of these same metabolic pathways are directly regulated by cell autonomous circadian clocks, and recent studies suggest that disruption of daily rhythms in metabolism contributes to multiple common cardiometabolic diseases (including non-alcoholic fatty liver disease. However, it is not known whether ethanol disrupts the core molecular clock in the liver, nor whether this, in turn, alters rhythms in lipid metabolism. Herein, we tested the hypothesis that chronic ethanol consumption disrupts the molecular circadian clock in the liver and potentially changes the diurnal expression patterns of lipid metabolism genes. Consistent with previous studies, male C57BL/6J mice fed an ethanol-containing diet exhibited higher levels of liver triglycerides compared to control mice, indicating hepatic steatosis. Further, the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2 and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN. These results were confirmed in Per2(Luciferase knock-in mice, in which ethanol induced a phase advance in PER2::LUC bioluminescence oscillations in liver, but not SCN. Further, there was greater variability in the phase of PER2::LUC oscillations in livers from ethanol-fed mice. Ethanol consumption also affected the diurnal oscillations of metabolic genes, including Adh1, Cpt1a, Cyp2e1, Pck1, Pdk4, Ppargc1a, Ppargc1b and Srebp1c, in the livers of C57BL/6J mice. In summary, chronic ethanol consumption alters the function of the circadian clock in liver. Importantly, these results suggest that chronic ethanol consumption, at levels sufficient to

  10. Bayesian comparison of Markov models of molecular dynamics with detailed balance constraint

    Science.gov (United States)

    Bacallado, Sergio; Chodera, John D.; Pande, Vijay

    2009-07-01

    Discrete-space Markov models are a convenient way of describing the kinetics of biomolecules. The most common strategies used to validate these models employ statistics from simulation data, such as the eigenvalue spectrum of the inferred rate matrix, which are often associated with large uncertainties. Here, we propose a Bayesian approach, which makes it possible to differentiate between models at a fixed lag time making use of short trajectories. The hierarchical definition of the models allows one to compare instances with any number of states. We apply a conjugate prior for reversible Markov chains, which was recently introduced in the statistics literature. The method is tested in two different systems, a Monte Carlo dynamics simulation of a two-dimensional model system and molecular dynamics simulations of the terminally blocked alanine dipeptide.

  11. 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,

  12. Circadian Tick-Talking Across the Neuroendocrine System and Suprachiasmatic Nuclei Circuits: The Enigmatic Communication Between the Molecular and Electrical Membrane Clocks.

    Science.gov (United States)

    Belle, M D C

    2015-07-01

    As with many processes in nature, appropriate timing in biological systems is of paramount importance. In the neuroendocrine system, the efficacy of hormonal influence on major bodily functions, such as reproduction, metabolism and growth, relies on timely communication within and across many of the brain's homeostatic systems. The activity of these circuits is tightly orchestrated with the animal's internal physiological demands and external solar cycle by a master circadian clock. In mammals, this master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), where the ensemble activity of thousands of clock neurones generates and communicates circadian time cues to the rest of the brain and body. Many regions of the brain, including areas with neuroendocrine function, also contain local daily clocks that can provide feedback signals to the SCN. Although much is known about the molecular processes underpinning endogenous circadian rhythm generation in SCN neurones and, to a lesser extent, extra-SCN cells, the electrical membrane clock that acts in partnership with the molecular clockwork to communicate circadian timing across the brain is poorly understood. The present review focuses on some circadian aspects of reproductive neuroendocrinology and processes involved in circadian rhythm communication in the SCN, aiming to identify key gaps in our knowledge of cross-talk between our daily master clock and neuroendocrine function. The intention is to highlight our surprisingly limited understanding of their interaction in the hope that this will stimulate future work in these areas. © 2015 The Author. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of The British Society for Neuroendocrinology.

  13. Genomic-Enabled Prediction Based on Molecular Markers and Pedigree Using the Bayesian Linear Regression Package in R

    Directory of Open Access Journals (Sweden)

    Paulino Pérez

    2010-09-01

    Full Text Available The availability of dense molecular markers has made possible the use of genomic selection in plant and animal breeding. However, models for genomic selection pose several computational and statistical challenges and require specialized computer programs, not always available to the end user and not implemented in standard statistical software yet. The R-package BLR (Bayesian Linear Regression implements several statistical procedures (e.g., Bayesian Ridge Regression, Bayesian LASSO in a unified framework that allows including marker genotypes and pedigree data jointly. This article describes the classes of models implemented in the BLR package and illustrates their use through examples. Some challenges faced when applying genomic-enabled selection, such as model choice, evaluation of predictive ability through cross-validation, and choice of hyper-parameters, are also addressed.

  14. Genomic-Enabled Prediction Based on Molecular Markers and Pedigree Using the Bayesian Linear Regression Package in R.

    Science.gov (United States)

    Pérez, Paulino; de Los Campos, Gustavo; Crossa, José; Gianola, Daniel

    2010-01-01

    The availability of dense molecular markers has made possible the use of genomic selection in plant and animal breeding. However, models for genomic selection pose several computational and statistical challenges and require specialized computer programs, not always available to the end user and not implemented in standard statistical software yet. The R-package BLR (Bayesian Linear Regression) implements several statistical procedures (e.g., Bayesian Ridge Regression, Bayesian LASSO) in a unifi ed framework that allows including marker genotypes and pedigree data jointly. This article describes the classes of models implemented in the BLR package and illustrates their use through examples. Some challenges faced when applying genomic-enabled selection, such as model choice, evaluation of predictive ability through cross-validation, and choice of hyper-parameters, are also addressed.

  15. 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

  16. Accounting for calibration uncertainty: Bayesian molecular dating as a "doubly intractable" problem.

    Science.gov (United States)

    Guindon, Stéphane

    2018-01-27

    This study introduces a new Bayesian technique for molecular dating that explicitly accommodates for uncertainty in the phylogenetic position of calibrated nodes derived from the analysis of fossil data. The proposed approach thus defines an adequate framework for incorporating expert knowledge and/or prior information about the way fossils were collected in the inference of node ages. Although it belongs to the class of "node-dating" methods, this method shares interesting properties with "tip-dating" techniques. Yet, it alleviates some of the computational and modeling difficulties that hamper tip-dating approaches. The influence of fossil data on the probabilistic distribution of trees is the crux of the matter considered here. More specifically, among all the phylogenies that a tree model (e.g., the birth death process) generates, only a fraction of them "agree" with the fossil data. Bayesian inference under the new model requires taking this fraction into account. However, evaluating this quantity is difficult in practice. A generic solution to this issue is presented here. The proposed approach relies on a recent statistical technique, the so-called exchange algorithm, dedicated to drawing samples from "doubly intractable" distributions. A small example illustrates the problem of interest and the impact of uncertainty in the placement of calibration constraints in the phylogeny given fossil data. An analysis of land plant sequences and multiple fossils further highlights the pertinence of the proposed approach. © The Author(s) 2018. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Flying rocks and flying clocks: disparity in fossil and molecular dates for birds.

    Science.gov (United States)

    Ksepka, Daniel T; Ware, Jessica L; Lamm, Kristin S

    2014-08-07

    Major disparities are recognized between molecular divergence dates and fossil ages for critical nodes in the Tree of Life, but broad patterns and underlying drivers remain elusive. We harvested 458 molecular age estimates for the stem and crown divergences of 67 avian clades to explore empirical patterns between these alternate sources of temporal information. These divergence estimates were, on average, over twice the age of the oldest fossil in these clades. Mitochondrial studies yielded older ages than nuclear studies for the vast majority of clades. Unexpectedly, disparity between molecular estimates and the fossil record was higher for divergences within major clades (crown divergences) than divergences between major clades (stem divergences). Comparisons of dates from studies classed by analytical methods revealed few significant differences. Because true divergence ages can never be known with certainty, our study does not answer the question of whether fossil gaps or molecular dating error account for a greater proportion of observed disparity. However, empirical patterns observed here suggest systemic overestimates for shallow nodes in existing molecular divergence dates for birds. We discuss underlying biases that may drive these patterns. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  18. Evidence for grain growth in molecular clouds: A Bayesian examination of the extinction law in Perseus

    Science.gov (United States)

    Foster, Jonathan B.; Mandel, Kaisey S.; Pineda, Jaime E.; Covey, Kevin R.; Arce, Héctor G.; Goodman, Alyssa A.

    2013-01-01

    We investigate the shape of the extinction law in two 1° square fields of the Perseus molecular cloud complex. We combine deep red-optical (r, i and z band) observations obtained using Megacam on the MMT with UKIRT (United Kingdom Infrared Telescope) Infrared Deep Sky Survey near-infrared (J, H and K band) data to measure the colours of background stars. We develop a new hierarchical Bayesian statistical model, including measurement error, intrinsic colour variation, spectral type and dust reddening, to simultaneously infer parameters for individual stars and characteristics of the population. We implement an efficient Markov chain Monte Carlo algorithm utilizing generalized Gibbs sampling to compute coherent probabilistic inferences. We find a strong correlation between the extinction (AV) and the slope of the extinction law (parametrized by RV). Because the majority of the extinction towards our stars comes from the Perseus molecular cloud, we interpret this correlation as evidence of grain growth at moderate optical depths. The extinction law changes from the `diffuse' value of RV ˜ 3 to the `dense cloud' value of RV ˜ 5 as the column density rises from AV = 2 to 10 mag. This relationship is similar for the two regions in our study, despite their different physical conditions, suggesting that dust grain growth is a fairly universal process.

  19. Are pollen fossils useful for calibrating relaxed molecular clock dating of phylogenies? A comparative study using Myrtaceae.

    Science.gov (United States)

    Thornhill, Andrew H; Popple, Lindsay W; Carter, Richard J; Ho, Simon Y W; Crisp, Michael D

    2012-04-01

    The identification and application of reliable fossil calibrations represents a key component of many molecular studies of evolutionary timescales. In studies of plants, most paleontological calibrations are associated with macrofossils. However, the pollen record can also inform age calibrations if fossils matching extant pollen groups are found. Recent work has shown that pollen of the myrtle family, Myrtaceae, can be classified into a number of morphological groups that are synapomorphic with molecular groups. By assembling a data matrix of pollen morphological characters from extant and fossil Myrtaceae, we were able to measure the fit of 26 pollen fossils to a molecular phylogenetic tree using parsimony optimisation of characters. We identified eight Myrtaceidites fossils as appropriate for calibration based on the most parsimonious placements of these fossils on the tree. These fossils were used to inform age constraints in a Bayesian phylogenetic analysis of a sequence alignment comprising two sequences from the chloroplast genome (matK and ndhF) and one nuclear locus (ITS), sampled from 106 taxa representing 80 genera. Three additional analyses were calibrated by placing pollen fossils using geographic and morphological information (eight calibrations), macrofossils (five calibrations), and macrofossils and pollen fossils in combination (12 calibrations). The addition of new fossil pollen calibrations led to older crown ages than have previously been found for tribes such as Eucalypteae and Myrteae. Estimates of rate variation among lineages were affected by the choice of calibrations, suggesting that the use of multiple calibrations can improve estimates of rate heterogeneity among lineages. This study illustrates the potential of including pollen-based calibrations in molecular studies of divergence times. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Evolutionary history of the PER3 variable number of tandem repeats (VNTR): idiosyncratic aspect of primate molecular circadian clock.

    Science.gov (United States)

    Sabino, Flávia Cal; Ribeiro, Amanda Oliveira; Tufik, Sérgio; Torres, Laila Brito; Oliveira, José Américo; Mello, Luiz Eugênio Araújo Moraes; Cavalcante, Jeferson Souza; Pedrazzoli, Mario

    2014-01-01

    The PER3 gene is one of the clock genes, which function in the core mammalian molecular circadian system. A variable number of tandem repeats (VNTR) locus in the 18th exon of this gene has been strongly associated to circadian rhythm phenotypes and sleep organization in humans, but it has not been identified in other mammals except primates. To better understand the evolution and the placement of the PER3 VNTR in a phylogenetical context, the present study enlarges the investigation about the presence and the structure of this variable region in a large sample of primate species and other mammals. The analysis of the results has revealed that the PER3 VNTR occurs exclusively in simiiforme primates and that the number of copies of the primitive unit ranges from 2 to 11 across different primate species. Two transposable elements surrounding the 18th exon of PER3 were found in primates with published genome sequences, including the tarsiiforme Tarsius syrichta, which lacks the VNTR. These results suggest that this VNTR may have evolved in a common ancestor of the simiiforme branch and that the evolutionary copy number differentiation of this VNTR may be associated with primate simiiformes sleep and circadian phenotype patterns.

  1. Evolutionary history of the PER3 variable number of tandem repeats (VNTR: idiosyncratic aspect of primate molecular circadian clock.

    Directory of Open Access Journals (Sweden)

    Flávia Cal Sabino

    Full Text Available The PER3 gene is one of the clock genes, which function in the core mammalian molecular circadian system. A variable number of tandem repeats (VNTR locus in the 18th exon of this gene has been strongly associated to circadian rhythm phenotypes and sleep organization in humans, but it has not been identified in other mammals except primates. To better understand the evolution and the placement of the PER3 VNTR in a phylogenetical context, the present study enlarges the investigation about the presence and the structure of this variable region in a large sample of primate species and other mammals. The analysis of the results has revealed that the PER3 VNTR occurs exclusively in simiiforme primates and that the number of copies of the primitive unit ranges from 2 to 11 across different primate species. Two transposable elements surrounding the 18th exon of PER3 were found in primates with published genome sequences, including the tarsiiforme Tarsius syrichta, which lacks the VNTR. These results suggest that this VNTR may have evolved in a common ancestor of the simiiforme branch and that the evolutionary copy number differentiation of this VNTR may be associated with primate simiiformes sleep and circadian phenotype patterns.

  2. Functional molecular analysis of a circadian clock gene timeless promoter from the drosophilid fly Chymomyza costata

    Czech Academy of Sciences Publication Activity Database

    Kobelková, Alena; Bajgar, Adam; Doležel, David

    2010-01-01

    Roč. 25, č. 6 (2010), s. 399-409 ISSN 0748-7304 R&D Projects: GA ČR GP204/08/P579; GA ČR(CZ) GA204/07/1032; GA AV ČR IAA500960802 Institutional research plan: CEZ:AV0Z50070508 Keywords : timeless promoter * E-box * Chymomyza costata Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.309, year: 2010

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

    Science.gov (United States)

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

    2015-10-06

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

  4. Mitochondrial molecular clocks and the origin of the major Otocephalan clades (Pisces: Teleostei)

    DEFF Research Database (Denmark)

    Peng, Zuogang; He, Shunping; Wang, Jun

    2006-01-01

    older than the oldest fossils of each of these groups suggest. Some of these recent papers explicitly defend a Pangean origin for some otocephalan groups such as the Siluriformes or Cypriniformes. To know whether or not the otocephalans as a whole, and particularly the mainly freshwater, cosmopolitan....... The present study is thus, among the studies dealing with molecular divergence times of teleosts, the one in which a greater number of otocephalan species are included. The divergence times obtained support that the major otocephalan groups had a much older origin than the oldest fossil records available...

  5. Molecular clocks indicate turnover and diversification of modern coleoid cephalopods during the Mesozoic Marine Revolution.

    Science.gov (United States)

    Tanner, Alastair R; Fuchs, Dirk; Winkelmann, Inger E; Gilbert, M Thomas P; Pankey, M Sabrina; Ribeiro, Ângela M; Kocot, Kevin M; Halanych, Kenneth M; Oakley, Todd H; da Fonseca, Rute R; Pisani, Davide; Vinther, Jakob

    2017-03-15

    Coleoid cephalopod molluscs comprise squid, cuttlefish and octopuses, and represent nearly the entire diversity of modern cephalopods. Sophisticated adaptations such as the use of colour for camouflage and communication, jet propulsion and the ink sac highlight the unique nature of the group. Despite these striking adaptations, there are clear parallels in ecology between coleoids and bony fishes. The coleoid fossil record is limited, however, hindering confident analysis of the tempo and pattern of their evolution. Here we use a molecular dataset (180 genes, approx. 36 000 amino acids) of 26 cephalopod species to explore the phylogeny and timing of cephalopod evolution. We show that crown cephalopods diverged in the Silurian-Devonian, while crown coleoids had origins in the latest Palaeozoic. While the deep-sea vampire squid and dumbo octopuses have ancient origins extending to the Early Mesozoic Era, 242 ± 38 Ma, incirrate octopuses and the decabrachian coleoids (10-armed squid) diversified in the Jurassic Period. These divergence estimates highlight the modern diversity of coleoid cephalopods emerging in the Mesozoic Marine Revolution, a period that also witnessed the radiation of most ray-finned fish groups in addition to several other marine vertebrates. This suggests that that the origin of modern cephalopod biodiversity was contingent on ecological competition with marine vertebrates. © 2017 The Authors.

  6. The molecular architecture of the yeast spindle pole body core determined by Bayesian integrative modeling.

    Science.gov (United States)

    Viswanath, Shruthi; Bonomi, Massimiliano; Kim, Seung Joong; Klenchin, Vadim A; Taylor, Keenan C; Yabut, King C; Umbreit, Neil T; Van Epps, Heather A; Meehl, Janet; Jones, Michele H; Russel, Daniel; Velazquez-Muriel, Javier A; Winey, Mark; Rayment, Ivan; Davis, Trisha N; Sali, Andrej; Muller, Eric G

    2017-11-07

    Microtubule-organizing centers (MTOCs) form, anchor, and stabilize the polarized network of microtubules in a cell. The central MTOC is the centrosome that duplicates during the cell cycle and assembles a bipolar spindle during mitosis to capture and segregate sister chromatids. Yet, despite their importance in cell biology, the physical structure of MTOCs is poorly understood. Here we determine the molecular architecture of the core of the yeast spindle pole body (SPB) by Bayesian integrative structure modeling based on in vivo fluorescence resonance energy transfer (FRET), small-angle x-ray scattering (SAXS), x-ray crystallography, electron microscopy, and two-hybrid analysis. The model is validated by several methods that include a genetic analysis of the conserved PACT domain that recruits Spc110, a protein related to pericentrin, to the SPB. The model suggests that calmodulin can act as a protein cross-linker and Spc29 is an extended, flexible protein. The model led to the identification of a single, essential heptad in the coiled-coil of Spc110 and a minimal PACT domain. It also led to a proposed pathway for the integration of Spc110 into the SPB. © 2017 Viswanath, Bonomi, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  7. The circadian clock and asthma.

    Science.gov (United States)

    Durrington, Hannah J; Farrow, Stuart N; Loudon, Andrew S; Ray, David W

    2014-01-01

    It is characteristic of asthma that symptoms worsen overnight, particularly in the early hours of the morning. Nocturnal symptoms in asthma are common and are an important indicator for escalation of treatment. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyper-responsiveness. The molecular apparatus that underpins circadian variations, controlled by so called 'clock' genes, has recently been characterised. Clock genes control circadian rhythms both centrally, in the suprachiasmatic nucleus of the brain and peripherally, within every organ of the body. Here, we will discuss how clock genes regulate circadian rhythms. We will focus particularly on the peripheral lung clock and the peripheral immune clock and discuss how these might relate to both the pathogenesis and treatment of asthma.

  8. On-the-fly analysis of molecular dynamics simulation trajectories of proteins using the Bayesian inference method

    Science.gov (United States)

    Miyashita, Naoyuki; Yonezawa, Yasushige

    2017-09-01

    Robust and reliable analyses of long trajectories from molecular dynamics simulations are important for investigations of functions and mechanisms of proteins. Structural fitting is necessary for various analyses of protein dynamics, thus removing time-dependent translational and rotational movements. However, the fitting is often difficult for highly flexible molecules. Thus, to address the issues, we proposed a fitting algorithm that uses the Bayesian inference method in combination with rotational fitting-weight improvements, and the well-studied globular protein systems trpcage and lysozyme were used for investigations. The present method clearly identified rigid core regions that fluctuate less than other regions and also separated core regions from highly fluctuating regions with greater accuracy than conventional methods. Our method also provided simultaneous variance-covariance matrix elements composed of atomic coordinates, allowing us to perform principle component analysis and prepare domain cross-correlation map during molecular dynamics simulations in an on-the-fly manner.

  9. A molecular clock dates the common ancestor of European-type porcine reproductive and respiratory syndrome virus at more than 10 years before the emergence of disease

    DEFF Research Database (Denmark)

    Forsberg, Roald; Oleksiewicz, Martin B.; Krabbe Petersen, Anne Mette

    2001-01-01

    an accurate molecular clock for the European PRRSV ORF 3 gene, place the root in the genealogy, estimate the rate of nucleotide substitution, and date the most recent common viral ancestor of the data set to 1979; more than 10 years before the onset of the European epidemic. Based on these findings, we...... conclude that PRRSV virus most likely entered the pig population some time before the epidemic emergence of the virus, and hence, that emergence of European-type PRRSV is not the result of a recent species transmission event. Together, our results show that ORF3 sequencing is a valuable epidemiologic tool...... for examining the emergence and spread of PRRSV in Europe. As such, the panel of well-characterized and highly divergent ORF3 sequences described in this study provides a reference point for future molecular epidemiologic studies....

  10. TreeTime: an extensible C++ software package for Bayesian phylogeny reconstruction with time-calibration.

    Science.gov (United States)

    Himmelmann, Lin; Metzler, Dirk

    2009-09-15

    For the estimation of phylogenetic trees from molecular data, it is worthwhile to take prior paleontologic knowledge into account, if available. To calibrate the branch lengths of the tree with times assigned to geo-historical events or fossils, it is necessary to select a relaxed molecular clock model to specify how mutation rates can change along the phylogeny. We present the software TreeTime for Bayesian phylogeny estimation. It can take prior information about the topology of the tree and about branching times into account. Several relaxed molecular clock models are implemented in TreeTime. TreeTime is written in C++ and designed to be efficient and extensible. TreeTime is freely available from http://evol.bio.lmu.de/statgen/software/treetime under the terms of the GNU General Public Licence (GPL, version 3 or later).

  11. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors

    Energy Technology Data Exchange (ETDEWEB)

    Carriger, John F. [U.S. Environmental Protection Agency, Office of Research and Development, Gulf Ecology Division, Gulf Breeze, FL, 32561 (United States); Martin, Todd M. [U.S. Environmental Protection Agency, Office of Research and Development, Sustainable Technology Division, Cincinnati, OH, 45220 (United States); Barron, Mace G., E-mail: barron.mace@epa.gov [U.S. Environmental Protection Agency, Office of Research and Development, Gulf Ecology Division, Gulf Breeze, FL, 32561 (United States)

    2016-11-15

    Highlights: • A Bayesian network was developed to classify chemical mode of action (MoA). • The network was based on the aquatic toxicity MoA for over 1000 chemicals. • A Markov blanket algorithm selected a subset of theoretical molecular descriptors. • Sensitivity analyses found influential descriptors for classifying the MoAs. • Overall precision of the Bayesian MoA classification model was 80%. - Abstract: The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity, but development of predictive MoA classification models in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity MoA using a recently published dataset containing over one thousand chemicals with MoA assignments for aquatic animal toxicity. Two dimensional theoretical chemical descriptors were generated for each chemical using the Toxicity Estimation Software Tool. The model was developed through augmented Markov blanket discovery from the dataset of 1098 chemicals with the MoA broad classifications as a target node. From cross validation, the overall precision for the model was 80.2%. The best precision was for the AChEI MoA (93.5%) where 257 chemicals out of 275 were correctly classified. Model precision was poorest for the reactivity MoA (48.5%) where 48 out of 99 reactive chemicals were correctly classified. Narcosis represented the largest class within the MoA dataset and had a precision and reliability of 80.0%, reflecting the global precision across all of the MoAs. False negatives for narcosis most often fell into electron transport inhibition, neurotoxicity or reactivity MoAs. False negatives for all other MoAs were most often narcosis. A probabilistic sensitivity analysis was undertaken for each MoA to examine the sensitivity to individual and multiple descriptor findings. The results show that the Markov blanket of a structurally complex dataset can simplify analysis and interpretation by

  12. 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. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. The impact of the representation of fossil calibrations on Bayesian estimation of species divergence times.

    Science.gov (United States)

    Inoue, Jun; Donoghue, Philip C J; Yang, Ziheng

    2010-01-01

    Bayesian inference provides a powerful framework for integrating different sources of information (in particular, molecules and fossils) to derive estimates of species divergence times. Indeed, it is currently the only framework that can adequately account for uncertainties in fossil calibrations. We use 2 Bayesian Markov chain Monte Carlo programs, MULTIDIVTIME and MCMCTREE, to analyze 3 empirical datasets to estimate divergence times in amphibians, actinopterygians, and felids. We evaluate the impact of various factors, including the priors on rates and times, fossil calibrations, substitution model, the violation of the molecular clock and the rate-drift model, and the exact and approximate likelihood calculation. Assuming the molecular clock caused seriously biased time estimates when the clock is violated, but 2 different rate-drift models produced similar estimates. The prior on times, which incorporates fossil-calibration information, had the greatest impact on posterior time estimation. In particular, the strategies used by the 2 programs to incorporate minimum- and maximum-age bounds led to very different time priors and were responsible for large differences in posterior time estimates in a previous study. The results highlight the critical importance of fossil calibrations to molecular dating and the need for probabilistic modeling of fossil depositions, preservations, and sampling to provide statistical summaries of information in the fossil record concerning species divergence times.

  14. 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.

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

    DEFF Research Database (Denmark)

    Yang, Yaoming; Duguay, David; Bédard, Nathalie

    2012-01-01

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

  16. Novel transcriptional networks regulated by CLOCK in human neurons.

    Science.gov (United States)

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

    2017-11-01

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

  17. Deep Space Atomic Clock

    Data.gov (United States)

    National Aeronautics and Space Administration — The Deep Space Atomic Clock (DSAC) project will develop a small, low mass atomic clock based on mercury-ion trap technology and demonstrate it in space providing the...

  18. Clocks and their discovery

    OpenAIRE

    Dugan, David

    2004-01-01

    Does technology, or the need for technology in the culture come first? Simon Schaffer in St Alban’s Abbey reflects on the connection between Christianity and clocks. God as the omniscient clock-maker.

  19. Bayesian phylogenetic estimation of fossil ages.

    Science.gov (United States)

    Drummond, Alexei J; Stadler, Tanja

    2016-07-19

    Recent advances have allowed for both morphological fossil evidence and molecular sequences to be integrated into a single combined inference of divergence dates under the rule of Bayesian probability. In particular, the fossilized birth-death tree prior and the Lewis-Mk model of discrete morphological evolution allow for the estimation of both divergence times and phylogenetic relationships between fossil and extant taxa. We exploit this statistical framework to investigate the internal consistency of these models by producing phylogenetic estimates of the age of each fossil in turn, within two rich and well-characterized datasets of fossil and extant species (penguins and canids). We find that the estimation accuracy of fossil ages is generally high with credible intervals seldom excluding the true age and median relative error in the two datasets of 5.7% and 13.2%, respectively. The median relative standard error (RSD) was 9.2% and 7.2%, respectively, suggesting good precision, although with some outliers. In fact, in the two datasets we analyse, the phylogenetic estimate of fossil age is on average less than 2 Myr from the mid-point age of the geological strata from which it was excavated. The high level of internal consistency found in our analyses suggests that the Bayesian statistical model employed is an adequate fit for both the geological and morphological data, and provides evidence from real data that the framework used can accurately model the evolution of discrete morphological traits coded from fossil and extant taxa. We anticipate that this approach will have diverse applications beyond divergence time dating, including dating fossils that are temporally unconstrained, testing of the 'morphological clock', and for uncovering potential model misspecification and/or data errors when controversial phylogenetic hypotheses are obtained based on combined divergence dating analyses.This article is part of the themed issue 'Dating species divergences using

  20. Molecular Counting with Localization Microscopy: A Bayesian Estimate Based on Fluorophore Statistics.

    Science.gov (United States)

    Nino, Daniel; Rafiei, Nafiseh; Wang, Yong; Zilman, Anton; Milstein, Joshua N

    2017-05-09

    Superresolved localization microscopy has the potential to serve as an accurate, single-cell technique for counting the abundance of intracellular molecules. However, the stochastic blinking of single fluorophores can introduce large uncertainties into the final count. Here we provide a theoretical foundation for applying superresolved localization microscopy to the problem of molecular counting based on the distribution of blinking events from a single fluorophore. We also show that by redundantly tagging single molecules with multiple, blinking fluorophores, the accuracy of the technique can be enhanced by harnessing the central limit theorem. The coefficient of variation then, for the number of molecules M estimated from a given number of blinks B, scales like ∼1/N l , where N l is the mean number of labels on a target. As an example, we apply our theory to the challenging problem of quantifying the cell-to-cell variability of plasmid copy number in bacteria. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  1. Free access to a running-wheel advances the phase of behavioral and physiological circadian rhythms and peripheral molecular clocks in mice.

    Directory of Open Access Journals (Sweden)

    Yuki Yasumoto

    Full Text Available Behavioral and physiological circadian rhythms are controlled by endogenous oscillators in animals. Voluntary wheel-running in rodents is thought to be an appropriate model of aerobic exercise in humans. We evaluated the effects of chronic voluntary exercise on the circadian system by analyzing temporal profiles of feeding, core body temperature, plasma hormone concentrations and peripheral expression of clock and clock-controlled genes in mice housed under sedentary (SED conditions or given free access to a running-wheel (RW for four weeks. Voluntary wheel-running activity advanced the circadian phases of increases in body temperature, food intake and corticosterone secretion in the mice. The circadian expression of clock and clock-controlled genes was tissue- and gene-specifically affected in the RW mice. The temporal expression of E-box-dependent circadian clock genes such as Per1, Per2, Nr1d1 and Dbp were slightly, but significantly phase-advanced in the liver and white adipose tissue, but not in brown adipose tissue and skeletal muscle. Peak levels of Per1, Per2 and Nr1d1 expression were significantly increased in the skeletal muscle of RW mice. The circadian phase and levels of hepatic mRNA expression of the clock-controlled genes that are involved in cholesterol and fatty acid metabolism significantly differed between SED and RW mice. These findings indicated that endogenous clock-governed voluntary wheel-running activity provides feedback to the central circadian clock that systemically governs behavioral and physiological rhythms.

  2. Avian Circadian Organization: A Chorus of Clocks

    Science.gov (United States)

    Cassone, Vincent M

    2013-01-01

    In birds, biological clock function pervades all aspects of biology, controlling daily changes in sleep: wake, visual function, song, migratory patterns and orientation, as well as seasonal patterns of reproduction, song and migration. The molecular bases for circadian clocks are highly conserved, and it is likely the avian molecular mechanisms are similar to those expressed in mammals, including humans. The central pacemakers in the avian pineal gland, retinae and SCN dynamically interact to maintain stable phase relationships and then influence downstream rhythms through entrainment of peripheral oscillators in the brain controlling behavior and peripheral tissues. Birds represent an excellent model for the role played by biological clocks in human neurobiology; unlike most rodent models, they are diurnal, they exhibit cognitively complex social interactions, and their circadian clocks are more sensitive to the hormone melatonin than are those of nocturnal rodents. PMID:24157655

  3. Clock Tree Power Analysis

    OpenAIRE

    Austbø, Knut

    2016-01-01

    The buffered clock tree structure is commonly used to distribute the clock signal to the memory elements in digital circuits. Since the clock signal is used as a temporal reference, it has to be distributed to the registers with decent timing characteristics and low skew. In order to achieve this, buffers and inverters are inserted in the clock tree, typically by a synthesis tool. The clock tree is a major contributor to the power consumption. This is a result of a combination of high swit...

  4. BEAST: Bayesian evolutionary analysis by sampling trees.

    Science.gov (United States)

    Drummond, Alexei J; Rambaut, Andrew

    2007-11-08

    The evolutionary analysis of molecular sequence variation is a statistical enterprise. This is reflected in the increased use of probabilistic models for phylogenetic inference, multiple sequence alignment, and molecular population genetics. Here we present BEAST: a fast, flexible software architecture for Bayesian analysis of molecular sequences related by an evolutionary tree. A large number of popular stochastic models of sequence evolution are provided and tree-based models suitable for both within- and between-species sequence data are implemented. BEAST version 1.4.6 consists of 81000 lines of Java source code, 779 classes and 81 packages. It provides models for DNA and protein sequence evolution, highly parametric coalescent analysis, relaxed clock phylogenetics, non-contemporaneous sequence data, statistical alignment and a wide range of options for prior distributions. BEAST source code is object-oriented, modular in design and freely available at http://beast-mcmc.googlecode.com/ under the GNU LGPL license. BEAST is a powerful and flexible evolutionary analysis package for molecular sequence variation. It also provides a resource for the further development of new models and statistical methods of evolutionary analysis.

  5. BEAST: Bayesian evolutionary analysis by sampling trees

    Directory of Open Access Journals (Sweden)

    Drummond Alexei J

    2007-11-01

    Full Text Available Abstract Background The evolutionary analysis of molecular sequence variation is a statistical enterprise. This is reflected in the increased use of probabilistic models for phylogenetic inference, multiple sequence alignment, and molecular population genetics. Here we present BEAST: a fast, flexible software architecture for Bayesian analysis of molecular sequences related by an evolutionary tree. A large number of popular stochastic models of sequence evolution are provided and tree-based models suitable for both within- and between-species sequence data are implemented. Results BEAST version 1.4.6 consists of 81000 lines of Java source code, 779 classes and 81 packages. It provides models for DNA and protein sequence evolution, highly parametric coalescent analysis, relaxed clock phylogenetics, non-contemporaneous sequence data, statistical alignment and a wide range of options for prior distributions. BEAST source code is object-oriented, modular in design and freely available at http://beast-mcmc.googlecode.com/ under the GNU LGPL license. Conclusion BEAST is a powerful and flexible evolutionary analysis package for molecular sequence variation. It also provides a resource for the further development of new models and statistical methods of evolutionary analysis.

  6. Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci.

    Science.gov (United States)

    Lee, Yool; Chun, Sung Kook; Kim, Kyungjin

    2015-10-01

    CLOCK-BMAL1 is a key transcription factor complex of the molecular clock system that generates circadian gene expression and physiology in mammals. Here, we demonstrate that sumoylation of BMAL1 mediates the rapid activation of CLOCK-BMAL1 by CREB-binding protein (CBP) in nuclear foci and also the resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation-based fluorescence resonance energy transfer (BiFC-FRET) assay revealed that CLOCK-BMAL1 rapidly dimerized and formed a ternary complex with CBP in discrete nuclear foci in response to serum stimuli. We found that the formation of this ternary complex requires sumoylation of BMAL1 by SUMO3. These processes were abolished by both the ectopic expression of the SUMP2/3-specific protease, SUSP1, and mutation of the major sumoylation site (Lys259) of BMAL1. Moreover, molecular inhibition of BMAL1 sumoylation abrogated acute Per1 transcription and severely dampened the circadian gene oscillation triggered by clock synchronization stimuli. Taken together, these findings suggest that sumoylation plays a critical role in the spatiotemporal co-activation of CLOCK-BMAL1 by CBP for immediate-early Per induction and the resetting of the circadian clock. Copyright © 2015. Published by Elsevier B.V.

  7. Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus.

    Science.gov (United States)

    Patton, Andrew P; Chesham, Johanna E; Hastings, Michael H

    2016-09-07

    activity of the CK1ε isoform. In conclusion, extreme period manipulation reveals unprecedented elasticity and temporal structure of the SCN circadian oscillation. The master circadian clock of the suprachiasmatic nucleus (SCN) encodes time-of-day information that allows mammals to predict and thereby adapt to daily environmental cycles. Using combined genetic and pharmacological interventions, we assessed the temporal elasticity of the SCN network. Despite having evolved to generate a 24 h circadian period, we show that the molecular clock is surprisingly elastic, able to reversibly sustain coherent periods between ≤17 and >42 h at the levels of individual cells and the overall circuit. Using quantitative techniques to analyze these extreme periodicities, we reveal that the oscillator progresses as a sequence of distinct stages. These findings reveal new properties of how the SCN functions as a network and should inform biological and mathematical analyses of circadian timekeeping. Copyright © 2016 Patton et al.

  8. Bayesian analysis in plant pathology.

    Science.gov (United States)

    Mila, A L; Carriquiry, A L

    2004-09-01

    ABSTRACT Bayesian methods are currently much discussed and applied in several disciplines from molecular biology to engineering. Bayesian inference is the process of fitting a probability model to a set of data and summarizing the results via probability distributions on the parameters of the model and unobserved quantities such as predictions for new observations. In this paper, after a short introduction of Bayesian inference, we present the basic features of Bayesian methodology using examples from sequencing genomic fragments and analyzing microarray gene-expressing levels, reconstructing disease maps, and designing experiments.

  9. 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...

  10. 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,...

  11. Mini Review: Circadian Clocks, Stress and Immunity

    Directory of Open Access Journals (Sweden)

    Rebecca eDumbell

    2016-05-01

    Full Text Available In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic-pituitary-adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors – glucocorticoids – released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both, the HPA axis and the immune system, and discusses their interactions.

  12. Biological Clocks & Circadian Rhythms

    Science.gov (United States)

    Robertson, Laura; Jones, M. Gail

    2009-01-01

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

  13. Circadian clocks : from stem cells to tissue homeostasis and regeneration

    NARCIS (Netherlands)

    Dierickx, Pieterjan; Van Laake, Linda W; Geijsen, Niels

    2017-01-01

    The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock

  14. Do Caucasian and Asian clocks tick differently?

    Directory of Open Access Journals (Sweden)

    A.A. Barbosa

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

  15. 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.

  16. Bayesian biostatistics

    CERN Document Server

    Lesaffre, Emmanuel

    2012-01-01

    The growth of biostatistics has been phenomenal in recent years and has been marked by considerable technical innovation in both methodology and computational practicality. One area that has experienced significant growth is Bayesian methods. The growing use of Bayesian methodology has taken place partly due to an increasing number of practitioners valuing the Bayesian paradigm as matching that of scientific discovery. In addition, computational advances have allowed for more complex models to be fitted routinely to realistic data sets. Through examples, exercises and a combination of introd

  17. Molecular cloning, characterization, and temporal expression of the clock genes period and timeless in the oriental river prawn Macrobrachium nipponense during female reproductive development.

    Science.gov (United States)

    Chen, SuHua; Qiao, Hui; Fu, HongTuo; Sun, Shengming; Zhang, WenYi; Jin, ShuBo; Gong, Yongsheng; Jiang, Sufei; Xiong, Weiyi; YanWu

    2017-05-01

    The circadian clock is crucial for sustaining rhythmic biochemical, physiological, and behavioral processes in living creatures. In this study, we isolated and characterized two circadian clock genes in Macrobrachium nipponense, period (Mnper) and timeless (Mntim). The complete Mnper cDNA measures 4283bp in length with an open reading frame encoding 1292 amino acids, including functional domains such as PER-ARNT-SIM (PAS), cytoplasmic localization domain (CLD), TIM interaction site (TIS), and nuclear localization signal (NLS). The deduced Mntim protein comprises1540 amino acids with functional domains such as PER interaction site (PIS), NLS, and CLD. Tissue distribution analyses showed that the two genes were highly expressed in the eyestalk and brain in both males and females, as well as being expressed in the ovary. The expression profiles of Mnper and Mntim were determined in the eyestalk, brain, and ovary under simulated breeding season and non-breeding season conditions. The expression profiles of both Mnper and Mntim appeared to be unaffected in the eyestalk. However, the expression of both genes exhibited significant seasonal variations in the brain, and thus we assumed the brain to be their functional location. The expression profiles under different simulated seasons and the variations during different ovarian stages indicate that both genes might be involved with female reproduction. Especially the mRNA levels in the brain varied greatly during these stages indicating that the clock function in the brain is closely related to ovarian development and female reproduction. And the reproductive roles of clock genes need to be elucidated. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The historical biogeography of Pteroglossus aracaris (Aves, Piciformes, Ramphastidae based on Bayesian analysis of mitochondrial DNA sequences

    Directory of Open Access Journals (Sweden)

    Sérgio L. Pereira

    2008-01-01

    Full Text Available Most Neotropical birds, including Pteroglossus aracaris, do not have an adequate fossil record to be used as time constraints in molecular dating. Hence, the evolutionary timeframe of the avian biota can only be inferred using alternative time constraints. We applied a Bayesian relaxed clock approach to propose an alternative interpretation for the historical biogeography of Pteroglossus based on mitochondrial DNA sequences, using different combinations of outgroups and time constraints obtained from outgroup fossils, vicariant barriers and molecular time estimates. The results indicated that outgroup choice has little effect on the Bayesian posterior distribution of divergence times within Pteroglossus , that geological and molecular time constraints seem equally suitable to estimate the Bayesian posterior distribution of divergence times for Pteroglossus , and that the fossil record alone overestimates divergence times within the fossil-lacking ingroup. The Bayesian estimates of divergence times suggest that the radiation of Pteroglossus occurred from the Late Miocene to the Pliocene (three times older than estimated by the “standard” mitochondrial rate of 2% sequence divergence per million years, likely triggered by Andean uplift, multiple episodes of marine transgressions in South America, and formation of present-day river basins. The time estimates are in agreement with other Neotropical taxa with similar geographic distributions.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    The suprachiasmatic nucleus houses the central circadian clock and is characterized by the timely regulated expression of clock genes. However, neurons of the cerebellar cortex also contain a circadian oscillator with circadian expression of clock genes being controlled by the suprachiasmatic...... is involved in circadian physiology and food anticipation, we therefore by use of Cre-LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located...... in this cell type. We here report that deletion of Arntl heavily influences the molecular clock of the cerebellar cortex with significantly altered and arrhythmic expression of other central clock and clock-controlled genes. On the other hand, daily expression of clock genes in the suprachiasmatic nucleus...

  20. Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks

    Science.gov (United States)

    Tataroglu, Ozgur; Zhao, Xiaohu; Busza, Ania; Ling, Jinli; O’Neill, John S.; Emery, Patrick

    2015-01-01

    Summary Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles. PMID:26590423

  1. Bayesian phylogenetic estimation of fossil ages

    Science.gov (United States)

    Drummond, Alexei J.; Stadler, Tanja

    2016-01-01

    Recent advances have allowed for both morphological fossil evidence and molecular sequences to be integrated into a single combined inference of divergence dates under the rule of Bayesian probability. In particular, the fossilized birth–death tree prior and the Lewis-Mk model of discrete morphological evolution allow for the estimation of both divergence times and phylogenetic relationships between fossil and extant taxa. We exploit this statistical framework to investigate the internal consistency of these models by producing phylogenetic estimates of the age of each fossil in turn, within two rich and well-characterized datasets of fossil and extant species (penguins and canids). We find that the estimation accuracy of fossil ages is generally high with credible intervals seldom excluding the true age and median relative error in the two datasets of 5.7% and 13.2%, respectively. The median relative standard error (RSD) was 9.2% and 7.2%, respectively, suggesting good precision, although with some outliers. In fact, in the two datasets we analyse, the phylogenetic estimate of fossil age is on average less than 2 Myr from the mid-point age of the geological strata from which it was excavated. The high level of internal consistency found in our analyses suggests that the Bayesian statistical model employed is an adequate fit for both the geological and morphological data, and provides evidence from real data that the framework used can accurately model the evolution of discrete morphological traits coded from fossil and extant taxa. We anticipate that this approach will have diverse applications beyond divergence time dating, including dating fossils that are temporally unconstrained, testing of the ‘morphological clock', and for uncovering potential model misspecification and/or data errors when controversial phylogenetic hypotheses are obtained based on combined divergence dating analyses. This article is part of the themed issue ‘Dating species divergences

  2. 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.

  3. How does general anaesthesia affect the circadian clock?

    Science.gov (United States)

    Poulsen, Raewyn C; Warman, Guy R; Sleigh, Jamie; Ludin, Nicola M; Cheeseman, James F

    2018-02-01

    Post-operative patients experience sleep disturbances. Animal studies demonstrate that general anaesthesia (GA) can disrupt circadian rhythms and cause changes in the molecular clock, indicating that anaesthesia contributes to post-operative circadian disruption. Here we review the effect of anaesthesia on the circadian clock and its rhythms in order to summarise current findings outline commonalities between studies and propose mechanisms by which effects may be mediated. 1) GA has strong effects on the main neurotransmitter systems linked with circadian control (Gamma aminobutyric acid/N-methyl-D-aspartate (GABA/NMDA)) and may act by interfering with light-entrainment of the clock. 2) Expression of the core clock gene per2 is inhibited by GA (possibly via a NMDA/glycogen synthase kinase 3β (GSK3β) pathway). 3) GA's effect on circadian rhythms appears greatest when administered during animals' active phases 4) GA may have different effects when administered under free-running and entrained conditions. 5) Anaesthesia may mimic the mechanism involved in adaptation of the clock to changes in daylength. There is agreement that GA can strongly affect the circadian clock. How anaesthesia-induced changes in the molecular clock lead to changes in behaviour remains unclear. The answer, and what it may mean for patients post-operatively, will rely on systematic studies at molecular, behavioural, and clinical levels using standardised protocols. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Circadian clock-mediated regulation of blood pressure.

    Science.gov (United States)

    Douma, Lauren G; Gumz, Michelle L

    2017-12-02

    Most bodily functions vary over the course of a 24h day. Circadian rhythms in body temperature, sleep-wake cycles, metabolism, and blood pressure (BP) are just a few examples. These circadian rhythms are controlled by the central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks located throughout the body. Light and food cues entrain these clocks to the time of day and this synchronicity contributes to the regulation of a variety of physiological processes with effects on overall health. The kidney, brain, nervous system, vasculature, and heart have been identified through the use of mouse models and clinical trials as peripheral clock regulators of BP. The dysregulation of this circadian pattern of BP, with or without hypertension, is associated with increased risk for cardiovascular disease. The mechanism of this dysregulation is unknown and is a growing area of research. In this review, we highlight research of human and mouse circadian models that has provided insight into the roles of these molecular clocks and their effects on physiological functions. Additional tissue-specific studies of the molecular clock mechanism are needed, as well as clinical studies including more diverse populations (different races, female patients, etc.), which will be critical to fully understand the mechanism of circadian regulation of BP. Understanding how these molecular clocks regulate the circadian rhythm of BP is critical in the treatment of circadian BP dysregulation and hypertension. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Optical clocks and their contribution to gravity modeling

    Science.gov (United States)

    Naeimi, Mohammad; Mohamadhosseini, Babak; Hatami, Mohsen

    2016-04-01

    Optical clocks, as one of the latest achievements in atomic and molecular physics, have applications more than timing, due to their accuracy and stability. In general relativity, gravitational potential differences in space and time, cause frequency difference in optical clocks. Hence, ultra precise optical clocks can be used as a tool to observe potential differences and consequently as a new gravimetry technique. In this contribution, we investigate the latest optical clocks based on atomic transition in Al+ and derive a simple equation for frequency change related to geo-potential differences. Moreover, we consider the capability of optical clocks for gravity modeling in combination with other gravity observations. Finally, the possibility to detect potential changes in geo-dynamically active zones, such as East-Asia and the requirements for such studies are discussed.

  6. 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.

  7. The skeletal muscle circadian clock: current insights

    Directory of Open Access Journals (Sweden)

    Nakao R

    2017-11-01

    Full Text Available Reiko Nakao,1 Takeshi Nikawa,2 Katsutaka Oishi1,3,4 1Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST, Tsukuba, 2Department of Nutritional Physiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 3Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, 4Department of Computational and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan Abstract: Skeletal muscle functions in locomotion, postural support, and energy metabolism. The loss of skeletal muscle mass and function leads to diseases such as sarcopenia and metabolic disorders. Inactivity (lack of exercise and an imbalanced diet (increased fat or decreased protein intake are thought to be involved in the prevalence of such pathologies. On the other hand, recent epidemiological studies of humans have suggested that circadian disruption caused by shift work, jet lag, and sleep disorders is associated with obesity and metabolic syndrome. Experimental studies of mice deficient in clock genes have also identified skeletal muscle defects, suggesting a molecular link between circadian clock machinery and skeletal muscle physiology. Furthermore, accumulating evidence about chronotherapy, including chronopharmacology, chrononutrition, and chronoexercise, has indicated that timing is important to optimize medical intervention for various diseases. The present review addresses current understanding of the functional roles of the molecular clock with respect to skeletal muscle and the potential of chronotherapy for diseases associated with skeletal muscle. Keywords: biological rhythm, metabolic syndrome, physical activity, neural signal, chronotherapy

  8. Inferring Population Size History from Large Samples of Genome-Wide Molecular Data - An Approximate Bayesian Computation Approach.

    Directory of Open Access Journals (Sweden)

    Simon Boitard

    2016-03-01

    Full Text Available Inferring the ancestral dynamics of effective population size is a long-standing question in population genetics, which can now be tackled much more accurately thanks to the massive genomic data available in many species. Several promising methods that take advantage of whole-genome sequences have been recently developed in this context. However, they can only be applied to rather small samples, which limits their ability to estimate recent population size history. Besides, they can be very sensitive to sequencing or phasing errors. Here we introduce a new approximate Bayesian computation approach named PopSizeABC that allows estimating the evolution of the effective population size through time, using a large sample of complete genomes. This sample is summarized using the folded allele frequency spectrum and the average zygotic linkage disequilibrium at different bins of physical distance, two classes of statistics that are widely used in population genetics and can be easily computed from unphased and unpolarized SNP data. Our approach provides accurate estimations of past population sizes, from the very first generations before present back to the expected time to the most recent common ancestor of the sample, as shown by simulations under a wide range of demographic scenarios. When applied to samples of 15 or 25 complete genomes in four cattle breeds (Angus, Fleckvieh, Holstein and Jersey, PopSizeABC revealed a series of population declines, related to historical events such as domestication or modern breed creation. We further highlight that our approach is robust to sequencing errors, provided summary statistics are computed from SNPs with common alleles.

  9. Clock Reaction: Outreach Attraction

    Science.gov (United States)

    Carpenter, Yuen-ying; Phillips, Heather A.; Jakubinek, Michael B.

    2010-01-01

    Chemistry students are often introduced to the concept of reaction rates through demonstrations or laboratory activities involving the well-known iodine clock reaction. For example, a laboratory experiment involving thiosulfate as an iodine scavenger is part of the first-year general chemistry laboratory curriculum at Dalhousie University. With…

  10. Cryptochromes and Biological Clocks

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 7; Issue 9. Cryptochromes and Biological Clocks. V R Bhagwat. General Article Volume 7 Issue 9 September 2002 pp 36-48. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/007/09/0036-0048. Keywords.

  11. Decamp Clock Board Firmware

    International Nuclear Information System (INIS)

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

    2007-01-01

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

  12. 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.

  13. Machine Learning Helps Identify CHRONO as a Circadian Clock Component

    Science.gov (United States)

    Venkataraman, Anand; Ramanathan, Chidambaram; Kavakli, Ibrahim H.; Hughes, Michael E.; Baggs, Julie E.; Growe, Jacqueline; Liu, Andrew C.; Kim, Junhyong; Hogenesch, John B.

    2014-01-01

    Over the last decades, researchers have characterized a set of “clock genes” that drive daily rhythms in physiology and behavior. This arduous work has yielded results with far-reaching consequences in metabolic, psychiatric, and neoplastic disorders. Recent attempts to expand our understanding of circadian regulation have moved beyond the mutagenesis screens that identified the first clock components, employing higher throughput genomic and proteomic techniques. In order to further accelerate clock gene discovery, we utilized a computer-assisted approach to identify and prioritize candidate clock components. We used a simple form of probabilistic machine learning to integrate biologically relevant, genome-scale data and ranked genes on their similarity to known clock components. We then used a secondary experimental screen to characterize the top candidates. We found that several physically interact with known clock components in a mammalian two-hybrid screen and modulate in vitro cellular rhythms in an immortalized mouse fibroblast line (NIH 3T3). One candidate, Gene Model 129, interacts with BMAL1 and functionally represses the key driver of molecular rhythms, the BMAL1/CLOCK transcriptional complex. Given these results, we have renamed the gene CHRONO (computationally highlighted repressor of the network oscillator). Bi-molecular fluorescence complementation and co-immunoprecipitation demonstrate that CHRONO represses by abrogating the binding of BMAL1 to its transcriptional co-activator CBP. Most importantly, CHRONO knockout mice display a prolonged free-running circadian period similar to, or more drastic than, six other clock components. We conclude that CHRONO is a functional clock component providing a new layer of control on circadian molecular dynamics. PMID:24737000

  14. Reverse Engineering of Modified Genes by Bayesian Network Analysis Defines Molecular Determinants Critical to the Development of Glioblastoma

    Science.gov (United States)

    Kunkle, Brian W.; Yoo, Changwon; Roy, Deodutta

    2013-01-01

    In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I–IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96–100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential ‘hubs of activity’. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several ‘key genes’ may be required for the development of glioblastoma. Further studies are needed to validate these ‘key genes’ as useful tools for early detection and novel therapeutic options for these tumors. PMID:23737970

  15. CLOCK phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues.

    Science.gov (United States)

    Luciano, Amelia K; Zhou, Wenping; Santana, Jeans M; Kyriakides, Cleo; Velazquez, Heino; Sessa, William C

    2018-03-27

    Circadian locomotor output cycles kaput (CLOCK) is a transcription factor which activates transcription of clock-controlled genes (CCG) by heterodimerizing with BMAL1 and binding to E-box elements on DNA. While several phosphorylation sites on CLOCK have already been identified, this study characterizes a novel phosphorylation site at Serine 845 (S836 in humans). Here we show that CLOCK is a novel AKT substrate in vitro and in cells, and this phosphorylation site is a negative regulator of CLOCK nuclear localization by acting as a binding site for 14-3-3 proteins. To examine the role of CLOCK phosphorylation in vivo, Clock S845A knock-in mice were generated using CRISPR/Cas9 technology. Clock S845A mice are essentially normal with normal central circadian rhythms and hemodynamics. However, examination of core circadian gene expression from peripheral tissues demonstrated that Clock S845A mice have diminished expression of Per2, Reverba, Dbp and Npas2 in skeletal muscle and Per2, Reverba, Dbp, Per1, Rora and Npas2 in the liver during the circadian cycle. The reduction in Dbp levels is associated with reduced H3K9ac at E-boxes where CLOCK binds despite no change in total CLOCK levels. Thus, CLOCK phosphorylation by AKT on S845 regulates its nuclear translocation and the expression levels of certain core circadian genes in insulin sensitive tissues. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  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. Involvement of posttranscriptional regulation ofClockin the emergence of circadian clock oscillation during mouse development.

    Science.gov (United States)

    Umemura, Yasuhiro; Koike, Nobuya; Ohashi, Munehiro; Tsuchiya, Yoshiki; Meng, Qing Jun; Minami, Yoichi; Hara, Masayuki; Hisatomi, Moe; Yagita, Kazuhiro

    2017-09-05

    Circadian clock oscillation emerges in mouse embryo in the later developmental stages. Although circadian clock development is closely correlated with cellular differentiation, the mechanisms of its emergence during mammalian development are not well understood. Here, we demonstrate an essential role of the posttranscriptional regulation of Clock subsequent to the cellular differentiation for the emergence of circadian clock oscillation in mouse fetal hearts and mouse embryonic stem cells (ESCs). In mouse fetal hearts, no apparent oscillation of cell-autonomous molecular clock was detectable around E10, whereas oscillation was clearly visible in E18 hearts. Temporal RNA-sequencing analysis using mouse fetal hearts reveals many fewer rhythmic genes in E10-12 hearts (63, no core circadian genes) than in E17-19 hearts (483 genes), suggesting the lack of functional circadian transcriptional/translational feedback loops (TTFLs) of core circadian genes in E10 mouse fetal hearts. In both ESCs and E10 embryos, CLOCK protein was absent despite the expression of Clock mRNA, which we showed was due to Dicer/Dgcr8 -dependent translational suppression of CLOCK. The CLOCK protein is required for the discernible molecular oscillation in differentiated cells, and the posttranscriptional regulation of Clock plays a role in setting the timing for the emergence of the circadian clock oscillation during mammalian development.

  18. Bayesian programming

    CERN Document Server

    Bessiere, Pierre; Ahuactzin, Juan Manuel; Mekhnacha, Kamel

    2013-01-01

    Probability as an Alternative to Boolean LogicWhile logic is the mathematical foundation of rational reasoning and the fundamental principle of computing, it is restricted to problems where information is both complete and certain. However, many real-world problems, from financial investments to email filtering, are incomplete or uncertain in nature. Probability theory and Bayesian computing together provide an alternative framework to deal with incomplete and uncertain data. Decision-Making Tools and Methods for Incomplete and Uncertain DataEmphasizing probability as an alternative to Boolean

  19. Hypophysectomy abolishes rhythms in rat thyroid hormones but not in the thyroid clock

    DEFF Research Database (Denmark)

    Fahrenkrug, J; Georg, B; Hannibal, J

    2017-01-01

    The endocrine body rhythms including the hypothalamic-pituitary-thyroid axis seem to be regulated by the circadian timing system, and daily rhythmicity of circulating thyroid-stimulating hormone (TSH) is well established. The circadian rhythms are generated by endogenous clocks in the central brain...... oscillator located in the hypothalamic suprachiasmatic nucleus (SCN) as well as multiple peripheral clocks, but information on the existence and function of a thyroid clock is limited. The molecular machinery in all clock cells is composed of a number of clock genes and their gene products are connected...... by autoregulatory feedback loops. Here, we provide evidence for a thyroid clock in the rat by demonstrating 24-h antiphase oscillations for the mRNA of the canonical clock genes Per1 and Bmal1, which was unaffected by hypophysectomy. By immunostaining, we supported the existence of a core oscillator...

  20. CLOCK stabilizes CYCLE to initiate clock function inDrosophila.

    Science.gov (United States)

    Liu, Tianxin; Mahesh, Guruswamy; Yu, Wangjie; Hardin, Paul E

    2017-10-10

    The Drosophila circadian clock keeps time via transcriptional feedback loops. These feedback loops are initiated by CLOCK-CYCLE (CLK-CYC) heterodimers, which activate transcription of genes encoding the feedback repressors PERIOD and TIMELESS. Circadian clocks normally operate in ∼150 brain pacemaker neurons and in many peripheral tissues in the head and body, but can also be induced by expressing CLK in nonclock cells. These ectopic clocks also require cyc , yet CYC expression is restricted to canonical clock cells despite evidence that cyc mRNA is widely expressed. Here we show that CLK binds to and stabilizes CYC in cell culture and in nonclock cells in vivo. Ectopic clocks also require the blue light photoreceptor CRYPTOCHROME (CRY), which is required for both light entrainment and clock function in peripheral tissues. These experiments define the genetic architecture required to initiate circadian clock function in Drosophila , reveal mechanisms governing circadian activator stability that are conserved in perhaps all eukaryotes, and suggest that Clk , cyc , and cry expression is sufficient to drive clock expression in naive cells.

  1. Circadian Clock, Cancer, and Chemotherapy

    Science.gov (United States)

    2015-01-01

    The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock–DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID:25302769

  2. NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators.

    Directory of Open Access Journals (Sweden)

    Dominic Landgraf

    2016-02-01

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

  3. Circadian clock and oral cancer.

    Science.gov (United States)

    Nirvani, Minou; Khuu, Cuong; Utheim, Tor Paaske; Sand, Lars Peter; Sehic, Amer

    2018-02-01

    The circadian clock is comprised of a master component situated in the hypothalamic suprachiasmatic nucleus and subordinate clock genes in almost every cell of the body. The circadian clock genes and their encoded proteins govern the organism to follow the natural signals of time, and adapt to external changes in the environment. The majority of physiological processes in mammals exhibit variable circadian rhythms, which are generated and coordinated by an oscillation in the expression of the clock genes. A number of studies have reported that alteration in the expression level of clock genes is correlated with several pathological conditions, including cancer. However, little is known about the role of clock genes in homeostasis of the oral epithelium and their disturbances in oral carcinogenesis. The present review summarizes the current state of knowledge of the implications of clock genes in oral cancer. It has been demonstrated that the development of oral squamous cell carcinoma undergoes circadian oscillation in relation to tumor volume and proliferation rate. The circadian clock gene period ( PER)1 has been associated with oral cancer pathogenesis and it is suggested that changes in the expression of PER1 may exhibit an important role in the development, invasion, and metastasis of oral squamous cell carcinoma. However, its role remains elusive and there is a need for further research in order to understand the underlying mechanisms of the clock genes in oral cancer pathogenesis.

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

    Directory of Open Access Journals (Sweden)

    Katarina eStojkovic

    2014-08-01

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

  5. Clocks and special relativity

    International Nuclear Information System (INIS)

    MacRoberts, D.T.

    1980-01-01

    A kinematic theory without precise definitions of the 'space' and 'time' used is an uninterpreted calculus. The definition of 'time' in special relativity is based on light propagation and the 'constant velocity of light' is a tautological consequence of the definition. When this definition is reified in a 'clock' the phenomenon of 'time dilation' occurs, in terms of the defined time, but is not reciprocal between moving systems; the postulate of relativity is not observed. The new definition of time is compatible with an ether theory without the relativity principle. The derivation of the Lorentz transformations, which requires both postulates, is purely formalistic and is not ontologically sound. (Auth.)

  6. Methodologies for steering clocks

    Science.gov (United States)

    Chadsey, Harold

    1995-01-01

    One of the concerns of the PTTI community is the coordination of one time scale with another. This is accomplished through steering one clock system to another, with a goal of a zero or constant offset in time and frequency. In order to attain this goal, rate differences are calculated and allowed for by the steering algorithm. This paper will present several of these different methods of determining rate differences. Ideally, any change in rate should not cause the offset to change sign (overshoot) by any amount, but certainly not by as much as its previous absolute value. The advantages and disadvantages of each depend on the user's situation.

  7. 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…

  8. Master/slave clock arrangement for providing reliable clock signal

    Science.gov (United States)

    Abbey, Duane L. (Inventor)

    1977-01-01

    The outputs of two like frequency oscillators are combined to form a single reliable clock signal, with one oscillator functioning as a slave under the control of the other to achieve phase coincidence when the master is operative and in a free-running mode when the master is inoperative so that failure of either oscillator produces no effect on the clock signal.

  9. Evolutionary Analysis of Dengue Serotype 2 Viruses Using Phylogenetic and Bayesian Methods from New Delhi, India.

    Directory of Open Access Journals (Sweden)

    Nazia Afreen

    2016-03-01

    Full Text Available Dengue fever is the most important arboviral disease in the tropical and sub-tropical countries of the world. Delhi, the metropolitan capital state of India, has reported many dengue outbreaks, with the last outbreak occurring in 2013. We have recently reported predominance of dengue virus serotype 2 during 2011-2014 in Delhi. In the present study, we report molecular characterization and evolutionary analysis of dengue serotype 2 viruses which were detected in 2011-2014 in Delhi. Envelope genes of 42 DENV-2 strains were sequenced in the study. All DENV-2 strains grouped within the Cosmopolitan genotype and further clustered into three lineages; Lineage I, II and III. Lineage III replaced lineage I during dengue fever outbreak of 2013. Further, a novel mutation Thr404Ile was detected in the stem region of the envelope protein of a single DENV-2 strain in 2014. Nucleotide substitution rate and time to the most recent common ancestor were determined by molecular clock analysis using Bayesian methods. A change in effective population size of Indian DENV-2 viruses was investigated through Bayesian skyline plot. The study will be a vital road map for investigation of epidemiology and evolutionary pattern of dengue viruses in India.

  10. Evolutionary Analysis of Dengue Serotype 2 Viruses Using Phylogenetic and Bayesian Methods from New Delhi, India.

    Science.gov (United States)

    Afreen, Nazia; Naqvi, Irshad H; Broor, Shobha; Ahmed, Anwar; Kazim, Syed Naqui; Dohare, Ravins; Kumar, Manoj; Parveen, Shama

    2016-03-01

    Dengue fever is the most important arboviral disease in the tropical and sub-tropical countries of the world. Delhi, the metropolitan capital state of India, has reported many dengue outbreaks, with the last outbreak occurring in 2013. We have recently reported predominance of dengue virus serotype 2 during 2011-2014 in Delhi. In the present study, we report molecular characterization and evolutionary analysis of dengue serotype 2 viruses which were detected in 2011-2014 in Delhi. Envelope genes of 42 DENV-2 strains were sequenced in the study. All DENV-2 strains grouped within the Cosmopolitan genotype and further clustered into three lineages; Lineage I, II and III. Lineage III replaced lineage I during dengue fever outbreak of 2013. Further, a novel mutation Thr404Ile was detected in the stem region of the envelope protein of a single DENV-2 strain in 2014. Nucleotide substitution rate and time to the most recent common ancestor were determined by molecular clock analysis using Bayesian methods. A change in effective population size of Indian DENV-2 viruses was investigated through Bayesian skyline plot. The study will be a vital road map for investigation of epidemiology and evolutionary pattern of dengue viruses in India.

  11. Synchronizing clocks in distributed networks

    NARCIS (Netherlands)

    Xia, Weiguo; Cao, Ming

    2011-01-01

    Very recently it has been shown that clocks in distributed networks cannot be synchronized precisely even in idealized situations when asymmetric delays are present [1]. In this paper by determining the clock synchronization errors in the similar settings of the impossibility result just mentioned,

  12. Synchronizing clocks in distributed networks

    NARCIS (Netherlands)

    Xia, Weiguo; Cao, Ming

    2011-01-01

    While various time synchronization protocols for clocks in wired and/or wireless networks are under development, recently it has been shown by Freris, Graham and Kumar that clocks in distributed networks cannot be synchronized precisely even in idealized situations. In this paper by determining the

  13. High Precision Clock Bias Prediction Model in Clock Synchronization System

    Directory of Open Access Journals (Sweden)

    Zan Liu

    2016-01-01

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

  14. The adipocyte clock controls brown adipogenesis through the TGF-Beta and BMP signaling pathways

    Science.gov (United States)

    The molecular clock is intimately linked to metabolic regulation, and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here, we show that Bmal1 (also known as ARNTL), the essential...

  15. Avian Clock gene polymorphism : evidence for a latitudinal cline in allele frequencies

    NARCIS (Netherlands)

    Johnsen, A.; Fidler, A. E.; Kuhn, S.; Carter, K. L.; Hoffmann, A.; Barr, I. R.; Biard, C.; Charmantier, A.; Eens, M.; Korsten, P.; Siitari, H.; Tomiuk, J.; Kempenaers, B.

    2007-01-01

    In comparison with most animal behaviours, circadian rhythms have a well-characterized molecular genetic basis. Detailed studies of circadian clock genes in 'model' organisms provide a foundation for interpreting the functional and evolutionary significance of polymorphic circadian clock genes found

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

    Science.gov (United States)

    Suess, Matthias; Matsakis, Demetrios; Greenhall, Charles A.

    2010-01-01

    Using the GPS Toolkit, the GPS constellation is simulated using 31 satellites (SV) and a ground network of 17 monitor stations (MS). At every 15-minutes measurement epoch, the monitor stations measure the time signals of all satellites above a parameterized elevation angle. Once a day, the satellite clock estimates the station and satellite clocks. The first composite clock (B) is based on the Brown algorithm, and is now used by GPS. The second one (G) is based on the Greenhall algorithm. The composite clock of G and B performance are investigated using three ground-clock models. Model C simulates the current GPS configuration, in which all stations are equipped with cesium clocks, except for masers at USNO and Alternate Master Clock (AMC) sites. Model M is an improved situation in which every station is equipped with active hydrogen masers. Finally, Models F and O are future scenarios in which the USNO and AMC stations are equipped with fountain clocks instead of masers. Model F is a rubidium fountain, while Model O is more precise but futuristic Optical Fountain. Each model is evaluated using three performance metrics. The timing-related user range error having all satellites available is the first performance index (PI1). The second performance index (PI2) relates to the stability of the broadcast GPS system time itself. The third performance index (PI3) evaluates the stability of the time scales computed by the two composite clocks. A distinction is made between the "Signal-in-Space" accuracy and that available through a GNSS receiver.

  17. Introduction to Bayesian statistics

    CERN Document Server

    Bolstad, William M

    2017-01-01

    There is a strong upsurge in the use of Bayesian methods in applied statistical analysis, yet most introductory statistics texts only present frequentist methods. Bayesian statistics has many important advantages that students should learn about if they are going into fields where statistics will be used. In this Third Edition, four newly-added chapters address topics that reflect the rapid advances in the field of Bayesian staistics. The author continues to provide a Bayesian treatment of introductory statistical topics, such as scientific data gathering, discrete random variables, robust Bayesian methods, and Bayesian approaches to inferenfe cfor discrete random variables, bionomial proprotion, Poisson, normal mean, and simple linear regression. In addition, newly-developing topics in the field are presented in four new chapters: Bayesian inference with unknown mean and variance; Bayesian inference for Multivariate Normal mean vector; Bayesian inference for Multiple Linear RegressionModel; and Computati...

  18. Bayesian estimation of genetic parameters for multivariate threshold and continuous phenotypes and molecular genetic data in simulated horse populations using Gibbs sampling

    Directory of Open Access Journals (Sweden)

    Hoeschele Ina

    2007-05-01

    Full Text Available Abstract Background Requirements for successful implementation of multivariate animal threshold models including phenotypic and genotypic information are not known yet. Here simulated horse data were used to investigate the properties of multivariate estimators of genetic parameters for categorical, continuous and molecular genetic data in the context of important radiological health traits using mixed linear-threshold animal models via Gibbs sampling. The simulated pedigree comprised 7 generations and 40000 animals per generation. Additive genetic values, residuals and fixed effects for one continuous trait and liabilities of four binary traits were simulated, resembling situations encountered in the Warmblood horse. Quantitative trait locus (QTL effects and genetic marker information were simulated for one of the liabilities. Different scenarios with respect to recombination rate between genetic markers and QTL and polymorphism information content of genetic markers were studied. For each scenario ten replicates were sampled from the simulated population, and within each replicate six different datasets differing in number and distribution of animals with trait records and availability of genetic marker information were generated. (CoVariance components were estimated using a Bayesian mixed linear-threshold animal model via Gibbs sampling. Residual variances were fixed to zero and a proper prior was used for the genetic covariance matrix. Results Effective sample sizes (ESS and biases of genetic parameters differed significantly between datasets. Bias of heritability estimates was -6% to +6% for the continuous trait, -6% to +10% for the binary traits of moderate heritability, and -21% to +25% for the binary traits of low heritability. Additive genetic correlations were mostly underestimated between the continuous trait and binary traits of low heritability, under- or overestimated between the continuous trait and binary traits of moderate

  19. Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy.

    Science.gov (United States)

    Li, Peijun; Fu, Xiaoqin; Smith, Nathan A; Ziobro, Julie; Curiel, Julian; Tenga, Milagros J; Martin, Brandon; Freedman, Samuel; Cea-Del Rio, Christian A; Oboti, Livio; Tsuchida, Tammy N; Oluigbo, Chima; Yaun, Amanda; Magge, Suresh N; O'Neill, Brent; Kao, Amy; Zelleke, Tesfaye G; Depositario-Cabacar, Dewi T; Ghimbovschi, Svetlana; Knoblach, Susan; Ho, Chen-Ying; Corbin, Joshua G; Goodkin, Howard P; Vicini, Stefano; Huntsman, Molly M; Gaillard, William D; Valdez, Gregorio; Liu, Judy S

    2017-10-11

    Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clock flox/flox and PV-Cre; Clock flox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clock flox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clock flox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clock flox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clock flox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. CIRCADIAN CLOCK-ASSOCIATED 1 Inhibits Leaf Senescence in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Yi Song

    2018-03-01

    Full Text Available Leaf senescence is an integral part of plant development, and the timing and progressing rate of senescence could substantially affect the yield and quality of crops. It has been known that a circadian rhythm synchronized with external environmental cues is critical for the optimal coordination of various physiological and metabolic processes. However, the reciprocal interactions between the circadian clock and leaf senescence in plants remain unknown. Here, through measuring the physiological and molecular senescence related markers of several circadian components mutants, we found that CIRCADIAN CLOCK-ASSOCIATED 1 inhibits leaf senescence. Further molecular and genetic studies revealed that CCA1 directly activates GLK2 and suppresses ORE1 expression to counteract leaf senescence. As plants age, the expression and periodic amplitude of CCA1 declines and thus weakens the inhibition of senescence. Our findings reveal an age-dependent circadian clock component of the process of leaf senescence.

  1. Bayesian artificial intelligence

    CERN Document Server

    Korb, Kevin B

    2003-01-01

    As the power of Bayesian techniques has become more fully realized, the field of artificial intelligence has embraced Bayesian methodology and integrated it to the point where an introduction to Bayesian techniques is now a core course in many computer science programs. Unlike other books on the subject, Bayesian Artificial Intelligence keeps mathematical detail to a minimum and covers a broad range of topics. The authors integrate all of Bayesian net technology and learning Bayesian net technology and apply them both to knowledge engineering. They emphasize understanding and intuition but also provide the algorithms and technical background needed for applications. Software, exercises, and solutions are available on the authors' website.

  2. Bayesian artificial intelligence

    CERN Document Server

    Korb, Kevin B

    2010-01-01

    Updated and expanded, Bayesian Artificial Intelligence, Second Edition provides a practical and accessible introduction to the main concepts, foundation, and applications of Bayesian networks. It focuses on both the causal discovery of networks and Bayesian inference procedures. Adopting a causal interpretation of Bayesian networks, the authors discuss the use of Bayesian networks for causal modeling. They also draw on their own applied research to illustrate various applications of the technology.New to the Second EditionNew chapter on Bayesian network classifiersNew section on object-oriente

  3. Clock genes, ADHD and aggression.

    Science.gov (United States)

    Mogavero, Floriana; Jager, Amanda; Glennon, Jeffrey C

    2016-11-09

    Attention deficit/hyperactivity disorder (ADHD) is frequently associated with comorbid aggression and sleep disturbances. The sleep/wake cycle is under the control of the circadian system which is moderated by clock genes. Clock genes can regulate the transcription of monoamine oxidase A, which is involved in the degradation of monoamines. Disturbances in monoamine interaction with clock genes in those with monoamine gene polymorphisms may regulate susceptibility of ADHD and comorbid aggression/sleep disturbances. While monoamines influence circadian rhythm and clock gene expression, circadian rhythm components modulate aggressive behavior, and altered clock genes expression have been associated with ADHD. We propose a mechanism by which circadian rhythm and clock gene expression may influence ADHD and comorbid aggression through the modulation of neurotransmitters. The role of clock genes in ADHD patients with comorbid aggression awaits further research; therefore we also indicate directions for future studies to help increase understanding of the underlying mechanisms in ADHD with comorbid aggression and sleep disturbances. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Low Power Clock Network Design

    Directory of Open Access Journals (Sweden)

    Inna Vaisband

    2011-05-01

    Full Text Available Power is a primary concern in modern circuits. Clock distribution networks, in particular, are an essential element of a synchronous digital circuit and a significant power consumer. Clock distribution networks are subject to clock skew due to process, voltage, and temperature (PVT variations and load imbalances. A target skew between sequentially-adjacent registers can be obtained in a balanced low power clock tree using techniques such as buffer and wire sizing. Existing skew mitigation techniques in tree-based clock distribution networks, however, are not efficient in coping with post design variations; whereas the latest non-tree mesh-based solutions reliably handle skew variations, albeit with a significant increase in dissipated power. Alternatively, crosslink-based methods provide low power and variation-efficient skew solutions. Existing crosslink-based methods, however, only address skew at the network topology level and do not target low power consumption. Different methods to manage skew and skew variations within tree and non-tree clock distribution networks are reviewed and compared in this paper. Guidelines for inserting crosslinks within a buffered low power clock tree are provided. Metrics to determine the most power efficient technique for a given circuit are discussed and verified with simulation.

  5. Physiological links of circadian clock and biological clock of aging.

    Science.gov (United States)

    Liu, Fang; Chang, Hung-Chun

    2017-07-01

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

  6. Neurogenetics of Drosophila circadian clock: expect the unexpected.

    Science.gov (United States)

    Jarabo, Patricia; Martin, Francisco A

    2017-12-01

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

  7. 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

  8. Micro Mercury Ion Clock (MMIC)

    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...

  9. 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.

  10. Circadian clock and vascular disease.

    OpenAIRE

    Takeda, Norihiko; Maemura, Koji

    2010-01-01

    Cardiovascular functions, including blood pressure and vascular functions, show diurnal oscillation. Circadian variations have been clearly shown in the occurrence of cardiovascular events such as acute myocardial infarction. Circadian rhythm strongly influences human biology and pathology. The identification and characterization of mammalian clock genes revealed that they are expressed almost everywhere throughout the body in a circadian manner. In contrast to the central clock in the suprac...

  11. Time without clocks - an attempt

    International Nuclear Information System (INIS)

    Karpman, G.

    1978-01-01

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

  12. Clocked quantum-dot cellular automata shift register

    Science.gov (United States)

    Orlov, Alexei O.; Kummamuru, Ravi; Ramasubramaniam, R.; Lent, Craig S.; Bernstein, Gary H.; Snider, Gregory L.

    2003-06-01

    The quantum-dot cellular automata (QCA) computational paradigm provides a means to achieve ultimately low limits of power dissipation by replacing binary coding in currents and voltages with single-electron switching within arrays of quantum dots ("cells"). Clocked control over the cells allows the realization of power gain, memory and pipelining in QCA circuits. We present an experimental demonstration of a clocked QCA two-stage shift register (SR) and use it to mimic the operation of a multi-stage SR. Error-bit rates for binary switching operations in a metal tunnel junction device are experimentally investigated, and discussed for future molecular QCAs.

  13. Inferring rooted species trees from unrooted gene trees using approximate Bayesian computation.

    Science.gov (United States)

    Alanzi, Ayed R A; Degnan, James H

    2017-11-01

    Methods for inferring species trees from gene trees motivated by incomplete lineage sorting typically use either rooted gene trees to infer a rooted species tree, or use unrooted gene trees to infer an unrooted species tree, which is then typically rooted using one or more outgroups. Theoretically, however, it has been known since 2011 that it is possible to consistently infer the root of the species tree directly from unrooted gene trees without assuming an outgroup. Here, we use approximate Bayesian computation to infer the root of the species tree from unrooted gene trees assuming the multispecies coalescent model. It is hoped that this approach will be useful in cases where an appropriate outgroup is difficult to find and gene trees do not follow a molecular clock. We use approximate Bayesian computation to infer the root of the species tree from unrooted gene trees. This approach could also be useful when there is prior information that makes a small number of root locations plausible in an unrooted species tree. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Daily Rhythmicity of Clock Gene Transcripts in Atlantic Cod Fast Skeletal Muscle

    Science.gov (United States)

    Lazado, Carlo C.; Kumaratunga, Hiruni P. S.; Nagasawa, Kazue; Babiak, Igor; Giannetto, Alessia; Fernandes, Jorge M. O.

    2014-01-01

    The classical notion of a centralized clock that governs circadian rhythmicity has been challenged with the discovery of peripheral oscillators that enable organisms to cope with daily changes in their environment. The present study aimed to identify the molecular clock components in Atlantic cod (Gadus morhua) and to investigate their daily gene expression in fast skeletal muscle. Atlantic cod clock genes were closely related to their orthologs in teleosts and tetrapods. Synteny was conserved to varying degrees in the majority of the 18 clock genes examined. In particular, aryl hydrocarbon receptor nuclear translocator-like 2 (arntl2), RAR-related orphan receptor A (rora) and timeless (tim) displayed high degrees of conservation. Expression profiling during the early ontogenesis revealed that some transcripts were maternally transferred, namely arntl2, cryptochrome 1b and 2 (cry1b and cry2), and period 2a and 2b (per2a and per2b). Most clock genes were ubiquitously expressed in various tissues, suggesting the possible existence of multiple peripheral clock systems in Atlantic cod. In particular, they were all detected in fast skeletal muscle, with the exception of neuronal PAS (Per-Arnt-Single-minded) domain-containing protein (npas1) and rora. Rhythmicity analysis revealed 8 clock genes with daily rhythmic expression, namely arntl2, circadian locomotor output cycles kaput (clock), npas2, cry2, cry3 per2a, nuclear receptor subfamily 1, group D, member 1 (nr1d1), and nr1d2a. Transcript levels of the myogenic genes myogenic factor 5 (myf5) and muscleblind-like 1 (mbnl1) strongly correlated with clock gene expression. This is the first study to unravel the molecular components of peripheral clocks in Atlantic cod. Taken together, our data suggest that the putative clock system in fast skeletal muscle of Atlantic cod has regulatory implications on muscle physiology, particularly in the expression of genes related to myogenesis. PMID:24921252

  15. Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism.

    Science.gov (United States)

    Sato, Fuyuki; Kohsaka, Akira; Bhawal, Ujjal K; Muragaki, Yasuteru

    2018-03-08

    The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 ( Bhlhe40 / Stra13 / Sharp2 ), Dec2 ( Bhlhe41 / Sharp1 ), and Bmal1 ( Mop3 / Arntl ) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1 , Dec2 , and Bmal1 in coordinating the circadian and metabolic pathways.

  16. Polytomies and Bayesian phylogenetic inference.

    Science.gov (United States)

    Lewis, Paul O; Holder, Mark T; Holsinger, Kent E

    2005-04-01

    Bayesian phylogenetic analyses are now very popular in systematics and molecular evolution because they allow the use of much more realistic models than currently possible with maximum likelihood methods. There are, however, a growing number of examples in which large Bayesian posterior clade probabilities are associated with very short branch lengths and low values for non-Bayesian measures of support such as nonparametric bootstrapping. For the four-taxon case when the true tree is the star phylogeny, Bayesian analyses become increasingly unpredictable in their preference for one of the three possible resolved tree topologies as data set size increases. This leads to the prediction that hard (or near-hard) polytomies in nature will cause unpredictable behavior in Bayesian analyses, with arbitrary resolutions of the polytomy receiving very high posterior probabilities in some cases. We present a simple solution to this problem involving a reversible-jump Markov chain Monte Carlo (MCMC) algorithm that allows exploration of all of tree space, including unresolved tree topologies with one or more polytomies. The reversible-jump MCMC approach allows prior distributions to place some weight on less-resolved tree topologies, which eliminates misleadingly high posteriors associated with arbitrary resolutions of hard polytomies. Fortunately, assigning some prior probability to polytomous tree topologies does not appear to come with a significant cost in terms of the ability to assess the level of support for edges that do exist in the true tree. Methods are discussed for applying arbitrary prior distributions to tree topologies of varying resolution, and an empirical example showing evidence of polytomies is analyzed and discussed.

  17. Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues.

    Science.gov (United States)

    Tamaru, Teruya; Takamatsu, Ken

    2018-01-03

    Circadian clocks dictate various physiological functions by brain SCN (a central clock) -orchestrating the temporal harmony of peripheral clocks of tissues/organs in the whole body, with adaptability to environments by resetting their timings. Dysfunction of this circadian adaptation system (CAS) occasionally causes/exacerbates diseases. CAS is based on cell-autonomous molecular clocks, which oscillate via a core transcriptional/translational feedback loop with clock genes/proteins, e.g., BMAL1: CLOCK circadian transcription driver and CRY1/2 and PER1/2 suppressors, and is modulated by various regulatory loops including clock protein modifications. Among mutants with a single clock gene, BMAL1-deficient mice exhibit the most drastic loss of circadian functions. Here, we highlight on numerous circadian protein modifications of mammalian BMAL1, e.g., multiple phosphorylations, SUMOylation, ubiquitination, acetylation, O-GlcNAcylation and S-nitrosylation, which mutually interplay to control molecular clocks and coordinate physiological functions from the brain to peripheral tissues through the input and output of the clocks. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Sound Clocks and Sonic Relativity

    Science.gov (United States)

    Todd, Scott L.; Menicucci, Nicolas C.

    2017-10-01

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

  19. Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body.

    Science.gov (United States)

    Evans, Jennifer A; Suen, Ting-Chung; Callif, Ben L; Mitchell, Andrew S; Castanon-Cervantes, Oscar; Baker, Kimberly M; Kloehn, Ian; Baba, Kenkichi; Teubner, Brett J W; Ehlen, J Christopher; Paul, Ketema N; Bartness, Timothy J; Tosini, Gianluca; Leise, Tanya; Davidson, Alec J

    2015-06-23

    Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50-75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.

  20. Analysis of the overdispersed clock in the short-term evolution of hepatitis C virus: Using the E1/E2 gene sequences to infer infection dates in a single source outbreak.

    Science.gov (United States)

    Wróbel, Borys; Torres-Puente, Manuela; Jiménez, Nuria; Bracho, María Alma; García-Robles, Inmaculada; Moya, Andrés; González-Candelas, Fernando

    2006-06-01

    The assumption of a molecular clock for dating events from sequence information is often frustrated by the presence of heterogeneity among evolutionary rates due, among other factors, to positively selected sites. In this work, our goal is to explore methods to estimate infection dates from sequence analysis. One such method, based on site stripping for clock detection, was proposed to unravel the clocklike molecular evolution in sequences showing high variability of evolutionary rates and in the presence of positive selection. Other alternatives imply accommodating heterogeneity in evolutionary rates at various levels, without eliminating any information from the data. Here we present the analysis of a data set of hepatitis C virus (HCV) sequences from 24 patients infected by a single individual with known dates of infection. We first used a simple criterion of relative substitution rate for site removal prior to a regression analysis. Time was regressed on maximum likelihood pairwise evolutionary distances between the sequences sampled from the source individual and infected patients. We show that it is indeed the fastest evolving sites that disturb the molecular clock and that these sites correspond to positively selected codons. The high computational efficiency of the regression analysis allowed us to compare the site-stripping scheme with random removal of sites. We demonstrate that removing the fast-evolving sites significantly increases the accuracy of estimation of infection times based on a single substitution rate. However, the time-of-infection estimations improved substantially when a more sophisticated and computationally demanding Bayesian method was used. This method was used with the same data set but keeping all the sequence positions in the analysis. Consequently, despite the distortion introduced by positive selection on evolutionary rates, it is possible to obtain quite accurate estimates of infection dates, a result of especial relevance for

  1. Circadian clocks : Translation lost

    NARCIS (Netherlands)

    Roenneberg, T; Merrow, M

    2005-01-01

    One of the big questions in biological rhythms research is how a stable and precise circa-24 hour oscillation is generated on the molecular level. While increasing complexity seemed to be the key, a recent report suggests that circa-24 hour rhythms can be generated by just four molecules incubated

  2. Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior.

    Science.gov (United States)

    Top, Deniz; Young, Michael W

    2017-09-11

    Specialized groups of neurons in the brain are key mediators of circadian rhythms, receiving daily environmental cues and communicating those signals to other tissues in the organism for entrainment and to organize circadian physiology. In Drosophila , the "circadian clock" is housed in seven neuronal clusters, which are defined by their expression of the main circadian proteins, Period, Timeless, Clock, and Cycle. These clusters are distributed across the fly brain and are thereby subject to the respective environments associated with their anatomical locations. While these core components are universally expressed in all neurons of the circadian network, additional regulatory proteins that act on these components are differentially expressed, giving rise to "local clocks" within the network that nonetheless converge to regulate coherent behavioral rhythms. In this review, we describe the communication between the neurons of the circadian network and the molecular differences within neurons of this network. We focus on differences in protein-expression patterns and discuss how such variation can impart functional differences in each local clock. Finally, we summarize our current understanding of how communication within the circadian network intersects with intracellular biochemical mechanisms to ultimately specify behavioral rhythms. We propose that additional efforts are required to identify regulatory mechanisms within each neuronal cluster to understand the molecular basis of circadian behavior. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  3. Acting with the Clock: Clocking Practices in Early Childhood

    Science.gov (United States)

    Pacini-Ketchabaw, Veronica

    2012-01-01

    In this article, the author addresses intra-actions that take place among humans and non-human others--the physical world, the materials--in early childhood education's everyday practices. Her object of study is the clock. Specifically, she provides an example of what it might mean to account for the intra-activity of the material-discursive…

  4. Naming analog clocks conceptually facilitates naming digital clocks

    NARCIS (Netherlands)

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

    2004-01-01

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

  5. Diurnal Preference Predicts Phase Differences in Expression of Human Peripheral Circadian Clock Genes.

    Science.gov (United States)

    Ferrante, Andrew; Gellerman, David; Ay, Ahmet; Woods, Kerri Pruitt; Filipowicz, Allan Michael; Jain, Kriti; Bearden, Neil; Ingram, Krista Kenyon

    2015-06-05

    Circadian rhythms play an integral role in human behavior, physiology and health. Individual differences in daily rhythms (chronotypes) can affect individual sleep-wake cycles, activity patterns and behavioral choices. Diurnal preference, the tendency towards morningness or eveningness among individuals, has been associated with interpersonal variation in circadian clock-related output measures, including body temperature, melatonin levels and clock gene mRNA in blood, oral mucosa, and dermal fibroblast cell cultures. Here we report gene expression data from two principal clock genes sampled from hair follicle cells, a peripheral circadian clock. Hair follicle cells from fourteen individuals of extreme morning or evening chronotype were sampled at three time points. RNA was extracted and quantitative PCR assays were used to measure mRNA expression patterns of two clock genes, Per3 and Nr1d2. We found significant differences in clock gene expression over time between chronotype groups, independent of gender or age of participants. Extreme evening chronotypes have a delay in phase of circadian clock gene oscillation relative to extreme morning types. Variation in the molecular clockwork of chronotype groups represents nearly three-hour phase differences (Per3: 2.61 hours; Nr1d2: 3.08 hours, both: 2.86) in circadian oscillations of these clock genes. The measurement of gene expression from hair follicles at three time points allows for a direct, efficient method of estimating phase shifts of a peripheral circadian clock in real-life conditions. The robust phase differences in temporal expression of clock genes associated with diurnal preferences provide the framework for further studies of the molecular mechanisms and gene-by-environment interactions underlying chronotype-specific behavioral phenomena, including social jetlag.

  6. Understanding Computational Bayesian Statistics

    CERN Document Server

    Bolstad, William M

    2011-01-01

    A hands-on introduction to computational statistics from a Bayesian point of view Providing a solid grounding in statistics while uniquely covering the topics from a Bayesian perspective, Understanding Computational Bayesian Statistics successfully guides readers through this new, cutting-edge approach. With its hands-on treatment of the topic, the book shows how samples can be drawn from the posterior distribution when the formula giving its shape is all that is known, and how Bayesian inferences can be based on these samples from the posterior. These ideas are illustrated on common statistic

  7. Bayesian statistics an introduction

    CERN Document Server

    Lee, Peter M

    2012-01-01

    Bayesian Statistics is the school of thought that combines prior beliefs with the likelihood of a hypothesis to arrive at posterior beliefs. The first edition of Peter Lee’s book appeared in 1989, but the subject has moved ever onwards, with increasing emphasis on Monte Carlo based techniques. This new fourth edition looks at recent techniques such as variational methods, Bayesian importance sampling, approximate Bayesian computation and Reversible Jump Markov Chain Monte Carlo (RJMCMC), providing a concise account of the way in which the Bayesian approach to statistics develops as wel

  8. Single-transistor-clocked flip-flop

    Energy Technology Data Exchange (ETDEWEB)

    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. Evaluating fossil calibrations for dating phylogenies in light of rates of molecular evolution: a comparison of three approaches.

    Science.gov (United States)

    Lukoschek, Vimoksalehi; Scott Keogh, J; Avise, John C

    2012-01-01

    Evolutionary and biogeographic studies increasingly rely on calibrated molecular clocks to date key events. Although there has been significant recent progress in development of the techniques used for molecular dating, many issues remain. In particular, controversies abound over the appropriate use and placement of fossils for calibrating molecular clocks. Several methods have been proposed for evaluating candidate fossils; however, few studies have compared the results obtained by different approaches. Moreover, no previous study has incorporated the effects of nucleotide saturation from different data types in the evaluation of candidate fossils. In order to address these issues, we compared three approaches for evaluating fossil calibrations: the single-fossil cross-validation method of Near, Meylan, and Shaffer (2005. Assessing concordance of fossil calibration points in molecular clock studies: an example using turtles. Am. Nat. 165:137-146), the empirical fossil coverage method of Marshall (2008. A simple method for bracketing absolute divergence times on molecular phylogenies using multiple fossil calibration points. Am. Nat. 171:726-742), and the Bayesian multicalibration method of Sanders and Lee (2007. Evaluating molecular clock calibrations using Bayesian analyses with soft and hard bounds. Biol. Lett. 3:275-279) and explicitly incorporate the effects of data type (nuclear vs. mitochondrial DNA) for identifying the most reliable or congruent fossil calibrations. We used advanced (Caenophidian) snakes as a case study; however, our results are applicable to any taxonomic group with multiple candidate fossils, provided appropriate taxon sampling and sufficient molecular sequence data are available. We found that data type strongly influenced which fossil calibrations were identified as outliers, regardless of which method was used. Despite the use of complex partitioned models of sequence evolution and multiple calibrations throughout the tree, saturation

  10. 47 CFR 80.935 - Station clock.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Station clock. 80.935 Section 80.935... MARITIME SERVICES Compulsory Radiotelephone Installations for Small Passenger Boats § 80.935 Station clock. Each station subject to this subpart must have a working clock or timepiece readily available to the...

  11. A network of (autonomic) clock outputs

    NARCIS (Netherlands)

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

    2006-01-01

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

  12. A network of (autonomic) clock outputs

    NARCIS (Netherlands)

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

    2006-01-01

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

  13. Ras-mediated deregulation of the circadian clock in cancer.

    Directory of Open Access Journals (Sweden)

    Angela Relógio

    Full Text Available Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

  14. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    Science.gov (United States)

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

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

    Science.gov (United States)

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

  16. Gaming in Combinatorial Clock Auctions

    NARCIS (Netherlands)

    M.C.W. Janssen (Maarten); V.A. Karamychev (Vladimir)

    2013-01-01

    textabstractIn recent years, Combinatorial Clock Auctions (CCAs) have been used around the world to allocate frequency spectrum for mobile telecom licenses. CCAs are claimed to significantly reduce the scope for gaming or strategic bidding. In this paper, we show, however, that CCAs significantly

  17. Circadian Clocks : Running on Redox

    NARCIS (Netherlands)

    Merrow, Martha; Roenneberg, Till

    2001-01-01

    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

  18. Sundials: Ancestors of Our Clocks

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 16; Issue 1. Sundials: Ancestors of Our Clocks. P D Anoop. General Article Volume 16 Issue 1 January 2011 pp 29-37. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/016/01/0029-0037. Keywords. Sundial ...

  19. Teaching by the Body's Clock.

    Science.gov (United States)

    Loviglio, Lorraine

    1981-01-01

    Discusses studies by Donald LaSalle showing that students' performance can vary widely over the day according to the workings of their individual biological clocks. Presents exercises to help children identify their own "body rhythm prime time" and suggests rescheduling instruction to accommodate these differences. Condensed from…

  20. <=ryptochromes and Biological Clocks -36 ...

    Indian Academy of Sciences (India)

    form layer; GL - Gangli- onic layer; OF- Optic nerve fibres). The photorecep- tors for vision are present in rod and cone cells in the outer pig1)Jented epithelial layer, whereas the photo- receptors for the biologi- cal clock are located in the inner nuclear layer of the retina. Pigmented epithelial cell. Vitreous humor. Optic nerve.

  1. 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.

  2. Evaluating the Autonomy of the Drosophila Circadian Clock in Dissociated Neuronal Culture

    Directory of Open Access Journals (Sweden)

    Virginie Sabado

    2017-10-01

    Full Text Available Circadian behavioral rhythms offer an excellent model to study intricate interactions between the molecular and neuronal mechanisms of behavior. In mammals, pacemaker neurons in the suprachiasmatic nucleus (SCN generate rhythms cell-autonomously, which are synchronized by the network interactions within the circadian circuit to drive behavioral rhythms. However, whether this principle is universal to circadian systems in animals remains unanswered. Here, we examined the autonomy of the Drosophila circadian clock by monitoring transcriptional and post-transcriptional rhythms of individual clock neurons in dispersed culture with time-lapse microscopy. Expression patterns of the transcriptional reporter show that CLOCK/CYCLE (CLK/CYC-mediated transcription is constantly active in dissociated clock neurons. In contrast, the expression profile of the post-transcriptional reporter indicates that PERIOD (PER protein levels fluctuate and ~10% of cells display rhythms in PER levels with periods in the circadian range. Nevertheless, PER and TIM are enriched in the cytoplasm and no periodic PER nuclear accumulation was observed. These results suggest that repression of CLK/CYC-mediated transcription by nuclear PER is impaired, and thus the negative feedback loop of the molecular clock is incomplete in isolated clock neurons. We further demonstrate that, by pharmacological assays using the non-amidated form of neuropeptide pigment-dispersing factor (PDF, which could be specifically secreted from larval LNvs and adult s-LNvs, downstream events of the PDF signaling are partly impaired in dissociated larval clock neurons. Although non-amidated PDF is likely to be less active than the amidated one, these results point out the possibility that alteration in PDF downstream signaling may play a role in dampening of molecular rhythms in isolated clock neurons. Taken together, our results suggest that Drosophila clocks are weak oscillators that need to be in the

  3. The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research.

    Science.gov (United States)

    Schuch, Jaqueline B; Genro, Julia P; Bastos, Clarissa R; Ghisleni, Gabriele; Tovo-Rodrigues, Luciana

    2018-03-01

    The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders. © 2017 Wiley Periodicals, Inc.

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

    DEFF Research Database (Denmark)

    Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens

    2012-01-01

    The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular...... oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2...... a 24-h rhythmic expression in the adrenal of WT mice under L/D and dark conditions. During a L/D cycle, the adrenal clock gene rhythm in VPAC2-KO mice was phase-advanced by approximately 6 h compared to WT mice and became arrhythmic in constant darkness. A significant 24-h rhythmic variation...

  5. Bayesian Graphical Models

    DEFF Research Database (Denmark)

    Jensen, Finn Verner; Nielsen, Thomas Dyhre

    2016-01-01

    is largely due to the availability of efficient inference algorithms for answering probabilistic queries about the states of the variables in the network. Furthermore, to support the construction of Bayesian network models, learning algorithms are also available. We give an overview of the Bayesian network...

  6. The Bayesian Score Statistic

    NARCIS (Netherlands)

    Kleibergen, F.R.; Kleijn, R.; Paap, R.

    2000-01-01

    We propose a novel Bayesian test under a (noninformative) Jeffreys'priorspecification. We check whether the fixed scalar value of the so-calledBayesian Score Statistic (BSS) under the null hypothesis is aplausiblerealization from its known and standardized distribution under thealternative. Unlike

  7. Bayesian Mediation Analysis

    Science.gov (United States)

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    In this article, we propose Bayesian analysis of mediation effects. Compared with conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian…

  8. An Overview of Monthly Rhythms and Clocks

    Directory of Open Access Journals (Sweden)

    Florian Raible

    2017-05-01

    Full Text Available Organisms have evolved to cope with geophysical cycles of different period lengths. In this review, we focus on the adaptations of animals to the lunar cycle, specifically, on the occurrence of biological rhythms with monthly (circalunar or semi-monthly (circasemilunar period lengths. Systematic experimental investigation, starting in the early twentieth century, has allowed scientists to distinguish between mythological belief and scientific facts concerning the influence of the lunar cycle on animals. These studies revealed that marine animals of various taxa exhibit circalunar or circasemilunar reproductive rhythms. Some of these rely on endogenous oscillators (circalunar or circasemilunar clocks, whereas others are directly driven by external cues, such as the changes in nocturnal illuminance. We review current insight in the molecular and cellular mechanisms involved in circalunar rhythms, focusing on recent work in corals, annelid worms, midges, and fishes. In several of these model systems, the transcript levels of some core circadian clock genes are affected by both light and endogenous circalunar oscillations. How these and other molecular changes relate to the changes in physiology or behavior over the lunar cycle remains to be determined. We further review the possible relevance of circalunar rhythms for terrestrial species, with a particular focus on mammalian reproduction. Studies on circalunar rhythms of conception or birth rates extend to humans, where the lunar cycle was suggested to also affect sleep and mental health. While these reports remain controversial, factors like the increase in “light pollution” by artificial light might contribute to discrepancies between studies. We finally discuss the existence of circalunar oscillations in mammalian physiology. We speculate that these oscillations could be the remnant of ancient circalunar oscillators that were secondarily uncoupled from a natural entrainment mechanism, but

  9. Automatic control of clock duty cycle

    Science.gov (United States)

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

    2010-01-01

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

  10. 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.

  11. 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.

  12. Polyporus and Bupleuri radix effectively alter peripheral circadian clock phase acutely in male mice.

    Science.gov (United States)

    Motohashi, Hiroaki; Sukigara, Haruna; Tahara, Yu; Saito, Keisuke; Yamazaki, Mayu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Shibata, Shigenobu

    2017-07-01

    In mammals, daily physiological events are precisely regulated by an internal circadian clock system. An important function of this system is to readjust the phase of the clock daily. In Japan, traditional herb medicines, so-called crude drugs (Shoyaku), are widely used for many diseases, and some are reported to affect circadian clock impairment, suggesting that some of them might have an ability to modify clock gene expression rhythms. Therefore, from selected 40 crude drugs, finding candidates that control the circadian clock phases was the first purpose of this study. As there are several crude drugs used for liver- and/or kidney-related diseases, the second aim of the present study was to find some crude drugs affecting liver/kidney circadian clock in vivo. To assess phase changes in the daily circadian rhythm, bioluminescence from the core clock gene product Period 2 was continuously monitored in mouse embryonic fibroblasts in vitro and in some peripheral tissues (kidney, liver, and submandibular gland) of PERIOD2::LUCIFERASE knock-in mice in vivo. In our screening, Polyporus and Bupleuri radix were found to be good candidates to effectively manipulate the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. Interestingly, Polyporus and Bupleuri radix are traditional herb medicines use for treating edema and promoting diuresis, and for chronic hepatitis, respectively. These crude drugs may be therefore good modulators of the circadian peripheral clocks including liver and kidney, and circadian clock genes become new molecular targets for these crude drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Dynamics of the slowing segmentation clock reveal alternating two-segment periodicity.

    Science.gov (United States)

    Shih, Nathan P; François, Paul; Delaune, Emilie A; Amacher, Sharon L

    2015-05-15

    The formation of reiterated somites along the vertebrate body axis is controlled by the segmentation clock, a molecular oscillator expressed within presomitic mesoderm (PSM) cells. Although PSM cells oscillate autonomously, they coordinate with neighboring cells to generate a sweeping wave of cyclic gene expression through the PSM that has a periodicity equal to that of somite formation. The velocity of each wave slows as it moves anteriorly through the PSM, although the dynamics of clock slowing have not been well characterized. Here, we investigate segmentation clock dynamics in the anterior PSM in developing zebrafish embryos using an in vivo clock reporter, her1:her1-venus. The her1:her1-venus reporter has single-cell resolution, allowing us to follow segmentation clock oscillations in individual cells in real-time. By retrospectively tracking oscillations of future somite boundary cells, we find that clock reporter signal increases in anterior PSM cells and that the periodicity of reporter oscillations slows to about ∼1.5 times the periodicity in posterior PSM cells. This gradual slowing of the clock in the anterior PSM creates peaks of clock expression that are separated at a two-segment periodicity both spatially and temporally, a phenomenon we observe in single cells and in tissue-wide analyses. These results differ from previous predictions that clock oscillations stop or are stabilized in the anterior PSM. Instead, PSM cells oscillate until they incorporate into somites. Our findings suggest that the segmentation clock may signal somite formation using a phase gradient with a two-somite periodicity. © 2015. Published by The Company of Biologists Ltd.

  14. 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.

  15. Clock represses preadipocytes adipogenesis via GILZ.

    Science.gov (United States)

    Zhu, Zhu; Xu, Lirong; Cai, Tingting; Yuan, Gongsheng; Sun, Ning; Lu, Chao; Qian, Ruizhe

    2017-12-26

    Adiposity is a worldwide health threat that needs to be prevented. Circadian gene Clock (circadian locomotor output cycles kaput) is closely correlated to adiposity; for example, weight gain, adipocytes size expansion, and serum lipid level rise in Clock Δ19 mice compared to C57BL/6J mice. However, the precise role of Clock during adipogenic differentiation is unknown. Herein, the circadian gene Clock is shown to regulate adipogenesis mediated by GILZ. Clock-mediated attenuation and upregulation influenced lipid synthesis and affected the levels of adipogenic transcriptional factors, C/EBP-β, C/EBP-α, PPAR-γ, and FABP4, both in vivo and in vitro (primary adipose-derived stromal cells and 3T3-L1 cells). Chromatin immunoprecipitation (ChIP) assay, reporter gene assay, and serum shock assay found that Clock transcriptionally regulated the glucocorticoid-induced leucine zipper (GILZ). Furthermore, GILZ attenuation could relieve the inhibitory effect of Clock on lipid synthesis and GILZ overexpression also reduced the promotion role of Clock attenuation in adipogenesis suggesting that Clock inhibits adipogenic differentiation of preadipocytes via GILZ. The current results demonstrate how circadian genes are likely to regulate adiposity, affecting the adipogenic differentiation process, as well as, increasing the fat cells number. Therefore, this study may provide novel insights into the underlying mechanism explaining the correlation between Clock mutation and adiposity. © 2017 Wiley Periodicals, Inc.

  16. Entanglement of quantum clocks through gravity

    Science.gov (United States)

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

    2017-03-01

    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.

  17. Mammalian TIMELESS Is Involved in Period Determination and DNA Damage-Dependent Phase Advancing of the Circadian Clock

    NARCIS (Netherlands)

    M.P. Engelen (Erik); R. Janssens (Roel); K. Yagita (Kazuhiro); V.A.J. Smits (Veronique); G.T.J. van der Horst (Gijsbertus); F. Tamanini (Filippo)

    2013-01-01

    textabstractThe transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly

  18. Bayesian data analysis for newcomers.

    Science.gov (United States)

    Kruschke, John K; Liddell, Torrin M

    2018-02-01

    This article explains the foundational concepts of Bayesian data analysis using virtually no mathematical notation. Bayesian ideas already match your intuitions from everyday reasoning and from traditional data analysis. Simple examples of Bayesian data analysis are presented that illustrate how the information delivered by a Bayesian analysis can be directly interpreted. Bayesian approaches to null-value assessment are discussed. The article clarifies misconceptions about Bayesian methods that newcomers might have acquired elsewhere. We discuss prior distributions and explain how they are not a liability but an important asset. We discuss the relation of Bayesian data analysis to Bayesian models of mind, and we briefly discuss what methodological problems Bayesian data analysis is not meant to solve. After you have read this article, you should have a clear sense of how Bayesian data analysis works and the sort of information it delivers, and why that information is so intuitive and useful for drawing conclusions from data.

  19. SKIP is a component of the spliceosome linking alternative splicing and the circadian clock in Arabidopsis.

    Science.gov (United States)

    Wang, Xiaoxue; Wu, Fangming; Xie, Qiguang; Wang, Huamei; Wang, Ying; Yue, Yanling; Gahura, Ondrej; Ma, Shuangshuang; Liu, Lei; Cao, Ying; Jiao, Yuling; Puta, Frantisek; McClung, C Robertson; Xu, Xiaodong; Ma, Ligeng

    2012-08-01

    Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5' and 3' splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level.

  20. 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.

  1. Bayesian methods for data analysis

    CERN Document Server

    Carlin, Bradley P.

    2009-01-01

    Approaches for statistical inference Introduction Motivating Vignettes Defining the Approaches The Bayes-Frequentist Controversy Some Basic Bayesian Models The Bayes approach Introduction Prior Distributions Bayesian Inference Hierarchical Modeling Model Assessment Nonparametric Methods Bayesian computation Introduction Asymptotic Methods Noniterative Monte Carlo Methods Markov Chain Monte Carlo Methods Model criticism and selection Bayesian Modeling Bayesian Robustness Model Assessment Bayes Factors via Marginal Density Estimation Bayes Factors

  2. Digital clocks: simple Boolean models can quantitatively describe circadian systems.

    Science.gov (United States)

    Akman, Ozgur E; Watterson, Steven; Parton, Andrew; Binns, Nigel; Millar, Andrew J; Ghazal, Peter

    2012-09-07

    The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day-night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of more complex clocks, as well as other circuits with different qualitative dynamics. In particular, we anticipate

  3. Digital clocks: simple Boolean models can quantitatively describe circadian systems

    Science.gov (United States)

    Akman, Ozgur E.; Watterson, Steven; Parton, Andrew; Binns, Nigel; Millar, Andrew J.; Ghazal, Peter

    2012-01-01

    The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day–night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of more complex clocks, as well as other circuits with different qualitative dynamics. In particular, we

  4. Sexual Differentiation of Circadian Clock Function in the Adrenal Gland.

    Science.gov (United States)

    Kloehn, Ian; Pillai, Savin B; Officer, Laurel; Klement, Claire; Gasser, Paul J; Evans, Jennifer A

    2016-05-01

    Sex differences in glucocorticoid production are associated with increased responsiveness of the adrenal gland in females. However, the adrenal-intrinsic mechanisms that establish sexual dimorphic function remain ill defined. Glucocorticoid production is gated at the molecular level by the circadian clock, which may contribute to sexual dimorphic adrenal function. Here we examine sex differences in the adrenal gland using an optical reporter of circadian clock function. Adrenal glands were cultured from male and female Period2::Luciferase (PER2::LUC) mice to assess clock function in vitro in real time. We confirm that there is a pronounced sex difference in the intrinsic capacity to sustain PER2::LUC rhythms in vitro, with higher amplitude rhythms in adrenal glands collected from males than from females. Changes in adrenal PER2::LUC rhythms over the reproductive life span implicate T as an important factor in driving sex differences in adrenal clock function. By directly manipulating hormone levels in adult mice in vivo, we demonstrate that T increases the amplitude of PER2::LUC rhythms in adrenal glands of both male and female mice. In contrast, we find little evidence that ovarian hormones modify adrenal clock function. Lastly, we find that T in vitro can increase the amplitude of PER2::LUC rhythms in male adrenals but not female adrenals, which suggests the existence of sex differences in the mechanisms of T action in vivo. Collectively these results reveal that activational effects of T alter circadian timekeeping in the adrenal gland, which may have implications for sex differences in stress reactivity and stress-related disorders.

  5. Statistics: a Bayesian perspective

    National Research Council Canada - National Science Library

    Berry, Donald A

    1996-01-01

    ...: it is the only introductory textbook based on Bayesian ideas, it combines concepts and methods, it presents statistics as a means of integrating data into the significant process, it develops ideas...

  6. Noncausal Bayesian Vector Autoregression

    DEFF Research Database (Denmark)

    Lanne, Markku; Luoto, Jani

    We propose a Bayesian inferential procedure for the noncausal vector autoregressive (VAR) model that is capable of capturing nonlinearities and incorporating effects of missing variables. In particular, we devise a fast and reliable posterior simulator that yields the predictive distribution...

  7. Practical Bayesian tomography

    Science.gov (United States)

    Granade, Christopher; Combes, Joshua; Cory, D. G.

    2016-03-01

    In recent years, Bayesian methods have been proposed as a solution to a wide range of issues in quantum state and process tomography. State-of-the-art Bayesian tomography solutions suffer from three problems: numerical intractability, a lack of informative prior distributions, and an inability to track time-dependent processes. Here, we address all three problems. First, we use modern statistical methods, as pioneered by Huszár and Houlsby (2012 Phys. Rev. A 85 052120) and by Ferrie (2014 New J. Phys. 16 093035), to make Bayesian tomography numerically tractable. Our approach allows for practical computation of Bayesian point and region estimators for quantum states and channels. Second, we propose the first priors on quantum states and channels that allow for including useful experimental insight. Finally, we develop a method that allows tracking of time-dependent states and estimates the drift and diffusion processes affecting a state. We provide source code and animated visual examples for our methods.

  8. Assessment of the sensitivity and specificity of serological (IFAT) and molecular (direct-PCR) techniques for diagnosis of leishmaniasis in lagomorphs using a Bayesian approach.

    Science.gov (United States)

    de la Cruz, María Luisa; Pérez, Andres; Domínguez, Mercedes; Moreno, Inmaculada; García, Nerea; Martínez, Irene; Navarro, Alejandro; Domínguez, Lucas; Álvarez, Julio

    2016-08-01

    Leishmaniasis, caused by Leishmania infantum , is a vector-borne zoonotic disease that is endemic to the Mediterranean basin. The potential of rabbits and hares to serve as competent reservoirs for the disease has recently been demonstrated, although assessment of the importance of their role on disease dynamics is hampered by the absence of quantitative knowledge on the accuracy of diagnostic techniques in these species. A Bayesian latent-class model was used here to estimate the sensitivity and specificity of the Immuno-fluorescence antibody test (IFAT) in serum and a Leishmania -nested PCR (Ln-PCR) in skin for samples collected from 217 rabbits and 70 hares from two different populations in the region of Madrid, Spain. A two-population model, assuming conditional independence between test results and incorporating prior information on the performance of the tests in other animal species obtained from the literature, was used. Two alternative cut-off values were assumed for the interpretation of the IFAT results: 1/50 for conservative and 1/25 for sensitive interpretation. Results suggest that sensitivity and specificity of the IFAT were around 70-80%, whereas the Ln-PCR was highly specific (96%) but had a limited sensitivity (28.9% applying the conservative interpretation and 21.3% with the sensitive one). Prevalence was higher in the rabbit population (50.5% and 72.6%, for the conservative and sensitive interpretation, respectively) than in hares (6.7% and 13.2%). Our results demonstrate that the IFAT may be a useful screening tool for diagnosis of leishmaniasis in rabbits and hares. These results will help to design and implement surveillance programmes in wild species, with the ultimate objective of early detecting and preventing incursions of the disease into domestic and human populations.

  9. Mechanism of the circadian clock in physiology

    Science.gov (United States)

    Richards, Jacob

    2013-01-01

    It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiological process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of “clock-independent effects” of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed. PMID:23576606

  10. 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.

  11. Variational Bayesian Filtering

    Czech Academy of Sciences Publication Activity Database

    Šmídl, Václav; Quinn, A.

    2008-01-01

    Roč. 56, č. 10 (2008), s. 5020-5030 ISSN 1053-587X R&D Projects: GA MŠk 1M0572 Institutional research plan: CEZ:AV0Z10750506 Keywords : Bayesian filtering * particle filtering * Variational Bayes Subject RIV: BC - Control Systems Theory Impact factor: 2.335, year: 2008 http://library.utia.cas.cz/separaty/2008/AS/smidl-variational bayesian filtering.pdf

  12. Bayesian Networks An Introduction

    CERN Document Server

    Koski, Timo

    2009-01-01

    Bayesian Networks: An Introduction provides a self-contained introduction to the theory and applications of Bayesian networks, a topic of interest and importance for statisticians, computer scientists and those involved in modelling complex data sets. The material has been extensively tested in classroom teaching and assumes a basic knowledge of probability, statistics and mathematics. All notions are carefully explained and feature exercises throughout. Features include:.: An introduction to Dirichlet Distribution, Exponential Families and their applications.; A detailed description of learni

  13. Melatonin, clock genes and mitochondria in sepsis.

    Science.gov (United States)

    Acuña-Castroviejo, Darío; Rahim, Ibtissem; Acuña-Fernández, Carlos; Fernández-Ortiz, Marisol; Solera-Marín, Jorge; Sayed, Ramy K A; Díaz-Casado, María E; Rusanova, Iryna; López, Luis C; Escames, Germaine

    2017-11-01

    After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.

  14. 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…

  15. Local area network distributed realtime clock synchronization

    Science.gov (United States)

    Wilcox, D. R.

    1991-11-01

    This report applies the strobe realtime clock synchronization technique to serial busses and local area networks in general, and to the IEEE 802.5 and the Fiber Distributed Data Interface token ring local area network standards in particular. Section 2 examines miscellaneous material relating to adjustable-rate realtime clocks. Section 3 presents adjustable rate realtime clock hardware implementation methods considered superior to those in an earlier report. Section 4 presents a hardware implementation of an IEEE 802.5 strobe detector.

  16. A role for the clock period circadian regulator 2 gene in regulating the clock gene network in human oral squamous cell carcinoma cells.

    Science.gov (United States)

    Ao, Yiran; Zhao, Qin; Yang, Kai; Zheng, Gang; Lv, Xiaoqing; Su, Xiaoli

    2018-04-01

    Clock genes are the core of the circadian rhythms in the human body and are important in regulating normal physiological functions. To date, research has indicated that the clock gene, period circadian clock 2 ( PER2 ), is downregulated in numerous types of cancer, and that it is associated with cancer occurrence and progression via the regulation of various downstream cell cycle genes. However, it remains unclear whether the decreased expression of PER2 influences the expression of other clock genes in cancer cells. In the present study, short hairpin RNA interference was used to knockdown PER2 effectively in human oral squamous cell carcinoma SCC15 cells. Quantitative polymerase chain reaction was used to assess the mRNA expression levels of various clock genes and revealed that, following the knockdown of PER2 in SCC15 cells, the mRNA expression levels of PER3 , brain and muscle ARNT-like 1, deleted in esophageal cancer (DEC)1, DEC2 , cryptochrome circadian clock ( CRY )2, timeless circadian clock, retinoic acid receptor-related orphan receptor-alpha and neuronal PAS domain protein 2 were significantly downregulated, while the mRNA expression levels of PER1 and nuclear receptor subfamily 1 group D member 1 were significantly upregulated. In addition, flow cytometric analysis demonstrated that proliferation was enhanced and apoptosis was reduced following PER2 knockdown in SCC15 cells (Pclock genes of the clock gene network in cancer cells. This is of great significance in elucidating the molecular function and tumor suppression mechanism of PER2 .

  17. The clock gene cycle plays an important role in the circadian clock of the cricket Gryllus bimaculatus.

    Science.gov (United States)

    Uryu, Outa; Karpova, Svetlana G; Tomioka, Kenji

    2013-07-01

    To dissect the molecular oscillatory mechanism of the circadian clock in the cricket Gryllus bimaculatus, we have cloned a cDNA of the clock gene cycle (Gb'cyc) and analyzed its structure and function. Gb'cyc contains four functional domains, i.e. bHLH, PAS-A, PAS-B and BCTR domains, and is expressed rhythmically in light dark cycles, peaking at mid night. The RNA interference (RNAi) of Clock (Gb'Clk) and period (Gb'per) reduced the Gb'cyc mRNA levels and abolished the rhythmic expression, suggesting that the rhythmic expression of Gb'cyc is regulated by a mechanism including Gb'Clk and Gb'per. These features are more similar to those of mammalian orthologue of cyc (Bmal1) than those of Drosophila cyc. A single treatment with double-stranded RNA (dsRNA) of Gb'cyc effectively knocked down the Gb'cyc mRNA level and abolished its rhythmic expression. The cyc RNAi failed to disrupt the locomotor rhythm, but lengthened its free-running period in constant darkness (DD). It is thus likely that Gb'cyc is involved in the circadian clock machinery of the cricket. The cyc RNAi crickets showed a rhythmic expression of Gb'per and timeless (Gb'tim) in the optic lobe in DD, explaining the persistence of the locomotor rhythm. Surprisingly, cyc RNAi revealed a rhythmic expression of Gb'Clk in DD which is otherwise rather constitutively expressed in the optic lobe. These facts suggest that the cricket might have a unique clock oscillatory mechanism in which both Gb'cyc and Gb'Clk are rhythmically controlled and that under abundant expression of Gb'cyc the rhythmic expression of Gb'Clk may be concealed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. A role for the PERIOD:PERIOD homodimer in the Drosophila circadian clock.

    Directory of Open Access Journals (Sweden)

    Johannes Landskron

    2009-04-01

    Full Text Available Circadian clocks in eukaryotes rely on transcriptional feedback loops, in which clock genes repress their own transcription resulting in molecular oscillations with a period of approximately 24 h. In Drosophila, the clock proteins Period (PER and Timeless (TIM operate in such a feedback loop, whereby they first accumulate in the cytoplasm of clock cells as a heterodimer. Nuclear translocation of the complex or the individual PER and TIM proteins is followed by repression of per and tim transcription, whereby PER seems to act as the prime repressor. We found that in addition to PER:TIM complexes, functional PER:PER homodimers exist in flies. Specific disruption of PER homodimers results in drastically impaired behavioral and molecular rhythmicity, pointing the biological importance of this clock protein complex. Analysis of PER subcellular distribution and repressor competence in the PER dimer mutant revealed defects in PER nuclear translocation and a disruption of rhythmic period transcription. The striking similarity of these phenotypes with that of reduced CKII activity suggests that the formation or function of the PER dimer is closely linked to this kinase. Our results confirm a previous structural model for PER and provide strong evidence that PER homodimers are important for circadian clock function.

  19. 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.

  20. 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.

  1. 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.

  2. Altered expression of circadian clock genes in polyglandular autoimmune syndrome type III.

    Science.gov (United States)

    Angelousi, Anna; Nasiri-Ansari, Narjes; Spilioti, Eliana; Mantzou, Emilia; Kalotyxou, Vasiliki; Chrousos, George; Kaltsas, Gregory; Kassi, Eva

    2018-01-01

    Circadian timing system is a highly conserved, ubiquitous molecular "clock" which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PAS type III). Nineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence. There were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (R pm/am ) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (F pm/am ) was positively correlated with GILZ mRNA circadian pattern (R pm/am ) in the patient group and with the GR-a mRNA (R pm/am ) in the control group. Our findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease.

  3. Hypophysectomy abolishes rhythms in rat thyroid hormones but not in the thyroid clock.

    Science.gov (United States)

    Fahrenkrug, J; Georg, B; Hannibal, J; Jørgensen, H L

    2017-06-01

    The endocrine body rhythms including the hypothalamic-pituitary-thyroid axis seem to be regulated by the circadian timing system, and daily rhythmicity of circulating thyroid-stimulating hormone (TSH) is well established. The circadian rhythms are generated by endogenous clocks in the central brain oscillator located in the hypothalamic suprachiasmatic nucleus (SCN) as well as multiple peripheral clocks, but information on the existence and function of a thyroid clock is limited. The molecular machinery in all clock cells is composed of a number of clock genes and their gene products are connected by autoregulatory feedback loops. Here, we provide evidence for a thyroid clock in the rat by demonstrating 24-h antiphase oscillations for the mRNA of the canonical clock genes Per1 and Bmal1 , which was unaffected by hypophysectomy. By immunostaining, we supported the existence of a core oscillator in the individual thyroid cells by demonstrating a daily cytoplasmatic-nuclear shuttling of PER1 protein. In normal rats, we found a significant daily rhythmicity in the circulating thyroid hormones preceded by a peak in TSH. In hypophysectomised rats, although the thyroid clock was not affected, the oscillations in circulating thyroid hormones were abolished and the levels were markedly lowered. No daily oscillations in the expression of TSH receptor mRNA were observed in neither control rats nor hypophysectomised rats. Our findings indicate that the daily rhythm of thyroid hormone secretion is governed by SCN signalling via the rhythmic TSH secretion rather than by the local thyroid clock, which was still ticking after hypophysectomy. © 2017 The authors.

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

    Directory of Open Access Journals (Sweden)

    Mauro Agostino Zordan

    2015-04-01

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

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

    Science.gov (United States)

    Zordan, Mauro Agostino; Sandrelli, Federica

    2015-01-01

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

  6. Bayesian phylogeography finds its roots.

    Directory of Open Access Journals (Sweden)

    Philippe Lemey

    2009-09-01

    Full Text Available As a key factor in endemic and epidemic dynamics, the geographical distribution of viruses has been frequently interpreted in the light of their genetic histories. Unfortunately, inference of historical dispersal or migration patterns of viruses has mainly been restricted to model-free heuristic approaches that provide little insight into the temporal setting of the spatial dynamics. The introduction of probabilistic models of evolution, however, offers unique opportunities to engage in this statistical endeavor. Here we introduce a Bayesian framework for inference, visualization and hypothesis testing of phylogeographic history. By implementing character mapping in a Bayesian software that samples time-scaled phylogenies, we enable the reconstruction of timed viral dispersal patterns while accommodating phylogenetic uncertainty. Standard Markov model inference is extended with a stochastic search variable selection procedure that identifies the parsimonious descriptions of the diffusion process. In addition, we propose priors that can incorporate geographical sampling distributions or characterize alternative hypotheses about the spatial dynamics. To visualize the spatial and temporal information, we summarize inferences using virtual globe software. We describe how Bayesian phylogeography compares with previous parsimony analysis in the investigation of the influenza A H5N1 origin and H5N1 epidemiological linkage among sampling localities. Analysis of rabies in West African dog populations reveals how virus diffusion may enable endemic maintenance through continuous epidemic cycles. From these analyses, we conclude that our phylogeographic framework will make an important asset in molecular epidemiology that can be easily generalized to infer biogeogeography from genetic data for many organisms.

  7. Multiscale Clock Ensembling Using Wavelets

    Science.gov (United States)

    2010-11-01

    allows an energy decomposition of the signal as well, referred to as the wavelet variance. This variance is defined by ) var ()( 2 llX Wv  (11...and it can be shown that for a very wide class of signals and for an appropriately chosen wavelet that ) var ()( 1 2 Xv l lX     . One such...42 nd Annual Precise Time and Time Interval (PTTI) Meeting 527 MULTISCALE CLOCK ENSEMBLING USING WAVELETS Ken Senior Naval Center

  8. Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice

    Science.gov (United States)

    Shimomura, Kazuhiro; Kumar, Vivek; Koike, Nobuya; Kim, Tae-Kyung; Chong, Jason; Buhr, Ethan D; Whiteley, Andrew R; Low, Sharon S; Omura, Chiaki; Fenner, Deborah; Owens, Joseph R; Richards, Marc; Yoo, Seung-Hee; Hong, Hee-Kyung; Vitaterna, Martha H; Bass, Joseph; Pletcher, Mathew T; Wiltshire, Tim; Hogenesch, John; Lowrey, Phillip L; Takahashi, Joseph S

    2013-01-01

    Genetic and molecular approaches have been critical for elucidating the mechanism of the mammalian circadian clock. Here, we demonstrate that the ClockΔ19 mutant behavioral phenotype is significantly modified by mouse strain genetic background. We map a suppressor of the ClockΔ19 mutation to a ∼900 kb interval on mouse chromosome 1 and identify the transcription factor, Usf1, as the responsible gene. A SNP in the promoter of Usf1 causes elevation of its transcript and protein in strains that suppress the Clock mutant phenotype. USF1 competes with the CLOCK:BMAL1 complex for binding to E-box sites in target genes. Saturation binding experiments demonstrate reduced affinity of the CLOCKΔ19:BMAL1 complex for E-box sites, thereby permitting increased USF1 occupancy on a genome-wide basis. We propose that USF1 is an important modulator of molecular and behavioral circadian rhythms in mammals. DOI: http://dx.doi.org/10.7554/eLife.00426.001 PMID:23580255

  9. High Performance Clocks and Gravity Field Determination

    Science.gov (United States)

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

    2018-02-01

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

  10. Atypical expression of circadian clock genes in denervated mouse skeletal muscle.

    Science.gov (United States)

    Nakao, Reiko; Yamamoto, Saori; Horikawa, Kazumasa; Yasumoto, Yuki; Nikawa, Takeshi; Mukai, Chiaki; Oishi, Katsutaka

    2015-05-01

    The central circadian clock in the suprachiasmatic nucleus of the hypothalamus synchronizes peripheral clocks through neural and humoral signals in most mammalian tissues. Here, we analyzed the effects of unilateral sciatic denervation on the expression of circadian clock- and clock-controlled genes in the gastrocnemius muscles of mice twice per day on days 0, 3, 7, 9, 11 and 14 after denervation and six times on each of days 7 and 28 after denervation to assess the regulation mechanism of the circadian clock in skeletal muscle. Sciatic denervation did not affect systemic circadian rhythms since core body temperature (Day 7), corticosterone secretion (Days 7 and 28), and hepatic clock gene expression remained intact (Days 7 and 28). Expression levels of most circadian clock-related genes such as Arntl, Per1, Rora, Nr1d1 and Dbp were reduced in accordance with the extent of muscle atrophy, although circadian Per2 expression was significantly augmented (Day 28). Cosinor analysis revealed that the circadian expression of Arntl (Days 7 and 28) and Dbp (Day 28) was phase advanced in denervated muscle. The mRNA expression of Clock was significantly increased in denervated muscle on Day 3 when the severe atrophy was absent, and it was not affected by atrophic progression for 28 days. Sciatic denervation did not affect the expression of these genes in the contralateral muscle (Days 7 and 28), suggesting that humoral changes were not involved in denervation-induced muscle clock disruption. We then analyzed genome-wide gene expression using microarrays to determine the effects of disrupting the molecular clock in muscle on circadian rhythms at Day 7. Among 478 circadian genes, 313 lost rhythmicity in the denervated muscles. These denervation-sensitive genes included the lipid metabolism-related genes, Nrip1, Bbs1, Ptgis, Acot1, Scd2, Hpgd, Insig1, Dhcr24, Ldlr and Mboat1. Our findings revealed that sciatic denervation disrupts the circadian expression of clock and clock

  11. 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

  12. Systematic Effects in Atomic Fountain Clocks

    Science.gov (United States)

    Gibble, Kurt

    2016-06-01

    We describe recent advances in the accuracies of atomic fountain clocks. New rigorous treatments of the previously large systematic uncertainties, distributed cavity phase, microwave lensing, and background gas collisions, enabled these advances. We also discuss background gas collisions of optical lattice and ion clocks and derive the smooth transition of the microwave lensing frequency shift to photon recoil shifts for large atomic wave packets.

  13. 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.

  14. Circadian clock components in the rat neocortex

    DEFF Research Database (Denmark)

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

    2013-01-01

    in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene...

  15. 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...

  16. A molecular palaeobiological hypothesis for the origin of aplacophoran molluscs and their derivation from chiton-like ancestors.

    Science.gov (United States)

    Vinther, Jakob; Sperling, Erik A; Briggs, Derek E G; Peterson, Kevin J

    2012-04-07

    Aplacophorans have long been argued to be basal molluscs. We present a molecular phylogeny, including the aplacophorans Neomeniomorpha (Solenogastres) and Chaetodermomorpha (Caudofoveata), which recovered instead the clade Aculifera (Aplacophora + Polyplacophora). Our relaxed Bayesian molecular clock estimates an Early Ordovician appearance of the aculiferan crown group consistent with the presence of chiton-like molluscs with seven or eight dorsal shell plates by the Late Cambrian (approx. 501-490 Ma). Molecular, embryological and palaeontological data indicate that aplacophorans, as well as chitons, evolved from a paraphyletic assemblage of chiton-like ancestors. The recovery of cephalopods as a sister group to aculiferans suggests that the plesiomorphic condition in molluscs might be a morphology similar to that found in monoplacophorans.

  17. Cell type-specific functions of period genes revealed by novel adipocyte and hepatocyte circadian clock models.

    Directory of Open Access Journals (Sweden)

    Chidambaram Ramanathan

    2014-04-01

    Full Text Available In animals, circadian rhythms in physiology and behavior result from coherent rhythmic interactions between clocks in the brain and those throughout the body. Despite the many tissue specific clocks, most understanding of the molecular core clock mechanism comes from studies of the suprachiasmatic nuclei (SCN of the hypothalamus and a few other cell types. Here we report establishment and genetic characterization of three cell-autonomous mouse clock models: 3T3 fibroblasts, 3T3-L1 adipocytes, and MMH-D3 hepatocytes. Each model is genetically tractable and has an integrated luciferase reporter that allows for longitudinal luminescence recording of rhythmic clock gene expression using an inexpensive off-the-shelf microplate reader. To test these cellular models, we generated a library of short hairpin RNAs (shRNAs against a panel of known clock genes and evaluated their impact on circadian rhythms. Knockdown of Bmal1, Clock, Cry1, and Cry2 each resulted in similar phenotypes in all three models, consistent with previous studies. However, we observed cell type-specific knockdown phenotypes for the Period and Rev-Erb families of clock genes. In particular, Per1 and Per2, which have strong behavioral effects in knockout mice, appear to play different roles in regulating period length and amplitude in these peripheral systems. Per3, which has relatively modest behavioral effects in knockout mice, substantially affects period length in the three cellular models and in dissociated SCN neurons. In summary, this study establishes new cell-autonomous clock models that are of particular relevance to metabolism and suitable for screening for clock modifiers, and reveals previously under-appreciated cell type-specific functions of clock genes.

  18. Circadian clock gene expression in the coral Favia fragum over diel and lunar reproductive cycles.

    Directory of Open Access Journals (Sweden)

    Kenneth D Hoadley

    Full Text Available Natural light cycles synchronize behavioral and physiological cycles over varying time periods in both plants and animals. Many scleractinian corals exhibit diel cycles of polyp expansion and contraction entrained by diel sunlight patterns, and monthly cycles of spawning or planulation that correspond to lunar moonlight cycles. The molecular mechanisms for regulating such cycles are poorly understood. In this study, we identified four molecular clock genes (cry1, cry2, clock and cycle in the scleractinian coral, Favia fragum, and investigated patterns of gene expression hypothesized to be involved in the corals' diel polyp behavior and lunar reproductive cycles. Using quantitative PCR, we measured fluctuations in expression of these clock genes over both diel and monthly spawning timeframes. Additionally, we assayed gene expression and polyp expansion-contraction behavior in experimental corals in normal light:dark (control or constant dark treatments. Well-defined and reproducible diel patterns in cry1, cry2, and clock expression were observed in both field-collected and the experimental colonies maintained under control light:dark conditions, but no pattern was observed for cycle. Colonies in the control light:dark treatment also displayed diel rhythms of tentacle expansion and contraction. Experimental colonies in the constant dark treatment lost diel patterns in cry1, cry2, and clock expression and displayed a diminished and less synchronous pattern of tentacle expansion and contraction. We observed no pattern in cry1, cry2, clock, or cycle expression correlated with monthly spawning events suggesting these genes are not involved in the entrainment of reproductive cycles to lunar light cycles in F. fragum. Our results suggest a molecular clock mechanism, potentially similar to that in described in fruit flies, exists within F. fragum.

  19. 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.

  20. A clock reaction based on molybdenum blue.

    Science.gov (United States)

    Neuenschwander, Ulrich; Negron, Arnaldo; Jensen, Klavs F

    2013-05-30

    Clock reactions are rare kinetic phenomena, so far limited mostly to systems with ionic oxoacids and oxoanions in water. We report a new clock reaction in cyclohexanol that forms molybdenum blue from a noncharged, yellow molybdenum complex as precursor, in the presence of hydrogen peroxide. Interestingly, the concomitant color change is reversible, enabling multiple clock cycles to be executed consecutively. The kinetics of the clock reaction were experimentally characterized, and by adding insights from quantum chemical calculations, a plausible reaction mechanism was postulated. Key elementary reaction steps comprise sigmatropic rearrangements with five-membered or bicyclo[3.1.0] transition states. Importantly, numerical kinetic modeling demonstrated the mechanism's ability to reproduce the experimental findings. It also revealed that clock behavior is intimately connected to the sudden exhaustion of hydrogen peroxide. Due to the stoichiometric coproduction of ketone, the reaction bears potential for application in alcohol oxidation catalysis.

  1. Bayesian Exploratory Factor Analysis

    DEFF Research Database (Denmark)

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corr......This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor......, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates...

  2. Fast Bayesian Non-Negative Matrix Factorisation and Tri-Factorisation

    DEFF Research Database (Denmark)

    Brouwer, Thomas; Frellsen, Jes; Liò, Pietro

    We present a fast variational Bayesian algorithm for performing non-negative matrix factorisation and tri-factorisation. We show that our approach achieves faster convergence per iteration and timestep (wall-clock) than Gibbs sampling and non-probabilistic approaches, and do not require additional...... samples to estimate the posterior. We show that in particular for matrix tri-factorisation convergence is difficult, but our variational Bayesian approach offers a fast solution, allowing the tri-factorisation approach to be used more effectively....

  3. Bayesian Decision Support

    Science.gov (United States)

    Berliner, M.

    2017-12-01

    Bayesian statistical decision theory offers a natural framework for decision-policy making in the presence of uncertainty. Key advantages of the approach include efficient incorporation of information and observations. However, in complicated settings it is very difficult, perhaps essentially impossible, to formalize the mathematical inputs needed in the approach. Nevertheless, using the approach as a template is useful for decision support; that is, organizing and communicating our analyses. Bayesian hierarchical modeling is valuable in quantifying and managing uncertainty such cases. I review some aspects of the idea emphasizing statistical model development and use in the context of sea-level rise.

  4. Bayesian Exploratory Factor Analysis

    Science.gov (United States)

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.; Piatek, Rémi

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  5. Induction of the CLOCK Gene by E2-ERα Signaling Promotes the Proliferation of Breast Cancer Cells

    Science.gov (United States)

    Bi, Hailian; Li, Shujing; Wang, Miao; Xing, Xinrong; Wu, Huijian

    2014-01-01

    Growing genetic and epidemiological evidence suggests a direct connection between the disruption of circadian rhythm and breast cancer. Moreover, the expression of several molecular components constituting the circadian clock machinery has been found to be modulated by estrogen-estrogen receptor α (E2-ERα) signaling in ERα-positive breast cancer cells. In this study, we investigated the regulation of CLOCK expression by ERα and its roles in cell proliferation. Immunohistochemical analysis of human breast tumor samples revealed high expression of CLOCK in ERα-positive breast tumor samples. Subsequent experiments using ERα-positive human breast cancer cell lines showed that both protein and mRNA levels of CLOCK were up-regulated by E2 and ERα. In these cells, E2 promoted the binding of ERα to the EREs (estrogen-response elements) of CLOCK promoter, thereby up-regulating the transcription of CLOCK. Knockdown of CLOCK attenuated cell proliferation in ERα-positive breast cancer cells. Taken together, these results demonstrated that CLOCK could be an important gene that mediates cell proliferation in breast cancer cells. PMID:24789043

  6. Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA processing granule of male germ cells.

    Directory of Open Access Journals (Sweden)

    Rita L Peruquetti

    Full Text Available Spermatogenesis is a complex differentiation process that involves genetic and epigenetic regulation, sophisticated hormonal control, and extensive structural changes in male germ cells. RNA nuclear and cytoplasmic bodies appear to be critical for the progress of spermatogenesis. The chromatoid body (CB is a cytoplasmic organelle playing an important role in RNA post-transcriptional and translation regulation during the late steps of germ cell differentiation. The CB is also important for fertility determination since mutations of genes encoding its components cause infertility by spermatogenesis arrest. Targeted ablation of the Bmal1 and Clock genes, which encode central regulators of the circadian clock also result in fertility defects caused by problems other than spermatogenesis alterations. We show that the circadian proteins CLOCK and BMAL1 are localized in the CB in a stage-specific manner of germ cells. Both BMAL1 and CLOCK proteins physically interact with the ATP-dependent DEAD-box RNA helicase MVH (mouse VASA homolog, a hallmark component of the CB. BMAL1 is differentially expressed during the spermatogenic cycle of seminiferous tubules, and Bmal1 and Clock deficient mice display significant CB morphological alterations due to BMAL1 ablation or low expression. These findings suggest that both BMAL1 and CLOCK contribute to CB assembly and physiology, raising questions on the role of the circadian clock in reproduction and on the molecular function that CLOCK and BMAL1 could potentially have in the CB assembly and physiology.

  7. Circadian proteins CLOCK and BMAL1 in the chromatoid body, a RNA processing granule of male germ cells.

    Science.gov (United States)

    Peruquetti, Rita L; de Mateo, Sara; Sassone-Corsi, Paolo

    2012-01-01

    Spermatogenesis is a complex differentiation process that involves genetic and epigenetic regulation, sophisticated hormonal control, and extensive structural changes in male germ cells. RNA nuclear and cytoplasmic bodies appear to be critical for the progress of spermatogenesis. The chromatoid body (CB) is a cytoplasmic organelle playing an important role in RNA post-transcriptional and translation regulation during the late steps of germ cell differentiation. The CB is also important for fertility determination since mutations of genes encoding its components cause infertility by spermatogenesis arrest. Targeted ablation of the Bmal1 and Clock genes, which encode central regulators of the circadian clock also result in fertility defects caused by problems other than spermatogenesis alterations. We show that the circadian proteins CLOCK and BMAL1 are localized in the CB in a stage-specific manner of germ cells. Both BMAL1 and CLOCK proteins physically interact with the ATP-dependent DEAD-box RNA helicase MVH (mouse VASA homolog), a hallmark component of the CB. BMAL1 is differentially expressed during the spermatogenic cycle of seminiferous tubules, and Bmal1 and Clock deficient mice display significant CB morphological alterations due to BMAL1 ablation or low expression. These findings suggest that both BMAL1 and CLOCK contribute to CB assembly and physiology, raising questions on the role of the circadian clock in reproduction and on the molecular function that CLOCK and BMAL1 could potentially have in the CB assembly and physiology.

  8. Causes and consequences of hyperexcitation in central clock neurons.

    Directory of Open Access Journals (Sweden)

    Casey O Diekman

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

  9. The Importance of the Circadian Clock in Regulating Plant Metabolism

    Directory of Open Access Journals (Sweden)

    Jin A Kim

    2017-12-01

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

  10. Temporal Regulation of Cytokines by the Circadian Clock

    Directory of Open Access Journals (Sweden)

    Atsuhito Nakao

    2014-01-01

    Full Text Available Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines.

  11. Bayesian historical earthquake relocation: an example from the 1909 Taipei earthquake

    Science.gov (United States)

    Minson, Sarah E.; Lee, William H. K.

    2014-09-01

    Locating earthquakes from the beginning of the modern instrumental period is complicated by the fact that there are few good-quality seismograms and what traveltimes do exist may be corrupted by both large phase-pick errors and clock errors. Here, we outline a Bayesian approach to simultaneous inference of not only the hypocentre location but also the clock errors at each station and the origin time of the earthquake. This methodology improves the solution for the source location and also provides an uncertainty analysis on all of the parameters included in the inversion. As an example, we applied this Bayesian approach to the well-studied 1909 Mw 7 Taipei earthquake. While our epicentre location and origin time for the 1909 Taipei earthquake are consistent with earlier studies, our focal depth is significantly shallower suggesting a higher seismic hazard to the populous Taipei metropolitan area than previously supposed.

  12. Bayesian historical earthquake relocation: an example from the 1909 Taipei earthquake

    Science.gov (United States)

    Minson, Sarah E.; Lee, William H.K.

    2014-01-01

    Locating earthquakes from the beginning of the modern instrumental period is complicated by the fact that there are few good-quality seismograms and what traveltimes do exist may be corrupted by both large phase-pick errors and clock errors. Here, we outline a Bayesian approach to simultaneous inference of not only the hypocentre location but also the clock errors at each station and the origin time of the earthquake. This methodology improves the solution for the source location and also provides an uncertainty analysis on all of the parameters included in the inversion. As an example, we applied this Bayesian approach to the well-studied 1909 Mw 7 Taipei earthquake. While our epicentre location and origin time for the 1909 Taipei earthquake are consistent with earlier studies, our focal depth is significantly shallower suggesting a higher seismic hazard to the populous Taipei metropolitan area than previously supposed.

  13. Evolution of the CLOCK and BMAL1 genes in a subterranean rodent species (Lasiopodomys mandarinus).

    Science.gov (United States)

    Sun, Hong; Zhang, Yifeng; Shi, Yuhua; Li, Yangwei; Li, Wei; Wang, Zhenlong

    2018-04-01

    Lasiopodomys mandarinus, a subterranean rodent, spends its entire life underground. To test whether the CLOCK and BMAL1 genes of L. mandarinus have undergone adaptive evolution to underground darkness, we cloned and analyzed their complete cDNA sequences, using Lasiopodomys brandtii as a control. The phylogenetic trees of the CLOCK and BMAL1 genes were similar to the trees of the conserved Cyt b gene,further, L. mandarinus clustered with L. brandtii and Microtus ochrogaster in the phylogenetic tree. The Q-rich region of the CLOCK gene in L. mandarinus was different from that of other subterranean rodents. Using phylogenetic analysis maximum likelihood (PAML), the ω value (ωCLOCK gene, most of which were located in the trans-transcription activation domain (TAD). In conclusion, CLOCK and BMAL1 genes did not exhibit convergent molecular evolution in subterranean rodents. Moreover, our study highlights the important functionality of the TAD, which is putatively of functional relevance to CLOCK protein activity. The present findings provide novel insights into adaptation to underground darkness, at the gene level, in subterranean rodents. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Central and peripheral circadian clocks and their role in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ruchi Chauhan

    2017-10-01

    Full Text Available Molecular and cellular oscillations constitute an internal clock that tracks the time of day and permits organisms to optimize their behaviour and metabolism to suit the daily demands they face. The workings of this internal clock become impaired with age. In this review, we discuss whether such age-related impairments in the circadian clock interact with age-related neurodegenerative disorders, such as Alzheimer's disease. Findings from mouse and fly models of Alzheimer's disease have accelerated our understanding of the interaction between neurodegeneration and circadian biology. These models show that neurodegeneration likely impairs circadian rhythms either by damaging the central clock or by blocking its communication with other brain areas and with peripheral tissues. The consequent sleep and metabolic deficits could enhance the susceptibility of the brain to further degenerative processes. Thus, circadian dysfunction might be both a cause and an effect of neurodegeneration. We also discuss the primary role of light in the entrainment of the central clock and describe important, alternative time signals, such as food, that play a role in entraining central and peripheral circadian clocks. Finally, we propose how these recent insights could inform efforts to develop novel therapeutic approaches to re-entrain arrhythmic individuals with neurodegenerative disease.

  15. Biological clocks and rhythms in intertidal crustaceans.

    Science.gov (United States)

    de la Iglesia, Horacio O; Hsu, Yun-Wei A

    2010-06-01

    Animals with habitats within the intertidal zone are exposed to environmental cycles that include the ebb and flow of tidal waters, changes in tidal levels associated with the lunar month, the light-dark cycle and the alternation of seasons. This intricate temporal environment results in the selection of biological timing systems with endogenous clocks that can oscillate with this wide range of periodicities. Whereas great progress has been made in our understanding of the molecular and neural bases of circadian rhythms, that is, endogenous rhythms synchronized to the solar day, there is little understanding on how circatidal rhythms, namely endogenous rhythms synchronized to tides, are generated. Intertidal crustaceans have been a pivotal group for the demonstration of the endogenous nature of circatidal rhythms and their mechanisms of entrainment. We review here some of the classic work using intertidal crustaceans to unmask basic properties of circatidal systems, as well as work from our laboratory that aims to identify putative chemical signals that could be involved in the circatidal systems of decapod crustaceans.

  16. Maternal feeding controls fetal biological clock.

    Directory of Open Access Journals (Sweden)

    Hidenobu Ohta

    Full Text Available BACKGROUND: It is widely accepted that circadian physiological rhythms of the fetus are affected by oscillators in the maternal brain that are coupled to the environmental light-dark (LD cycle. METHODOLOGY/PRINCIPAL FINDINGS: To study the link between fetal and maternal biological clocks, we investigated the effects of cycles of maternal food availability on the rhythms of Per1 gene expression in the fetal suprachiasmatic nucleus (SCN and liver using a transgenic rat model whose tissues express luciferase in vitro. Although the maternal SCN remained phase-locked to the LD cycle, maternal restricted feeding phase-advanced the fetal SCN and liver by 5 and 7 hours respectively within the 22-day pregnancy. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that maternal feeding entrains the fetal SCN and liver independently of both the maternal SCN and the LD cycle. This indicates that maternal-feeding signals can be more influential for the fetal SCN and particular organ oscillators than hormonal signals controlled by the maternal SCN, suggesting the importance of a regular maternal feeding schedule for appropriate fetal molecular clockwork during pregnancy.

  17. The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

    Science.gov (United States)

    Zhang, Yuxiang; Papazyan, Romeo; Damle, Manashree; Fang, Bin; Jager, Jennifer; Feng, Dan; Peed, Lindsey C.; Guan, Dongyin; Sun, Zheng; Lazar, Mitchell A.

    2017-01-01

    Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders. PMID:28747429

  18. Clockwork orange encodes a transcriptional repressor important for circadian-clock amplitude in Drosophila.

    Science.gov (United States)

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

    2007-06-19

    Gene transcription is a central timekeeping process in animal clocks. In Drosophila, the basic helix-loop helix (bHLH)-PAS transcription-factor heterodimer, CLOCK/CYCLE (CLK/CYC), transcriptionally activates the clock components period (per), timeless (tim), Par domain protein 1 (Pdp1), and vrille (vri), which feed back and regulate distinct features of CLK/CYC function. Microarray studies have identified numerous rhythmically expressed transcripts, some of which are potential direct CLK targets. Here we demonstrate a circadian function for one such target, a bHLH-Orange repressor, CG17100/CLOCKWORK ORANGE (CWO). cwo is rhythmically expressed, and levels are reduced in Clk mutants, suggesting that cwo is CLK activated in vivo. cwo mutants display reduced-amplitude molecular and behavioral rhythms with lengthened periods. Molecular analysis suggests that CWO acts, in part, by repressing CLK target genes. We propose that CWO acts as a transcriptional and behavioral rhythm amplifier.

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

    Science.gov (United States)

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

    2007-01-01

    Summary Gene transcription is a central timekeeping process in animal clocks. In Drosophila, the basic helix-loop helix (bHLH)-PAS transcription factor heterodimer, CLOCK (CLK)/CYCLE(CYC) transcriptionally activates the clock components period (per), timeless (tim), Par domain protein 1 (Pdp1), and vrille (vri) that feedback and regulate distinct features of CLK/CYC function [1]. Microarray studies have identified numerous rhythmically expressed transcripts [2-7], some of which are potential direct CLK targets [7]. Here we demonstrate a circadian function for one such target, a bHLH-Orange repressor CG17100/CLOCKWORK ORANGE (CWO). cwo is rhythmically expressed and levels are reduced in Clk mutants, suggesting that cwo is CLK-activated in vivo. cwo mutants display reduced amplitude molecular and behavioral rhythms with lengthened periods. Molecular analysis suggests CWO acts, in part, by repressing CLK target genes. We propose that CWO acts as a transcriptional and behavioral rhythm amplifier. PMID:17555964

  20. Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock

    Science.gov (United States)

    Dang, Fabin; Sun, Xiujie; Ma, Xiang; Wu, Rong; Zhang, Deyi; Chen, Yaqiong; Xu, Qian; Wu, Yuting; Liu, Yi

    2016-01-01

    Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms. PMID:27576939

  1. Circadian-clock system in mouse liver affected by insulin resistance.

    Science.gov (United States)

    Yang, Shu-Chuan; Tseng, Huey-Lin; Shieh, Kun-Ruey

    2013-07-01

    Circadian rhythms are exhibited in the physiological and behavioral processes of all mammals; they are generated by intracellular levels of circadian oscillators, which are named as a set of circadian-clock genes. These genes compose the transcriptional/translational feedback loops to regulate not only circadian rhythmicity, but also energy metabolism. Previous studies have shown that obesity and diabetes cause the dysregulation of the circadian-clock system, and vice versa. However, some diabetes subjects are lean with insulin resistance and the mechanisms of insulin resistance without obesity are much less well known. Therefore, whether insulin resistance alone is enough to influence the expression of circadian-clock genes is uncertain. This study employs a neonatal streptozotocin (STZ)-treated paradigm in mice to model the molecular and physiological progress of nonobese insulin resistance. A single injection of STZ into 2-d-old male C57BL/6 mice induces nonobese, hyperglycemic and hyperinsulinemic conditions, and the levels of gene expression in the liver by a real-time quantitative polymerase chain reaction are then measured. Although the levels of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2), and Cry1 (cryptochrome 1) mRNA expression in the liver change during the progress of insulin resistance conditions, the gene expression patterns still show circadian rhythmicity. This study suggests that changes in the hepatic circadian-clock gene expression mark an early event in the metabolic disruption associated with insulin resistance. Furthermore, 2 wks of treatment with the thiazolidinedione, pioglitazone, fully resolve the dysfunction in metabolic parameters and the changes in circadian-clock gene expression from early insulin resistance conditions. These results indicate that the circadian-clock system is sensitive to insulin resistance, and that treatment with thiazolidinediones can resolve changes in the circadian-clock system in a timely

  2. Diurnal rhythmicity of the canonical clock genes Per1, per2 and Bmal1 in the rat adrenal gland is unaltered after hypophysectomy

    DEFF Research Database (Denmark)

    Fahrenkrug, J.; Hannibal, J.; Georg, B.

    2008-01-01

    Circadian rhythms are generated by endogenous clocks in the central brain oscillator, the suprachiasmatic nucleus (SCN), and peripheral tissues. The molecular basis for the circadian clock consists of a number of genes and proteins that form transcriptional/translational feedback loops. Rhythmic...... expression of clock genes in the adrenal glands has previously been reported. Since the central clock in the SCN communicates with the adrenal glands via circadian release of adrenocorticotrophic hormone, we quantified the mRNAs for the canonical clock genes, Per1, Per2 and Bmal1 in the adrenal glands...... by real-time reverse transcription-polymerase chain reaction during a 24-h-cycle in normal and hypophysectomised rats. The mRNAs for all the three clock genes disclosed rhythmic oscillations with a period of 24 h and the phase did not differ between the hypophysectomised and intact rats. The expression...

  3. Bayesian methods for hackers probabilistic programming and Bayesian inference

    CERN Document Server

    Davidson-Pilon, Cameron

    2016-01-01

    Bayesian methods of inference are deeply natural and extremely powerful. However, most discussions of Bayesian inference rely on intensely complex mathematical analyses and artificial examples, making it inaccessible to anyone without a strong mathematical background. Now, though, Cameron Davidson-Pilon introduces Bayesian inference from a computational perspective, bridging theory to practice–freeing you to get results using computing power. Bayesian Methods for Hackers illuminates Bayesian inference through probabilistic programming with the powerful PyMC language and the closely related Python tools NumPy, SciPy, and Matplotlib. Using this approach, you can reach effective solutions in small increments, without extensive mathematical intervention. Davidson-Pilon begins by introducing the concepts underlying Bayesian inference, comparing it with other techniques and guiding you through building and training your first Bayesian model. Next, he introduces PyMC through a series of detailed examples a...

  4. Bayesian logistic regression analysis

    NARCIS (Netherlands)

    Van Erp, H.R.N.; Van Gelder, P.H.A.J.M.

    2012-01-01

    In this paper we present a Bayesian logistic regression analysis. It is found that if one wishes to derive the posterior distribution of the probability of some event, then, together with the traditional Bayes Theorem and the integrating out of nuissance parameters, the Jacobian transformation is an

  5. Bayesian statistical inference

    Directory of Open Access Journals (Sweden)

    Bruno De Finetti

    2017-04-01

    Full Text Available This work was translated into English and published in the volume: Bruno De Finetti, Induction and Probability, Biblioteca di Statistica, eds. P. Monari, D. Cocchi, Clueb, Bologna, 1993.Bayesian statistical Inference is one of the last fundamental philosophical papers in which we can find the essential De Finetti's approach to the statistical inference.

  6. The endogenous circadian clock programs animals to eat at certain times of the 24-hour day: What if we ignore the clock?

    Science.gov (United States)

    Jiang, Peng; Turek, Fred W

    2018-04-16

    The discovery of the molecular mechanisms underlying the circadian clock, which functions in virtually every cell throughout the body to coordinate biological processes to anticipate and better adapt to daily rhythmic changes in the environment, is one of the major biomedical breakthroughs in the 20th century. Twenty years after this breakthrough, the biomedical community is now at a new frontier to incorporate the circadian clock mechanisms into many areas of biomedical research, as studies continue to reveal an important role of the circadian clock in a wide range of biological functions and diseases. A forefront of this exciting area is the research of interactions between the clock and energy metabolism. In this review, we summarize animal and human studies linking disruptions of the circadian clock, either environmental or genetic, to metabolic dysfunctions associated with obesity, diabetes, and other metabolic disorders. We also discuss how these advances in circadian biology may pave the way to revolutionize clinical practice in the era of precision medicine. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Clock genes alterations and endocrine disorders.

    Science.gov (United States)

    Angelousi, Anna; Kassi, Eva; Nasiri-Ansari, Narjes; Weickert, Martin O; Randeva, Harpal; Kaltsas, Gregory

    2018-03-25

    Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. Various human single nucleotide polymorphisms of BMAL1 and CLOCK genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue specific way whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK, and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscilliations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2 as well as between prolactin and CLOCK was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility whereas estradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. Clock genes are associated with various endocrine disorders through complex mechanisms. However data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. Control of daily transcript oscillations in Drosophila by light and the circadian clock.

    Directory of Open Access Journals (Sweden)

    Herman Wijnen

    2006-03-01

    Full Text Available The transcriptional circuits of circadian clocks control physiological and behavioral rhythms. Light may affect such overt rhythms in two ways: (1 by entraining the clock circuits and (2 via clock-independent molecular pathways. In this study we examine the relationship between autonomous transcript oscillations and light-driven transcript responses. Transcript profiles of wild-type and arrhythmic mutant Drosophila were recorded both in the presence of an environmental photocycle and in constant darkness. Systematic autonomous oscillations in the 12- to 48-h period range were detectable only in wild-type flies and occurred preferentially at the circadian period length. However, an extensive program of light-driven expression was confirmed in arrhythmic mutant flies. Many light-responsive transcripts are preferentially expressed in the compound eyes and the phospholipase C component of phototransduction, NORPA (no receptor potential, is required for their light-dependent regulation. Although there is evidence for the existence of multiple molecular clock circuits in cyanobacteria, protists, plants, and fungi, Drosophila appears to possess only one such system. The sustained photic expression responses identified here are partially coupled to the circadian clock and may reflect a mechanism for flies to modulate functions such as visual sensitivity and synaptic transmission in response to seasonal changes in photoperiod.

  9. 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.

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

    Science.gov (United States)

    Fathallah-Shaykh, Hassan M

    2010-10-13

    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. 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. 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. Bayesian optimization for materials science

    CERN Document Server

    Packwood, Daniel

    2017-01-01

    This book provides a short and concise introduction to Bayesian optimization specifically for experimental and computational materials scientists. After explaining the basic idea behind Bayesian optimization and some applications to materials science in Chapter 1, the mathematical theory of Bayesian optimization is outlined in Chapter 2. Finally, Chapter 3 discusses an application of Bayesian optimization to a complicated structure optimization problem in computational surface science. Bayesian optimization is a promising global optimization technique that originates in the field of machine learning and is starting to gain attention in materials science. For the purpose of materials design, Bayesian optimization can be used to predict new materials with novel properties without extensive screening of candidate materials. For the purpose of computational materials science, Bayesian optimization can be incorporated into first-principles calculations to perform efficient, global structure optimizations. While re...

  12. 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

  13. The circadian clock in cancer development and therapy

    Science.gov (United States)

    Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The...

  14. Regulation of circadian clock transcriptional output by CLOCK:BMAL1.

    Science.gov (United States)

    Trott, Alexandra J; Menet, Jerome S

    2018-01-01

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

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

    Science.gov (United States)

    Chen, Peii; Goedert, Kelly M.

    2012-01-01

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

  16. Small heterodimer partner (NROB2) coordinates nutrient signaling and the circadian clock in mice

    Science.gov (United States)

    Circadian rhythm regulates multiple metabolic processes and in turn is readily entrained by feeding-fasting cycles. However, the molecular mechanisms by which the peripheral clock senses nutrition availability remain largely unknown. Bile acids are under circadian control and also increase postprand...

  17. Insulin-FOXO3 signaling modulates circadian rhythms via regulation of clock transcription

    NARCIS (Netherlands)

    Chaves, I.; van der Horst, G.T.J.; Schellevis, R.; Nijman, R.M.; Groot Koerkamp, M.; Holstege, F.C.P.; Smidt, M.P.; Hoekman, M.F.M.

    2014-01-01

    Circadian rhythms are responsive to external and internal cues, light and metabolism being among the most important. In mammals, the light signal is sensed by the retina and transmitted to the suprachiasmatic nucleus (SCN) master clock [1], where it is integrated into the molecular oscillator via

  18. Genetic Disruption of the Core Circadian Clock Impairs Hippocampus-Dependent Memory

    Science.gov (United States)

    Wardlaw, Sarah M.; Phan, Trongha X.; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R.

    2014-01-01

    Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1[superscript -/-] mice, which are arrhythmic…

  19. Gremlin-2 is a BMP antagonist that is regulated by the circadian clock

    DEFF Research Database (Denmark)

    Yeung, Ching-Yan Chloé; Gossan, Nicole; Lu, Yinhui

    2014-01-01

    knowledge of tendon gene regulation is essential for a complete understanding of FCT biology. Here we show autonomous circadian rhythms in mouse tendon and primary human tenocytes, controlled by an intrinsic molecular circadian clock. Time-series microarrays identified the first circadian transcriptome...

  20. Selective Inhibition of Casein Kinase 1 epsilon Minimally Alters Circadian Clock Period

    Czech Academy of Sciences Publication Activity Database

    Walton, K. M.; Fisher, K.; Rubitski, D.; Marconi, M.; Meng, Q.-J.; Sládek, Martin; Adams, J.; Bass, M.; Chandrasekaran, R.; Butler, T.; Griffor, M.; Rajamohan, F.; Serpa, M.; Chen, Y.; Claffey, M.; Hastings, M.; Loudon, A.; Maywood, E.; Ohren, J.; Doran, A.; Wager, T. T.

    2009-01-01

    Roč. 330, č. 2 (2009), s. 430-439 ISSN 0022-3565 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * casein kinase 1 epsilon * inhibitor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.093, year: 2009

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    WANG Fuhong

    2016-12-01

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

  3. The Chemical and Educational Appeal of the Orange Juice Clock

    Science.gov (United States)

    Kelter, Paul B.; Carr, James D.; Johnson, Tanya; Mauricio Castro-Acuña, Carlos

    1996-12-01

    editted by Jerry Jacobson at the University of Wisconsin - Madison. The Chemistry Basics When we ask students or precollege teacher groups about the reduction and oxidation reactions that are occurring, they invariably answer that the magnesium metal is being oxidized and the copper metal is being reduced. This response is important because we use it to impress upon students and workshop participants the importance of looking carefully at the system before giving what might seem like an obvious answer. The copper cannot be reduced because there is no copper ion in solution, and transition metals cannot be reduced to anions. Given what is actually in solution, participants can conclude that hydrogen ion can be reduced to molecular hydrogen (in orange juice) or that hydrogen in the water molecule is being reduced to molecular hydrogen (in hard tap water). In distilled water, the clock does not run because the internal resistance of the solution is too high, thus forcing the current to be very small. The reactions of interest are given as eqs 1-3: oxidation: Mg -> Mg2+ + 2e- Eo = 2.37 vs. SHE (1) reduction 2H+ + 2e- -> H2 Eo = 0.00 vs. SHE (2) (acid solution) reduction (water) 2H2O + 2e- -> H2 + 2OH- Eo = -0.8277 vs. SHE (3) where Eo = the voltage under standard conditions and SHE = standard hydrogen electrode. At standard conditions, under zero load (all activities equal to one and 298 K) the cell voltage should theoretically be 2.37 V in acid (pH = 1) and about 1.54 V in neutral solution, either of which is enough to allow the clock to run. It is important to remember the IUPAC convention for electrochemical cells: that voltage of the cell equals voltage of the cathodic half-cell minus voltage of the anodic half-cell. In this case, Eo = 0.00 V - (-2.37 V) = 2.37 V The standard free energy calculation is straightforward in each case (eq 4), DeltaGo = -nFEo in which n = number of moles of electrons transferred, as dictated by the stoichiometry of the reaction (in all

  4. Cellular Reprogramming–Turning the Clock Back

    Indian Academy of Sciences (India)

    Cellular Reprogramming - Turning the Clock Back - Nobel Prize in Physiology or Medicine, 2012. Deepa Subramanyam ... Keywords. Embryonic stem cells; pluripotency; reprogramming; differentiation; Nobel Prize 2012. ... National Centre for Cell Science University of Pune Campus Ganeshkhind Pune 411 007, India.

  5. Crime clocks and target performance maps

    CSIR Research Space (South Africa)

    Cooper, Antony K

    1999-12-01

    Full Text Available for the prevention and management of crime. This paper describes two innovative techniques that were developed by CSIR for analysing crime: "crime clocks" and "target performance maps"....

  6. Entrainment of the Neurospora circadian clock

    NARCIS (Netherlands)

    Merrow, M; Boesl, C; Ricken, J; Messerschmitt, M; Goedel, M; Roenneberg, T

    2006-01-01

    Neurospora crassa has been systematically investigated for circadian entrainment behavior. Many aspects of synchronization can be investigated in this simple, cellular system, ranging from systematic entrainment and drivenness to masking. Clock gene expression during entrainment and entrainment

  7. CDDIS_GNSS_products_clocks_rapid

    Data.gov (United States)

    National Aeronautics and Space Administration — Satellite and receiver clock products derived from analysis of Global Navigation Satellite System (GNSS) data. These products are the generated by analysis centers...

  8. Targeting the Circadian Clock to Treat Cancer

    Science.gov (United States)

    Two compounds that target components of the circadian clock killed several types of cancer cells in the lab and slowed the growth of brain cancer in mice without harming healthy cells, as this Cancer Currents post reports.

  9. CDDIS_GNSS_products_clocks_final

    Data.gov (United States)

    National Aeronautics and Space Administration — Satellite and receiver clock products derived from analysis of Global Navigation Satellite System (GNSS) data. These products are the generated by analysis centers...

  10. Clock jitter generator with picoseconds resolution

    Science.gov (United States)

    Jovanović, Goran; Stojčev, Mile; Nikolić, Tatjana

    2013-06-01

    The clock is one of the most critical signals in any synchronous system. As CMOS technology has scaled, supply voltages have dropped chip power consumption has increased and the effects of jitter due to clock frequency increase have become critical and jitter budget has become tighter. This article describes design and development of low-cost mixed-signal programmable jitter generator with high resolution. The digital technique is used for coarse-grain and an analogue technique for fine-grain clock phase shifting. Its structure allows injection of various random and deterministic jitter components in a controllable and programmable fashion. Each jitter component can be switched on or off. The jitter generator can be used in jitter tolerance test and jitter transfer function measurement of high-speed synchronous digital circuits. At operating system clock frequency of 220 MHz, a jitter with 4 ps resolution can be injected.

  11. 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...

  12. 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.

  13. 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.

  14. Cell-permeable Circadian Clock Proteins

    National Research Council Canada - National Science Library

    Johnson, Carl

    2002-01-01

    .... These 'biological clocks' are important to human physiology. For example, psychiatric and medical studies have shown that circadian rhythmicity is involved in some forms of depressive illness, 'jet lag', drug tolerance/efficacy, memory, and insomnia...

  15. Cellular Reprogramming–Turning the Clock Back

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 6. Cellular Reprogramming - Turning the Clock Back - Nobel Prize in Physiology or Medicine, 2012. Deepa Subramanyam. General Article Volume 18 Issue 6 June 2013 pp 514-521 ...

  16. CDDIS_GNSS_products_clocks_realtime

    Data.gov (United States)

    National Aeronautics and Space Administration — Satellite and receiver clock products derived from analysis of Global Navigation Satellite System (GNSS) data. These products are the generated by analysis centers...

  17. 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.

  18. Direct Laser Cooling Al{}^{+} Ion Optical Clocks

    Science.gov (United States)

    Zhang, Jie; Deng, Ke; Luo, Jun; Lu, Ze-Huang

    2017-05-01

    The Al{}+ ion optical clock is a very promising optical frequency standard candidate due to its extremely small black-body radiation shift. It has been successfully demonstrated with the 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{}+ ion optical clocks where both the stability and accuracy of the clocks are greatly improved. In the proposed scheme, two Al{}+ 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{}+ ion 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× {10}-17/\\sqrt{τ }. For the second trap, in addition to 167 nm laser Doppler cooling, a second stage pulsed 234 nm two-photon cooling laser is utilized to further improve the accuracy of the clock laser. The total systematic uncertainty can be reduced to about 1× {10}-18. The proposed Al{}+ ion optical clock has the potential to become the most accurate and stable optical clock. Supported by the National Basic Research Program of China under Grant No 2012CB821300, the National Natural Science Foundation of China under Grant Nos 91336213, 11304109, 91536116 and 11174095, and the Program for New Century Excellent Talents by the Ministry of Education under Grant No NCET-11-0176.

  19. Dynamic Power Reduction of Digital Circuits by ClockGating

    OpenAIRE

    Varsha Dewre; Rakesh Mandliya

    2017-01-01

    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, ther...

  20. The hepatic circadian clock modulates xenobiotic metabolism in mice

    OpenAIRE

    DeBruyne, Jason P; Weaver, David R; Dallmann, Robert

    2014-01-01

    The circadian clock generates daily cycles of gene expression that regulate physiological processes. The liver plays an important role in xenobiotic metabolism, and also has been shown to possess its own cell-based clock. The liver clock is synchronized by the master clock in the brain, and a portion of rhythmic gene expression can be driven by behavior of the organism as a whole even when the hepatic clock is suppressed. So far, however, there is relatively little evidence indicating whether...

  1. Optical atomic clocks with suppressed black body radiation shift

    OpenAIRE

    Kozlov, Alexander; Dzuba, Vladimir; Flambaum, Victor

    2014-01-01

    We study a wide range of neutral atoms and ions suitable for ultra-precise atomic optical clocks with naturally suppressed black body radiation shift of clock transition frequency. Calculations show that scalar polarizabilities of clock states cancel each other for at least one order of magnitude for considered systems. Results for calculations of frequencies, quadrupole moments of the states, clock transition amplitudes and natural widths of upper clock states are presented.

  2. Bayesian Independent Component Analysis

    DEFF Research Database (Denmark)

    Winther, Ole; Petersen, Kaare Brandt

    2007-01-01

    In this paper we present an empirical Bayesian framework for independent component analysis. The framework provides estimates of the sources, the mixing matrix and the noise parameters, and is flexible with respect to choice of source prior and the number of sources and sensors. Inside the engine...... in a Matlab toolbox, is demonstrated for non-negative decompositions and compared with non-negative matrix factorization.......In this paper we present an empirical Bayesian framework for independent component analysis. The framework provides estimates of the sources, the mixing matrix and the noise parameters, and is flexible with respect to choice of source prior and the number of sources and sensors. Inside the engine...

  3. Bayesian coronal seismology

    Science.gov (United States)

    Arregui, Iñigo

    2018-01-01

    In contrast to the situation in a laboratory, the study of the solar atmosphere has to be pursued without direct access to the physical conditions of interest. Information is therefore incomplete and uncertain and inference methods need to be employed to diagnose the physical conditions and processes. One of such methods, solar atmospheric seismology, makes use of observed and theoretically predicted properties of waves to infer plasma and magnetic field properties. A recent development in solar atmospheric seismology consists in the use of inversion and model comparison methods based on Bayesian analysis. In this paper, the philosophy and methodology of Bayesian analysis are first explained. Then, we provide an account of what has been achieved so far from the application of these techniques to solar atmospheric seismology and a prospect of possible future extensions.

  4. Bayesian community detection.

    Science.gov (United States)

    Mørup, Morten; Schmidt, Mikkel N

    2012-09-01

    Many networks of scientific interest naturally decompose into clusters or communities with comparatively fewer external than internal links; however, current Bayesian models of network communities do not exert this intuitive notion of communities. We formulate a nonparametric Bayesian model for community detection consistent with an intuitive definition of communities and present a Markov chain Monte Carlo procedure for inferring the community structure. A Matlab toolbox with the proposed inference procedure is available for download. On synthetic and real networks, our model detects communities consistent with ground truth, and on real networks, it outperforms existing approaches in predicting missing links. This suggests that community structure is an important structural property of networks that should be explicitly modeled.

  5. Probability and Bayesian statistics

    CERN Document Server

    1987-01-01

    This book contains selected and refereed contributions to the "Inter­ national Symposium on Probability and Bayesian Statistics" which was orga­ nized to celebrate the 80th birthday of Professor Bruno de Finetti at his birthplace Innsbruck in Austria. Since Professor de Finetti died in 1985 the symposium was dedicated to the memory of Bruno de Finetti and took place at Igls near Innsbruck from 23 to 26 September 1986. Some of the pa­ pers are published especially by the relationship to Bruno de Finetti's scientific work. The evolution of stochastics shows growing importance of probability as coherent assessment of numerical values as degrees of believe in certain events. This is the basis for Bayesian inference in the sense of modern statistics. The contributions in this volume cover a broad spectrum ranging from foundations of probability across psychological aspects of formulating sub­ jective probability statements, abstract measure theoretical considerations, contributions to theoretical statistics an...

  6. Hydrogen Maser Clock (HMC) Experiment

    Science.gov (United States)

    Vessot, Robert F. C.; Mattison, Edward M.

    1997-01-01

    The Hydrogen Maser Clock (HMC) project was originally conceived to fly on a reflight of the European Space Agency (ESA) free flying platform, the European Recoverable Carrier (EURECA) that had been launched into space and recovered by NASA's Space Transportation System (STS). A Phase B study for operation of HMC as one of the twelve EURECA payload components was begun in July 1991, and completed a year later. Phase C/D of HMC began in August 1992 and continued into early 1995. At that time ESA decided not to refly EURECA, leaving HMC without access to space. Approximately 80% of the flight support electronics are presently operating the HMC's physics package in a vacuum tank at the Smithsonian Astrophysical Observatory, and are now considered to be well-tested flight electronics. The package will continue to be operated until the end of 1997 or until a flight opportunity becomes avaiable. Appendices: letters and trip report; proceedings of the symposium on frequency standards and metrology; milli-celsius-stability thermal control for an orbiting frequency standard.

  7. Bayesian Hypothesis Testing

    Energy Technology Data Exchange (ETDEWEB)

    Andrews, Stephen A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Sigeti, David E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-11-15

    These are a set of slides about Bayesian hypothesis testing, where many hypotheses are tested. The conclusions are the following: The value of the Bayes factor obtained when using the median of the posterior marginal is almost the minimum value of the Bayes factor. The value of τ2 which minimizes the Bayes factor is a reasonable choice for this parameter. This allows a likelihood ratio to be computed with is the least favorable to H0.

  8. Bayesian networks in reliability

    Energy Technology Data Exchange (ETDEWEB)

    Langseth, Helge [Department of Mathematical Sciences, Norwegian University of Science and Technology, N-7491 Trondheim (Norway)]. E-mail: helgel@math.ntnu.no; Portinale, Luigi [Department of Computer Science, University of Eastern Piedmont ' Amedeo Avogadro' , 15100 Alessandria (Italy)]. E-mail: portinal@di.unipmn.it

    2007-01-15

    Over the last decade, Bayesian networks (BNs) have become a popular tool for modelling many kinds of statistical problems. We have also seen a growing interest for using BNs in the reliability analysis community. In this paper we will discuss the properties of the modelling framework that make BNs particularly well suited for reliability applications, and point to ongoing research that is relevant for practitioners in reliability.

  9. Subjective Bayesian Beliefs

    DEFF Research Database (Denmark)

    Antoniou, Constantinos; Harrison, Glenn W.; Lau, Morten I.

    2015-01-01

    A large literature suggests that many individuals do not apply Bayes’ Rule when making decisions that depend on them correctly pooling prior information and sample data. We replicate and extend a classic experimental study of Bayesian updating from psychology, employing the methods of experimental...... economics, with careful controls for the confounding effects of risk aversion. Our results show that risk aversion significantly alters inferences on deviations from Bayes’ Rule....

  10. Approximate Bayesian recursive estimation

    Czech Academy of Sciences Publication Activity Database

    Kárný, Miroslav

    2014-01-01

    Roč. 285, č. 1 (2014), s. 100-111 ISSN 0020-0255 R&D Projects: GA ČR GA13-13502S Institutional support: RVO:67985556 Keywords : Approximate parameter estimation * Bayesian recursive estimation * Kullback–Leibler divergence * Forgetting Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 4.038, year: 2014 http://library.utia.cas.cz/separaty/2014/AS/karny-0425539.pdf

  11. Bayesian theory and applications

    CERN Document Server

    Dellaportas, Petros; Polson, Nicholas G; Stephens, David A

    2013-01-01

    The development of hierarchical models and Markov chain Monte Carlo (MCMC) techniques forms one of the most profound advances in Bayesian analysis since the 1970s and provides the basis for advances in virtually all areas of applied and theoretical Bayesian statistics. This volume guides the reader along a statistical journey that begins with the basic structure of Bayesian theory, and then provides details on most of the past and present advances in this field. The book has a unique format. There is an explanatory chapter devoted to each conceptual advance followed by journal-style chapters that provide applications or further advances on the concept. Thus, the volume is both a textbook and a compendium of papers covering a vast range of topics. It is appropriate for a well-informed novice interested in understanding the basic approach, methods and recent applications. Because of its advanced chapters and recent work, it is also appropriate for a more mature reader interested in recent applications and devel...

  12. Timing Embryo Segmentation: Dynamics and Regulatory Mechanisms of the Vertebrate Segmentation Clock

    Directory of Open Access Journals (Sweden)

    Tatiana P. Resende

    2014-01-01

    Full Text Available All vertebrate species present a segmented body, easily observed in the vertebrate column and its associated components, which provides a high degree of motility to the adult body and efficient protection of the internal organs. The sequential formation of the segmented precursors of the vertebral column during embryonic development, the somites, is governed by an oscillating genetic network, the somitogenesis molecular clock. Herein, we provide an overview of the molecular clock operating during somite formation and its underlying molecular regulatory mechanisms. Human congenital vertebral malformations have been associated with perturbations in these oscillatory mechanisms. Thus, a better comprehension of the molecular mechanisms regulating somite formation is required in order to fully understand the origin of human skeletal malformations.

  13. SKIP Is a Component of the Spliceosome Linking Alternative Splicing and the Circadian Clock in Arabidopsis[W

    Science.gov (United States)

    Wang, Xiaoxue; Wu, Fangming; Xie, Qiguang; Wang, Huamei; Wang, Ying; Yue, Yanling; Gahura, Ondrej; Ma, Shuangshuang; Liu, Lei; Cao, Ying; Jiao, Yuling; Puta, Frantisek; McClung, C. Robertson; Xu, Xiaodong; Ma, Ligeng

    2012-01-01

    Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5′ and 3′ splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level. PMID:22942380

  14. Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK.

    Science.gov (United States)

    Lu, Yilu; Zheng, Xulei; Hu, Wei; Bian, Shasha; Zhang, Zhiwei; Tao, Dachang; Liu, Yunqiang; Ma, Yongxin

    2017-08-15

    Circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by appropriate functions of clock proteins. Rhythmic degradation of the circadian clock proteins is critical for maintenance of the circadian oscillations. Notably, circadian clock does not work during spermatogenesis and can be disrupted in tumors. However, the underlying mechanism that suppresses circadian rhythms in germ cells and cancer cells remains largely unknown. Here we report that the cancer/testis antigen PIWIL2 can repress circadian rhythms both in the testis and cancer cells. By facilitating SRC binding with PI3K, PIWIL2 activates the PI3K-AKT pathway to phosphorylate and deactivate GSK3β, suppressing GSK3β-induced phosphorylation and degradation of circadian protein BMAL1 and CLOCK. Meanwhile, PIWIL2 can bind with E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate the transcriptional activation activity of promoters of clock-controlled genes. Taken together, our results first described a function for the germline-specific protein PIWIL2 in regulation of the circadian clock, providing a molecular link between spermatogenesis as well as tumorigenesis to the dysfunction of circadian rhythms.

  15. The clock in the cell : Entrainment of the circadian clock in Neurospora crassa

    NARCIS (Netherlands)

    Madeti Jyothi-Boesl, Cornelia

    2008-01-01

    Since reports of daily leaf movements 2000 years ago, a so-called circadian clock (‘circa diem’ meaning ‘about a day’) has been described in organisms from almost all phyla. The work presented in this thesis gives special emphasis on the circadian clock in the fungus Neurospora crassa, a rather

  16. Genetics and Neurobiology of Circadian Clocks in Mammals

    Science.gov (United States)

    Park, Junghea; Lee, Choogon; Takahashi, Joseph S.

    2013-01-01

    In animals circadian behavior can be analyzed as an integrated system - beginning with genes leading ultimately to behavioral outputs. In the last decade, the molecular mechanism of circadian clocks has been unraveled primarily by the use of phenotype-driven (forward) genetic analysis in a number of model systems. Circadian oscillations are generated by a set of genes forming a transcriptional autoregulatory feedback loop. In mammals, there is a “core” set of circadian genes that form the primary negative feedback loop of the clock mechanism (Clock/Npas2, Bmal1, Per1, Per2, Cry1, Cry2 and CK1ε). Another dozen candidate genes have been identified and play additional roles in the circadian gene network such as the feedback loop involving Rev-erbα. Despite this remarkable progress, it is clear that a significant number of genes that strongly influence and regulate circadian rhythms in mammals remain to be discovered and identified. As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen using a wide range of nervous system and behavioral phenotypes, we have identified a number of new circadian mutants in mice. Here we describe a new short period circadian mutant, part-time (prtm), which is caused by a loss-of-function mutation in the Cryptochrome1 gene. We also describe a long period circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3 a component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss-of-function in FBXL3 which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and

  17. Quantifying fluctuations in reversible enzymatic cycles and clocks

    Science.gov (United States)

    Wierenga, Harmen; ten Wolde, Pieter Rein; Becker, Nils B.

    2018-04-01

    Biochemical reactions are fundamentally noisy at a molecular scale. This limits the precision of reaction networks, but it also allows fluctuation measurements that may reveal the structure and dynamics of the underlying biochemical network. Here, we study nonequilibrium reaction cycles, such as the mechanochemical cycle of molecular motors, the phosphorylation cycle of circadian clock proteins, or the transition state cycle of enzymes. Fluctuations in such cycles may be measured using either of two classical definitions of the randomness parameter, which we show to be equivalent in general microscopically reversible cycles. We define a stochastic period for reversible cycles and present analytical solutions for its moments. Furthermore, we associate the two forms of the randomness parameter with the thermodynamic uncertainty relation, which sets limits on the timing precision of the cycle in terms of thermodynamic quantities. Our results should prove useful also for the study of temporal fluctuations in more general networks.

  18. 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.

  19. A model of guarded recursion with clock synchronisation

    DEFF Research Database (Denmark)

    Bizjak, Aleš; Møgelberg, Rasmus Ejlers

    2015-01-01

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

  20. Applied Bayesian modelling

    CERN Document Server

    Congdon, Peter

    2014-01-01

    This book provides an accessible approach to Bayesian computing and data analysis, with an emphasis on the interpretation of real data sets. Following in the tradition of the successful first edition, this book aims to make a wide range of statistical modeling applications accessible using tested code that can be readily adapted to the reader's own applications. The second edition has been thoroughly reworked and updated to take account of advances in the field. A new set of worked examples is included. The novel aspect of the first edition was the coverage of statistical modeling using WinBU

  1. Bayesian nonparametric data analysis

    CERN Document Server

    Müller, Peter; Jara, Alejandro; Hanson, Tim

    2015-01-01

    This book reviews nonparametric Bayesian methods and models that have proven useful in the context of data analysis. Rather than providing an encyclopedic review of probability models, the book’s structure follows a data analysis perspective. As such, the chapters are organized by traditional data analysis problems. In selecting specific nonparametric models, simpler and more traditional models are favored over specialized ones. The discussed methods are illustrated with a wealth of examples, including applications ranging from stylized examples to case studies from recent literature. The book also includes an extensive discussion of computational methods and details on their implementation. R code for many examples is included in on-line software pages.

  2. Classification using Bayesian neural nets

    NARCIS (Netherlands)

    J.C. Bioch (Cor); O. van der Meer; R. Potharst (Rob)

    1995-01-01

    textabstractRecently, Bayesian methods have been proposed for neural networks to solve regression and classification problems. These methods claim to overcome some difficulties encountered in the standard approach such as overfitting. However, an implementation of the full Bayesian approach to

  3. Bayesian Data Analysis (lecture 1)

    CERN Multimedia

    CERN. Geneva

    2018-01-01

    framework but we will also go into more detail and discuss for example the role of the prior. The second part of the lecture will cover further examples and applications that heavily rely on the bayesian approach, as well as some computational tools needed to perform a bayesian analysis.

  4. Bayesian Data Analysis (lecture 2)

    CERN Multimedia

    CERN. Geneva

    2018-01-01

    framework but we will also go into more detail and discuss for example the role of the prior. The second part of the lecture will cover further examples and applications that heavily rely on the bayesian approach, as well as some computational tools needed to perform a bayesian analysis.

  5. The Deep Space Atomic Clock Mission

    Science.gov (United States)

    Ely, Todd A.; Koch, Timothy; Kuang, Da; Lee, Karen; Murphy, David; Prestage, John; Tjoelker, Robert; Seubert, Jill

    2012-01-01

    The Deep Space Atomic Clock (DSAC) mission will demonstrate the space flight performance of a small, low-mass, high-stability mercury-ion atomic clock with long term stability and accuracy on par with that of the Deep Space Network. The timing stability introduced by DSAC allows for a 1-Way radiometric tracking paradigm for deep space navigation, with benefits including increased tracking via utilization of the DSN's Multiple Spacecraft Per Aperture (MSPA) capability and full ground station-spacecraft view periods, more accurate radio occultation signals, decreased single-frequency measurement noise, and the possibility for fully autonomous on-board navigation. Specific examples of navigation and radio science benefits to deep space missions are highlighted through simulations of Mars orbiter and Europa flyby missions. Additionally, this paper provides an overview of the mercury-ion trap technology behind DSAC, details of and options for the upcoming 2015/2016 space demonstration, and expected on-orbit clock performance.

  6. 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.

  7. The Bayesian Covariance Lasso.

    Science.gov (United States)

    Khondker, Zakaria S; Zhu, Hongtu; Chu, Haitao; Lin, Weili; Ibrahim, Joseph G

    2013-04-01

    Estimation of sparse covariance matrices and their inverse subject to positive definiteness constraints has drawn a lot of attention in recent years. The abundance of high-dimensional data, where the sample size ( n ) is less than the dimension ( d ), requires shrinkage estimation methods since the maximum likelihood estimator is not positive definite in this case. Furthermore, when n is larger than d but not sufficiently larger, shrinkage estimation is more stable than maximum likelihood as it reduces the condition number of the precision matrix. Frequentist methods have utilized penalized likelihood methods, whereas Bayesian approaches rely on matrix decompositions or Wishart priors for shrinkage. In this paper we propose a new method, called the Bayesian Covariance Lasso (BCLASSO), for the shrinkage estimation of a precision (covariance) matrix. We consider a class of priors for the precision matrix that leads to the popular frequentist penalties as special cases, develop a Bayes estimator for the precision matrix, and propose an efficient sampling scheme that does not precalculate boundaries for positive definiteness. The proposed method is permutation invariant and performs shrinkage and estimation simultaneously for non-full rank data. Simulations show that the proposed BCLASSO performs similarly as frequentist methods for non-full rank data.

  8. Approximate Bayesian computation.

    Directory of Open Access Journals (Sweden)

    Mikael Sunnåker

    Full Text Available Approximate Bayesian computation (ABC constitutes a class of computational methods rooted in Bayesian statistics. In all model-based statistical inference, the likelihood function is of central importance, since it expresses the probability of the observed data under a particular statistical model, and thus quantifies the support data lend to particular values of parameters and to choices among different models. For simple models, an analytical formula for the likelihood function can typically be derived. However, for more complex models, an analytical formula might be elusive or the likelihood function might be computationally very costly to evaluate. ABC methods bypass the evaluation of the likelihood function. In this way, ABC methods widen the realm of models for which statistical inference can be considered. ABC methods are mathematically well-founded, but they inevitably make assumptions and approximations whose impact needs to be carefully assessed. Furthermore, the wider application domain of ABC exacerbates the challenges of parameter estimation and model selection. ABC has rapidly gained popularity over the last years and in particular for the analysis of complex problems arising in biological sciences (e.g., in population genetics, ecology, epidemiology, and systems biology.

  9. 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.

  10. Bayesian inference with ecological applications

    CERN Document Server

    Link, William A

    2009-01-01

    This text is written to provide a mathematically sound but accessible and engaging introduction to Bayesian inference specifically for environmental scientists, ecologists and wildlife biologists. It emphasizes the power and usefulness of Bayesian methods in an ecological context. The advent of fast personal computers and easily available software has simplified the use of Bayesian and hierarchical models . One obstacle remains for ecologists and wildlife biologists, namely the near absence of Bayesian texts written specifically for them. The book includes many relevant examples, is supported by software and examples on a companion website and will become an essential grounding in this approach for students and research ecologists. Engagingly written text specifically designed to demystify a complex subject Examples drawn from ecology and wildlife research An essential grounding for graduate and research ecologists in the increasingly prevalent Bayesian approach to inference Companion website with analyt...

  11. Bayesian Inference on Gravitational Waves

    Directory of Open Access Journals (Sweden)

    Asad Ali

    2015-12-01

    Full Text Available The Bayesian approach is increasingly becoming popular among the astrophysics data analysis communities. However, the Pakistan statistics communities are unaware of this fertile interaction between the two disciplines. Bayesian methods have been in use to address astronomical problems since the very birth of the Bayes probability in eighteenth century. Today the Bayesian methods for the detection and parameter estimation of gravitational waves have solid theoretical grounds with a strong promise for the realistic applications. This article aims to introduce the Pakistan statistics communities to the applications of Bayesian Monte Carlo methods in the analysis of gravitational wave data with an  overview of the Bayesian signal detection and estimation methods and demonstration by a couple of simplified examples.

  12. Crime clocks and target performance maps

    CSIR Research Space (South Africa)

    Cooper, Anthony K

    1999-12-01

    Full Text Available View), spreadsheets (eg: Excel) and data bases (eg: Access). 2. Crime clocks A map of crime clocks displays the distribution of crime in time and space using scaled pie charts to show the relative crime rates for the selected period being analysed. Each... pie chart shows the total aggregated crime for an area (eg: CAS Block or precinct) and is positioned on the centroid of the relevant area. Hence, the size of each pie chart is proportional to the amount of crime that occurred in that area over...

  13. Clock frequency estimation under spontaneous emission

    Science.gov (United States)

    Qin, Xi-Zhou; Huang, Jia-Hao; Zhong, Hong-Hua; Lee, Chaohong

    2018-02-01

    We investigate the quantum dynamics of a driven two-level system under spontaneous emission and its application in clock frequency estimation. By using the Lindblad equation to describe the system, we analytically obtain its exact solutions, which show three different regimes: Rabi oscillation, damped oscillation, and overdamped decay. From the analytical solutions, we explore how the spontaneous emission affects the clock frequency estimation. We find that under a moderate spontaneous emission rate, the transition frequency can still be inferred from the Rabi oscillation. Our results enable potential practical applications in frequency measurement and quantum control under decoherence.

  14. Hourly Updated GNSS Orbit and Clock

    Science.gov (United States)

    Song, S.; Xue, J.

    2016-12-01

    With the development of the performance of GNSS, the hourly updated orbit and clock of GNSS are paid much more attention and used by more and more users because of the timeliness and high accuracy. The hourly GNSS orbit and clock are produced routinely in Shanghai Analysis Center(AC) of the International GNSS Monitoring and Assessment Service (iGMAS).In this article, the accuracy of hourly and 6-hourly updated ultra-rapid GPS,GLONASS,GALILEO,BDS orbit and clock (SHU1 and SHU6) are analyzed relative to the final production in detail. The analysis show that, in calculation session, there's no much difference between the mean SHU1 and SHU6 RMS and STD for GNSS orbit and clock. However, for BDS clock in prediction session, the RMS and STD of BDS SHU1 are 2.6ns and 0.5ns respectively, the RMS of BDS SHU6 increase from 2.7ns to 4.5ns from the 1st to the 6th hour prediction session, but there's no much changes of STD. For GPS clock in prediction session, the RMS and STD of GPS SHU1 is quite stable with 0.5ns and 0.2ns.The RMS of GPS SHU6 clock increase from 0.6ns to 1.0ns from the 1st to the 6th hour, but STD is stable at about 0.2ns.For the orbit in calculate session, the RMS of BDS SHU1 is a little less than that of SHU6,the RMS of GPS SHU1 and SHU6 orbit are approximately at the same level. In prediction session, the RMS of IGSO/MEO for BDS SHU1 is relative stable, but the RMS of SHU6 1st-6th hour prediction session increase from about 26.5cm to 32.7cm. The RMS of GPS SHU1 orbit's prediction session is about 3.4cm,but which increase from 3.3cm to 4.3cm for GPS SHU6 1st-6th hour prediction session.The comparison of GLONASS and GALILEO orbit and clock also will be described.The results show that the hourly update is more important for BDS at this stage.Moreover,some problems appearing in satellites and stations can be found earlier by 1 hourly updated frequency.

  15. 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....

  16. 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.

  17. Critical role of the circadian clock in memory formation: lessons from Aplysia.

    Science.gov (United States)

    Lyons, Lisa C

    2011-01-01

    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.

  18. The clock in the cell: Entrainment of the circadian clock in Neurospora crassa

    OpenAIRE

    Madeti Jyothi-Boesl, Cornelia

    2008-01-01

    Since reports of daily leaf movements 2000 years ago, a so-called circadian clock (‘circa diem’ meaning ‘about a day’) has been described in organisms from almost all phyla. The work presented in this thesis gives special emphasis on the circadian clock in the fungus Neurospora crassa, a rather simple cellular system. Neurospora was used to elucidate basic clock mechanisms are that are comparable to those in more complex organisms. To that end, we investigated chronoecological questions as we...

  19. Pulsed optically pumped atomic clock with zero-dead-time

    Science.gov (United States)

    Lin, Haixiao; Lin, Jinda; Deng, Jianliao; Zhang, Song; Wang, Yuzhu

    2017-12-01

    By alternatively operating two pulsed optically pumped (POP) atomic clocks, the dead time in a single clock can be eliminated, and the local oscillator can be discriminated continuously. A POP atomic clock with a zero-dead-time (ZDT) method is then insensitive to the microwave phase noise. From τ = 0.01 to 1 s, the Allan deviation of the ZDT-POP clock is reduced as nearly τ-1, which is significantly faster than τ-1/2 of a conventional clock. During 1-40 s, the Allan deviation returns to τ-1/2. Moreover, the frequency stability of the ZDT-POP clock is improved by one order of magnitude compared with that of the conventional POP clock. We also analyze the main factors that limit the short-term frequency stability of the POP atomic clock.

  20. On the Evolution of Memory: A Time for Clocks

    Directory of Open Access Journals (Sweden)

    Jason Robert Gerstner

    2012-02-01

    Full Text Available What was the earliest engram? Biology has evolved to encode representations of past events, and in neuroscience, we are attempting to link experience-dependent changes in molecular signaling with cellular processes that ultimately lead to behavioral output. The theory of evolution has guided biological research for decades, and since phylogenetically conserved mechanisms drive circadian rhythms, these processes may serve as common predecessors underlying more complex behavioral phenotypes. For example, the cAMP/MAPK/CREB cascade is interwoven with the clock to trigger circadian output, and is also known to affect memory formation. Time-of-day dependent changes have been observed in long-term potentiation (LTP within the mammalian suprachiasmatic nucleus and hippocampus, along with light-induced circadian phase resetting and fear conditioning behaviors. Together this suggests during evolution, similar processes underlying metaplasticity in more simple circuits may have been redeployed in higher-order brain regions. Therefore, this notion predicts a model that LTP and metaplasticity may exist in clock-forming circuits of lower-order species, through phylogenetically conserved pathways, leading to several testable hypotheses.

  1. Robustness from flexibility in the fungal circadian clock

    Directory of Open Access Journals (Sweden)

    Akman Ozgur E

    2010-06-01

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

  2. Delayed Cryptochrome Degradation Asymmetrically Alters the Daily Rhythm in Suprachiasmatic Clock Neuron Excitability.

    Science.gov (United States)

    Wegner, Sven; Belle, Mino D C; Hughes, Alun T L; Diekman, Casey O; Piggins, Hugh D

    2017-08-16

    Suprachiasmatic nuclei (SCN) neurons contain an intracellular molecular circadian clock and the Cryptochromes (CRY1/2), key transcriptional repressors of this molecular apparatus, are subject to post-translational modification through ubiquitination and targeting for proteosomal degradation by the ubiquitin E3 ligase complex. Loss-of-function point mutations in a component of this ligase complex, Fbxl3, delay CRY1/2 degradation, reduce circadian rhythm strength, and lengthen the circadian period by ∼2.5 h. The molecular clock drives circadian changes in the membrane properties of SCN neurons, but it is unclear how alterations in CRY1/2 stability affect SCN neurophysiology. Here we use male and female Afterhours mice which carry the circadian period lengthening loss-of-function Fbxl3 Afh mutation and perform patch-clamp recordings from SCN brain slices across the projected day/night cycle. We find that the daily rhythm in membrane excitability in the ventral SCN (vSCN) was enhanced in amplitude and delayed in timing in Fbxl3 Afh/Afh mice. At night, vSCN cells from Fbxl3 Afh/Afh mice were more hyperpolarized, receiving more GABAergic input than their Fbxl3 +/+ counterparts. Unexpectedly, the progression to daytime hyperexcited states was slowed by Afh mutation, whereas the decline to hypoexcited states was accelerated. In long-term bioluminescence recordings, GABA A receptor blockade desynchronized the Fbxl3 +/+ but not the Fbxl3 Afh/Afh vSCN neuronal network. Further, a neurochemical mimic of the light input pathway evoked larger shifts in molecular clock rhythms in Fbxl3 Afh/Afh compared with Fbxl3 +/+ SCN slices. These results reveal unanticipated consequences of delaying CRY degradation, indicating that the Afh mutation prolongs nighttime hyperpolarized states of vSCN cells through increased GABAergic synaptic transmission. SIGNIFICANCE STATEMENT The intracellular molecular clock drives changes in SCN neuronal excitability, but it is unclear how mutations

  3. cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock.

    Science.gov (United States)

    Oster, Henrik; Werner, Claudia; Magnone, Maria Chiara; Mayser, Helmut; Feil, Robert; Seeliger, Mathias W; Hofmann, Franz; Albrecht, Urs

    2003-04-29

    In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock. We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals. cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.

  4. Clock Synchronization for Multi-hop Ad hoc Networks

    OpenAIRE

    O'Connor, Neil

    2003-01-01

    Clock syncronization is one of the basic requirements of a distributed real-time systems. The greater the precision achievable by the clock synchronization algorithm used, the harder the real-time guarantees that can be given by the system. Numerous clock synchronization algoritms for wired networks have been proposed, which provide varying degrees of precision. Wireless networks provide a number of challenges which clock synchronization algorithms for wired networks do not address satisf...

  5. 47 CFR 80.865 - Radiotelephone station clock.

    Science.gov (United States)

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Radiotelephone station clock. 80.865 Section 80.865 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES... W § 80.865 Radiotelephone station clock. A clock having a face of at least 12.7 cm (5 in.) in...

  6. A practical clock synchronization algorithm for UWB positioning systems

    NARCIS (Netherlands)

    Xie, Y.; Janssen, G.J.M.; van der Veen, A.J.; Dong, Min; Zheng, Thomas Fang

    2016-01-01

    A clock synchronization scheme is crucial for obtaining accuracy in time-based positioning systems. Existing clock synchronization schemes are mostly based on a simplified linear clock model, which unfortunately have a poor long-term synchronization accuracy. Assuming a two-way time transfer

  7. On synchronization of clocks in general space-times

    Directory of Open Access Journals (Sweden)

    M. R. H Khajehpour

    2005-09-01

    Full Text Available   Einstein and transport synchronizations of infinitesimally spaced and distant clocks are considered in a general Riemannian space-time. It is shown that infinitesimally spaced clocks can always be synchronized. In general one can not find observers for whom distant clock are Einstein synchronized but transport synchronized observers do always exit. Whenever both procedures are possible, they are equivalent.

  8. The Circadian Clock Gene BMAL1 Coordinates Intestinal RegenerationSummary

    Directory of Open Access Journals (Sweden)

    Kyle Stokes

    2017-07-01

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

  9. Bayesian nonparametric hierarchical modeling.

    Science.gov (United States)

    Dunson, David B

    2009-04-01

    In biomedical research, hierarchical models are very widely used to accommodate dependence in multivariate and longitudinal data and for borrowing of information across data from different sources. A primary concern in hierarchical modeling is sensitivity to parametric assumptions, such as linearity and normality of the random effects. Parametric assumptions on latent variable distributions can be challenging to check and are typically unwarranted, given available prior knowledge. This article reviews some recent developments in Bayesian nonparametric methods motivated by complex, multivariate and functional data collected in biomedical studies. The author provides a brief review of flexible parametric approaches relying on finite mixtures and latent class modeling. Dirichlet process mixture models are motivated by the need to generalize these approaches to avoid assuming a fixed finite number of classes. Focusing on an epidemiology application, the author illustrates the practical utility and potential of nonparametric Bayes methods.

  10. Bayesian grid matching

    DEFF Research Database (Denmark)

    Hartelius, Karsten; Carstensen, Jens Michael

    2003-01-01

    A method for locating distorted grid structures in images is presented. The method is based on the theories of template matching and Bayesian image restoration. The grid is modeled as a deformable template. Prior knowledge of the grid is described through a Markov random field (MRF) model which...... represents the spatial coordinates of the grid nodes. Knowledge of how grid nodes are depicted in the observed image is described through the observation model. The prior consists of a node prior and an arc (edge) prior, both modeled as Gaussian MRFs. The node prior models variations in the positions of grid...... nodes and the arc prior models variations in row and column spacing across the grid. Grid matching is done by placing an initial rough grid over the image and applying an ensemble annealing scheme to maximize the posterior distribution of the grid. The method can be applied to noisy images with missing...

  11. Bayesian supervised dimensionality reduction.

    Science.gov (United States)

    Gönen, Mehmet

    2013-12-01

    Dimensionality reduction is commonly used as a preprocessing step before training a supervised learner. However, coupled training of dimensionality reduction and supervised learning steps may improve the prediction performance. In this paper, we introduce a simple and novel Bayesian supervised dimensionality reduction method that combines linear dimensionality reduction and linear supervised learning in a principled way. We present both Gibbs sampling and variational approximation approaches to learn the proposed probabilistic model for multiclass classification. We also extend our formulation toward model selection using automatic relevance determination in order to find the intrinsic dimensionality. Classification experiments on three benchmark data sets show that the new model significantly outperforms seven baseline linear dimensionality reduction algorithms on very low dimensions in terms of generalization performance on test data. The proposed model also obtains the best results on an image recognition task in terms of classification and retrieval performances.

  12. Bayesian Geostatistical Design

    DEFF Research Database (Denmark)

    Diggle, Peter; Lophaven, Søren Nymand

    2006-01-01

    This paper describes the use of model-based geostatistics for choosing the set of sampling locations, collectively called the design, to be used in a geostatistical analysis. Two types of design situation are considered. These are retrospective design, which concerns the addition of sampling...... locations to, or deletion of locations from, an existing design, and prospective design, which consists of choosing positions for a new set of sampling locations. We propose a Bayesian design criterion which focuses on the goal of efficient spatial prediction whilst allowing for the fact that model...... parameter values are unknown. The results show that in this situation a wide range of interpoint distances should be included in the design, and the widely used regular design is often not the best choice....

  13. Tick Tock, a Vitamin C Clock.

    Science.gov (United States)

    Wright, Stephen W.

    2002-01-01

    Presents an activity that uses supermarket chemicals to perform a clock reaction in which the endpoint is signaled by an abrupt change in the appearance from colorless to blue-black. This activity can be used to explore reaction kinetics and the effect of reactant concentrations on the apparent rate of reaction. (DDR)

  14. Central and peripheral clocks in ontogeny

    Czech Academy of Sciences Publication Activity Database

    Sumová, Alena; Bendová, Zdeňka; Sládek, Martin; El-Hennamy, Rehab; Laurinová, Kristýna; Jindráková, Zuzana; Illnerová, Helena

    2006-01-01

    Roč. 273, č. S1 (2006), s. 6-6 ISSN 1742-464X. [FEBS Congress /31./. 24.06.2006-29.06.2006, Istanbul] Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * peripheral tissue * ontogeny Subject RIV: FH - Neurology

  15. The Clocks Are Ticking: No More Delays!

    DEFF Research Database (Denmark)

    Bahr, Patrick; Grathwohl, Hans Bugge; Møgelberg, Rasmus Ejlers

    2017-01-01

    these applications can be carried out and machine-checked. In this paper, we take a step towards this goal by devising a suitable reduction semantics. We present Clocked Type Theory, a new type theory for guarded recursion that is more suitable for reduction semantics than the existing ones. We prove confluence...

  16. Food at work around the clock

    DEFF Research Database (Denmark)

    Dahl Lassen, Anne; Beck, Anne Marie; Thorsen, Anne Vibeke

    This report brings together 12 invited presentations and outcomes of a workshop on food and meals for employees working irregular hours “around the clock”. The workshop, “Food at work around the clock – The Nordic Model”, was hosted by the National Food Institute at the Technical University...

  17. Brain clocks for morning and evening behaviour

    Indian Academy of Sciences (India)

    Unknown

    Different subgroups of cells that regu- late the morning and evening components of activity are ... tion of time from circadian pacemaker to target organs? At least two decades ago, a model of circadian clocks .... type behaviour (with robust morning and evening bouts of activity) by expressing UAS-per in the CRY+ cells.

  18. 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…

  19. Pittendrigh: The Darwinian Clock-Watcher

    Indian Academy of Sciences (India)

    cyanobacteria. The abysmal numbers of plant and protists in particular is a reminder that current chronobiology research is very animal-centered, primarily due to the pressure to use models that can be functionally linked to the analyses of human disease. Back in the 1960s when nothing was known about clock genes and ...

  20. Analytic clock frequency selection for global DVFS

    NARCIS (Netherlands)

    Gerards, Marco Egbertus Theodorus; Hurink, Johann L.; Holzenspies, P.K.F.; Kuper, Jan; Smit, Gerardus Johannes Maria

    2014-01-01

    Computers can reduce their power consumption by decreasing their speed using Dynamic Voltage and Frequency Scaling (DVFS). A form of DVFS for multicore processors is global DVFS, where the voltage and clock frequency is shared among all processor cores. Because global DVFS is efficient and cheap to

  1. Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in β-Cell Maturation Process.

    Science.gov (United States)

    Rakshit, Kuntol; Qian, Jingyi; Gaonkar, Krutika Satish; Dhawan, Sangeeta; Colwell, Christopher S; Matveyenko, Aleksey V

    2018-03-02

    Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. Circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown. To address this, we studied wild type Sprague Dawley as well as Period1 luciferase transgenic rats ( Per1 :LUC) to determine circadian clock function, clock protein expression and diurnal insulin secretion during islet development and maturation process. We additionally studied β-cell-specific Bmal1 deficient mice to elucidate potential role of this key circadian transcription factor in β-cell functional and transcriptional maturation. We report that emergence of the islet circadian clock 1) occurs during early postnatal period, 2) depends on the establishment of global behavioral circadian rhythms and 3) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose-stimulated insulin secretion and associated transcriptional network. Postnatal development of the islet circadian clock contributes to early life β-cell maturation and should be considered for optimal design of future β-cell replacement strategies in diabetes. © 2018 by the American Diabetes Association.

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

    Science.gov (United States)

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

    2016-07-01

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

  3. Untimely oxidative stress in β-cells leads to diabetes - Role of circadian clock in β-cell function.

    Science.gov (United States)

    Lee, J; Ma, K; Moulik, M; Yechoor, V

    2018-02-16

    Diabetes results from a loss of β-cell function. With the number of people with diabetes reaching epidemic proportions globally, understanding mechanisms that are contributing to this increasing prevalence is critical. One such factor has been circadian disruption, with shift-work, light pollution, jet-lag, increased screen time, all acting as potential contributory factors. Though circadian disruption has been epidemiologically associated with diabetes and other metabolic disorders for many decades, it is only recently that there has been a better understanding of the underlying molecular mechanisms. Experimental circadian disruption, via manipulation of environmental or genetic factors using gene-deletion mouse models, has demonstrated the importance of circadian rhythms in whole body metabolism. Genetic disruption of core clock genes, specifically in the β-cells in mice, have, now demonstrated the importance of the intrinsic β-cell clock in regulating function. Recent work has also shown the interaction of the circadian clock and enhancers in β-cells, indicating a highly integrated regulation of transcription and cellular function by the circadian clock. Disruption of either the whole body or only the β-cell clock leads to significant impairment of mitochondrial function, uncoupling, impaired vesicular transport, oxidative stress in β-cells and finally impaired glucose-stimulated insulin secretion and diabetes. In this review, we explore the role of the circadian clock in mitigating oxidative stress and preserving β-cell function. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Circadian CLOCK gene polymorphisms in relation to sleep patterns and obesity in African Americans: findings from the Jackson heart study.

    Science.gov (United States)

    Riestra, Pia; Gebreab, Samson Y; Xu, Ruihua; Khan, Rumana J; Gaye, Amadou; Correa, Adolfo; Min, Nancy; Sims, Mario; Davis, Sharon K

    2017-06-23

    Circadian rhythms regulate key biological processes and the dysregulation of the intrinsic clock mechanism affects sleep patterns and obesity onset. The CLOCK (circadian locomotor output cycles protein kaput) gene encodes a core transcription factor of the molecular circadian clock influencing diverse metabolic pathways, including glucose and lipid homeostasis. The primary objective of this study was to evaluate the associations between CLOCK single nucleotide polymorphisms (SNPs) and body mass index (BMI). We also evaluated the association of SNPs with BMI related factors such as sleep duration and quality, adiponectin and leptin, in 2962 participants (1116 men and 1810 women) from the Jackson Heart Study. Genotype data for the selected 23 CLOCK gene SNPS was obtained by imputation with IMPUTE2 software and reference phase data from the 1000 genome project. Genetic analyses were conducted with PLINK RESULTS: We found a significant association between the CLOCK SNP rs2070062 and sleep duration, participants carriers of the T allele showed significantly shorter sleep duration compared to non-carriers after the adjustment for individual proportions of European ancestry (PEA), socio economic status (SES), body mass index (BMI), alcohol consumption and smoking status that reach the significance threshold after multiple testing correction. In addition, we found nominal associations of the CLOCK SNP rs6853192 with longer sleep duration and the rs6820823, rs3792603 and rs11726609 with BMI. However, these associations did not reach the significance threshold after correction for multiple testing. In this work, CLOCK gene variants were associated with sleep duration and BMI suggesting that the effects of these polymorphisms on circadian rhythmicity may affect sleep duration and body weight regulation in Africans Americans.

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

    Science.gov (United States)

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

    2016-09-01

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

  6. 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.

  7. Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

    Science.gov (United States)

    Lin, Changpo; Tang, Xiao; Xu, Lirong; Qian, Ruizhe; Shi, Zhenyu; Wang, Lixin; Cai, Tingting; Yan, Dong; Fu, Weiguo; Guo, Daqiao

    2017-07-10

    The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions. Seven health donors' normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits. The circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs. The results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

  8. 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

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

    NARCIS (Netherlands)

    Wu, Ying-Hui; Fischer, David F.; Kalsbeek, Andries; Garidou-Boof, Marie-Laure; van der Vliet, Jan; van Heijningen, Caroline; Liu, Rong-Yu; Zhou, Jiang-Ning; Swaab, Dick 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

  10. Bayesian adaptive methods for clinical trials

    CERN Document Server

    Berry, Scott M; Muller, Peter

    2010-01-01

    Already popular in the analysis of medical device trials, adaptive Bayesian designs are increasingly being used in drug development for a wide variety of diseases and conditions, from Alzheimer's disease and multiple sclerosis to obesity, diabetes, hepatitis C, and HIV. Written by leading pioneers of Bayesian clinical trial designs, Bayesian Adaptive Methods for Clinical Trials explores the growing role of Bayesian thinking in the rapidly changing world of clinical trial analysis. The book first summarizes the current state of clinical trial design and analysis and introduces the main ideas and potential benefits of a Bayesian alternative. It then gives an overview of basic Bayesian methodological and computational tools needed for Bayesian clinical trials. With a focus on Bayesian designs that achieve good power and Type I error, the next chapters present Bayesian tools useful in early (Phase I) and middle (Phase II) clinical trials as well as two recent Bayesian adaptive Phase II studies: the BATTLE and ISP...

  11. Current trends in Bayesian methodology with applications

    CERN Document Server

    Upadhyay, Satyanshu K; Dey, Dipak K; Loganathan, Appaia

    2015-01-01

    Collecting Bayesian material scattered throughout the literature, Current Trends in Bayesian Methodology with Applications examines the latest methodological and applied aspects of Bayesian statistics. The book covers biostatistics, econometrics, reliability and risk analysis, spatial statistics, image analysis, shape analysis, Bayesian computation, clustering, uncertainty assessment, high-energy astrophysics, neural networking, fuzzy information, objective Bayesian methodologies, empirical Bayes methods, small area estimation, and many more topics.Each chapter is self-contained and focuses on

  12. Bayesian Inference: with ecological applications

    Science.gov (United States)

    Link, William A.; Barker, Richard J.

    2010-01-01

    This text provides a mathematically rigorous yet accessible and engaging introduction to Bayesian inference with relevant examples that will be of interest to biologists working in the fields of ecology, wildlife management and environmental studies as well as students in advanced undergraduate statistics.. This text opens the door to Bayesian inference, taking advantage of modern computational efficiencies and easily accessible software to evaluate complex hierarchical models.

  13. Bayesian image restoration, using configurations

    OpenAIRE

    Thorarinsdottir, Thordis

    2006-01-01

    In this paper, we develop a Bayesian procedure for removing noise from images that can be viewed as noisy realisations of random sets in the plane. The procedure utilises recent advances in configuration theory for noise free random sets, where the probabilities of observing the different boundary configurations are expressed in terms of the mean normal measure of the random set. These probabilities are used as prior probabilities in a Bayesian image restoration approach. Estimation of the re...

  14. A balance of positive and negative regulators determines the pace of the segmentation clock

    Science.gov (United States)

    Wiedermann, Guy; Bone, Robert Alexander; Silva, Joana Clara; Bjorklund, Mia

    2015-01-01

    Somitogenesis is regulated by a molecular oscillator that drives dynamic gene expression within the pre-somitic mesoderm. Previous mathematical models of the somitogenesis clock that invoke the mechanism of delayed negative feedback predict that its oscillation period depends on the sum of delays inherent to negative-feedback loops and inhibitor half-lives. We develop a mathematical model that explores the possibility that positive feedback also plays a role in determining the period of clock oscillations. The model predicts that increasing the half-life of the positive regulator, Notch intracellular domain (NICD), can lead to elevated NICD levels and an increase in the oscillation period. To test this hypothesis, we investigate a phenotype induced by various small molecule inhibitors in which the clock is slowed. We observe elevated levels and a prolonged half-life of NICD. Reducing NICD production rescues these effects. These data provide the first indication that tight control of the turnover of positive as well as negative regulators of the clock determines its periodicity. DOI: http://dx.doi.org/10.7554/eLife.05842.001 PMID:26357015

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

    Directory of Open Access Journals (Sweden)

    Annaëlle Charrier

    2017-04-01

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

  16. Involvement of circadian clock in crowing of red jungle fowls (Gallus gallus).

    Science.gov (United States)

    Ito, Shuichi; Hori, Shuho; Hirose, Makiko; Iwahara, Mari; Yatsushiro, Azusa; Matsumoto, Atsushi; Tanaka, Masayuki; Okamoto, Chinobu; Yayou, Ken-Ichi; Shimmura, Tsuyoshi

    2017-04-01

    The rhythmic locomotor behavior of flies and mice provides a phenotype for the identification of clock genes, and the underlying molecular mechanism is well studied. However, interestingly, when examining locomotor rhythm in the wild, several key laboratory-based assumptions on circadian behavior are not supported in natural conditions. The rooster crowing 'cock-a-doodle-doo' is a symbol of the break of dawn in many countries. Previously, we used domestic inbred roosters and showed that the timing of roosters' crowing is regulated by the circadian clock under laboratory conditions. However, it is still unknown whether the regulation of crowing by circadian clock is observed under natural conditions. Therefore, here we used red jungle fowls and first confirmed that similar crowing rhythms with domesticated chickens are observed in red jungle fowls under the laboratory conditions. Red jungle fowls show predawn crowing before light onset under 12:12 light : dim light conditions and the free-running rhythm of crowing under total dim light conditions. We next examined the crowing rhythms under semi-wild conditions. Although the crowing of red jungle fowls changed seasonally under semi-wild conditions, predawn crowing was observed before sunrise in all seasons. This evidence suggests that seasonally changed crowing of red jungle fowls is under the control of a circadian clock. © 2016 Japanese Society of Animal Science.

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

    Science.gov (United States)

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

    2017-04-29

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

  18. Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

    Directory of Open Access Journals (Sweden)

    Chun Wang

    2014-07-01

    Full Text Available The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function.

  19. Expression of clock genes /period/ and /timeless /in the central nervous system of the mediterranean flour moth, Ephestia kuehniella

    Czech Academy of Sciences Publication Activity Database

    Kobelková, Alena; Závodská, Radka; Šauman, Ivo; Bazalová, Olga; Doležel, David

    2015-01-01

    Roč. 30, č. 2 (2015), s. 104-116 ISSN 0748-7304 R&D Projects: GA ČR GC14-32654J Institutional support: RVO:60077344 Keywords : circadian clock * activity rhythms * eclosion rhythm Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.824, year: 2015

  20. Metabolism and the Circadian Clock Converge

    Science.gov (United States)

    Eckel-Mahan, Kristin

    2013-01-01

    Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. PMID:23303907

  1. Supporting Family Awareness with the Whereabouts Clock

    Science.gov (United States)

    Sellen, Abigail; Taylor, Alex S.; Kaye, Joseph ‘Jofish'; Brown, Barry; Izadi, Shahram

    We report the results of a field trial of a situated awareness device for families called the “Whereabouts Clock”. The Clock displays the location of family members using cellphone data as one of four privacy-preserving, deliberately coarse-grained categories ( HOME, WORK, SCHOOL or ELSEWHERE). The results show that awareness of others through the Clock supports not only family communication and coordination but also more emotive aspects of family life such as reassurance, connectedness, identity and social touch. We discuss how the term “awareness” means many things in practice and highlight the importance of designing not just for family activities, but in order to support the emotional, social and even moral aspects of family life.

  2. 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.

  3. Effects of mass defect in atomic clocks

    Science.gov (United States)

    Taichenachev, A. V.; Yudin, V. I.

    2018-01-01

    We consider some implications of the mass defect on the frequency of atomic transitions. We have found that some well-known frequency shifts (such as gravitational and quadratic Doppler shifts) can be interpreted as consequences of the mass defect, i.e., without the need for the concept of time dilation used in special and general relativity theories. Moreover, we show that the inclusion of the mass defect leads to previously unknown shifts for clocks based on trapped ions..

  4. 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.

  5. Early evolution of the land plant circadian clock.

    Science.gov (United States)

    Linde, Anna-Malin; Eklund, D Magnus; Kubota, Akane; Pederson, Eric R A; Holm, Karl; Gyllenstrand, Niclas; Nishihama, Ryuichi; Cronberg, Nils; Muranaka, Tomoaki; Oyama, Tokitaka; Kohchi, Takayuki; Lagercrantz, Ulf

    2017-10-01

    While angiosperm clocks can be described as an intricate network of interlocked transcriptional feedback loops, clocks of green algae have been modelled as a loop of only two genes. To investigate the transition from a simple clock in algae to a complex one in angiosperms, we performed an inventory of circadian clock genes in bryophytes and charophytes. Additionally, we performed functional characterization of putative core clock genes in the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis. Phylogenetic construction was combined with studies of spatiotemporal expression patterns and analysis of M. polymorpha clock gene mutants. Homologues to core clock genes identified in Arabidopsis were found not only in bryophytes but also in charophytes, albeit in fewer copies. Circadian rhythms were detected for most identified genes in M. polymorpha and A. agrestis, and mutant analysis supports a role for putative clock genes in M. polymorpha. Our data are in line with a recent hypothesis that adaptation to terrestrial life occurred earlier than previously expected in the evolutionary history of charophyte algae. Both gene duplication and acquisition of new genes was important in the evolution of the plant circadian clock, but gene loss has also contributed to shaping the clock of bryophytes. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  6. The hepatic circadian clock modulates xenobiotic metabolism in mice.

    Science.gov (United States)

    DeBruyne, Jason P; Weaver, David R; Dallmann, Robert

    2014-08-01

    The circadian clock generates daily cycles of gene expression that regulate physiological processes. The liver plays an important role in xenobiotic metabolism and also has been shown to possess its own cell-based clock. The liver clock is synchronized by the master clock in the brain, and a portion of rhythmic gene expression can be driven by behavior of the organism as a whole even when the hepatic clock is suppressed. So far, however, there is relatively little evidence indicating whether the liver clock is functionally important in modulating xenobiotic metabolism. Thus, mice lacking circadian clock function in the whole body or specifically in liver were challenged with pentobarbital and acetaminophen, and pentobarbital sleep time (PBST) and acetaminophen toxicity, respectively, was assessed at different times of day in mutant and control mice. The results suggest that the liver clock is essential for rhythmic changes in xenobiotic detoxification. Surprisingly, it seems that the way in which the clock is disrupted determines the rate of xenobiotic metabolism in the liver. CLOCK-deficient mice are remarkably resistant to acetaminophen and exhibit a longer PBST, while PERIOD-deficient mice have a short PBST. These results indicate an essential role of the tissue-intrinsic peripheral circadian oscillator in the liver in regulating xenobiotic metabolism. © 2014 The Author(s).

  7. Glutamine synthetase gene evolution: A good molecular clock

    International Nuclear Information System (INIS)

    Pesole, G.; Lanvave, C.; Saccone, C.; Bozzetti, M.P.; Preparata, G.

    1991-01-01

    Glutamine synthetase gene evolution in various animals, plants, and bacteria was evaluated by a general stationary Markov model. The evolutionary process proved to be unexpectedly regular even for a time span as long as that between the divergence of prokaryotes from eukaryotes. This enabled us to draw phylogenetic trees for species whose phylogeny cannot be easily reconstructed from the fossil record. The calculation of the times of divergence of the various organelle-specific enzymes led us to hypothesize that the pea and bean chloroplast genes for these enzymes originated from the duplication of nuclear genes as a result of the different metabolic needs of the various species. The data indicate that the duplication of plastid glutamine synthetase genes occurred long after the endosymbiotic events that produced the organelles themselves

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

    Indian Academy of Sciences (India)

    Prakash

    2009-10-30

    Oct 30, 2009 ... Ankle bone morphology provides important information about attachment surfaces for muscles and tendons and hence the functional adaptations of the animal during its life and phylogenetic relationships. Based on tarsal bone morphology, it was inferred that Deccanolestes was. Divergence time estimates ...

  9. Bayesian seismic AVO inversion

    Energy Technology Data Exchange (ETDEWEB)

    Buland, Arild

    2002-07-01

    A new linearized AVO inversion technique is developed in a Bayesian framework. The objective is to obtain posterior distributions for P-wave velocity, S-wave velocity and density. Distributions for other elastic parameters can also be assessed, for example acoustic impedance, shear impedance and P-wave to S-wave velocity ratio. The inversion algorithm is based on the convolutional model and a linearized weak contrast approximation of the Zoeppritz equation. The solution is represented by a Gaussian posterior distribution with explicit expressions for the posterior expectation and covariance, hence exact prediction intervals for the inverted parameters can be computed under the specified model. The explicit analytical form of the posterior distribution provides a computationally fast inversion method. Tests on synthetic data show that all inverted parameters were almost perfectly retrieved when the noise approached zero. With realistic noise levels, acoustic impedance was the best determined parameter, while the inversion provided practically no information about the density. The inversion algorithm has also been tested on a real 3-D dataset from the Sleipner Field. The results show good agreement with well logs but the uncertainty is high. The stochastic model includes uncertainties of both the elastic parameters, the wavelet and the seismic and well log data. The posterior distribution is explored by Markov chain Monte Carlo simulation using the Gibbs sampler algorithm. The inversion algorithm has been tested on a seismic line from the Heidrun Field with two wells located on the line. The uncertainty of the estimated wavelet is low. In the Heidrun examples the effect of including uncertainty of the wavelet and the noise level was marginal with respect to the AVO inversion results. We have developed a 3-D linearized AVO inversion method with spatially coupled model parameters where the objective is to obtain posterior distributions for P-wave velocity, S

  10. Bayesian microsaccade detection

    Science.gov (United States)

    Mihali, Andra; van Opheusden, Bas; Ma, Wei Ji

    2017-01-01

    Microsaccades are high-velocity fixational eye movements, with special roles in perception and cognition. The default microsaccade detection method is to determine when the smoothed eye velocity exceeds a threshold. We have developed a new method, Bayesian microsaccade detection (BMD), which performs inference based on a simple statistical model of eye positions. In this model, a hidden state variable changes between drift and microsaccade states at random times. The eye position is a biased random walk with different velocity distributions for each state. BMD generates samples from the posterior probability distribution over the eye state time series given the eye position time series. Applied to simulated data, BMD recovers the “true” microsaccades with fewer errors than alternative algorithms, especially at high noise. Applied to EyeLink eye tracker data, BMD detects almost all the microsaccades detected by the default method, but also apparent microsaccades embedded in high noise—although these can also be interpreted as false positives. Next we apply the algorithms to data collected with a Dual Purkinje Image eye tracker, whose higher precision justifies defining the inferred microsaccades as ground truth. When we add artificial measurement noise, the inferences of all algorithms degrade; however, at noise levels comparable to EyeLink data, BMD recovers the “true” microsaccades with 54% fewer errors than the default algorithm. Though unsuitable for online detection, BMD has other advantages: It returns probabilities rather than binary judgments, and it can be straightforwardly adapted as the generative model is refined. We make our algorithm available as a software package. PMID:28114483

  11. Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock.

    Science.gov (United States)

    DiTacchio, Luciano; Le, Hiep D; Vollmers, Christopher; Hatori, Megumi; Witcher, Michael; Secombe, Julie; Panda, Satchidananda

    2011-09-30

    In animals, circadian oscillators are based on a transcription-translation circuit that revolves around the transcription factors CLOCK and BMAL1. We found that the JumonjiC (JmjC) and ARID domain-containing histone lysine demethylase 1a (JARID1a) formed a complex with CLOCK-BMAL1, which was recruited to the Per2 promoter. JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the Jarid1a homolog, lid, had lowered Per expression and similarly altered circadian rhythms. JARID1a thus has a nonredundant role in circadian oscillator function.

  12. Kernel Bayesian ART and ARTMAP.

    Science.gov (United States)

    Masuyama, Naoki; Loo, Chu Kiong; Dawood, Farhan

    2018-02-01

    Adaptive Resonance Theory (ART) is one of the successful approaches to resolving "the plasticity-stability dilemma" in neural networks, and its supervised learning model called ARTMAP is a powerful tool for classification. Among several improvements, such as Fuzzy or Gaussian based models, the state of art model is Bayesian based one, while solving the drawbacks of others. However, it is known that the Bayesian approach for the high dimensional and a large number of data requires high computational cost, and the covariance matrix in likelihood becomes unstable. This paper introduces Kernel Bayesian ART (KBA) and ARTMAP (KBAM) by integrating Kernel Bayes' Rule (KBR) and Correntropy Induced Metric (CIM) to Bayesian ART (BA) and ARTMAP (BAM), respectively, while maintaining the properties of BA and BAM. The kernel frameworks in KBA and KBAM are able to avoid the curse of dimensionality. In addition, the covariance-free Bayesian computation by KBR provides the efficient and stable computational capability to KBA and KBAM. Furthermore, Correntropy-based similarity measurement allows improving the noise reduction ability even in the high dimensional space. The simulation experiments show that KBA performs an outstanding self-organizing capability than BA, and KBAM provides the superior classification ability than BAM, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA.

    Directory of Open Access Journals (Sweden)

    Guo-Xiang Ruan

    2008-10-01

    Full Text Available The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER

  14. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock.

    Directory of Open Access Journals (Sweden)

    Benoît Kornmann

    2007-02-01

    Full Text Available The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBalpha represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.

  15. 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.

  16. The Effects of Clock Drift on the Mars Exploration Rovers

    Science.gov (United States)

    Ali, Khaled S.; Vanelli, C. Anthony

    2012-01-01

    All clocks drift by some amount, and the mission clock on the Mars Exploration Rovers (MER) is no exception. The mission clock on both MER rovers drifted significantly since the rovers were launched, and it is still drifting on the Opportunity rover. The drift rate is temperature dependent. Clock drift causes problems for onboard behaviors and spacecraft operations, such as attitude estimation, driving, operation of the robotic arm, pointing for imaging, power analysis, and telecom analysis. The MER operations team has techniques to deal with some of these problems. There are a few techniques for reducing and eliminating the clock drift, but each has drawbacks. This paper presents an explanation of what is meant by clock drift on the rovers, its relationship to temperature, how we measure it, what problems it causes, how we deal with those problems, and techniques for reducing the drift.

  17. Clock-dependent and system-driven oscillators interact in the suprachiasmatic nuclei to pace mammalian circadian rhythms.

    Directory of Open Access Journals (Sweden)

    Karine Abitbol

    Full Text Available Circadian clocks drive biological rhythms with a period of approximately 24 hours and keep in time with the outside world through daily resetting by environmental cues. While this external entrainment has been extensively investigated in the suprachiasmatic nuclei (SCN, the role of internal systemic rhythms, including daily fluctuations in core temperature or circulating hormones remains debated. Here, we show that lactating mice, which exhibit dampened systemic rhythms, possess normal molecular clockwork but impaired rhythms in both heat shock response gene expression and electrophysiological output in their SCN. This suggests that body rhythms regulate SCN activity downstream of the clock. Mathematical modeling predicts that systemic feedback upon the SCN functions as an internal oscillator that accounts for in vivo and ex vivo observations. Thus we are able to propose a new bottom-up hierarchical organization of circadian timekeeping in mammals, based on the interaction in the SCN between clock-dependent and system-driven oscillators.

  18. Bayesian analysis of CCDM models

    Energy Technology Data Exchange (ETDEWEB)

    Jesus, J.F. [Universidade Estadual Paulista (Unesp), Câmpus Experimental de Itapeva, Rua Geraldo Alckmin 519, Vila N. Sra. de Fátima, Itapeva, SP, 18409-010 Brazil (Brazil); Valentim, R. [Departamento de Física, Instituto de Ciências Ambientais, Químicas e Farmacêuticas—ICAQF, Universidade Federal de São Paulo (UNIFESP), Unidade José Alencar, Rua São Nicolau No. 210, Diadema, SP, 09913-030 Brazil (Brazil); Andrade-Oliveira, F., E-mail: jfjesus@itapeva.unesp.br, E-mail: valentim.rodolfo@unifesp.br, E-mail: felipe.oliveira@port.ac.uk [Institute of Cosmology and Gravitation—University of Portsmouth, Burnaby Road, Portsmouth, PO1 3FX United Kingdom (United Kingdom)

    2017-09-01

    Creation of Cold Dark Matter (CCDM), in the context of Einstein Field Equations, produces a negative pressure term which can be used to explain the accelerated expansion of the Universe. In this work we tested six different spatially flat models for matter creation using statistical criteria, in light of SNe Ia data: Akaike Information Criterion (AIC), Bayesian Information Criterion (BIC) and Bayesian Evidence (BE). These criteria allow to compare models considering goodness of fit and number of free parameters, penalizing excess of complexity. We find that JO model is slightly favoured over LJO/ΛCDM model, however, neither of these, nor Γ = 3α H {sub 0} model can be discarded from the current analysis. Three other scenarios are discarded either because poor fitting or because of the excess of free parameters. A method of increasing Bayesian evidence through reparameterization in order to reducing parameter degeneracy is also developed.

  19. FAD regulates CRYPTOCHROME protein stability and circadian clock in mice

    OpenAIRE

    Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui; Ptáček, Louis J.

    2017-01-01

    The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin ki...

  20. Relativity theory and time perception: single or multiple clocks?

    Science.gov (United States)

    Buhusi, Catalin V; Meck, Warren H

    2009-07-22

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

  1. Relativity theory and time perception: single or multiple clocks?

    Directory of Open Access Journals (Sweden)

    Catalin V Buhusi

    2009-07-01

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

  2. System-wide power management control via clock distribution network

    Science.gov (United States)

    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.

  3. Synthesizing genetic sequential logic circuit with clock pulse generator

    OpenAIRE

    Chuang, Chia-Hua; Lin, Chun-Liang

    2014-01-01

    Background 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. Results This paper presents a genetic sequential logic circuit with a clock pulse generator based on a synthesized genetic oscillator, which generates a consecut...

  4. Bayesian modeling using WinBUGS

    CERN Document Server

    Ntzoufras, Ioannis

    2009-01-01

    A hands-on introduction to the principles of Bayesian modeling using WinBUGS Bayesian Modeling Using WinBUGS provides an easily accessible introduction to the use of WinBUGS programming techniques in a variety of Bayesian modeling settings. The author provides an accessible treatment of the topic, offering readers a smooth introduction to the principles of Bayesian modeling with detailed guidance on the practical implementation of key principles. The book begins with a basic introduction to Bayesian inference and the WinBUGS software and goes on to cover key topics, including: Markov Chain Monte Carlo algorithms in Bayesian inference Generalized linear models Bayesian hierarchical models Predictive distribution and model checking Bayesian model and variable evaluation Computational notes and screen captures illustrate the use of both WinBUGS as well as R software to apply the discussed techniques. Exercises at the end of each chapter allow readers to test their understanding of the presented concepts and all ...

  5. Inside the Melanoplinae: new molecular evidence for the evolutionary history of the Eurasian Podismini (Orthoptera: Acrididae).

    Science.gov (United States)

    Chintauan-Marquier, Ioana C; Amédégnato, Christiane; Nichols, Richard A; Pompanon, François; Grandcolas, Philippe; Desutter-Grandcolas, Laure

    2014-02-01

    The Podismini are melanopline grasshoppers with a Holarctic distribution and well represented in the Eurasian fauna. To investigate their controversial taxonomy and evolutionary history, we studied 86%, 78% and 33% respectively of the Eurasian, European and Asian Palaearctic genera (Otte, 1995; Eades et al., 2013). We reconstructed parsimony, maximum likelihood and Bayesian phylogenies using fragments of four genes (ITS1, 16S, 12S, CO2). We applied a Bayesian molecular clock to estimate the times of species divergence, and the event-based parsimony method to depict the biogeographic framework of the diversification. Our results suggest that the selected Eurasian Podismini constitute a monophyletic group inside the Melanoplinae, provided it includes the North American genus Phaulotettix. The clades proposed by the present study inside the Podismini do not fit the older morphological or cytological classifications, but are in agreement with more recent proposals. Furthermore, our results can be explained by a plausible biogeographic history in which the present geographical distribution of the Eurasian Podismini resulted from known changes, to the Cenozoic climate and vegetation, induced by major geological events including the genesis of high mountain chains (e.g., Himalayas, Altay, Alps) and large deserts (e.g., Gobi, Karakoum, Taklamakan), and the opening of marginal seas (e.g., Bering, Japanese and Yellow Seas). Copyright © 2014. Published by Elsevier Inc.

  6. Green Web or megabiased clock? Plant fossils from Gondwanan Patagonia speak on evolutionary radiations.

    Science.gov (United States)

    Wilf, Peter; Escapa, Ignacio H

    2015-07-01

    Evolutionary divergence-age estimates derived from molecular 'clocks' are frequently correlated with paleogeographic, paleoclimatic and extinction events. One prominent hypothesis based on molecular data states that the dominant pattern of Southern Hemisphere biogeography is post-Gondwanan clade origins and subsequent dispersal across the oceans in a metaphoric 'Green Web'. We tested this idea against well-dated Patagonian fossils of 19 plant lineages, representing organisms that actually lived on Gondwana. Most of these occurrences are substantially older than their respective, often post-Gondwanan molecular dates. The Green Web interpretation probably results from directional bias in molecular results. Gondwanan history remains fundamental to understanding Southern Hemisphere plant radiations, and we urge significantly greater caution when using molecular dating to interpret the biological impacts of geological events. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  7. The mammalian circadian clock gene Per2 modulates cell death in response to oxidative stress

    Directory of Open Access Journals (Sweden)

    Maria Chiara Magnone

    2015-01-01

    Full Text Available Living in the earth’s oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS. Here we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell’s response to oxidative stress. Mouse embryonic fibroblasts (MEFs containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild type cells which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD+ ratio in the mutant cells is reversed by introduction of the wild type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process.

  8. The Mammalian circadian clock gene per2 modulates cell death in response to oxidative stress.

    Science.gov (United States)

    Magnone, Maria Chiara; Langmesser, Sonja; Bezdek, April Candice; Tallone, Tiziano; Rusconi, Sandro; Albrecht, Urs

    2014-01-01

    Living in the earth's oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS). Here, we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell's response to oxidative stress. Mouse embryonic fibroblasts (MEFs) containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild-type cells, which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD(+) ratio in the mutant cells is reversed by introduction of the wild-type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process.

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

    Directory of Open Access Journals (Sweden)

    Takao Hirai

    2015-11-01

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

  10. 3D Bayesian contextual classifiers

    DEFF Research Database (Denmark)

    Larsen, Rasmus

    2000-01-01

    We extend a series of multivariate Bayesian 2-D contextual classifiers to 3-D by specifying a simultaneous Gaussian distribution for the feature vectors as well as a prior distribution of the class variables of a pixel and its 6 nearest 3-D neighbours.......We extend a series of multivariate Bayesian 2-D contextual classifiers to 3-D by specifying a simultaneous Gaussian distribution for the feature vectors as well as a prior distribution of the class variables of a pixel and its 6 nearest 3-D neighbours....

  11. Bayesian image restoration, using configurations

    DEFF Research Database (Denmark)

    Thorarinsdottir, Thordis Linda

    2006-01-01

    In this paper, we develop a Bayesian procedure for removing noise from images that can be viewed as noisy realisations of random sets in the plane. The procedure utilises recent advances in configuration theory for noise free random sets, where the probabilities of observing the different boundary...... configurations are expressed in terms of the mean normal measure of the random set. These probabilities are used as prior probabilities in a Bayesian image restoration approach. Estimation of the remaining parameters in the model is outlined for the salt and pepper noise. The inference in the model is discussed...

  12. Bayesian image restoration, using configurations

    DEFF Research Database (Denmark)

    Thorarinsdottir, Thordis

    In this paper, we develop a Bayesian procedure for removing noise from images that can be viewed as noisy realisations of random sets in the plane. The procedure utilises recent advances in configuration theory for noise free random sets, where the probabilities of observing the different boundary...... configurations are expressed in terms of the mean normal measure of the random set. These probabilities are used as prior probabilities in a Bayesian image restoration approach. Estimation of the remaining parameters in the model is outlined for salt and pepper noise. The inference in the model is discussed...

  13. Bayesian variable selection in regression

    Energy Technology Data Exchange (ETDEWEB)

    Mitchell, T.J.; Beauchamp, J.J.

    1987-01-01

    This paper is concerned with the selection of subsets of ''predictor'' variables in a linear regression model for the prediction of a ''dependent'' variable. We take a Bayesian approach and assign a probability distribution to the dependent variable through a specification of prior distributions for the unknown parameters in the regression model. The appropriate posterior probabilities are derived for each submodel and methods are proposed for evaluating the family of prior distributions. Examples are given that show the application of the Bayesian methodology. 23 refs., 3 figs.

  14. Inference in hybrid Bayesian networks

    DEFF Research Database (Denmark)

    Lanseth, Helge; Nielsen, Thomas Dyhre; Rumí, Rafael

    2009-01-01

    Since the 1980s, Bayesian Networks (BNs) have become increasingly popular for building statistical models of complex systems. This is particularly true for boolean systems, where BNs often prove to be a more efficient modelling framework than traditional reliability-techniques (like fault trees a...... decade's research on inference in hybrid Bayesian networks. The discussions are linked to an example model for estimating human reliability....... and reliability block diagrams). However, limitations in the BNs' calculation engine have prevented BNs from becoming equally popular for domains containing mixtures of both discrete and continuous variables (so-called hybrid domains). In this paper we focus on these difficulties, and summarize some of the last...

  15. A Sizing Algorithm for Non-Overlapping Clock Signal Generators

    OpenAIRE

    Kavak, Fatih

    2004-01-01

    The non-overlapping clock signal generator circuits are key elements in switched capacitor circuits since non-overlapping clock signals are generally required. Non-overlapping clock signals means signals running at the same frequency and there is a time between the pulses that none of them is high. This time (when both pulses are logic 0) takes place when the pulses are switching from logic 1 to logic 0 or from logic 0 to logic 1. In this thesis this type of clock signal generators are analyz...

  16. 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.

  17. Diamond Electron-Spin Clocks For Space Navigation and Communication

    Data.gov (United States)

    National Aeronautics and Space Administration — Precision clocks are needed in a broad range of applications, including satellite communication, high-bandwidth wireless communication, computing systems, and...

  18. Crosstalk between the circadian clock and innate immunity in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Chong Zhang

    Full Text Available The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity.

  19. Improvement of an Atomic Clock using Squeezed Vacuum

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  20. Clock Genes: Critical Modulators of Breast Cancer Risk

    National Research Council Canada - National Science Library

    Kennaway, David J; Butler, Lisa M; Tilley, Wayne D

    2005-01-01

    .... Circadian rhythms are regulated by a panel of specific transcription factors, called clock genes, and our current understanding of endogenous cellular rhythmicity is that both positive and negative...

  1. Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda) Eyestalk.

    Science.gov (United States)

    Sbragaglia, Valerio; Lamanna, Francesco; M Mat, Audrey; Rotllant, Guiomar; Joly, Silvia; Ketmaier, Valerio; de la Iglesia, Horacio O; Aguzzi, Jacopo

    2015-01-01

    The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h) governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12-12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions) obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50) was equal to 1796 (light) and 2055 (darkness). We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI) with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79%) and Macrobrachium rosenbergii (clock: 100%). We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster.

  2. Bayesian methods for proteomic biomarker development

    Directory of Open Access Journals (Sweden)

    Belinda Hernández

    2015-12-01

    In this review we provide an introduction to Bayesian inference and demonstrate some of the advantages of using a Bayesian framework. We summarize how Bayesian methods have been used previously in proteomics and other areas of bioinformatics. Finally, we describe some popular and emerging Bayesian models from the statistical literature and provide a worked tutorial including code snippets to show how these methods may be applied for the evaluation of proteomic biomarkers.

  3. Bayesian variable order Markov models: Towards Bayesian predictive state representations

    NARCIS (Netherlands)

    Dimitrakakis, C.

    2009-01-01

    We present a Bayesian variable order Markov model that shares many similarities with predictive state representations. The resulting models are compact and much easier to specify and learn than classical predictive state representations. Moreover, we show that they significantly outperform a more

  4. The humble Bayesian : Model checking from a fully Bayesian perspective

    NARCIS (Netherlands)

    Morey, Richard D.; Romeijn, Jan-Willem; Rouder, Jeffrey N.

    Gelman and Shalizi (2012) criticize what they call the usual story in Bayesian statistics: that the distribution over hypotheses or models is the sole means of statistical inference, thus excluding model checking and revision, and that inference is inductivist rather than deductivist. They present

  5. The intestinal microbiota regulates body composition through NFIL3and the circadian clock.

    Science.gov (United States)

    Wang, Yuhao; Kuang, Zheng; Yu, Xiaofei; Ruhn, Kelly A; Kubo, Masato; Hooper, Lora V

    2017-09-01

    The intestinal microbiota has been identified as an environmental factor that markedly affects energy storage and body-fat accumulation in mammals, yet the underlying mechanisms remain unclear. Here we show that the microbiota regulates body composition through the circadian transcription factor NFIL3. Nfil3 transcription oscillates diurnally in intestinal epithelial cells, and the amplitude of the circadian oscillation is controlled by the microbiota through group 3 innate lymphoid cells, STAT3 (signal transducer and activator of transcription 3), and the epithelial cell circadian clock. NFIL3 controls expression of a circadian lipid metabolic program and regulates lipid absorption and export in intestinal epithelial cells. These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism. Copyright © 2017, American Association for the Advancement of Science.

  6. The Root Growth-Regulating Brevicompanine Natural Products Modulate the Plant Circadian Clock.

    Science.gov (United States)

    de Montaigu, Amaury; Oeljeklaus, Julian; Krahn, Jan H; Suliman, Mohamed N S; Halder, Vivek; de Ansorena, Elisa; Nickel, Sabrina; Schlicht, Markus; Plíhal, Ondřej; Kubiasová, Karolina; Radová, Lenka; Kracher, Barbara; Tóth, Réka; Kaschani, Farnusch; Coupland, George; Kombrink, Erich; Kaiser, Markus

    2017-06-16

    Plant growth regulating properties of brevicompanines (Brvs), natural products of the fungus Penicillium brevicompactum, have been known for several years, but further investigations into the molecular mechanism of their bioactivity have not been performed. Following chemical synthesis of brevicompanine derivatives, we studied their activity in the model plant Arabidopsis by a combination of plant growth assays, transcriptional profiling, and numerous additional bioassays. These studies demonstrated that brevicompanines cause transcriptional misregulation of core components of the circadian clock, whereas other biological read-outs were not affected. Brevicompanines thus represent promising chemical tools for investigating the regulation of the plant circadian clock. In addition, our study also illustrates the potential of an unbiased -omics-based characterization of bioactive compounds for identifying the often cryptic modes of action of small molecules.

  7. Bayesian Model Averaging for Propensity Score Analysis

    Science.gov (United States)

    Kaplan, David; Chen, Jianshen

    2013-01-01

    The purpose of this study is to explore Bayesian model averaging in the propensity score context. Previous research on Bayesian propensity score analysis does not take into account model uncertainty. In this regard, an internally consistent Bayesian framework for model building and estimation must also account for model uncertainty. The…

  8. Bayesian models in cognitive neuroscience: A tutorial

    NARCIS (Netherlands)

    O'Reilly, J.X.; Mars, R.B.

    2015-01-01

    This chapter provides an introduction to Bayesian models and their application in cognitive neuroscience. The central feature of Bayesian models, as opposed to other classes of models, is that Bayesian models represent the beliefs of an observer as probability distributions, allowing them to

  9. A Bayesian framework for risk perception

    NARCIS (Netherlands)

    van Erp, H.R.N.

    2017-01-01

    We present here a Bayesian framework of risk perception. This framework encompasses plausibility judgments, decision making, and question asking. Plausibility judgments are modeled by way of Bayesian probability theory, decision making is modeled by way of a Bayesian decision theory, and relevancy

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

    Czech Academy of Sciences Publication Activity Database

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

    2013-01-01

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

  11. Code-Phase Clock Bias and Frequency Offset in PPP Clock Solutions.

    Science.gov (United States)

    Defraigne, Pascale; Sleewaegen, Jean-Marie

    2016-07-01

    Precise point positioning (PPP) is a zero-difference single-station technique that has proved to be very effective for time and frequency transfer, enabling the comparison of atomic clocks with a precision of a hundred picoseconds and a one-day stability below the 1e-15 level. It was, however, noted that for some receivers, a frequency difference is observed between the clock solution based on the code measurements and the clock solution based on the carrier-phase measurements. These observations reveal some inconsistency either between the code and carrier phases measured by the receiver or between the data analysis strategy of codes and carrier phases. One explanation for this discrepancy is the time offset that can exist for some receivers between the code and the carrier-phase latching. This paper explains how a code-phase bias in the receiver hardware can induce a frequency difference between the code and the carrier-phase clock solutions. The impact on PPP is then quantified. Finally, the possibility to determine this code-phase bias in the PPP modeling is investigated, and the first results are shown to be inappropriate due to the high level of code noise.

  12. Circadian expression of clock genes and clock-controlled genes in the rat retina

    NARCIS (Netherlands)

    Kamphuis, Willem; Cailotto, Cathy; Dijk, Frederike; Bergen, Arthur; Buijs, Ruud M.

    2005-01-01

    The circadian expression patterns of genes encoding for proteins that make up the core of the circadian clock were measured in rat retina using real-time quantitative PCR (qPCR). Transcript levels of several genes previously used for normalization of qPCR assays were determined and the effect of

  13. Comparisons of Synchronous-Clocking SFQ Adders

    Science.gov (United States)

    Takagi, Naofumi; Tanaka, Masamitsu

    Recent advances of superconducting single-flux-quantum (SFQ) circuit technology make it attractive to investigate computing systems using SFQ circuits, where arithmetic circuits play important roles. In order to develop excellent SFQ arithmetic circuits, we have to design or select their underlying algorithms, called hardware algorithms, from different point of view than CMOS circuits, because SFQ circuits work by pulse logic while CMOS circuits work by level logic. In this paper, we compare implementations of hardware algorithms for addition by synchronous-clocking SFQ circuits. We show that a set of individual bit-serial adders and Kogge-Stone adder are superior to others.

  14. Mass defect effects in atomic clocks

    Science.gov (United States)

    Yudin, Valeriy; Taichenachev, Alexey

    2018-03-01

    We consider some implications of the mass defect on the frequency of atomic transitions. We have found that some well-known frequency shifts (the gravitational shift and motion-induced shifts such as quadratic Doppler and micromotion shifts) can be interpreted as consequences of the mass defect in quantum atomic physics, i.e. without the need for the concept of time dilation used in special and general relativity theories. Moreover, we show that the inclusion of the mass defect leads to previously unknown shifts for clocks based on trapped ions.

  15. Laser Cooled Atomic Clocks in Space

    Science.gov (United States)

    Thompson, R. J.; Kohel, J.; Klipstein, W. M.; Seidel, D. J.; Maleki, L.

    2000-01-01

    The goals of the Glovebox Laser-cooled Atomic Clock Experiment (GLACE) are: (1) first utilization of tunable, frequency-stabilized lasers in space, (2) demonstrate laser cooling and trapping in microgravity, (3) demonstrate longest 'perturbation-free' interaction time for a precision measurement on neutral atoms, (4) Resolve Ramsey fringes 2-10 times narrower than achievable on Earth. The approach taken is: the use of COTS components, and the utilization of prototype hardware from LCAP flight definition experiments. The launch date is scheduled for Oct. 2002. The Microgravity Science Glovebox (MSG) specifications are reviewed, and a picture of the MSG is shown.

  16. TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced inflammatory cytokines in human keratinocytes.

    Science.gov (United States)

    Park, Sunyoung; Kim, Kyuhan; Bae, Il-Hong; Lee, Sung Hoon; Jung, Jiyong; Lee, Tae Ryong; Cho, Eun-Gyung

    2018-03-01

    As the outermost physical barrier of an organism, the skin is diurnally exposed to UV radiation (UVR). Recent studies have revealed that the skin exhibits a circadian rhythm in various functions, and this oscillation is disturbed and reset via a strong environmental cue, the UVR. However, a molecular link between circadian perturbation by UVR and UVR-induced cellular responses has not been investigated. We identified tissue inhibitor of metalloproteinase ( TIMP)- 3 as a novel circadian locomotor output cycles kaput (CLOCK)-dependent diurnal gene by using a CLOCK-knockdown strategy in human keratinocytes. Among dozens of identified transcripts down-regulated by CLOCK knockdown, TIMP3 displayed a rhythmic expression in a CLOCK-dependent manner, in which the expression of matrix metalloproteinase (MMP)-1 and inflammatory cytokines, such as TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and IL-8, were inversely regulated. Upon UVB exposure, the expression of CLOCK and TIMP3 was down-regulated, which led to an up-regulation of secretion of MMP1 and TNF-α proteins and in the transcription of CXCL1 and IL-8 via CCAAT-enhancer binding protein (C/EBP)-α. UVB-induced TNF-α secretion increased further or decreased by knockdown or overexpression of TIMP3, respectively, as well as by CLOCK. As a novel CLOCK-dependent diurnal gene, TIMP3 inhibits the expression of inflammatory cytokines that are up-regulated by UV irradiation in human keratinocytes. Thus, our work suggests a molecular link between circadian perturbation by UVR and UVR-induced inflammation.-Park, S., Kim, K., Bae, I.-H., Lee, S. H., Jung, J., Lee, T. R., Cho, E.-G. TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced inflammatory cytokines in human keratinocytes.

  17. Alteration of the circadian clock in children with Smith-Magenis syndrome.

    Science.gov (United States)

    Nováková, Marta; Nevsímalová, Sona; Príhodová, Iva; Sládek, Martin; Sumová, Alena

    2012-02-01

    Smith-Magenis syndrome (SMS) is associated with sleep disturbances and disrupted melatonin production. The study aimed to ascertain whether the sleep and melatonin production anomalies in SMS patients may be due to an alteration of the molecular mechanism of the circadian clock. Five SMS patients (3-17 yr old) and five healthy age-matched control subjects were involved in the study. Saliva and buccal scrub samples were collected every 4 h during a 24-h period. Daily profiles of melatonin were determined in saliva using a direct double-antibody radioimmunoassay. Daily profiles of clock gene mRNA levels (Per1, Per2, and Rev-erbα) were determined in buccal scrub samples by RT-PCR. In controls, melatonin levels were elevated during the nighttime and very low during the daytime. Daily profiles of clock genes, Per1, Per2, and Rev-erbα, mRNA levels in buccal mucosa exhibited significant and mutually synchronized circadian variations (Per1 and Rev-erbα: P < 0.001; Per2: P < 0.05); the mRNA levels were elevated during the daytime and decreased during the nighttime. In SMS patients, melatonin profiles were significantly altered compared with controls, being phase reversed, phase advanced, depressed, or abolished. Only Per1 and Rev-erbα mRNA profiles exhibited significant circadian rhythms (P < 0.05); the Per2 expression exhibited high variability, and the profile was out of phase with the other clock genes. Our findings suggest that the anomalies in melatonin profiles of SMS patients might be due to a disturbance of the molecular circadian clockwork.

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

    NARCIS (Netherlands)

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

    2017-01-01

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

  19. Differentiated Bayesian Conjoint Choice Designs

    NARCIS (Netherlands)

    Z. Sándor (Zsolt); M. Wedel (Michel)

    2003-01-01

    textabstractPrevious conjoint choice design construction procedures have produced a single design that is administered to all subjects. This paper proposes to construct a limited set of different designs. The designs are constructed in a Bayesian fashion, taking into account prior uncertainty about

  20. Bayesian networks in levee reliability

    NARCIS (Netherlands)

    Roscoe, K.; Hanea, A.

    2015-01-01

    We applied a Bayesian network to a system of levees for which the results of traditional reliability analysis showed high failure probabilities, which conflicted with the intuition and experience of those managing the levees. We made use of forty proven strength observations - high water levels with

  1. Bayesian Classification of Image Structures

    DEFF Research Database (Denmark)

    Goswami, Dibyendu; Kalkan, Sinan; Krüger, Norbert

    2009-01-01

    In this paper, we describe work on Bayesian classi ers for distinguishing between homogeneous structures, textures, edges and junctions. We build semi-local classiers from hand-labeled images to distinguish between these four different kinds of structures based on the concept of intrinsic...... dimensionality. The built classi er is tested on standard and non-standard images...

  2. Computational Neuropsychology and Bayesian Inference.

    Science.gov (United States)

    Parr, Thomas; Rees, Geraint; Friston, Karl J

    2018-01-01

    Computational theories of brain function have become very influential in neuroscience. They have facilitated the growth of formal approaches to disease, particularly in psychiatric research. In this paper, we provide a narrative review of the body of computational research addressing neuropsychological syndromes, and focus on those that employ Bayesian frameworks. Bayesian approaches to understanding brain function formulate perception and action as inferential processes. These inferences combine 'prior' beliefs with a generative (predictive) model to explain the causes of sensations. Under this view, neuropsychological deficits can be thought of as false inferences that arise due to aberrant prior beliefs (that are poor fits to the real world). This draws upon the notion of a Bayes optimal pathology - optimal inference with suboptimal priors - and provides a means for computational phenotyping. In principle, any given neuropsychological disorder could be characterized by the set of prior beliefs that would make a patient's behavior appear Bayes optimal. We start with an overview of some key theoretical constructs and use these to motivate a form of computational neuropsychology that relates anatomical structures in the brain to the computations they perform. Throughout, we draw upon computational accounts of neuropsychological syndromes. These are selected to emphasize the key features of a Bayesian approach, and the possible types of pathological prior that may be present. They range from visual neglect through hallucinations to autism. Through these illustrative examples, we review the use of Bayesian approaches to understand the link between biology and computation that is at the heart of neuropsychology.

  3. Bayesian Alternation During Tactile Augmentation

    Directory of Open Access Journals (Sweden)

    Caspar Mathias Goeke

    2016-10-01

    Full Text Available A large number of studies suggest that the integration of multisensory signals by humans is well described by Bayesian principles. However, there are very few reports about cue combination between a native and an augmented sense. In particular, we asked the question whether adult participants are able to integrate an augmented sensory cue with existing native sensory information. Hence for the purpose of this study we build a tactile augmentation device. Consequently, we compared different hypotheses of how untrained adult participants combine information from a native and an augmented sense. In a two-interval forced choice (2 IFC task, while subjects were blindfolded and seated on a rotating platform, our sensory augmentation device translated information on whole body yaw rotation to tactile stimulation. Three conditions were realized: tactile stimulation only (augmented condition, rotation only (native condition, and both augmented and native information (bimodal condition. Participants had to choose one out of two consecutive rotations with higher angular rotation. For the analysis, we fitted the participants’ responses with a probit model and calculated the just notable difference (JND. Then we compared several models for predicting bimodal from unimodal responses. An objective Bayesian alternation model yielded a better prediction (χred2 = 1.67 than the Bayesian integration model (χred2= 4.34. Slightly higher accuracy showed a non-Bayesian winner takes all model (χred2= 1.64, which either used only native or only augmented values per subject for prediction. However the performance of the Bayesian alternation model could be substantially improved (χred2= 1.09 utilizing subjective weights obtained by a questionnaire. As a result, the subjective Bayesian alternation model predicted bimodal performance most accurately among all tested models. These results suggest that information from augmented and existing sensory modalities in

  4. Topics in Bayesian statistics and maximum entropy

    International Nuclear Information System (INIS)

    Mutihac, R.; Cicuttin, A.; Cerdeira, A.; Stanciulescu, C.

    1998-12-01

    Notions of Bayesian decision theory and maximum entropy methods are reviewed with particular emphasis on probabilistic inference and Bayesian modeling. The axiomatic approach is considered as the best justification of Bayesian analysis and maximum entropy principle applied in natural sciences. Particular emphasis is put on solving the inverse problem in digital image restoration and Bayesian modeling of neural networks. Further topics addressed briefly include language modeling, neutron scattering, multiuser detection and channel equalization in digital communications, genetic information, and Bayesian court decision-making. (author)

  5. Bayesian analysis of rare events

    Science.gov (United States)

    Straub, Daniel; Papaioannou, Iason; Betz, Wolfgang

    2016-06-01

    In many areas of engineering and science there is an interest in predicting the probability of rare events, in particular in applications related to safety and security. Increasingly, such predictions are made through computer models of physical systems in an uncertainty quantification framework. Additionally, with advances in IT, monitoring and sensor technology, an increasing amount of data on the performance of the systems is collected. This data can be used to reduce uncertainty, improve the probability estimates and consequently enhance the management of rare events and associated risks. Bayesian analysis is the ideal method to include the data into the probabilistic model. It ensures a consistent probabilistic treatment of uncertainty, which is central in the prediction of rare events, where extrapolation from the domain of observation is common. We present a framework for performing Bayesian updating of rare event probabilities, termed BUS. It is based on a reinterpretation of the classical rejection-sampling approach to Bayesian analysis, which enables the use of established methods for estimating probabilities of rare events. By drawing upon these methods, the framework makes use of their computational efficiency. These methods include the First-Order Reliability Method (FORM), tailored importance sampling (IS) methods and Subset Simulation (SuS). In this contribution, we briefly review these methods in the context of the BUS framework and investigate their applicability to Bayesian analysis of rare events in different settings. We find that, for some applications, FORM can be highly efficient and is surprisingly accurate, enabling Bayesian analysis of rare events with just a few model evaluations. In a general setting, BUS implemented through IS and SuS is more robust and flexible.

  6. The Renaissance or the cuckoo clock.

    Science.gov (United States)

    Pines, Jonathon; Hagan, Iain

    2011-12-27

    '…in Italy, for thirty years under the Borgias, they had warfare, terror, murder and bloodshed, but they produced Michelangelo, Leonardo da Vinci and the Renaissance. In Switzerland, they had brotherly love, they had five hundred years of democracy and peace-and what did that produce? The cuckoo clock'. Orson Welles as Harry Lime: The Third Man. Orson Welles might have been a little unfair on the Swiss, after all cuckoo clocks were developed in the Schwartzwald, but, more importantly, Swiss democracy gives remarkably stable government with considerable decision-making at the local level. The alternative is the battling city-states of Renaissance Italy: culturally rich but chaotic at a higher level of organization. As our understanding of the cell cycle improves, it appears that the cell is organized more along the lines of Switzerland than Renaissance Italy, and one major challenge is to determine how local decisions are made and coordinated to produce the robust cell cycle mechanisms that we observe in the cell as a whole.

  7. Synthetic clock transitions via continuous dynamical decoupling

    Science.gov (United States)

    Trypogeorgos, D.; Valdés-Curiel, A.; Lundblad, N.; Spielman, I. B.

    2018-01-01

    Decoherence of quantum systems due to uncontrolled fluctuations of the environment presents fundamental obstacles in quantum science. Clock transitions which are insensitive to such fluctuations are used to improve coherence, however, they are not present in all systems or for arbitrary system parameters. Here we create a trio of synthetic clock transitions using continuous dynamical decoupling in a spin-1 Bose-Einstein condensate in which we observe a reduction of sensitivity to magnetic-field noise of up to four orders of magnitude; this work complements the parallel work by Anderson et al. [R. P. Anderson et al., following paper, Phys. Rev. A 97, 013408 (2018), 10.1103/PhysRevA.97.013408]. In addition, using a concatenated scheme, we demonstrate suppression of sensitivity to fluctuations in our control fields. These field-insensitive states represent an ideal foundation for the next generation of cold-atom experiments focused on fragile many-body phases relevant to quantum magnetism, artificial gauge fields, and topological matter.

  8. Temperature-Compensated Clock Skew Adjustment

    Directory of Open Access Journals (Sweden)

    Joaquín Olivares

    2013-08-01

    Full Text Available This work analyzes several drift compensation mechanisms in wireless sensor networks (WSN. Temperature is an environmental factor that greatly affects oscillators shipped in every WSN mote. This behavior creates the need of improving drift compensation mechanisms in synchronization protocols. Using the Flooding Time Synchronization Protocol (FTSP, this work demonstrates that crystal oscillators are affected by temperature variations. Thus, the influence of temperature provokes a low performance of FTSP in changing conditions of temperature. This article proposes an innovative correction factor that minimizes the impact of temperature in the clock skew. By means of this factor, two new mechanisms are proposed in this paper: the Adjusted Temperature (AT and the Advanced Adjusted Temperature (A2T. These mechanisms have been combined with FTSP to produce AT-FTSP and A2T-FTSP. Both have been tested in a network of TelosB motes running TinyOS. Results show that both AT-FTSP and A2T-FTSP improve the average synchronization errors compared to FTSP and other temperature-compensated protocols (Environment-Aware Clock Skew Estimation and Synchronization for WSN (EACS and Temperature Compensated Time Synchronization (TCTS.

  9. The Clock Gene Rev-Erbα Regulates Methamphetamine Actions on Circadian Timekeeping in the Mouse Brain.

    Science.gov (United States)

    Salaberry, Nora L; Mateo, Maria; Mendoza, Jorge

    2017-09-01

    Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction.

  10. Circadian clock genes universally control key agricultural traits

    Science.gov (United States)

    Circadian clocks are endogenous timers that enable plants to synchronize biological processes with daily and seasonal environmental conditions in order to allocate resources during the most beneficial times of day and year. The circadian clock regulates a number of central plant activities, includin...

  11. Verge and Foliot Clock Escapement: A Simple Dynamical System

    Science.gov (United States)

    Denny, Mark

    2010-01-01

    The earliest mechanical clocks appeared in Europe in the 13th century. From about 1250 CE to 1670 CE, these simple clocks consisted of a weight suspended from a rope or chain that was wrapped around a horizontal axle. To tell time, the weight must fall with a slow uniform speed, but, under the action of gravity alone, such a suspended weight would…

  12. A CONSTANT-FREQUENCY POWER SUPPLY FOR SHIPBOARD ELECTRIC CLOCKS,

    Science.gov (United States)

    static inverter-type power supply , capable of powering up to six internally illuminated clocks per MIL-C-23339, with timekeeping accuracy better than...of a development model of this power supply are described. It is recommended that units of this type be procured for installation in control spaces of ships equipped with electric clocks. (Author)

  13. Self-clocked sequential circuits: - a design example | Aghdasi ...

    African Journals Online (AJOL)

    A number of new design methodologies which involve locally generating a clock and using it to self synchronize the machine have been proposed. Such clock signals are generated whenever an input changes, or by controlled excitation whenever a change of inputs necessitates a change of state. All such designs, where ...

  14. Optimal Infinite Runs in One-Clock Priced Timed Automata

    DEFF Research Database (Denmark)

    David, Alexandre; Ejsing-Duun, Daniel; Fontani, Lisa

    We address the problem of finding an infinite run with the optimal cost-time ratio in a one-clock priced timed automaton and pro- vide an algorithmic solution. Through refinements of the quotient graph obtained by strong time-abstracting bisimulation partitioning, we con- struct a graph with time...... of the one-clock priced timed automaton....

  15. Determination of clock synchronization errors in distributed networks

    NARCIS (Netherlands)

    Xia, Weiguo; Cao, Ming

    2018-01-01

    It has been shown by Freris, Graham and Kumar that clocks in distributed networks cannot be synchronized precisely in the presence of asymmetric time delays even in idealized situations. Motivated by that impossibility result, we test under similar settings the performance of some existing clock

  16. A Novel Method of Clock Synchronization in Distributed Systems

    Science.gov (United States)

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

    2017-04-01

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

  17. The circadian clock regulates auxin signaling and responses in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Michael F Covington

    2007-08-01

    Full Text Available The circadian clock plays a pervasive role in the temporal regulation of plant physiology, environmental responsiveness, and development. In contrast, the phytohormone auxin plays a similarly far-reaching role in the spatial regulation of plant growth and development. Went and Thimann noted 70 years ago that plant sensitivity to auxin varied according to the time of day, an observation that they could not explain. Here we present work that explains this puzzle, demonstrating that the circadian clock regulates auxin signal transduction. Using genome-wide transcriptional profiling, we found many auxin-induced genes are under clock regulation. We verified that endogenous auxin signaling is clock regulated with a luciferase-based assay. Exogenous auxin has only modest effects on the plant clock, but the clock controls plant sensitivity to applied auxin. Notably, we found both transcriptional and growth responses to exogenous auxin are gated by the clock. Thus the circadian clock regulates some, and perhaps all, auxin responses. Consequently, many aspects of plant physiology not previously thought to be under circadian control may show time-of-day-specific sensitivity, with likely important consequences for plant growth and environmental responses.

  18. 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

  19. Frequency comparison of optical lattice clocks beyond the Dick limit

    Science.gov (United States)

    Takamoto, Masao; Takano, Tetsushi; Katori, Hidetoshi

    2011-05-01

    The supreme accuracy of atomic clocks relies on the universality of atomic transition frequencies. The stability of a clock, meanwhile, measures how quickly the clock's statistical uncertainties are reduced. The ultimate measure of stability is provided by the quantum projection noise, which improves as 1/√N by measuring N uncorrelated atoms. Quantum projection noise limited stabilities have been demonstrated in caesium clocks and in single-ion optical clocks, where the quantum noise overwhelms the Dick effect attributed to local oscillator noise. Here, we demonstrate a synchronous frequency comparison of two optical lattice clocks using 87Sr and 88Sr atoms, respectively, for which the Allan standard deviation reached 1 × 10-17 in an averaging time of 1,600 s by cancelling out the Dick effect to approach the quantum projection noise limit. The scheme demonstrates the advantage of using a large number (N ~ 1,000) of atoms in optical clocks and paves the way to investigating the inherent uncertainties of clocks and relativistic geodesy on a timescale of tens of minutes.

  20. Development and entrainment of the colonic circadian clock during ontogenesis

    Czech Academy of Sciences Publication Activity Database

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

    2014-01-01

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

  1. LC-oscillator as a clock for data conversion

    NARCIS (Netherlands)

    Philips, K.J.P.; Verlinden, J.J.A.M.

    2006-01-01

    Following the ever-improving performance of data converters, the accuracy of the clock that is sampling the converter, needs to improveat the same pace. The clock accuracy is especially a problem for high-resolution, wide bandwidth converters.The aim of this project isto provide for a

  2. Clock synchronisation experiment in India using symphonie satellite

    Science.gov (United States)

    Somayajulu, Y. V.; Mathur, B. S.; Banerjee, P.; Garg, S. C.; Singh, L.; Sood, P. C.; Tyagi, T. R.; Jain, C. L.; Kumar, K.

    1979-01-01

    A recent clock synchronization experiment between the National Physical Laboratory (NPL), New Delhi and Space Applications Center (SAC), Ahemedabad, in India via geostationary satellite symphonie 2, stationed at 49 E longitude, is reported. A two-way transmission using a microwave transponder considered to provide the greatest precision in synchronization of two remote clocks is described.

  3. Bayesian methods for measures of agreement

    CERN Document Server

    Broemeling, Lyle D

    2009-01-01

    Using WinBUGS to implement Bayesian inferences of estimation and testing hypotheses, Bayesian Methods for Measures of Agreement presents useful methods for the design and analysis of agreement studies. It focuses on agreement among the various players in the diagnostic process.The author employs a Bayesian approach to provide statistical inferences based on various models of intra- and interrater agreement. He presents many examples that illustrate the Bayesian mode of reasoning and explains elements of a Bayesian application, including prior information, experimental information, the likelihood function, posterior distribution, and predictive distribution. The appendices provide the necessary theoretical foundation to understand Bayesian methods as well as introduce the fundamentals of programming and executing the WinBUGS software.Taking a Bayesian approach to inference, this hands-on book explores numerous measures of agreement, including the Kappa coefficient, the G coefficient, and intraclass correlation...

  4. The quantum beat principles and applications of atomic clocks

    CERN Document Server

    Major, F

    2007-01-01

    This work attempts to convey a broad understanding of the physical principles underlying the workings of these quantum-based atomic clocks, with introductory chapters placing them in context with the early development of mechanical clocks and the introduction of electronic time-keeping as embodied in the quartz-controlled clocks. While the book makes no pretense at being a history of atomic clocks, it nevertheless takes a historical perspective in its treatment of the subject. Intended for nonspecialists with some knowledge of physics or engineering, The Quantum Beat covers a wide range of salient topics relevant to atomic clocks, treated in a broad intuitive manner with a minimum of mathematical formalism. Detailed descriptions are given of the design principles of the rubidium, cesium, hydrogen maser, and mercury ion standards; the revolutionary changes that the advent of the laser has made possible, such as laser cooling, optical pumping, the formation of "optical molasses," and the cesium "fountain" stand...

  5. A self-interfering clock as a "which path" witness.

    Science.gov (United States)

    Margalit, Yair; Zhou, Zhifan; Machluf, Shimon; Rohrlich, Daniel; Japha, Yonathan; Folman, Ron

    2015-09-11

    In Einstein's general theory of relativity, time depends locally on gravity; in standard quantum theory, time is global-all clocks "tick" uniformly. We demonstrate a new tool for investigating time in the overlap of these two theories: a self-interfering clock, comprising two atomic spin states. We prepare the clock in a spatial superposition of quantum wave packets, which evolve coherently along two paths into a stable interference pattern. If we make the clock wave packets "tick" at different rates, to simulate a gravitational time lag, the clock time along each path yields "which path" information, degrading the pattern's visibility. In contrast, in standard interferometry, time cannot yield "which path" information. This proof-of-principle experiment may have implications for the study of time and general relativity and their impact on fundamental effects such as decoherence and the emergence of a classical world. Copyright © 2015, American Association for the Advancement of Science.

  6. Standard Clock in primordial density perturbations and cosmic microwave background

    International Nuclear Information System (INIS)

    Chen, Xingang; Namjoo, Mohammad Hossein

    2014-01-01

    Standard Clocks in the primordial epoch leave a special type of features in the primordial perturbations, which can be used to directly measure the scale factor of the primordial universe as a function of time a(t), thus discriminating between inflation and alternatives. We have started to search for such signals in the Planck 2013 data using the key predictions of the Standard Clock. In this Letter, we summarize the key predictions of the Standard Clock and present an interesting candidate example in Planck 2013 data. Motivated by this candidate, we construct and compute full Standard Clock models and use the more complete prediction to make more extensive comparison with data. Although this candidate is not yet statistically significant, we use it to illustrate how Standard Clocks appear in Cosmic Microwave Background (CMB) and how they can be further tested by future data. We also use it to motivate more detailed theoretical model building

  7. The absolute frequency of the 87Sr optical clock transition

    DEFF Research Database (Denmark)

    Campbell, Gretchen K.; Ludlow, Andrew D.; Blatt, Sebastian

    2008-01-01

    The absolute frequency of the 1S0–3P0 clock transition of 87Sr has been measured to be 429 228 004 229 873.65 (37) Hz using lattice-confined atoms, where the fractional uncertainty of 8.6 × 10-16 represents one of the most accurate measurements of an atomic transition frequency to date. After...... a detailed study of systematic effects, which reduced the total systematic uncertainty of the Sr lattice clock to 1.5 × 10-16, the clock frequency is measured against a hydrogen maser which is simultaneously calibrated to the US primary frequency standard, the NIST Cs fountain clock, NIST-F1. The comparison...... is made possible using a femtosecond laser based optical frequency comb to phase coherently connect the optical and microwave spectral regions and by a 3.5 km fibre transfer scheme to compare the remotely located clock signals....

  8. Hyperpolarizability and Operational Magic Wavelength in an Optical Lattice Clock

    Science.gov (United States)

    Brown, R. C.; Phillips, N. B.; Beloy, K.; McGrew, W. F.; Schioppo, M.; Fasano, R. J.; Milani, G.; Zhang, X.; Hinkley, N.; Leopardi, H.; Yoon, T. H.; Nicolodi, D.; Fortier, T. M.; Ludlow, A. D.

    2017-12-01

    Optical clocks benefit from tight atomic confinement enabling extended interrogation times as well as Doppler- and recoil-free operation. However, these benefits come at the cost of frequency shifts that, if not properly controlled, may degrade clock accuracy. Numerous theoretical studies have predicted optical lattice clock frequency shifts that scale nonlinearly with trap depth. To experimentally observe and constrain these shifts in an 171Yb optical lattice clock, we construct a lattice enhancement cavity that exaggerates the light shifts. We observe an atomic temperature that is proportional to the optical trap depth, fundamentally altering the scaling of trap-induced light shifts and simplifying their parametrization. We identify an "operational" magic wavelength where frequency shifts are insensitive to changes in trap depth. These measurements and scaling analysis constitute an essential systematic characterization for clock operation at the 10-18 level and beyond.

  9. Standard Clock in primordial density perturbations and cosmic microwave background

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    Xingang Chen

    2014-12-01

    Full Text Available Standard Clocks in the primordial epoch leave a special type of features in the primordial perturbations, which can be used to directly measure the scale factor of the primordial universe as a function of time a(t, thus discriminating between inflation and alternatives. We have started to search for such signals in the Planck 2013 data using the key predictions of the Standard Clock. In this Letter, we summarize the key predictions of the Standard Clock and present an interesting candidate example in Planck 2013 data. Motivated by this candidate, we construct and compute full Standard Clock models and use the more complete prediction to make more extensive comparison with data. Although this candidate is not yet statistically significant, we use it to illustrate how Standard Clocks appear in Cosmic Microwave Background (CMB and how they can be further tested by future data. We also use it to motivate more detailed theoretical model building.

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

    Science.gov (United States)

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

    2009-01-01

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

  11. The Retina and other Light Sensitive Ocular Clocks

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    Besharse, Joseph C.; McMahon, Douglas G.

    2017-01-01

    Ocular clocks, first identified in the retina, are also found in the retinal pigment epithelium (RPE), cornea and ciliary body. The retina is a complex tissue of many cell types and considerable effort has gone into determining which cell types exhibit clock properties. Current data suggest that photoreceptors as well as inner retinal neurons exhibit clock properties with photoreceptors dominating in non-mammalian vertebrates and inner retinal neurons dominating in mice. However, these differences may in part reflect the choice of circadian output, and it is likely that clock properties are widely dispersed among many retinal cell types. The phase of the retinal clock can be set directly by light. In non-mammalian vertebrates direct light sensitivity is commonplace among body clocks, but in mice only the retina and cornea retain direct light-dependent phase regulation. This distinguishes the retina and possibly other ocular clocks from peripheral oscillators whose phase depends on the pace-making properties of the hypothalamic central brain clock, the suprachiasmatic nuclei (SCN). However, in mice retinal circadian oscillations dampen quickly in isolation due to weak coupling of its individual cell autonomous oscillators and there is no evidence that retinal clocks are directly controlled through input from other oscillators. Retinal circadian regulation in both mammals and non-mammalian vertebrates uses melatonin and dopamine as dark- and light-adaptive neuromodulators respectively, and light can regulate circadian phase indirectly through dopamine signaling. The melatonin/dopamine system appears to have evolved among non-mammalian vertebrates and retained with modification in mammals. Circadian clocks in the eye are critical for optimum visual function where they play a role fine tuning visual sensitivity, and their disruption can impact diseases such as glaucoma or retinal degeneration syndromes. PMID:27095816

  12. Circadian Clock Involvement in Zooplankton Diel Vertical Migration.

    Science.gov (United States)

    Häfker, N Sören; Meyer, Bettina; Last, Kim S; Pond, David W; Hüppe, Lukas; Teschke, Mathias

    2017-07-24

    Biological clocks are a ubiquitous ancient and adaptive mechanism enabling organisms to anticipate environmental cycles and to regulate behavioral and physiological processes accordingly [1]. Although terrestrial circadian clocks are well understood, knowledge of clocks in marine organisms is still very limited [2-5]. This is particularly true for abundant species displaying large-scale rhythms like diel vertical migration (DVM) that contribute significantly to shaping their respective ecosystems [6]. Here we describe exogenous cycles and endogenous rhythms associated with DVM of the ecologically important and highly abundant planktic copepod Calanus finmarchicus. In the laboratory, C. finmarchicus shows circadian rhythms of DVM, metabolism, and most core circadian clock genes (clock, period1, period2, timeless, cryptochrome2, and clockwork orange). Most of these genes also cycle in animals assessed in the wild, though expression is less rhythmic at depth (50-140 m) relative to shallow-caught animals (0-50 m). Further, peak expressions of clock genes generally occurred at either sunset or sunrise, coinciding with peak migration times. Including one of the first field investigations of clock genes in a marine species [5, 7], this study couples clock gene measurements with laboratory and field data on DVM. While the mechanistic connection remains elusive, our results imply a high degree of causality between clock gene expression and one of the planet's largest daily migrations of biomass. We thus suggest that circadian clocks increase zooplankton fitness by optimizing the temporal trade-off between feeding and predator avoidance, especially when environmental drivers are weak or absent [8]. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Math Clock: Perangkat Penunjuk Waktu Kreatif untuk Olahraga Otak

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    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.

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

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    Idan eElbaz

    2013-02-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  16. Circadian clock of Aedes aegypti: effects of blood-feeding, insemination and RNA interference

    Science.gov (United States)

    Gentile, Carla; Rivas, Gustavo Bueno da S; Lima, José BP; Bruno, Rafaela Vieira; Peixoto, Alexandre Afranio

    2013-01-01

    Mosquitoes are the culprits of some of the most important vector borne diseases. A species’ potential as a vector is directly dependent on their pattern of behaviour, which is known to change according to the female’s physiological status such as whether the female is virgin/mated and unfed/blood-fed. However, the molecular mechanism triggered by and/or responsible for such modulations in behaviour is poorly understood. Clock genes are known to be responsible for the control of circadian behaviour in several species. Here we investigate the impact mating and blood-feeding have upon the expression of these genes in the mosquito Aedes aegypti . We show that blood intake, but not insemination, is responsible for the down-regulation of clock genes. Using RNA interference, we observe a slight reduction in the evening activity peak in the fourth day after dstim injection. These data suggest that, as in Drosophila , clock gene expression, circadian behaviour and environmental light regimens are interconnected in Ae. aegypti . PMID:24473806

  17. 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

  18. Circulation of HIV-1 CRF02_AG among MSM Population in Central Italy: A Molecular Epidemiology-Based Study

    Directory of Open Access Journals (Sweden)

    Massimo Giuliani

    2013-01-01

    Full Text Available Introduction. The evolutionary and demographic history of the circular recombinant form CRF02_AG in a selected retrospective group of HIV-1 infected men who have sex with men (MSM resident in Central Italy was investigated. Methods. A total of 55 HIV-1 subtype CRF02_AG pol sequences were analyzed using Bayesian methods and a relaxed molecular clock to reconstruct their dated phylogeny and estimate population dynamics. Results. Dated phylogeny indicated that the HIV-1 CRF02_AG strains currently circulating in Central Italy originated in the early 90's. Bayesian phylogenetic analysis revealed the existence of a main HIV-1 CRF02_AG clade, introduced in the area of Rome before 2000 and subsequently differentiated in two different subclades with a different date of introduction (2000 versus 2005. All the sequences within clusters were interspersed, indicating that the MSM analyzed form a close and restricted network where the individuals, also moving within different clinical centers, attend the same places to meet and exchange sex. Conclusions. It was suggested that the HIV-1 CRF02_AG epidemic entered central Italy in the early 1990s, with a similar trend observed in western Europe.

  19. Natural selection against a circadian clock gene mutation in mice.

    Science.gov (United States)

    Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela

    2016-01-19

    Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.

  20. Coupled Leidenfrost states as a monodisperse granular clock

    Science.gov (United States)

    Liu, Rui; Yang, Mingcheng; Chen, Ke; Hou, Meiying; To, Kiwing

    2016-08-01

    Using an event-driven molecular dynamics simulation, we show that simple monodisperse granular beads confined in coupled columns may oscillate as a different type of granular clock. To trigger this oscillation, the system needs to be driven against gravity into a density-inverted state, with a high-density clustering phase supported from below by a gaslike low-density phase (Leidenfrost effect) in each column. Our analysis reveals that the density-inverted structure and the relaxation dynamics between the phases can amplify any small asymmetry between the columns, and lead to a giant oscillation. The oscillation occurs only for an intermediate range of the coupling strength, and the corresponding phase diagram can be universally described with a characteristic height of the density-inverted structure. A minimal two-phase model is proposed and a linear stability analysis shows that the triggering mechanism of the oscillation can be explained as a switchable two-parameter Andronov-Hopf bifurcation. Numerical solutions of the model also reproduce similar oscillatory dynamics to the simulation results.