WorldWideScience

Sample records for circadian clock system

  1. Retinal circadian clocks and non-visual photoreceptors: light input to the circadian system.

    OpenAIRE

    Ouria Dkhissi-Benyahya

    2013-01-01

    The mammalian retina contains an endogenous pacemaker that regulates retinal physiology and adjusts daily the temporal phase of the central circadian timing system with environmental time. This entrainment process involves rods, cones and melanopsin-expressing retinal ganglion cells. In contrast with non mammalian retinas, in which the clock has been identified in photoreceptors, the location of the retinal circadian clock in mammals is still controversial. In addition, the impact of specific...

  2. The circadian clock goes genomic

    OpenAIRE

    Staiger, D; Shin, J; Johansson, M; Davis, S

    2013-01-01

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

  3. Circadian Clocks, Stress, and Immunity

    Science.gov (United States)

    Dumbell, Rebecca; Matveeva, Olga; Oster, Henrik

    2016-01-01

    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. PMID:27199894

  4. When the circadian clock meets the melanin pigmentary system.

    Science.gov (United States)

    Slominski, Andrzej T; Hardeland, Rüdiger; Reiter, Russel J

    2015-04-01

    Silencing of BMAL1 and PER1 stimulates melanogenic activity of follicular and epidermal melanocytes, indicating a novel role for peripheral circadian clock processes in the regulation of melanin pigmentation. Linking the expression levels of BMAL1/PER1 with changes in melanogenesis opens exciting opportunities to study the role of the local molecular clock in modulation of melanocyte functions in the hair follicle and the epidermis with attendant effects on epidermal barrier functions in general. PMID:25785947

  5. 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.

  6. 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…

  7. Unraveling the circadian clock in Arabidopsis

    OpenAIRE

    Wang, Xiaoxue; Ma, Ligeng

    2012-01-01

    The circadian clock is an endogenous timing system responsible for coordinating an organism’s biological processes with its environment. Interlocked transcriptional feedback loops constitute the fundamental architecture of the circadian clock. In Arabidopsis, three feedback loops, the core loop, morning loop and evening loop, comprise a network that is the basis of the circadian clock. The components of these three loops are regulated in distinct ways, including transcriptional, post-transcri...

  8. A colorful model of the circadian clock.

    Science.gov (United States)

    Reppert, Steven M

    2006-01-27

    The migration of the colorful monarch butterfly provides biologists with a unique model system with which to study the cellular and molecular mechanisms underlying a sophisticated circadian clock. The monarch circadian clock is involved in the induction of the migratory state and navigation over long distances, using the sun as a compass. PMID:16439193

  9. Circadian clock components in the rat neocortex

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  10. 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 with

  11. Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system

    Indian Academy of Sciences (India)

    Jason P. Debruyne

    2008-12-01

    A functional mouse CLOCK protein has long been thought to be essential for mammalian circadian clockwork function, based mainly on studies of mice bearing a dominant negative, antimorphic mutation in the Clock gene. However, new discoveries using recently developed Clock-null mutant mice have shaken up this view. In this review, I discuss how this recent work impacts and alters the previous view of the role of CLOCK in the mouse circadian clockwork.

  12. The circadian clock in mammals

    OpenAIRE

    Zordan, Mauro; Kyriacou, Charalambos P

    2000-01-01

    The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship be...

  13. The circadian clock in mammals

    OpenAIRE

    Zordan, M. A.; Kyriacou, C P

    2005-01-01

    The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship be...

  14. Circadian Clock Control of Liver Metabolic Functions.

    Science.gov (United States)

    Reinke, Hans; Asher, Gad

    2016-03-01

    The circadian clock is an endogenous biological timekeeping system that synchronizes physiology and behavior to day/night cycles. A wide variety of processes throughout the entire gastrointestinal tract and notably the liver appear to be under circadian control. These include various metabolic functions such as nutrient uptake, processing, and detoxification, which align organ function to cycle with nutrient supply and demand. Remarkably, genetic or environmental disruption of the circadian clock can cause metabolic diseases or exacerbate pathological states. In addition, modern lifestyles force more and more people worldwide into asynchrony between the external time and their circadian clock, resulting in a constant state of social jetlag. Recent evidence indicates that interactions between altered energy metabolism and disruptions in the circadian clock create a downward spiral that can lead to diabetes and other metabolic diseases. In this review, we provide an overview of rhythmic processes in the liver and highlight the functions of circadian clock genes under physiological and pathological conditions; we focus on their roles in regulation of hepatic glucose as well as lipid and bile acid metabolism and detoxification and their potential effects on the development of fatty liver and nonalcoholic steatohepatitis. PMID:26657326

  15. The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks

    Directory of Open Access Journals (Sweden)

    Yasuda Akio

    2006-02-01

    Full Text Available Abstract Background Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure. Results We developed the in vitro real-time oscillation monitoring system (IV-ROMS by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, a natural ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ, triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Rorα mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-γ – and MAPKs (ERK, JNK, p38MAPK-independent. Conclusion Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight

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

    Directory of Open Access Journals (Sweden)

    Mathias Teschke

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

  17. Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders.

    Science.gov (United States)

    Barandas, Rita; Landgraf, Dominic; McCarthy, Michael J; Welsh, David K

    2015-12-01

    Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms. PMID:26483181

  18. Photoperiodic plasticity in circadian clock neurons in insects

    Directory of Open Access Journals (Sweden)

    Sakiko eShiga

    2013-08-01

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

  19. Design principles underlying circadian clocks.

    OpenAIRE

    Rand, D.A.; Shulgin, B. V.; D. Salazar; Millar, A. J.

    2004-01-01

    A fundamental problem for regulatory networks is to understand the relation between form and function: to uncover the underlying design principles of the network. Circadian clocks present a particularly interesting instance, as recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. While several authors have speculated on the reasons for this, a convincing explanation is still lacking.We analyse both t...

  20. The circadian clock and cell cycle: Interconnected biological circuits

    OpenAIRE

    Masri, Selma; Cervantes, Marlene; Sassone-Corsi, Paolo

    2013-01-01

    The circadian clock governs biological timekeeping on a systemic level, helping to regulate and maintain physiological processes, including endocrine and metabolic pathways with a periodicity of 24-hours. Disruption within the circadian clock machinery has been linked to numerous pathological conditions, including cancer, suggesting that clock-dependent regulation of the cell cycle is an essential control mechanism. This review will highlight recent advances on the ‘gating’ controls of the ci...

  1. The circadian clock coordinates ribosome biogenesis.

    Directory of Open Access Journals (Sweden)

    Céline Jouffe

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

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

    Directory of Open Access Journals (Sweden)

    Juliana Marcolino-Gomes

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

  3. Circadian clocks are designed optimally

    CERN Document Server

    Hasegawa, Yoshihiko

    2014-01-01

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

  4. Coordination of the maize transcriptome by a conserved circadian clock

    Directory of Open Access Journals (Sweden)

    Harmon Frank G

    2010-06-01

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

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

    Science.gov (United States)

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

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in 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. PMID:26473939

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

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

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

  7. Circadian clock, cell cycle and cancer

    OpenAIRE

    Cansu Özbayer; İrfan Değirmenci

    2011-01-01

    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 ...

  8. Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health

    OpenAIRE

    Ramkisoensing, Ashna; Meijer, Johanna H.

    2015-01-01

    In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude...

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

    Science.gov (United States)

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

    2015-08-01

    The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms. PMID:24297467

  10. Circadian Clock Proteins in Mood Regulation

    OpenAIRE

    Partonen, Timo

    2015-01-01

    Mood regulation is known to be affected by the change of seasons. Recent research findings have suggested that mood regulation may be influenced by the function of circadian clocks. In addition, the activity of brown adipocytes has been hypothesized to contribute to mood regulation. Here, the overarching link to mood disorders might be the circadian clock protein nuclear receptor subfamily 1, group D, member 1.

  11. Circadian clock proteins in mood regulation

    Directory of Open Access Journals (Sweden)

    Timo ePartonen

    2015-01-01

    Full Text Available Mood regulation is known to be affected by the change of seasons. Recent research findings have suggested that mood regulation may be influenced by the function of circadian clocks. In addition, the activity of brown adipocytes has been hypothesized to contribute to mood regulation. Here, the overarching link to mood disorders might be the circadian clock protein NR1D1 (nuclear receptor subfamily 1, group D, member 1.

  12. 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.

  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. Circadian Clock Regulates Bone Resorption in Mice.

    Science.gov (United States)

    Xu, Cheng; Ochi, Hiroki; Fukuda, Toru; Sato, Shingo; Sunamura, Satoko; Takarada, Takeshi; Hinoi, Eiichi; Okawa, Atsushi; Takeda, Shu

    2016-07-01

    The circadian clock controls many behavioral and physiological processes beyond daily rhythms. Circadian dysfunction increases the risk of cancer, obesity, and cardiovascular and metabolic diseases. Although clinical studies have shown that bone resorption is controlled by circadian rhythm, as indicated by diurnal variations in bone resorption, the molecular mechanism of circadian clock-dependent bone resorption remains unknown. To clarify the role of circadian rhythm in bone resorption, aryl hydrocarbon receptor nuclear translocator-like (Bmal1), a prototype circadian gene, was knocked out specifically in osteoclasts. Osteoclast-specific Bmal1-knockout mice showed a high bone mass phenotype due to reduced osteoclast differentiation. A cell-based assay revealed that BMAL1 upregulated nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (Nfatc1) transcription through its binding to an E-box element located on the Nfatc1 promoter in cooperation with circadian locomotor output cycles kaput (CLOCK), a heterodimer partner of BMAL1. Moreover, steroid receptor coactivator (SRC) family members were shown to interact with and upregulate BMAL1:CLOCK transcriptional activity. Collectively, these data suggest that bone resorption is controlled by osteoclastic BMAL1 through interactions with the SRC family and binding to the Nfatc1 promoter. © 2016 American Society for Bone and Mineral Research. PMID:26841172

  15. Cardiovascular tissues contain independent circadian clocks

    Science.gov (United States)

    Davidson, A. J.; London, B.; Block, G. D.; Menaker, M.

    2005-01-01

    Acute cardiovascular events exhibit a circadian rhythm in the frequency of occurrence. The mechanisms underlying these phenomena are not yet fully understood, but they may be due to rhythmicity inherent in the cardiovascular system. We have begun to characterize rhythmicity of the clock gene mPer1 in the rat cardiovascular system. Luciferase activity driven by the mPer1 gene promoter is rhythmic in vitro in heart tissue explants and a wide variety of veins and arteries cultured from the transgenic Per1-luc rat. The tissues showed between 3 and 12 circadian cycles of gene expression in vitro before damping. Whereas peak per1-driven bioluminescence consistently occurred during the late night in the heart and all arteries sampled, the phases of the rhythms in veins varied significantly by anatomical location. Varying the time of the culture procedure relative to the donor animal's light:dark cycle revealed that, unlike some other rat tissues such as liver, the phases of in vitro rhythms of arteries, veins, and heart explants were affected by culture time. However, phase relationships among tissues were consistent across culture times; this suggests diversity in circadian regulation among components of the cardiovascular system.

  16. 'The clocks that time us'-circadian rhythms in neurodegenerative disorders

    NARCIS (Netherlands)

    Videnovic, A.; Lazar, A.S.; Barker, R.A.; Overeem, S.

    2014-01-01

    Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodeg

  17. Human Peripheral Clocks: Applications for Studying Circadian Phenotypes in Physiology and Pathophysiology

    OpenAIRE

    Saini, Camille; Brown, Steven A.; Dibner, Charna

    2015-01-01

    Most light-sensitive organisms on earth have acquired an internal system of circadian clocks allowing the anticipation of light or darkness. In humans, the circadian system governs nearly all aspects of physiology and behavior. Circadian phenotypes, including chronotype, vary dramatically among individuals and over individual lifespan. Recent studies have revealed that the characteristics of human skin fibroblast clocks correlate with donor chronotype. Given the complexity of circadian phenot...

  18. Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health.

    Science.gov (United States)

    Ramkisoensing, Ashna; Meijer, Johanna H

    2015-01-01

    In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude of the SCN's electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise) has a positive effect on amplitude. Given that the amplitude of the SCN's electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-h rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders. PMID:26097465

  19. Synchronization of biological clock neurons by light and peripheral feedback systems promotes circadian rhythms and health

    Directory of Open Access Journals (Sweden)

    Ashna eRamkisoensing

    2015-06-01

    Full Text Available In mammals, the suprachiasmatic nucleus (SCN functions as a circadian clock that drives 24-hour rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase synchronization between individual cells have consequences on the amplitude of the SCN’s electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise has a positive effect on amplitude. Given that the amplitude of the SCN’s electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-hour rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders.

  20. Avian Circadian Organization: A Chorus of Clocks

    OpenAIRE

    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...

  1. Optimal implementations for reliable circadian clocks.

    Science.gov (United States)

    Hasegawa, Yoshihiko; Arita, Masanori

    2014-09-01

    Circadian rhythms are acquired through evolution to increase the chances for survival through synchronizing with the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. We find by using a phase model with multiple inputs that achieving the maximal limit of regularity and entrainability entails many inherent features of the circadian mechanism. At the molecular level, we demonstrate the role sharing of two light inputs, phase advance and delay, as is well observed in mammals. At the behavioral level, the optimal phase-response curve inevitably contains a dead zone, a time during which light pulses neither advance nor delay the clock. We reproduce the results of phase-controlling experiments entrained by two types of periodic light pulses. Our results indicate that circadian clocks are designed optimally for reliable clockwork through evolution. PMID:25238386

  2. Circadian Rhythms: Hijacking the Cyanobacterial Clock

    Science.gov (United States)

    Hoyle, Nathaniel P.; O’Neill, John S

    2016-01-01

    The production of limitless carbon-free energy is a long-sought dream of scientists and politicians alike. One strategy for achieving this aim is the production of hydrogen by photosynthetic microorganisms – harnessing the effectively limitless power of the sun to power our cars, toasters and PCR machines. It may be tempting to think of host expression systems as miniature factories given over entirely to the production our molecule of interest. However, the biological nature of the host must be taken into account if we are to maximize productivity. The circadian rhythm, an organism’s entrainable oscillation of biological processes with a period of around 24 hours, is one such aspect that has received scant attention but is likely to be of particular importance to photosynthetic host systems. In this issue of current biology Xu et al. describe how our knowledge of the Synechococcus elongatus circadian clock can be leveraged to improve the production of exogeneous proteins, including those involved in the production of hydrogen [1]. PMID:24309283

  3. 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 systemcircadian 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.

  4. Circadian clock and the onset of cardiovascular events.

    Science.gov (United States)

    Takeda, Norihiko; Maemura, Koji

    2016-06-01

    The onset of cardiovascular diseases often shows time-of-day variation. Acute myocardial infarction or ventricular arrhythmia such as ventricular tachycardia occurs mainly in the early morning. Multiple biochemical and physiological parameters show circadian rhythm, which may account for the diurnal variation of cardiovascular events. These include the variations in blood pressure, activity of the autonomic nervous system and renin-angiotensin axis, coagulation cascade, vascular tone and the intracellular metabolism of cardiomyocytes. Importantly, the molecular clock system seems to underlie the circadian variation of these parameters. The center of the biological clock, also known as the central clock, exists in the suprachiasmatic nucleus. In contrast, the molecular clock system is also activated in each cell of the peripheral organs and constitute the peripheral clock. The biological clock system is currently considered to have a beneficial role in maintaining the homeostasis of each organ. Discoordination, however, between the peripheral clock and external environment could potentially underlie the development of cardiovascular events. Therefore, understanding the molecular and cellular pathways by which cardiovascular events occur in a diurnal oscillatory pattern will help the establishment of a novel therapeutic approach to the management of cardiovascular disorders. PMID:26888119

  5. Rapid attenuation of circadian clock gene oscillations in the rat heart following ischemia-reperfusion

    Science.gov (United States)

    The intracellular circadian clock consists of a series of transcriptional modulators that together allow the cell to perceive the time of day. Circadian clocks have been identified within various components of the cardiovascular system (e.g., cardiomyocytes, vascular smooth muscle cells) and possess...

  6. Functional Development of the Circadian Clock in the Zebrafish Pineal Gland

    OpenAIRE

    Zohar Ben-Moshe; Foulkes, Nicholas S.; Yoav Gothilf

    2014-01-01

    The zebrafish constitutes a powerful model organism with unique advantages for investigating the vertebrate circadian timing system and its regulation by light. In particular, the remarkably early and rapid development of the zebrafish circadian system has facilitated exploring the factors that control the onset of circadian clock function during embryogenesis. Here, we review our understanding of the molecular basis underlying functional development of the central clock in the zebrafish pine...

  7. The circadian clock, reward and memory

    OpenAIRE

    Urs eAlbrecht

    2011-01-01

    During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance, and reward may be related to one another. This review will summarize data that describe the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes.

  8. AMPK at the crossroads of circadian clocks and metabolism

    OpenAIRE

    Jordan, Sabine D.; Lamia, Katja A.

    2012-01-01

    Circadian clocks coordinate behavior and physiology with daily environmental cycles and thereby optimize the timing of metabolic processes such as glucose production and insulin secretion. Such circadian regulation of metabolism provides an adaptive advantage in diverse organisms. Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain an...

  9. When clocks go bad: neurobehavioural consequences of disrupted circadian timing.

    Directory of Open Access Journals (Sweden)

    Alun R Barnard

    2008-05-01

    Full Text Available Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain's critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.

  10. Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK

    Directory of Open Access Journals (Sweden)

    Bordon Alain

    2008-04-01

    Full Text Available Abstract Background Circadian oscillation of clock-controlled gene expression is mainly regulated at the transcriptional level. Heterodimers of CLOCK and BMAL1 act as activators of target gene transcription; however, interactions of PER and CRY proteins with the heterodimer abolish its transcriptional activation capacity. PER and CRY are therefore referred to as negative regulators of the circadian clock. To further elucidate the mechanism how positive and negative components of the clock interplay, we characterized the interactions of PER2, CRY1 and CRY2 with BMAL1 and CLOCK using a mammalian two-hybrid system and co-immunoprecipitation assays. Results Both PER2 and the CRY proteins were found to interact with BMAL1 whereas only PER2 interacts with CLOCK. CRY proteins seem to have a higher affinity to BMAL1 than PER2. Moreover, we provide evidence that PER2, CRY1 and CRY2 bind to different domains in the BMAL1 protein. Conclusion The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. Our data supports the hypothesis that CRY proteins, especially CRY1, are stronger repressors than PER proteins.

  11. Complementary approaches to understanding the plant circadian clock

    CERN Document Server

    Akman, Ozgur E; Loewe, Laurence; Troein, Carl; 10.4204/EPTCS.19.1

    2010-01-01

    Circadian clocks are oscillatory genetic networks that help organisms adapt to the 24-hour day/night cycle. The clock of the green alga Ostreococcus tauri is the simplest plant clock discovered so far. Its many advantages as an experimental system facilitate the testing of computational predictions. We present a model of the Ostreococcus clock in the stochastic process algebra Bio-PEPA and exploit its mapping to different analysis techniques, such as ordinary differential equations, stochastic simulation algorithms and model-checking. The small number of molecules reported for this system tests the limits of the continuous approximation underlying differential equations. We investigate the difference between continuous-deterministic and discrete-stochastic approaches. Stochastic simulation and model-checking allow us to formulate new hypotheses on the system behaviour, such as the presence of self-sustained oscillations in single cells under constant light conditions. We investigate how to model the timing of...

  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 pe

  13. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock

    OpenAIRE

    DeBruyne, Jason P.; Weaver, David R.; Reppert, Steven M.

    2007-01-01

    Heterodimers of CLOCK and BMAL1, bHLH-PAS transcription factors, are believed to be the major transcriptional regulators of the circadian clock mechanism in mammals. However, a recent study shows that CLOCK-deficient mice continue to exhibit robust behavioral and molecular rhythms. Here we report that the transcription factor NPAS2 (MOP4) is able to functionally substitute for CLOCK in the master brain clock in mice to regulate circadian rhythmicity.

  14. The Circadian Clock-Controlled Transcriptome of Developing Soybean Seeds.

    Science.gov (United States)

    A number of metabolic and physiological processes in plants are controlled by the circadian clock, which enables the plant to anticipate daily changes in the environment. Microarray expression profiling was used to identify circadian clock controlled genes expressed in developing soybean seeds. 1.8...

  15. 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...

  16. 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

  17. Phase resetting of the mammalian circadian clock by DNA damage

    NARCIS (Netherlands)

    Oklejewicz, Malgorzata; Destici, Eugin; Tamanini, Filippo; Hut, Roelof A.; Janssens, Roel; van der Horst, Gijsbertus T. J.

    2008-01-01

    To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian

  18. Working around the clock: circadian rhythms and skeletal muscle

    OpenAIRE

    ZHANG, XIPING; Dube, Thomas J.; Esser, Karyn A.

    2009-01-01

    The study of the circadian molecular clock in skeletal muscle is in the very early stages. Initial research has demonstrated the presence of the molecular clock in skeletal muscle and that skeletal muscle of a clock-compromised mouse, Clock mutant, exhibits significant disruption in normal expression of many genes required for adult muscle structure and metabolism. In light of the growing association between the molecular clock, metabolism, and metabolic disease, it will also be important to ...

  19. Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK

    OpenAIRE

    Bordon Alain; Tallone Tiziano; Langmesser Sonja; Rusconi Sandro; Albrecht Urs

    2008-01-01

    Abstract Background Circadian oscillation of clock-controlled gene expression is mainly regulated at the transcriptional level. Heterodimers of CLOCK and BMAL1 act as activators of target gene transcription; however, interactions of PER and CRY proteins with the heterodimer abolish its transcriptional activation capacity. PER and CRY are therefore referred to as negative regulators of the circadian clock. To further elucidate the mechanism how positive and negative components of the clock int...

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

    Institute of Scientific and Technical Information of China (English)

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

    2014-01-01

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

  1. 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…

  2. Interaction of MAGED1 with nuclear receptors affects circadian clock function

    Science.gov (United States)

    Wang, Xiaohan; Tang, Jing; Xing, Lijuan; Shi, Guangsen; Ruan, Haibin; Gu, Xiwen; Liu, Zhiwei; Wu, Xi; Gao, Xiang; Xu, Ying

    2010-01-01

    The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest–activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indicating that MAGED1 binds to RORα to bring about positive and negative effects on core clock genes of Bmal1, Rev-erbα and E4bp4 expression through the Rev-Erbα/ROR responsive elements (RORE). Maged1 is a non-rhythmic gene that, by binding RORα in non-circadian way, enhances rhythmic input and buffers the circadian system from irrelevant, perturbing stimuli or noise. We have thus identified and defined a novel circadian regulator, Maged1, which is indispensable for the robustness of the circadian clock to better serve the organism. PMID:20300063

  3. 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. PMID:26715747

  4. Temperature regulates transcription in the zebrafish circadian clock.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available It has been well-documented that temperature influences key aspects of the circadian clock. Temperature cycles entrain the clock, while the period length of the circadian cycle is adjusted so that it remains relatively constant over a wide range of temperatures (temperature compensation. In vertebrates, the molecular basis of these properties is poorly understood. Here, using the zebrafish as an ectothermic model, we demonstrate first that in the absence of light, exposure of embryos and primary cell lines to temperature cycles entrains circadian rhythms of clock gene expression. Temperature steps drive changes in the basal expression of certain clock genes in a gene-specific manner, a mechanism potentially contributing to entrainment. In the case of the per4 gene, while E-box promoter elements mediate circadian clock regulation, they do not direct the temperature-driven changes in transcription. Second, by studying E-box-regulated transcription as a reporter of the core clock mechanism, we reveal that the zebrafish clock is temperature-compensated. In addition, temperature strongly influences the amplitude of circadian transcriptional rhythms during and following entrainment by light-dark cycles, a property that could confer temperature compensation. Finally, we show temperature-dependent changes in the expression levels, phosphorylation, and function of the clock protein, CLK. This suggests a mechanism that could account for changes in the amplitude of the E-box-directed rhythm. Together, our results imply that several key transcriptional regulatory elements at the core of the zebrafish clock respond to temperature.

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

    OpenAIRE

    Landgraf, Dominic; Wang, Lexie L.; Diemer, Tanja; Welsh, David K.

    2016-01-01

    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 periph...

  6. Caenorhabditis elegans opens up new insights into circadian clock mechanisms.

    Science.gov (United States)

    Hasegawa, Kenji; Saigusa, Tetsu; Tamai, Yoichi

    2005-01-01

    The roundworm, Caenorhabditis elegans, is known to carry homologues of clock genes such as per (=period) and tim (=timeless), which constitute the core of the circadian clock in Drosophila and mammals: lin-42 and tim-1. Analyses using WormBase (C. elegans gene database) have identified with relatively high identity analogous of the clock genes recognized in Drosophila and mammals, with the notable exception of cry (=cryptochrome), which is lacking in C. elegans. All of these C. elegans cognates of the clock genes appear to belong to members of the PAS-superfamily and to participate in development or responsiveness to the environment but apparently are not involved in the C. elegans circadian clock. Nevertheless, C. elegans exhibits convincing circadian rhythms in locomotor behavior in the adult stage and in resistance to hyperosmotic stress in starved larvae (L1) after hatching, indicating that it has a circadian clock with a core design entirely different from that of Drosophila and mammals. Here two possibilities are considered. First, the core of the C. elegans circadian clock includes transcriptional/translational feedback loops between genes and their protein products that are entirely different from those of Drosophila and mammals. Second, a more basic principle such as homeostasis governs the circadian cellular physiology, and was established primarily to minimize the accumulation of DNA damage in response to an environment cycling at 24 h intervals. PMID:15865318

  7. Methylphenidate Modifies the Motion of the Circadian Clock

    OpenAIRE

    Antle, Michael C.; van Diepen, Hester C; Deboer, Tom; Pedram, Pardis; Pereira, Rob Rodrigues; Meijer, Johanna H.

    2012-01-01

    People with attention-deficit/hyperactivity disorder (ADHD) often experience sleep problems, and these are frequently exacerbated by the methylphenidate they take to manage their ADHD symptoms. Many of the changes to sleep are consistent with a change in the underlying circadian clock. The present study was designed to determine if methylphenidate alone could alter properties of the circadian clock. Young male mice were examined in light–dark cycles and in constant darkness and recordings wer...

  8. Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

    OpenAIRE

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

    2011-01-01

    Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock me...

  9. A novel protein, CHRONO, functions as a core component of the mammalian circadian clock.

    Directory of Open Access Journals (Sweden)

    Akihiro Goriki

    2014-04-01

    Full Text Available Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1-CLOCK activity in a histone deacetylase (HDAC -dependent manner. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock.

  10. Mass spectrometry-based absolute quantification reveals rhythmic variation of mouse circadian clock proteins.

    Science.gov (United States)

    Narumi, Ryohei; Shimizu, Yoshihiro; Ukai-Tadenuma, Maki; Ode, Koji L; Kanda, Genki N; Shinohara, Yuta; Sato, Aya; Matsumoto, Katsuhiko; Ueda, Hiroki R

    2016-06-14

    Absolute values of protein expression levels in cells are crucial information for understanding cellular biological systems. Precise quantification of proteins can be achieved by liquid chromatography (LC)-mass spectrometry (MS) analysis of enzymatic digests of proteins in the presence of isotope-labeled internal standards. Thus, development of a simple and easy way for the preparation of internal standards is advantageous for the analyses of multiple target proteins, which will allow systems-level studies. Here we describe a method, termed MS-based Quantification By isotope-labeled Cell-free products (MS-QBiC), which provides the simple and high-throughput preparation of internal standards by using a reconstituted cell-free protein synthesis system, and thereby facilitates both multiplexed and sensitive quantification of absolute amounts of target proteins. This method was applied to a systems-level dynamic analysis of mammalian circadian clock proteins, which consist of transcription factors and protein kinases that govern central and peripheral circadian clocks in mammals. Sixteen proteins from 20 selected circadian clock proteins were successfully quantified from mouse liver over a 24-h time series, and 14 proteins had circadian variations. Quantified values were applied to detect internal body time using a previously developed molecular timetable method. The analyses showed that single time-point data from wild-type mice can predict the endogenous state of the circadian clock, whereas data from clock mutant mice are not applicable because of the disappearance of circadian variation. PMID:27247408

  11. Regulated DNA Methylation and the Circadian Clock: Implications in Cancer

    Directory of Open Access Journals (Sweden)

    Tammy M. Joska

    2014-09-01

    Full Text Available Since the cloning and discovery of DNA methyltransferases (DNMT, there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has become evident that dynamic DNA methylation accompanies the circadian clock and is found at clock genes in Neurospora, mice and cancer cells. The relationship among the circadian clock, cancer and DNA methylation at clock genes suggests a correlative indication that improper DNA methylation may influence clock gene expression, contributing to the etiology of cancer. The molecular mechanism underlying DNA methylation at clock loci is best studied in the filamentous fungi, Neurospora crassa, and recent data indicate a mechanism analogous to the RNA-dependent DNA methylation (RdDM or RNAi-mediated facultative heterochromatin. Although it is still unclear, DNA methylation at clock genes may function as a terminal modification that serves to prevent the regulated removal of histone modifications. In this capacity, aberrant DNA methylation may serve as a readout of misregulated clock genes and not as the causative agent. This review explores the implications of DNA methylation at clock loci and describes what is currently known regarding the molecular mechanism underlying DNA methylation at circadian clock genes.

  12. 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.

  13. Nutrition and the circadian system.

    Science.gov (United States)

    Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J

    2016-08-01

    The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157

  14. ROS stress resets circadian clocks to coordinate pro-survival signals.

    Directory of Open Access Journals (Sweden)

    Teruya Tamaru

    Full Text Available Dysfunction of circadian clocks exacerbates various diseases, in part likely due to impaired stress resistance. It is unclear how circadian clock system responds toward critical stresses, to evoke life-protective adaptation. We identified a reactive oxygen species (ROS, H2O2 -responsive circadian pathway in mammals. Near-lethal doses of ROS-induced critical oxidative stress (cOS at the branch point of life and death resets circadian clocks, synergistically evoking protective responses for cell survival. The cOS-triggered clock resetting and pro-survival responses are mediated by transcription factor, central clock-regulatory BMAL1 and heat shock stress-responsive (HSR HSF1. Casein kinase II (CK2 -mediated phosphorylation regulates dimerization and function of BMAL1 and HSF1 to control the cOS-evoked responses. The core cOS-responsive transcriptome includes CK2-regulated crosstalk between the circadian, HSR, NF-kappa-B-mediated anti-apoptotic, and Nrf2-mediated anti-oxidant pathways. This novel circadian-adaptive signaling system likely plays fundamental protective roles in various ROS-inducible disorders, diseases, and death.

  15. 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.

  16. The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

    Science.gov (United States)

    Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that circadian clock within the cardiomyocyte plays a role in regulating myocardia...

  17. Osmotic stress at the barley root affects expression of circadian clock genes in the shoot.

    Science.gov (United States)

    Habte, Ermias; Müller, Lukas M; Shtaya, Munqez; Davis, Seth J; von Korff, Maria

    2014-06-01

    The circadian clock is an important timing system that controls physiological responses to abiotic stresses in plants. However, there is little information on the effects of the clock on stress adaptation in important crops, like barley. In addition, we do not know how osmotic stress perceived at the roots affect the shoot circadian clock. Barley genotypes, carrying natural variation at the photoperiod response and clock genes Ppd-H1 and HvELF3, were grown under control and osmotic stress conditions to record changes in the diurnal expression of clock and stress-response genes and in physiological traits. Variation at HvELF3 affected the expression phase and shape of clock and stress-response genes, while variation at Ppd-H1 only affected the expression levels of stress genes. Osmotic stress up-regulated expression of clock and stress-response genes and advanced their expression peaks. Clock genes controlled the expression of stress-response genes, but had minor effects on gas exchange and leaf transpiration. This study demonstrated that osmotic stress at the barley root altered clock gene expression in the shoot and acted as a spatial input signal into the clock. Unlike in Arabidopsis, barley primary assimilation was less controlled by the clock and more responsive to environmental perturbations, such as osmotic stress. PMID:24895755

  18. Neuroanatomy of the Extended Circadian Rhythm System

    OpenAIRE

    Morin, Lawrence P

    2012-01-01

    The suprachiasmatic nucleus (SCN), site of the primary clock in the circadian rhythm system, has three major afferent connections. The most important consists of a retinohypothalamic projection through which photic information, received by classical rod/cone photoreceptors and intrinsically photoreceptive retinal ganglion cells, gains access to the clock. This information influences phase and period of circadian rhythms. The two other robust afferent projections are the median raphe serotoner...

  19. Transcripts from the Circadian Clock: Telling Time and Season

    OpenAIRE

    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 periods of light and dark which define what we all experience as a ‘day’. This profound cyclic variation in solar energy is responsible for driving the evolution of adaptive responses as early as 3.8...

  20. Circadian clocks and the regulation of virulence in fungi: Getting up to speed.

    Science.gov (United States)

    Hevia, Montserrat A; Canessa, Paulo; Larrondo, Luis F

    2016-09-01

    You cannot escape time. Therefore, it seems wise to learn how to keep track of it and use it to your advantage. Circadian clocks are molecular circuits that allow organisms to temporally coordinate a plethora of processes, including gene expression, with a close to 24h rhythm, optimizing cellular function in synchrony with daily environmental cycles. The molecular bases of these clocks have been extensively studied in the fungus Neurospora crassa, providing a detailed molecular description. Surprisingly, there is scarce molecular information of clocks in fungi other than Neurospora, despite the existence of rhythmic phenomena in many fungal species, including pathogenic ones. This review will comment on the overall importance of clocks, what is known in Neurospora and what has been described in other fungi including new insights on the evolution of fungal clock components. The molecular description of the circadian system of the phytopathogenic fungus Botrytis cinerea will be revisited, as well as time-of-the-day variation in host-pathogen interaction dynamics, utilizing an Arabidopsis-Botrytis system, including also what is known regarding circadian regulation of defense mechanisms in the Arabidopsis thaliana plant model. Finally, this review will mention how little is known about circadian regulation of human pathogenic fungi, commenting on potential future directions and the overall perspective of fungal circadian studies. PMID:27039027

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

    International Nuclear Information System (INIS)

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

  2. 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

  3. Illuminating the circadian clock in monarch butterfly migration.

    Science.gov (United States)

    Froy, Oren; Gotter, Anthony L; Casselman, Amy L; Reppert, Steven M

    2003-05-23

    Migratory monarch butterflies use a time-compensated Sun compass to navigate to their overwintering grounds in Mexico. Here, we report that constant light, which disrupts circadian clock function at both the behavioral and molecular levels in monarchs, also disrupts the time-compensated component of flight navigation. We further show that ultraviolet light is important for flight navigation but is not required for photic entrainment of circadian rhythms. Tracing these distinct light-input pathways into the brain should aid our understanding of the clock-compass mechanisms necessary for successful migration. PMID:12764200

  4. Interactions between the circadian clock and metabolism: there are good times and bad times

    Institute of Scientific and Technical Information of China (English)

    Mi Shi; Xiangzhong Zheng

    2013-01-01

    An endogenous circadian (~24 h) clock regulates rhythmic processes of physiology,metabolism and behavior in most living organisms.While able to free-run under constant conditions,the circadian clock is coupled to day:night cycles to increase its amplitude and align the phase of circadian rhythms to the right time of the day.Disruptions of the circadian clock are correlated with brain dysfunctions,cardiovascular diseases and metabolic disorders.In this review,we focus on the interactions between the circadian clock and metabolism.We discuss recent findings on circadian clock regulation of feeding behavior and rhythmic expression of metabolic genes,and present evidence of metabolic input to the circadian clock.We emphasize how misalignment of circadian clocks within the body and with environmental cycles or daily schedules leads to the increasing prevalence of metabolic syndromes in modern society.

  5. New methods to assess circadian clocks in humans

    Czech Academy of Sciences Publication Activity Database

    Nováková, Marta; Sumová, Alena

    2014-01-01

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

  6. 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. PMID:25310881

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

    Science.gov (United States)

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

    2015-01-01

    Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer. PMID:26029155

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

    Directory of Open Access Journals (Sweden)

    Celine eFeillet

    2015-05-01

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

  9. Network properties of the mammalian circadian clock

    NARCIS (Netherlands)

    Rohling, Johannes Hermanus Theodoor

    2009-01-01

    The biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The neurons of the SCN endogenously generate a rhythm of approximately 24 hours. Under the influence of the l

  10. Circadian Clocks and the Interaction between Stress Axis and Adipose Function

    Directory of Open Access Journals (Sweden)

    Isa Kolbe

    2015-01-01

    Full Text Available Many physiological processes and most endocrine functions show fluctuations over the course of the day. These so-called circadian rhythms are governed by an endogenous network of cellular clocks and serve as an adaptation to daily and, thus, predictable changes in the organism’s environment. Circadian clocks have been described in several tissues of the stress axis and in adipose cells where they regulate the rhythmic and stimulated release of stress hormones, such as glucocorticoids, and various adipokine factors. Recent work suggests that both adipose and stress axis clock systems reciprocally influence each other and adrenal-adipose rhythms may be key players in the development and therapy of metabolic disorders. In this review, we summarize our current understanding of adrenal and adipose tissue rhythms and clocks and how they might interact to regulate energy homoeostasis and stress responses under physiological conditions. Potential chronotherapeutic strategies for the treatment of metabolic and stress disorders are discussed.

  11. Circadian clocks optimally adapt to sunlight for reliable synchronization

    CERN Document Server

    Hasegawa, Yoshihiko

    2014-01-01

    Circadian oscillation provides selection advantages through synchronization to the daylight cycle. However, a reliable clock must be designed through two conflicting properties: entrainability to properly respond to external stimuli such as sunlight, and regularity to oscillate with a precise period. These two aspects do not easily coexist because better entrainability favors higher sensitivity, which may sacrifice the regularity. To investigate conditions for satisfying the two properties, we analytically calculated the optimal phase-response curve with a variational method. Our result indicates an existence of a dead zone, i.e., a time during which external stimuli neither advance nor delay the clock. This result is independent of model details and a dead zone appears only when the input stimuli obey the time course of actual insolation. Our calculation demonstrates that every circadian clock with a dead zone is optimally adapted to the daylight cycle. Our result also explains the lack of a dead zone in osc...

  12. [Circadian clock and non-visual functions: the role of light in humans].

    Science.gov (United States)

    Gronfier, Claude

    2014-01-01

    Hormonal secretion, cognitive performance, motor activity, metabolic processes, the sleep wake cycle and, most recently shown, cell division and ADN repair show a 24 h rhythmicity that is driven by the circadian timing system (the biological clock). Their appropriate activity over the 24 h requires appropriate entrainment of the circadian clock, which is achieved through the synchronizing effects of ocular light exposure. The activation of melanopsin-expressing ganglion cells in the retina depends on timing, quality, intensity, and history of light exposure. Inappropriate lighting leads to inappropriate synchronization of the clock, and activation of non-visual functions (mood, wakefulness, cognition, etc.). In turn, a deficit of circadian entrainment to the 24 h is responsible for alterations of a large number of functions, and leads to altered sleep, wake, mood, neurobehavioral processes and cell division, but also to pathologies. The crucial role of the circadian clock and the nature of the non-visual functions activated by light give rise to the concept that light is a biological need fundamental to health. Without an appropriate light hygiene, the clock receives an odd tempo, and it is cacophony! PMID:25840452

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

    Directory of Open Access Journals (Sweden)

    Quentin Thommen

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

  14. Entrainment Dissociates Transcription and Translation of a Circadian Clock Gene in Neurospora

    NARCIS (Netherlands)

    Tan, Ying; Dragovic, Zdravko; Roenneberg, Till; Merrow, Martha

    2004-01-01

    Circadian systems coordinate the daily sequence of events in cells, tissues, and organisms. In constant conditions, the biological clock oscillates with its endogenous period, whereas it is synchronized to the 24 hr light:dark cycle in nature. Here, we investigate light entrainment of Neurospora cra

  15. Methylphenidate modifies the motion of the circadian clock.

    Science.gov (United States)

    Antle, Michael C; van Diepen, Hester C; Deboer, Tom; Pedram, Pardis; Pereira, Rob Rodrigues; Meijer, Johanna H

    2012-10-01

    People with attention-deficit/hyperactivity disorder (ADHD) often experience sleep problems, and these are frequently exacerbated by the methylphenidate they take to manage their ADHD symptoms. Many of the changes to sleep are consistent with a change in the underlying circadian clock. The present study was designed to determine if methylphenidate alone could alter properties of the circadian clock. Young male mice were examined in light-dark cycles and in constant darkness and recordings were performed on behavioral activity, sleep, and electrical activity in the suprachiasmatic nucleus (SCN) of freely moving mice. Methylphenidate in the drinking water (0.08%) significantly increased activity in the mid-to-late night, and led to a delay in the onset of activity and sleep relative to the light-dark cycle. While locomotor levels returned to baseline after treatment ended, the phase angle of entrainment required at least a week to return to baseline levels. In constant darkness, the free-running period of both wheel-running and general locomotor rhythms was lengthened by methylphenidate. When the treatment ended, the free-running period either remained stable or only partially reverted to baseline levels. Methylphenidate also altered the electrical firing rate rhythms in the SCN. It induced a delay in the trough of the rhythm, an increment in rhythm amplitude, and a reduction in rhythm variability. These observations suggest that methylphenidate alters the underlying circadian clock. The observed changes are consistent with clock alterations that would promote sleep-onset insomnia. PMID:22763623

  16. Machine learning helps identify CHRONO as a circadian clock component

    OpenAIRE

    Ron C Anafi; Yool Lee; Sato, Trey K; Anand Venkataraman; Chidambaram Ramanathan; Kavakli, Ibrahim H.; Michael E Hughes; Baggs, Julie E.; Jacqueline Growe; Andrew C Liu; Junhyong Kim; Hogenesch, John B.

    2014-01-01

    Machine Learning Helps Identify CHRONO as a Circadian Clock Component Ron C. Anafi1,2.*, Yool Lee3., Trey K. Sato3., Anand Venkataraman3, Chidambaram Ramanathan4, Ibrahim H. Kavakli5, Michael E. Hughes6, Julie E. Baggs7, Jacqueline Growe1,2, Andrew C. Liu4, Junhyong Kim8, John B. Hogenesch2,3* 1 Division of Sleep Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Center for Sleep and Circadian Neurobiology, Univer...

  17. Timing of Photoperiodic Flowering:Light Perception and Circadian Clock

    Institute of Scientific and Technical Information of China (English)

    Yun Zhou; Xiao-Dong Sun; Min Ni

    2007-01-01

    Flowering symbolizes the transition of a plant from vegetative phase to reproductive phase and is controlled by fairly complex and highly coordinated regulatory pathways. Over the last decade, genetic studies in Arabidopsis have aided the discovery of many signaling components involved in these pathways. In this review, we discuss how the timing of flowering is regulated by photoperiod and the involvement of light perception and the circadian clock in this process. The specific regulatory mechanisms on CONSTANS expression and CONSTANS stability by the circadian clock and photoreceptors are described in detail. In addition, the roles of CONSTANS, FLOWERING LOCUS T, and several other light signaling and circadiandependent components in photoperiodic flowering are also highlighted.

  18. 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

  19. Photoperiodic entrainment of the circadian clock in the mice SCN

    Czech Academy of Sciences Publication Activity Database

    Sosniyenko, Serhiy; Matějů, Kristýna; Sládek, Martin; Illnerová, Helena; Sumová, Alena

    Praha : FgÚ AV ČR, 2008. ---. [PhD Student Workshop of Institute of Physiology. 02.06.2008-04.06.2008, Seč] Grant ostatní: EUCLOCK(XE) 018741 Institutional research plan: CEZ:AV0Z50110509 Source of funding: R - rámcový projekt EK Keywords : spo2 * photoperiod * mice * circadian clock Subject RIV: FH - Neurology

  20. Colour as a signal for entraining the mammalian circadian clock.

    Directory of Open Access Journals (Sweden)

    Lauren Walmsley

    2015-04-01

    Full Text Available Twilight is characterised by changes in both quantity ("irradiance" and quality ("colour" of light. Animals use the variation in irradiance to adjust their internal circadian clocks, aligning their behaviour and physiology with the solar cycle. However, it is currently unknown whether changes in colour also contribute to this entrainment process. Using environmental measurements, we show here that mammalian blue-yellow colour discrimination provides a more reliable method of tracking twilight progression than simply measuring irradiance. We next use electrophysiological recordings to demonstrate that neurons in the mouse suprachiasmatic circadian clock display the cone-dependent spectral opponency required to make use of this information. Thus, our data show that some clock neurons are highly sensitive to changes in spectral composition occurring over twilight and that this input dictates their response to changes in irradiance. Finally, using mice housed under photoperiods with simulated dawn/dusk transitions, we confirm that spectral changes occurring during twilight are required for appropriate circadian alignment under natural conditions. Together, these data reveal a new sensory mechanism for telling time of day that would be available to any mammalian species capable of chromatic vision.

  1. Probing entrainment of Ostreococcus tauri circadian clock by blue and green light through a mathematical modeling approach

    Directory of Open Access Journals (Sweden)

    Quentin eThommen

    2015-02-01

    Full Text Available Most organisms anticipate daily environmental variations and orchestrate cellular functions thanks to a circadian clock which entrains robustly to the day/night cycle, despite fluctuations in light intensity due to weather or seasonal variations. Marine organisms are also subjected to fluctuations in light spectral composition as their depth varies, due to differential absorption of different wavelengths by sea water. Studying how light input pathways contribute to circadian clock robustness is therefore important.Ostreococcus tauri, a unicellular picoplanktonic marine green alga with low genomic complexity and simple cellular organization, has become a promising model organism for systems biology. Functional and modeling approaches have shown that a core circadian oscillator based on orthologs of Arabidopsis TOC1 and CCA1 clock genes accounts for most experimental data acquired under a wide range of conditions. Some evidence points at putative light input pathway(s consisting of a two-component signaling system (TCS controlled by the only two histidine kinases (HK of O. tauri. LOVHK is a blue light photoreceptor under circadian control, that is required for circadian clock function. An involvement of Rhodopsin-HK (RhodHK is also conceivable since rhodopsin photoreceptors mediate blue to green light input in animal circadian clocks.Here, we probe the role of LOVHK and RhodHK in mediating light input to the TOC1-CCA1 oscillator using a mathematical model incorporating the TCS hypothesis. This model agrees with clock gene expression time series representative of multiple environmental conditions in blue or green light, characterizing entrainment by light/dark cycles, free-running in constant light, and resetting. Experimental and theoretical results indicate that both blue and green light can reset O. tauri circadian clock. Moreover, our mathematical analysis suggests that Rhod-HK is a blue-green light receptor and drives the clock together with

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

    OpenAIRE

    Massimo Bracci; Veronica Ciarapica; Alfredo Copertaro; Mariella Barbaresi; Nicola Manzella; Marco Tomasetti; Simona Gaetani; Federica Monaco; Monica Amati; Matteo Valentino; Venerando Rapisarda; Lory Santarelli

    2016-01-01

    The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for...

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

    Directory of Open Access Journals (Sweden)

    Brigitte Grima

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

  4. Melanopsin resets circadian rhythms in cells by inducing clock gene Period1

    Science.gov (United States)

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

    2014-02-01

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

  5. Immunoreactivities to three circadian clock proteins in two ground crickets suggest interspecific diversity of the circadian clock structure

    Czech Academy of Sciences Publication Activity Database

    Shao, Q. M.; Sehadová, H.; Ichihara, N.; Sehnal, František; Takeda, M.

    2006-01-01

    Roč. 21, č. 2 (2006), s. 118-131. ISSN 0748-7304 Grant ostatní: Japan Society for the Promotion of Science(JP) JSPS 99L01205; Japan Society for the Promotion of Science(JP) ID No. P 04197 Institutional research plan: CEZ:AV0Z50070508 Keywords : circadian rhythm * photoperiodic clock * cryptochrome (CRY) Subject RIV: ED - Physiology Impact factor: 4.633, year: 2006

  6. Altered circadian clock gene expression in patients with schizophrenia.

    Science.gov (United States)

    Johansson, Anne-Sofie; Owe-Larsson, Björn; Hetta, Jerker; Lundkvist, Gabriella B

    2016-07-01

    Impaired circadian rhythmicity has been reported in several psychiatric disorders. Schizophrenia is commonly associated with aberrant sleep-wake cycles and insomnia. It is not known if schizophrenia is associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronic schizophrenia and from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, REV-ERBα and DBP. In fibroblasts obtained from patients with chronic schizophrenia, we found a loss of rhythmic expression of CRY1 and PER2 compared to cells from healthy controls. We also estimated the sleep quality in these patients and found that most of them suffered from poor sleep in comparison with the healthy controls. In another patient sample, we analyzed mononuclear blood cells from patients with schizophrenia experiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock in schizophrenia and have important implications in our understanding of the aberrant rhythms reported in this disease. PMID:27132483

  7. Sleep disturbances and circadian CLOCK genes in borderline personality disorder.

    Science.gov (United States)

    Fleischer, Monika; Schäfer, Michael; Coogan, Andrew; Häßler, Frank; Thome, Johannes

    2012-10-01

    Borderline personality disorder (BPD) is characterised by a deep-reaching pattern of affective instability, incoherent identity, self-injury, suicide attempts, and disturbed interpersonal relations and lifestyle. The daily activities of BPD patients are often chaotic and disorganized, with patients often staying up late while sleeping during the day. These behavioural patterns suggest that altered circadian rhythms may be associated with BPD. Furthermore, BPD patients frequently report suffering from sleep disturbances. In this review, we overview the evidence that circadian rhythms and sleep are disturbed in BPD, and we explore the possibility that personality traits that are pertinent for BPD may be associated with circadian typology, and perhaps to circadian genotypes. With regards to sleep architecture, we review the evidence that BPD patients display altered non-REM and REM sleep. A possible cue to a deeper understanding of this temporal dysregulation might be an analysis of the circadian clock at the molecular and cellular level, as well as behavioural studies using actigraphy and we suggest avenues for further exploration of these factors. PMID:22806005

  8. 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.

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

    OpenAIRE

    Tamaru, Teruya; Hattori, Mitsuru; Honda, Kousuke; Nakahata, Yasukazu; Sassone-Corsi, Paolo; van der Horst, Gijsbertus T. J.; Ozawa, Takeaki; Takamatsu, Ken

    2015-01-01

    Intracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we established a pivotal role for casein kinase (CK)-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P) in regulating central and peripheral core clocks. Subsequent analysis of the underlying mechanism showed a ...

  10. 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...

  11. Toward a detailed computational model for the mammalian circadian clock

    Science.gov (United States)

    Leloup, Jean-Christophe; Goldbeter, Albert

    2003-06-01

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

  12. Uncovering the Proteome Response of the Master Circadian Clock to Light Using an AutoProteome System*

    OpenAIRE

    Tian, Ruijun; Alvarez-Saavedra, Matias; Cheng, Hai-Ying M.; Figeys, Daniel

    2011-01-01

    In mammals, the suprachiasmatic nucleus (SCN) is the central circadian pacemaker that governs rhythmic fluctuations in behavior and physiology in a 24-hr cycle and synchronizes them to the external environment by daily resetting in response to light. The bilateral SCN is comprised of a mere ∼20,000 neurons serving as cellular oscillators, a fact that has, until now, hindered the systematic study of the SCN on a global proteome level. Here we developed a fully automated and integrated proteomi...

  13. Dissection of the couplings between cellular messengers and the circadian clock

    International Nuclear Information System (INIS)

    It has been known in recent years that living cells can exhibit circadian rhythms in totally different physiological processes. Intracellular messengers were demonstrated to mediate the entrained pathways linking rhythmic components between circadian clock and its output signalling. Levels of cyclic AMP and cyclic GMP in synchronized cells, and activities of the two key enzymes (AC and PDE) responsible for the cyclic AMP metabolism were measured by applying the isotopic techniques. Bimodal circadian oscillations of the messenger levels and the enzyme activities were disclosed in LD: 12, 12 cycle and constant darkness, as well as in the dividing and non-dividing cultures of the Euglena ZC mutant. Interference experiments with the enzyme activator and inhibitor such as forskolin, 8-Br-cGMP and LY 83583, and analysis of the cell division cycle (CDC) and coupling messengers suggested that the peak pulse of cyclic AMP, circadian oscillation of the AC-cAMP-PDE system and phase-dependent regulation by cyclic GMP might be important coupling factors in downstream mediation between the circadian clock and the CDC. (7 figs.)

  14. A Blind Circadian Clock in Cavefish Reveals that Opsins Mediate Peripheral Clock Photoreception

    OpenAIRE

    Cavallari, N; E.Frigato; Vallone, D.; N.Fröhlich; J.F. Lopez-Olmeda; A.Foà; R.De Berti; Sánchez-Vázquez, F. J.; C.Bertolucci; Foulkes, N S

    2011-01-01

    The circadian clock is a physiological timing mechanism that allows organisms to anticipate and adapt to the day-night cycle. Since it ticks with a period that is not precisely 24 h, it is vital that it is reset on a daily basis by signals such as light to ensure that it remains synchronized with the day-night cycle. The molecular mechanisms whereby light regulates the clock remain incompletely understood. Here we have studied a cavefish that has evolved for millions of years in the perpetual...

  15. The circadian clock-associated gene zea mays gigantea1 affects maize developmental transitions

    Science.gov (United States)

    The circadian clock is the internal timing mechanism that allows plants to make developmental decisions in accordance with environmental conditions. The genes of the maize circadian clock are not well defined. Gigantea (gi) genes are conserved across flowering plants, including maize. In model plant...

  16. Circadian systems biology: When time matters

    Directory of Open Access Journals (Sweden)

    Luise Fuhr

    2015-01-01

    In this manuscript we review the combination of experimental methodologies, bioinformatics and theoretical models that have been essential to explore this remarkable timing-system. Such an integrative and interdisciplinary approach may provide new strategies with regard to chronotherapeutic treatment and new insights concerning the restoration of the circadian timing in clock-associated diseases.

  17. Interaction of MAGED1 with nuclear receptors affects circadian clock function

    OpenAIRE

    Wang, Xiaohan; Tang, Jing; Xing, Lijuan; Shi, Guangsen; Ruan, Haibin; Gu, Xiwen; Liu, Zhiwei; Wu, Xi; Gao, Xiang; Xu, Ying

    2010-01-01

    The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest–activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indica...

  18. Ontogenesis of the circadian clock within the rat liver

    Czech Academy of Sciences Publication Activity Database

    Sládek, Martin; Sumová, Alena; Jindráková, Zuzana; Bendová, Zdeňka; Illnerová, Helena

    Florida : Sage Publications, 2006. s. 89-90. [Meeting of Society for Research on Biological Rhythms /10./. 21.05.2006-25.05.2006, Sandestin] R&D Projects: GA ČR(CZ) GA309/05/0350; GA AV ČR(CZ) IAA500110605; GA MŠk(CZ) LC554 Grant ostatní: EU 6th Framework Project EUCLOCK(XE) 018741 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * liver * ontogenesis Subject RIV: FH - Neurology

  19. Postnatal ontogenesis of the circadian clock within the rat liver

    Czech Academy of Sciences Publication Activity Database

    Sládek, Martin; Jindráková, Zuzana; Bendová, Zdeňka; Sumová, Alena

    2007-01-01

    Roč. 292, č. 3 (2007), R1224-R1229. ISSN 0363-6119 R&D Projects: GA ČR GA309/05/0350; GA MŠk(CZ) LC554 Grant ostatní: EUCLOCK(XE) LSH-2004-115-4-018741 Institutional research plan: CEZ:AV0Z50110509 Source of funding: R - rámcový projekt EK Keywords : circadian rhythms * development, * peripheral clock Subject RIV: FH - Neurology Impact factor: 3.661, year: 2007

  20. 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.

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

    Czech Academy of Sciences Publication Activity Database

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

    2012-01-01

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

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

    OpenAIRE

    Foulkes, Nicholas S.; Yoav Gothilf; Lior Appelbaum

    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 manipul...

  3. Clock is important for food and circadian regulation of macronutrient absorption in mice

    OpenAIRE

    Pan, Xiaoyue; Hussain, M. Mahmood

    2009-01-01

    Clock genes respond to external stimuli and exhibit circadian rhythms. This study investigated the expression of clock genes in the small intestine and their contribution in the regulation of nutrient absorption by enterocytes. We examined expression of clock genes and macronutrient transport proteins in the small intestines of wild-type and Clock mutant (Clkmt/mt) mice with free or limited access to food. In addition, we studied absorption of macronutrients in these mice. Intestinal clock ge...

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

    Science.gov (United States)

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

    2014-10-01

    The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. PMID:25227334

  5. Entrainment of the circadian clock in humans: mechanism and implications for sleep disorders.

    OpenAIRE

    David Metcalfe

    2007-01-01

    Humans exhibit behaviour and physiology controlled by a circadian clock. The circadian period is genetically determined and administered by a series of interlocked autoregulatory feedback loops largely in the suprachiasmatic nuclei of the hypothalamus. The phase of the clock is, however, synchronised by a number of external environmental cues such as light. A failure or change in any one of the requisite clock components may result in the onset of a long-term sleep disorder. This review discu...

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

    Directory of Open Access Journals (Sweden)

    Campoli Chiara

    2012-06-01

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

  7. Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature.

    Science.gov (United States)

    Chen, Chenghao; Buhl, Edgar; Xu, Min; Croset, Vincent; Rees, Johanna S; Lilley, Kathryn S; Benton, Richard; Hodge, James J L; Stanewsky, Ralf

    2015-11-26

    Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels. PMID:26580016

  8. Role for circadian clock genes in seasonal timing: testing the Bunning hypothesis.

    Directory of Open Access Journals (Sweden)

    Mirko Pegoraro

    2014-09-01

    Full Text Available A major question in chronobiology focuses around the "Bünning hypothesis" which implicates the circadian clock in photoperiodic (day-length measurement and is supported in some systems (e.g. plants but disputed in others. Here, we used the seasonally-regulated thermotolerance of Drosophila melanogaster to test the role of various clock genes in day-length measurement. In Drosophila, freezing temperatures induce reversible chill coma, a narcosis-like state. We have corroborated previous observations that wild-type flies developing under short photoperiods (winter-like exhibit significantly shorter chill-coma recovery times (CCRt than flies that were raised under long (summer-like photoperiods. Here, we show that arrhythmic mutant strains, per01, tim01 and ClkJrk, as well as variants that speed up or slow down the circadian period, disrupt the photoperiodic component of CCRt. Our results support an underlying circadian function mediating seasonal daylength measurement and indicate that clock genes are tightly involved in photo- and thermo-periodic measurements.

  9. Insights into the role of the habenular circadian clock in addiction

    Directory of Open Access Journals (Sweden)

    Nora L Salaberry

    2016-01-01

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

  10. Proteomics of the photoneuroendocrine circadian system of the brain

    DEFF Research Database (Denmark)

    Møller, Morten; Lund-Andersen, Casper; Rovsing, Louise;

    2010-01-01

    The photoneuroendocrine circadian system of the brain consists of (a) specialized photoreceptors in the retina, (b) a circadian generator located in the forebrain that contains "clock genes," (c) specialized nuclei in the forebrain involved in neuroendocrine secretion, and (d) the pineal gland. The...... circadian generator is a nucleus, called the suprachiasmatic nucleus (SCN). The neurons of this nucleus contain "clock genes," the transcription of which exhibits a circadian rhythm. Most circadian rhythms are generated by the neurons of this nucleus and, via neuronal and humoral connections, the SCN......-generating system in mammals is described, and recent proteomic studies that investigate day/night changes in the retina, SCN, and pineal gland are reviewed. Further circadian changes controlled by the SCN in gene and protein expression in the liver are discussed....

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

    NARCIS (Netherlands)

    T. Tamaru (Teruya); M. Hattori (Mitsuru); K. Honda (Kousuke); Y. Nakahata (Yasukazu); P. Sassone-Corsi (Paolo); G.T.J. van der Horst (Gijsbertus); T. Ozawa (Takeaki); K. Takamatsu (Ken)

    2015-01-01

    textabstractIntracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we establi

  12. Divergent roles of clock genes in retinal and suprachiasmatic nucleus circadian oscillators.

    Directory of Open Access Journals (Sweden)

    Guo-Xiang Ruan

    Full Text Available The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per 1 and 2, Cryptochrome (Cry 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN, the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC or Period1::luciferase (Per1::luc circadian reporters. Per1-, Cry1- and Clock-deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period.

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

    OpenAIRE

    Guo, Jin-Hu; Qu, Wei-Min; Chen, Shan-Guang; CHEN, XIAO-PING; Lv, Ke; Huang, Zhi-Li; Wu, Yi-Lan

    2014-01-01

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

  14. Heterogeneity of cellular circadian clocks in intact plants and its correction under light-dark cycles.

    Science.gov (United States)

    Muranaka, Tomoaki; Oyama, Tokitaka

    2016-07-01

    Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system. PMID:27453946

  15. Heterogeneity of cellular circadian clocks in intact plants and its correction under light-dark cycles

    Science.gov (United States)

    Muranaka, Tomoaki; Oyama, Tokitaka

    2016-01-01

    Recent advances in single-cell analysis have revealed the stochasticity and nongenetic heterogeneity inherent to cellular processes. However, our knowledge of the actual cellular behaviors in a living multicellular organism is still limited. By using a single-cell bioluminescence imaging technique on duckweed, Lemna gibba, we demonstrate that, under constant conditions, cells in the intact plant work as individual circadian clocks that oscillate with their own frequencies and respond independently to external stimuli. Quantitative analysis uncovered the heterogeneity and instability of cellular clocks and partial synchronization between neighboring cells. Furthermore, we found that cellular clocks in the plant body under light-dark cycles showed a centrifugal phase pattern in which the effect of cell-to-cell heterogeneity in period lengths was almost masked. The inherent heterogeneity in the properties of cellular clocks observed under constant conditions is corrected under light-dark cycles to coordinate the daily rhythms of the plant body. These findings provide a novel perspective of spatiotemporal architectures in the plant circadian system. PMID:27453946

  16. Entrainment of the circadian clock in humans: mechanism and implications for sleep disorders.

    Directory of Open Access Journals (Sweden)

    David Metcalfe

    2007-01-01

    Full Text Available Humans exhibit behaviour and physiology controlled by a circadian clock. The circadian period is genetically determined and administered by a series of interlocked autoregulatory feedback loops largely in the suprachiasmatic nuclei of the hypothalamus. The phase of the clock is, however, synchronised by a number of external environmental cues such as light. A failure or change in any one of the requisite clock components may result in the onset of a long-term sleep disorder. This review discusses the mechanism regulating circadian physiology in humans and explores how disturbances of this mechanism may result in sleep pathologies.

  17. Visualizing and Quantifying Intracellular Behavior and Abundance of the Core Circadian Clock Protein PERIOD2.

    Science.gov (United States)

    Smyllie, Nicola J; Pilorz, Violetta; Boyd, James; Meng, Qing-Jun; Saer, Ben; Chesham, Johanna E; Maywood, Elizabeth S; Krogager, Toke P; Spiller, David G; Boot-Handford, Raymond; White, Michael R H; Hastings, Michael H; Loudon, Andrew S I

    2016-07-25

    Transcriptional-translational feedback loops (TTFLs) are a conserved molecular motif of circadian clocks. The principal clock in mammals is the suprachiasmatic nucleus (SCN) of the hypothalamus. In SCN neurons, auto-regulatory feedback on core clock genes Period (Per) and Cryptochrome (Cry) following nuclear entry of their protein products is the basis of circadian oscillation [1, 2]. In Drosophila clock neurons, the movement of dPer into the nucleus is subject to a circadian gate that generates a delay in the TTFL, and this delay is thought to be critical for oscillation [3, 4]. Analysis of the Drosophila clock has strongly influenced models of the mammalian clock, and such models typically infer complex spatiotemporal, intracellular behaviors of mammalian clock proteins. There are, however, no direct measures of the intracellular behavior of endogenous circadian proteins to support this: dynamic analyses have been limited and often have no circadian dimension [5-7]. We therefore generated a knockin mouse expressing a fluorescent fusion of native PER2 protein (PER2::VENUS) for live imaging. PER2::VENUS recapitulates the circadian functions of wild-type PER2 and, importantly, the behavior of PER2::VENUS runs counter to the Drosophila model: it does not exhibit circadian gating of nuclear entry. Using fluorescent imaging of PER2::VENUS, we acquired the first measures of mobility, molecular concentration, and localization of an endogenous circadian protein in individual mammalian cells, and we showed how the mobility and nuclear translocation of PER2 are regulated by casein kinase. These results provide new qualitative and quantitative insights into the cellular mechanism of the mammalian circadian clock. PMID:27374340

  18. The ancestral circadian clock of monarch butterflies: role in time-compensated sun compass orientation.

    Science.gov (United States)

    Reppert, S M

    2007-01-01

    The circadian clock has a vital role in monarch butterfly (Danaus plexippus) migration by providing the timing component of time-compensated sun compass orientation, which contributes to navigation to the overwintering grounds. The location of circadian clock cells in monarch brain has been identified in the dorsolateral protocerebrum (pars lateralis); these cells express PERIOD, TIMELESS, and a Drosophila-like cryptochrome designated CRY1. Monarch butterflies, like all other nondrosophilid insects examined so far, express a second cry gene (designated insect CRY2) that encodes a vertebrate-like CRY that is also expressed in pars lateralis. An ancestral circadian clock mechanism has been defined in monarchs, in which CRY1 functions as a blue light photoreceptor for photic entrainment, whereas CRY2 functionswithin the clockwork as themajor transcriptional repressor of an intracellular negative transcriptional feedback loop. A CRY1-staining neural pathway has been identified that may connect the circadian (navigational) clock to polarized light input important for sun compass navigation, and a CRY2-positive neural pathway has been discovered that may communicate circadian information directly from the circadian clock to the central complex, the likely site of the sun compass. The monarch butterfly may thus use the CRY proteins as components of the circadian mechanism and also as output molecules that connect the clock to various aspects of the sun compass apparatus. PMID:18419268

  19. Temporal requirements of the fragile X mental retardation protein in modulating circadian clock circuit synaptic architecture

    Directory of Open Access Journals (Sweden)

    Cheryl L Gatto

    2009-08-01

    Full Text Available Loss of fragile X mental retardation 1 (FMR1 gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs, a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity.

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

    Directory of Open Access Journals (Sweden)

    Hedman Harald

    2010-06-01

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

  1. Melatonin administered during the fetal stage affects circadian clock in the suprachiasmatic nucleus but not in the liver

    Czech Academy of Sciences Publication Activity Database

    Houdek, Pavel; Polidarová, Lenka; Nováková, Marta; Matějů, Kristýna; Kubík, Štěpán; Sumová, Alena

    2015-01-01

    Roč. 75, č. 2 (2015), s. 131-144. ISSN 1932-8451 R&D Projects: GA ČR(CZ) GAP303/12/1108 Institutional support: RVO:67985823 Keywords : ontogenesis * circadian system * suprachiasmatic nuclei * clock gene * melatonin Subject RIV: FH - Neurology Impact factor: 3.370, year: 2014

  2. Newly Described Components and Regulatory Mechanisms of Circadian Clock Function in Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    Manuel Adrián Troncoso-Ponce; Paloma Mas

    2012-01-01

    The circadian clock temporally coordinates plant growth and metabolism in close synchronization with the diurnal and seasonal environmental changes.Research over the last decade has identified a number of clock components and a variety of regulatory mechanisms responsible for the rhythmic oscillations in metabolic and physiological activities.At the core of the clock,transcriptional/translational feedback loops modulate the expression of a significant proportion of the genome.In this article,we briefly describe some of the very recent advances that have improved our understanding of clock organization and function in Arabidopsis thaliana.The new studies illustrate the role of clock protein complex formation on circadian gating of plant growth and identify alternative splicing as a new regulatory mechanism for clock function.Examination of key clock properties such as temperature compensation has also opened new avenues for functional research within the plant clockwork.The emerging connections between the circadian clock and metabolism,hormone signaling and response to biotic and abiotic stress also add new layers of complexity to the clock network and underscore the significance of the circadian clock regulating the daily life of plants.

  3. Pinealectomy abolishes circadian behavior and interferes with circadian clock gene oscillations in brain and liver but not retina in a migratory songbird.

    Science.gov (United States)

    Trivedi, Amit Kumar; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod

    2016-03-15

    In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings. PMID:26801391

  4. The Importance of Stochastic Effects for Explaining Entrainment in the Zebrafish Circadian Clock

    Directory of Open Access Journals (Sweden)

    Raphaela Heussen

    2015-01-01

    Full Text Available The circadian clock plays a pivotal role in modulating physiological processes and has been implicated, either directly or indirectly, in a range of pathological states including cancer. Here we investigate how the circadian clock is entrained by external cues such as light. Working with zebrafish cell lines and combining light pulse experiments with simulation efforts focused on the role of synchronization effects, we find that even very modest doses of light exposure are sufficient to trigger some entrainment, whereby a higher light intensity or duration correlates with strength of the circadian signal. Moreover, we observe in the simulations that stochastic effects may be considered an essential feature of the circadian clock in order to explain the circadian signal decay in prolonged darkness, as well as light initiated resynchronization as a strong component of entrainment.

  5. Running a little late: chloroplast Fe status and the circadian clock

    OpenAIRE

    Wilson, Grandon T; Erin L Connolly

    2013-01-01

    Iron homeostasis is essential for plant growth and survival. Two papers now report that chloroplast Iron levels also regulate the period of the circadian clock, which might confer fitness advantage by linking iron status to daily changes in environmental conditions.

  6. A wheel of time: the circadian clock, nuclear receptors, and physiology

    OpenAIRE

    Yang, Xiaoyong

    2010-01-01

    It is a long-standing view that the circadian clock functions to proactively align internal physiology with the 24-h rotation of the earth. Recent studies, including one by Schmutz and colleagues (pp. 345–357) in the February 15, 2010, issue of Genes & Development, delineate strikingly complex connections between molecular clocks and nuclear receptor signaling pathways, implying the existence of a large-scale circadian regulatory network coordinating a diverse array of physiological processes...

  7. Interactions between circadian clocks and photosynthesis for the temporal and spatial coordination of metabolism

    OpenAIRE

    Dodd, Antony N; Belbin, Fiona E.; Frank, Alexander; Webb, Alex A. R.

    2015-01-01

    All plant productivity, including the food that we eat, arises from the capture of solar energy by plants. At most latitudes sunlight is available for only part of the 24 h day due to the rotation of the planet. This rhythmic and predictable alteration in the environment has driven the evolution of the circadian clock, which has an extremely pervasive influence upon plant molecular biology, physiology and phenology. A number of recent studies have demonstrated that the circadian clock is inte...

  8. Regulation of Fatty Acid Metabolism by Cell Autonomous Circadian Clocks: Time to Fatten up on Information?*

    OpenAIRE

    Bray, Molly S; Young, Martin E.

    2011-01-01

    Molecular, cellular, and animal-based studies have recently exposed circadian clocks as critical regulators of energy balance. Invariably, mouse models of genetically manipulated circadian clock components display features indicative of altered lipid/fatty acid metabolism, including differential adiposity and circulating lipids. The purpose of this minireview is to provide a comprehensive summary of current knowledge regarding the regulation of fatty acid metabolism by distinct cell autonomou...

  9. Circadian rhythms of cyanobacteria: monitoring the biological clocks of individual colonies by bioluminescence.

    OpenAIRE

    Kondo, T.; Ishiura, M

    1994-01-01

    Reproducible circadian rhythms of bioluminescence from individual colonies of cyanobacteria (Synechococcus sp. strain PCC 7942) has been observed. Phenotypic monitoring of colonies on agar plates will enable us to genetically analyze the molecular mechanism of the circadian clock of cyanobacteria by screening for clock mutants. By the introduction of a bacterial luciferase gene, we previously developed a transformed cyanobacterial strain (AMC149) that expresses luciferase as a bioluminescent ...

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

    Directory of Open Access Journals (Sweden)

    Brianne Alyssia Kent

    2014-09-01

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

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

    Science.gov (United States)

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

    2016-07-15

    A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. PMID:27091299

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

    Science.gov (United States)

    Bracci, Massimo; Ciarapica, Veronica; Copertaro, Alfredo; Barbaresi, Mariella; Manzella, Nicola; Tomasetti, Marco; Gaetani, Simona; Monaco, Federica; Amati, Monica; Valentino, Matteo; Rapisarda, Venerando; Santarelli, Lory

    2016-01-01

    The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for 24 h after a day off. Significant differences were observed in peripheral skin temperature and cortisol levels between shift and daytime nurses. No differences in melatonin levels were obtained. Per2 maximum values were significantly different between the two groups. Shift nurses exhibited lower circadian variations compared to daytime nurses, and this may indicate an adjustment of the circadian biological clock to continuous shift schedules. Non-invasive procedures, such as peripheral skin temperature measurement, determination of cortisol and melatonin in saliva, and analysis of clock genes in hair follicle cells, may be effective approaches to extensively study the circadian clock in shift workers. PMID:27128899

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

    Directory of Open Access Journals (Sweden)

    Massimo Bracci

    2016-04-01

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

  14. CUL1 Regulates TOC1 Protein Stability in the Arabidopsis Circadian Clock

    Science.gov (United States)

    The circadian clock is the endogenous timer that coordinates physiological processes with daily and seasonal environmental changes. In Arabidopsis thaliana, establishment of the circadian period relies on targeted degradation of TIMING OF CAB EXPRESSION 1 (TOC1) by the 26S proteasome. ZEITLUPE (ZTL)...

  15. Molecular mechanism of temperature sensing by the circadian clock of Neurospora crassa

    NARCIS (Netherlands)

    Diernfellner, ACR; Schafmeier, T; Merrow, MW; Brunner, M; Diernfellner, Axel C.R.

    2005-01-01

    Expression levels and ratios of the long (1) and short (s) isoforms of the Neurospora circadian clock protein FREQUENCY (FRQ) are crucial for temperature compensation of circadian rhythms. We show that the ratio of 1-FRQ versus s-FRQ is regulated by thermosensitive splicing of intron 6 of frq, a pro

  16. Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms.

    Science.gov (United States)

    Hrushesky, William J M; Grutsch, James; Wood, Patricia; Yang, Xiaoming; Oh, Eun-Young; Ansell, Christine; Kidder, Stephanie; Ferrans, Carol; Quiton, Dinah Faith T; Reynolds, Justin; Du-Quiton, Jovelyn; Levin, Robert; Lis, Christopher; Braun, Donald

    2009-12-01

    Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian

  17. Interactions of polymorphisms in different clock genes associated with circadian phenotypes in humans

    Directory of Open Access Journals (Sweden)

    Mario Pedrazzoli

    2010-01-01

    Full Text Available Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1 in people with extreme diurnal preferences (morning or evening. We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.

  18. Effects of temperature on circadian clock and chronotype: an experimental study in a passerine bird

    NARCIS (Netherlands)

    Lehmann, M.; Spoelstra, K.; Visser, M.E.; Helm, B.

    2012-01-01

    Daily schedules of many organisms, including birds, are thought to affect fitness. Timing in birds is based on circadian clocks that have a heritable period length, but fitness consequences for individuals in natural environments depend on the scheduling of entrained clocks. This chronotype, i.e., t

  19. Effects of Temperature on Circadian Clock and Chronotype : An Experimental Study on a Passerine Bird

    NARCIS (Netherlands)

    Lehmann, Marina; Spoelstra, Kamiel; Visser, Marcel E.; Helm, Barbara

    2012-01-01

    Daily schedules of many organisms, including birds, are thought to affect fitness. Timing in birds is based on circadian clocks that have a heritable period length, but fitness consequences for individuals in natural environments depend on the scheduling of entrained clocks. This chronotype, i.e., t

  20. Evidence Suggesting that the Cardiomyocyte Circadian Clock Modulates Responsiveness of the Heart to Hypertrophic Stimuli in Mice

    OpenAIRE

    Durgan, David J.; Tsai, Ju-Yun; Grenett, Maximiliano H.; Pat, Betty M.; Ratcliffe, William F.; Villegas-Montoya, Carolina; Garvey, Merissa E.; Nagendran, Jeevan; Dyck, Jason R. B.; Bray, Molly S.; Gamble, Karen L.; Gimble, Jeffrey M.; Young, Martin E.

    2011-01-01

    Circadian dyssynchrony of an organism (at the whole body level) with its environment, either through light/dark cycle or genetic manipulation of clock genes, augments various cardiometabolic diseases. The cardiomyocyte circadian clock has recently been shown to influence multiple myocardial processes, ranging from transcriptional regulation and energy metabolism, to contractile function. We therefore reasoned that chronic dyssychrony of the cardiomyocyte circadian clock with its environment w...

  1. 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.

  2. Balance equations can buffer noisy and sustained environmental perturbations of circadian clocks

    OpenAIRE

    Domijan, Mirela; Rand, David A.

    2010-01-01

    We present a new approach to understanding how regulatory networks such as circadian clocks might evolve robustness to environmental fluctuations. The approach is in terms of new balance equations that we derive. We use it to describe how an entrained clock can buffer the effects of daily fluctuations in light and temperature levels. We also use it to study a different approach to temperature compensation where instead of considering a free-running clock, we study temperature buffering of the...

  3. The Drosophila circadian clock is a variably coupled network of multiple peptidergic units

    OpenAIRE

    Z. Yao; Shafer, O.T.

    2014-01-01

    Daily rhythms in behavior emerge from networks of neurons that express molecular clocks. Drosophila’s clock neuron network consists of a diversity of cell types, yet is modeled as two hierarchically organized groups, one of which serves as a master pacemaker. Here we establish that the fly’s clock neuron network consists of multiple units of independent neuronal oscillators, each unified by its neuropeptide transmitter and mode of coupling to other units. Our work reveals that the circadian c...

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

    Directory of Open Access Journals (Sweden)

    Jana Husse

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

  5. Assembly of a comprehensive regulatory network for the mammalian circadian clock: a bioinformatics approach.

    Directory of Open Access Journals (Sweden)

    Robert Lehmann

    Full Text Available By regulating the timing of cellular processes, the circadian clock provides a way to adapt physiology and behaviour to the geophysical time. In mammals, a light-entrainable master clock located in the suprachiasmatic nucleus (SCN controls peripheral clocks that are present in virtually every body cell. Defective circadian timing is associated with several pathologies such as cancer and metabolic and sleep disorders. To better understand the circadian regulation of cellular processes, we developed a bioinformatics pipeline encompassing the analysis of high-throughput data sets and the exploitation of published knowledge by text-mining. We identified 118 novel potential clock-regulated genes and integrated them into an existing high-quality circadian network, generating the to-date most comprehensive network of circadian regulated genes (NCRG. To validate particular elements in our network, we assessed publicly available ChIP-seq data for BMAL1, REV-ERBα/β and RORα/γ proteins and found strong evidence for circadian regulation of Elavl1, Nme1, Dhx6, Med1 and Rbbp7 all of which are involved in the regulation of tumourigenesis. Furthermore, we identified Ncl and Ddx6, as targets of RORγ and REV-ERBα, β, respectively. Most interestingly, these genes were also reported to be involved in miRNA regulation; in particular, NCL regulates several miRNAs, all involved in cancer aggressiveness. Thus, NCL represents a novel potential link via which the circadian clock, and specifically RORγ, regulates the expression of miRNAs, with particular consequences in breast cancer progression. Our findings bring us one step forward towards a mechanistic understanding of mammalian circadian regulation, and provide further evidence of the influence of circadian deregulation in cancer.

  6. Time for a Nuclear Meeting: Protein Trafficking and Chromatin Dynamics Intersect in the Plant Circadian System

    Institute of Scientific and Technical Information of China (English)

    Eva Herrero; Seth J. Davis

    2012-01-01

    Circadian clocks mediate adaptation to the 24-h world.In Arabidopsis,most circadian-clock components act in the nucleus as transcriptional regulators and generate rhythmic oscillations of transcript accumulation.In this review,we focus on post-transcriptional events that modulate the activity of circadian-clock components,such as phosphorylation,ubiquitination and proteasome-mediated degradation,changes in cellular localization,and protein-protein interactions.These processes have been found to be essential for circadian function,not only in plants,but also in other circadian systems.Moreover,light and clock signaling networks are highly interconnected.In the nucleus,light and clock components work together to generate transcriptional rhythms,leading to a general control of the timing of plant physiological processes.

  7. 营养感知与生物时钟%Nutrient Sensing and the Circadian Clock

    Institute of Scientific and Technical Information of China (English)

    刘畅

    2014-01-01

    The circadian system synchronizes behavioral and physiological processes with daily changes in the external light-dark cycle,optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierar-chically,with neural clocks orchestrating the daily switch between periods of feeding and fasting,and peripheral clocks generating 24 h oscillations of energy storage and utilizations. Recent studies indicate that clocks respond to nutrient signals,and that high-fat diet influences the period of locomotor activity under free-running conditions,a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relationship between metabolic and circadian pathways. In this review, we will discuss the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems.%地球自转产生了昼夜明暗交替循环,为了适应这一环境,生物体进化出时钟系统,控制着行为和生理进程同步化于光线的周期变化,以使能量利用达到最优状态。时钟的分子结构分级组建,其中中枢时钟掌管着进食/禁食之间的日际转换,而外周时钟导致能量储存/利用的24 h周期振荡。最近的研究表明,生物时钟响应于营养信号,而且高脂饮食影响了动物自发运动的周期(时钟的核心特质之一)。生物时钟研究的一个主要目标是阐明代谢和时钟通路的交互对话。在本综述中,我们将讨论激素和作为营养信号的大分子如何整合时钟和代谢系统。

  8. The Potorous CPD photolyase rescues a cryptochrome-deficient mammalian circadian clock.

    Directory of Open Access Journals (Sweden)

    Inês Chaves

    Full Text Available Despite the sequence and structural conservation between cryptochromes and photolyases, members of the cryptochrome/photolyase (flavoprotein family, their functions are divergent. Whereas photolyases are DNA repair enzymes that use visible light to lesion-specifically remove UV-induced DNA damage, cryptochromes act as photoreceptors and circadian clock proteins. To address the functional diversity of cryptochromes and photolyases, we investigated the effect of ectopically expressed Arabidopsis thaliana (6-4PP photolyase and Potorous tridactylus CPD-photolyase (close and distant relatives of mammalian cryptochromes, respectively, on the performance of the mammalian cryptochromes in the mammalian circadian clock. Using photolyase transgenic mice, we show that Potorous CPD-photolyase affects the clock by shortening the period of behavioral rhythms. Furthermore, constitutively expressed CPD-photolyase is shown to reduce the amplitude of circadian oscillations in cultured cells and to inhibit CLOCK/BMAL1 driven transcription by interacting with CLOCK. Importantly, we show that Potorous CPD-photolyase can restore the molecular oscillator in the liver of (clock-deficient Cry1/Cry2 double knockout mice. These data demonstrate that a photolyase can act as a true cryptochrome. These findings shed new light on the importance of the core structure of mammalian cryptochromes in relation to its function in the circadian clock and contribute to our further understanding of the evolution of the cryptochrome/photolyase protein family.

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

    Directory of Open Access Journals (Sweden)

    Astha Malik

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

  10. Natural selection against a circadian clock gene mutation in mice

    NARCIS (Netherlands)

    Spoelstra, K.; Wikelski, Martin; Daan, Serge; Loudon, Andrew; Hau, Michaela

    2015-01-01

    Circadian rhythms with an endogenous period close 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 c

  11. Protein sequestration versus Hill-type repression in circadian clock models.

    Science.gov (United States)

    Kim, Jae Kyoung

    2016-08-01

    Circadian (∼24 h) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptional-translational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, the author discusses how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modelling of transcriptional repression mechanisms in molecular circadian clocks. PMID:27444022

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

    Indian Academy of Sciences (India)

    Malcolm Von Schantz

    2008-12-01

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

  13. Modelling of intercellular synchronization in the Drosophila circadian clock

    Institute of Scientific and Technical Information of China (English)

    Wang Jun-Wei; Chen Ai-Min; Zhang Jia-Jun; Yuan Zhan-Jiang; Zhou Tian-Shou

    2009-01-01

    In circadian rhythm generation, intercellular signaling factors are shown to play a crucial role in both sustaining intrinsic cellular rhythmicity and acquiring collective behaviours across a population of circadian neurons. However, the physical mechanism behind their role remains to be fully understood. In this paper, we propose an indirectly coupled multicellular model for the synchronization of Drosophila circadian oscillators combining both intracellular and intercellular dynamics. By simulating different experimental conditions, we find that such an indirect coupling way can synchronize both heterogeneous self-sustained circadian neurons and heterogeneous mutational damped circadian neurons. Moreover, they can also be entrained to ambient light-dark (LD) cycles depending on intercellular signaling.

  14. Computational modeling of protein interactions and phosphoform kinetics in the KaiABC cyanobacterial circadian clock

    CERN Document Server

    Byrne, Mark

    2014-01-01

    The KaiABC circadian clock from cyanobacteria is the only known three-protein oscillatory system which can be reconstituted outside the cell and which displays sustained periodic dynamics in various molecular state variables. Despite many recent experimental and theoretical studies there are several open questions regarding the central mechanism(s) responsible for creating this ~24 hour clock in terms of molecular assembly/disassembly of the proteins and site-dependent phosphorylation and dephosphorylation of KaiC monomers. Simulations of protein-protein interactions and phosphorylation reactions constrained by analytical fits to partial reaction experimental data support the central mechanism of oscillation as KaiB-induced KaiA sequestration in KaiABC complexes associated with the extent of Ser431 phosphorylation in KaiC hexamers. A simple two-state deterministic model in terms of the degree of phosphorylation of Ser431 and Thr432 sites alone can reproduce the previously observed circadian oscillation in the...

  15. PI3K regulates BMAL1/CLOCK-mediated circadian transcription from the Dbp promoter.

    Science.gov (United States)

    Morishita, Yoshikazu; Miura, Daiki; Kida, Satoshi

    2016-06-01

    The circadian rhythm generated by circadian clock underlies a molecular mechanism of rhythmic transcriptional regulation by transcription factor BMAL1/CLOCK. Importantly, the circadian clock is coordinated by exogenous cues to accommodate to changes in the external environment. However, the molecular mechanisms by which intracellular-signaling pathways mediate the adjustments of the circadian transcriptional rhythms remain unclear. In this study, we found that pharmacological inhibition or shRNA-mediated knockdown of phosphatidylinositol 3-kinase (PI3K) blocked upregulation of Dbp mRNA induced by serum shock in NIH 3T3 cells. Moreover, the inhibition of PI3K significantly reduced the promoter activity of the Dbp gene, as well as decreased the recruitment of BMAL1/CLOCK to the E-box in the Dbp promoter. Interestingly, the inhibition of PI3K blocked heterodimerization of BMAL1 and CLOCK. Our findings suggest that PI3K signaling plays a modulatory role in the regulation of the transcriptional rhythm of the Dbp gene by targeting BMAL1 and CLOCK. PMID:27022680

  16. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism.

    Science.gov (United States)

    Leone, Vanessa; Gibbons, Sean M; Martinez, Kristina; Hutchison, Alan L; Huang, Edmond Y; Cham, Candace M; Pierre, Joseph F; Heneghan, Aaron F; Nadimpalli, Anuradha; Hubert, Nathaniel; Zale, Elizabeth; Wang, Yunwei; Huang, Yong; Theriault, Betty; Dinner, Aaron R; Musch, Mark W; Kudsk, Kenneth A; Prendergast, Brian J; Gilbert, Jack A; Chang, Eugene B

    2015-05-13

    Circadian clocks and metabolism are inextricably intertwined, where central and hepatic circadian clocks coordinate metabolic events in response to light-dark and sleep-wake cycles. We reveal an additional key element involved in maintaining host circadian rhythms, the gut microbiome. Despite persistence of light-dark signals, germ-free mice fed low or high-fat diets exhibit markedly impaired central and hepatic circadian clock gene expression and do not gain weight compared to conventionally raised counterparts. Examination of gut microbiota in conventionally raised mice showed differential diurnal variation in microbial structure and function dependent upon dietary composition. Additionally, specific microbial metabolites induced under low- or high-fat feeding, particularly short-chain fatty acids, but not hydrogen sulfide, directly modulate circadian clock gene expression within hepatocytes. These results underscore the ability of microbially derived metabolites to regulate or modify central and hepatic circadian rhythm and host metabolic function, the latter following intake of a Westernized diet. PMID:25891358

  17. Differential contribution of rod and cone circadian clocks in driving retinal melatonin rhythms in Xenopus.

    Directory of Open Access Journals (Sweden)

    Naoto Hayasaka

    Full Text Available BACKGROUND: Although an endogenous circadian clock located in the retinal photoreceptor layer governs various physiological events including melatonin rhythms in Xenopus laevis, it remains unknown which of the photoreceptors, rod and/or cone, is responsible for the circadian regulation of melatonin release. METHODOLOGY/PRINCIPAL FINDINGS: We selectively disrupted circadian clock function in either the rod or cone photoreceptor cells by generating transgenic Xenopus tadpoles expressing a dominant-negative CLOCK (XCLΔQ under the control of a rod or cone-specific promoter. Eyecup culture and continuous melatonin measurement revealed that circadian rhythms of melatonin release were abolished in a majority of the rod-specific XCLΔQ transgenic tadpoles, although the percentage of arrhythmia was lower than that of transgenic tadpole eyes expressing XCLΔQ in both rods and cones. In contrast, whereas a higher percentage of arrhythmia was observed in the eyes of the cone-specific XCLΔQ transgenic tadpoles compare to wild-type counterparts, the rate was significantly lower than in rod-specific transgenics. The levels of the transgene expression were comparable between these two different types of transgenics. In addition, the average overall melatonin levels were not changed in the arrhythmic eyes, suggesting that CLOCK does not affect absolute levels of melatonin, only its temporal expression pattern. CONCLUSIONS/SIGNIFICANCE: These results suggest that although the Xenopus retina is made up of approximately equal numbers of rods and cones, the circadian clocks in the rod cells play a dominant role in driving circadian melatonin rhythmicity in the Xenopus retina, although some contribution of the clock in cone cells cannot be excluded.

  18. Modeling the emergence of circadian rhythms in a clock neuron network.

    Directory of Open Access Journals (Sweden)

    Luis Diambra

    Full Text Available Circadian rhythms in pacemaker cells persist for weeks in constant darkness, while in other types of cells the molecular oscillations that underlie circadian rhythms damp rapidly under the same conditions. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms leading to damped or self-sustained oscillations remain largely unknown. There exist many mathematical models that reproduce the circadian rhythms in the case of a single cell of the Drosophila fly. However, not much is known about the mechanisms leading to coherent circadian oscillation in clock neuron networks. In this work we have implemented a model for a network of interacting clock neurons to describe the emergence (or damping of circadian rhythms in Drosophila fly, in the absence of zeitgebers. Our model consists of an array of pacemakers that interact through the modulation of some parameters by a network feedback. The individual pacemakers are described by a well-known biochemical model for circadian oscillation, to which we have added degradation of PER protein by light and multiplicative noise. The network feedback is the PER protein level averaged over the whole network. In particular, we have investigated the effect of modulation of the parameters associated with (i the control of net entrance of PER into the nucleus and (ii the non-photic degradation of PER. Our results indicate that the modulation of PER entrance into the nucleus allows the synchronization of clock neurons, leading to coherent circadian oscillations under constant dark condition. On the other hand, the modulation of non-photic degradation cannot reset the phases of individual clocks subjected to intrinsic biochemical noise.

  19. Circadian Clock Genes: Effects on Dopamine, Reward and Addiction

    OpenAIRE

    Parekh, Puja K.; Ozburn, Angela R; McClung, Colleen A.

    2015-01-01

    Addiction is a widespread public health issue with social and economic ramifications. Substance abuse disorders are often accompanied by disruptions in circadian rhythms including sleep/wake cycles, which can exacerbate symptoms of addiction and dependence. Additionally, genetic disturbance of circadian molecular mechanisms can predispose some individuals to substance abuse disorders. In this review, we will discuss how circadian genes can regulate midbrain dopaminergic activity and subsequen...

  20. Defence responses of Arabidopsis thaliana to infection by Pseudomonas syringae are regulated by the circadian clock.

    Directory of Open Access Journals (Sweden)

    Vaibhav Bhardwaj

    Full Text Available 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.

  1. 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.

  2. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

    OpenAIRE

    Karatsoreos, Ilia N.; Bhagat, Sarah; Bloss, Erik B.; Morrison, John H.; McEwen, Bruce S.

    2011-01-01

    Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken....

  3. Circadian Clocks in the Cnidaria: Environmental Entrainment, Molecular Regulation, and Organismal Outputs

    OpenAIRE

    Reitzel, Adam M; Tarrant, Ann M.; Levy, Oren

    2013-01-01

    The circadian clock is a molecular network that translates predictable environmental signals, such as light levels, into organismal responses, including behavior and physiology. Regular oscillations of the molecular components of the clock enable individuals to anticipate regularly fluctuating environmental conditions. Cnidarians play important roles in benthic and pelagic marine environments and also occupy a key evolutionary position as the likely sister group to the bilaterians. Together, ...

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

    Czech Academy of Sciences Publication Activity Database

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

    2012-01-01

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

  5. Investigation of a non-invasive method of assessing the equine circadian clock using hair follicle cells

    OpenAIRE

    Watts, Lisa M; Browne, John A.; Murphy, Barbara A

    2012-01-01

    Background: A comprehensive understanding of the equine circadian clock involves the evaluation of circadian clock gene expression. A non-invasive and effective method for detecting equine clock gene expression has yet to be established. Currently, research surrounding this area has relied on collecting tissue biopsies or blood samples that can often be costly, time consuming and uncomfortable for the animal.Methods: Five mares were individually stabled under a light–dark (LD) cycle that mimi...

  6. Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock

    OpenAIRE

    Ye, Rui; Selby, Cristopher P.; Chiou, Yi-Ying; Ozkan-Dagliyan, Irem; Gaddameedhi, Shobhan; Sancar, Aziz

    2014-01-01

    The mammalian circadian clock is based on a transcription–translation feedback loop in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which encode proteins that repress CLOCK–BMAL1 with a periodicity of ∼ 24 h. Ye et al. show that CRY binds to CLOCK–BMAL1 at the promoter and inhibits CLOCK–BMAL1-dependent transcription without dissociating the complex. PER alone has no effect on CLOCK–BMAL1-activated transcription, but in the presence of CRY...

  7. Redox regulation and pro-oxidant reactions in the physiology of circadian systems.

    Science.gov (United States)

    Méndez, Isabel; Vázquez-Martínez, Olivia; Hernández-Muñoz, Rolando; Valente-Godínez, Héctor; Díaz-Muñoz, Mauricio

    2016-05-01

    Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes. PMID:25926044

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Paula S Nieto

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

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

    Science.gov (United States)

    Preußner, Marco; Heyd, Florian

    2016-06-01

    Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease. PMID:27108448

  11. Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging

    Science.gov (United States)

    Wang, Rui-Hong; Zhao, Tingrui; Cui, Kairong; Hu, Gangqing; Chen, Qiang; Chen, Weiping; Wang, Xin-Wei; Soto-Gutierrez, Alejandro; Zhao, Keji; Deng, Chu-Xia

    2016-01-01

    Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. PMID:27346580

  12. Inferring bi-directional interactions between circadian clock genes and metabolism with model ensembles.

    Science.gov (United States)

    Grzegorczyk, Marco; Aderhold, Andrej; Husmeier, Dirk

    2015-04-01

    There has been much interest in reconstructing bi-directional regulatory networks linking the circadian clock to metabolism in plants. A variety of reverse engineering methods from machine learning and computational statistics have been proposed and evaluated. The emphasis of the present paper is on combining models in a model ensemble to boost the network reconstruction accuracy, and to explore various model combination strategies to maximize the improvement. Our results demonstrate that a rich ensemble of predictors outperforms the best individual model, even if the ensemble includes poor predictors with inferior individual reconstruction accuracy. For our application to metabolomic and transcriptomic time series from various mutagenesis plants grown in different light-dark cycles we also show how to determine the optimal time lag between interactions, and we identify significant interactions with a randomization test. Our study predicts new statistically significant interactions between circadian clock genes and metabolites in Arabidopsis thaliana, and thus provides independent statistical evidence that the regulation of metabolism by the circadian clock is not uni-directional, but that there is a statistically significant feedback mechanism aiming from metabolism back to the circadian clock. PMID:25719342

  13. The association of circadian clock candidate genes to increased adiposity in the TIGER study

    Science.gov (United States)

    Obesity is a highly prevalent disease that has become a major health crisis in the United States. A number of studies have suggested a link between the altered sleep/wake patterns associated with our "24 hour" lifestyle and obesity. We hypothesize that disruption of the circadian clock intrinsic t...

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

    Czech Academy of Sciences Publication Activity Database

    Soták, Matúš; Sumová, Alena; Pácha, Jiří

    2014-01-01

    Roč. 46, č. 4 (2014), s. 221-232. ISSN 0785-3890 R&D Projects: GA ČR(CZ) GA13-08304S Institutional support: RVO:67985823 Keywords : apoptosis * cancer * cell cycle * circadian clock * MAPK cascade * proliferation * Wnt signaling Subject RIV: ED - Physiology Impact factor: 3.886, year: 2014

  15. 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

  16. Function of the Shaw potassium channel within the Drosophila circadian clock.

    Directory of Open Access Journals (Sweden)

    James J Hodge

    Full Text Available BACKGROUND: In addition to the molecular feedback loops, electrical activity has been shown to be important for the function of networks of clock neurons in generating rhythmic behavior. Most studies have used over-expression of foreign channels or pharmacological manipulations that alter membrane excitability. In order to determine the cellular mechanisms that regulate resting membrane potential (RMP in the native clock of Drosophila we modulated the function of Shaw, a widely expressed neuronal potassium (K(+ channel known to regulate RMP in Drosophila central neurons. METHODOLOGY/PRINCIPAL FINDINGS: We show that Shaw is endogenously expressed in clock neurons. Differential use of clock gene promoters was employed to express a range of transgenes that either increase or decrease Shaw function in different clusters of clock neurons. Under LD conditions, increasing Shaw levels in all clock neurons (LNv, LNd, DN(1, DN(2 and DN(3, or in subsets of clock neurons (LNd and DNs or DNs alone increases locomotor activity at night. In free-running conditions these manipulations result in arrhythmic locomotor activity without disruption of the molecular clock. Reducing Shaw in the DN alone caused a dramatic lengthening of the behavioral period. Changing Shaw levels in all clock neurons also disrupts the rhythmic accumulation and levels of Pigment Dispersing Factor (PDF in the dorsal projections of LNv neurons. However, changing Shaw levels solely in LNv neurons had little effect on locomotor activity or rhythmic accumulation of PDF. CONCLUSIONS/SIGNIFICANCE: Based on our results it is likely that Shaw modulates pacemaker and output neuronal electrical activity that controls circadian locomotor behavior by affecting rhythmic release of PDF. The results support an important role of the DN clock neurons in Shaw-mediated control of circadian behavior. In conclusion, we have demonstrated a central role of Shaw for coordinated and rhythmic output from clock

  17. Circadian mechanisms of food anticipatory rhythms in rats fed once or twice daily: clock gene and endocrine correlates.

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    Danica F Patton

    Full Text Available Circadian clocks in many brain regions and peripheral tissues are entrained by the daily rhythm of food intake. Clocks in one or more of these locations generate a daily rhythm of locomotor activity that anticipates a regular mealtime. Rats and mice can also anticipate two daily meals. Whether this involves 1 or 2 circadian clocks is unknown. To gain insight into how the circadian system adjusts to 2 daily mealtimes, male rats in a 12∶12 light-dark cycle were fed a 2 h meal either 4 h after lights-on or 4 h after lights-off, or a 1 h meal at both times. After 30 days, brain, blood, adrenal and stomach tissue were collected at 6 time points. Multiple clock genes from adrenals and stomachs were assayed by RT-PCR. Blood was assayed for corticosterone and ghrelin. Bmal1 expression was quantified in 14 brain regions by in situ hybridization. Clock gene rhythms in adrenal and stomach from day-fed rats oscillated in antiphase with the rhythms in night-fed rats, and at an intermediate phase in rats fed twice daily. Corticosterone and ghrelin in 1-meal rats peaked at or prior to the expected mealtime. In 2-meal rats, corticosterone peaked only prior the nighttime meal, while ghrelin peaked prior to the daytime meal and then remained elevated. The olfactory bulb, nucleus accumbens, dorsal striatum, cerebellum and arcuate nucleus exhibited significant daily rhythms of Bmal1 in the night-fed groups that were approximately in antiphase in the day-fed groups, and at intermediate levels (arrhythmic in rats anticipating 2 daily meals. The dissociations between anticipatory activity and the peripheral clocks and hormones in rats anticipating 2 daily meals argue against a role for these signals in the timing of behavioral rhythms. The absence of rhythmicity at the tissue level in brain regions from rats anticipating 2 daily meals support behavioral evidence that circadian clock cells in these tissues may reorganize into two populations coupled to different

  18. Drosophila spaghetti and doubletime link the circadian clock and light to caspases, apoptosis and tauopathy.

    Directory of Open Access Journals (Sweden)

    John C Means

    2015-05-01

    Full Text Available While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in

  19. Synchronization of circadian Per2 rhythms and HSF1-BMAL1:CLOCK interaction in mouse fibroblasts after short-term heat shock pulse.

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    Teruya Tamaru

    Full Text Available Circadian rhythms are the general physiological processes of adaptation to daily environmental changes, such as the temperature cycle. A change in temperature is a resetting cue for mammalian circadian oscillators, which are possibly regulated by the heat shock (HS pathway. The HS response (HSR is a universal process that provides protection against stressful conditions, which promote protein-denaturation. Heat shock factor 1 (HSF1 is essential for HSR. In the study presented here, we investigated whether a short-term HS pulse can reset circadian rhythms. Circadian Per2 rhythm and HSF1-mediated gene expression were monitored by a real-time bioluminescence assay for mPer2 promoter-driven luciferase and HS element (HSE; HSF1-binding site-driven luciferase activity, respectively. By an optimal duration HS pulse (43°C for approximately 30 minutes, circadian Per2 rhythm was observed in the whole mouse fibroblast culture, probably indicating the synchronization of the phases of each cell. This rhythm was preceded by an acute elevation in mPer2 and HSF1-mediated gene expression. Mutations in the two predicted HSE sites adjacent (one of them proximally to the E-box in the mPer2 promoter dramatically abolished circadian mPer2 rhythm. Circadian Per2 gene/protein expression was not observed in HSF1-deficient cells. These findings demonstrate that HSF1 is essential to the synchronization of circadian rhythms by the HS pulse. Importantly, the interaction between HSF1 and BMAL1:CLOCK heterodimer, a central circadian transcription factor, was observed after the HS pulse. These findings reveal that even a short-term HS pulse can reset circadian rhythms and cause the HSF1-BMAL1:CLOCK interaction, suggesting the pivotal role of crosstalk between the mammalian circadian and HSR systems.

  20. A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability.

    Science.gov (United States)

    Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L; White, Kevin P; Dinner, Aaron R; Lear, Bridget C; Ren, Dejian; Diekman, Casey O; Raman, Indira M; Allada, Ravi

    2015-08-13

    Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

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

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    Dominick A Matos

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

  2. On-chip clock error characterization for clock distribution system

    OpenAIRE

    Shan, Chuan; Galayko, Dimitri; Anceau, François

    2013-01-01

    In this paper, we investigate a test strategy for characterization of clock error statistics between two clock domains in high-speed clocking systems (gigahertz and more). The method allows an indirect measurement (not based on time interval measurement) of clock error distribution by observing the integrity of a periodic sequence transmitted between two clocking domains. The method is compatible with fully on-chip implementation, and the readout of result to off-chip signals is cadenced at l...

  3. An evolutionary fitness enhancement conferred by the circadian system in cyanobacteria

    International Nuclear Information System (INIS)

    Circadian clocks are found in a wide variety of organisms from cyanobacteria to mammals. Many believe that the circadian clock system evolved as an adaption to the daily cycles in light and temperature driven by the rotation of the earth. Studies on the cyanobacterium, Synechococcus elongatus PCC 7942, have confirmed that the circadian clock in resonance with environmental cycles confers an adaptive advantage to cyanobacterial strains with different clock properties when grown in competition under light–dark cycles. The results thus far suggest that in a cyclic environment, the cyanobacterial strains whose free running periods are closest to the environmental period are the most fit and the strains lacking a functional circadian clock are at a competitive disadvantage relative to strains with a functional clock. In contrast, the circadian system provides little or no advantage to cyanobacteria grown in competition in constant light. To explain the potential mechanism of this clock-mediated enhancement in fitness in cyanobacteria, several models have been proposed; these include the limiting resource model, the diffusible inhibitor model and the cell-to-cell communication model. None of these models have been excluded by the currently available experimental data and the mechanistic basis of clock-mediated fitness enhancement remains elusive

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

    Science.gov (United States)

    Tamaru, Teruya; Hattori, Mitsuru; Honda, Kousuke; Nakahata, Yasukazu; Sassone-Corsi, Paolo; van der Horst, Gijsbertus T. J.; Ozawa, Takeaki; Takamatsu, Ken

    2015-01-01

    Intracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we established a pivotal role for casein kinase (CK)-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P) in regulating central and peripheral core clocks. Subsequent analysis of the underlying mechanism showed a novel role of CRY as a repressor for protein kinase. Co-immunoprecipitation experiments and real-time monitoring of protein–protein interactions revealed that CRY-mediated periodic binding of CK2β to BMAL1 inhibits BMAL1-Ser90 phosphorylation by CK2α. The FAD binding domain of CRY1, two C-terminal BMAL1 domains, and particularly BMAL1-Lys537 acetylation/deacetylation by CLOCK/SIRT1, were shown to be critical for CRY-mediated BMAL1–CK2β binding. Reciprocally, BMAL1-Ser90 phosphorylation is prerequisite for BMAL1-Lys537 acetylation. We propose a dual negative-feedback model in which a CRY-dependent CK2-driven posttranslational BMAL1–P-BMAL1 loop is an integral part of the core clock oscillator. PMID:26562092

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

    Directory of Open Access Journals (Sweden)

    Teruya Tamaru

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

  6. [Cognitive Function and Calcium. Ca2+-dependent regulatory mechanism of circadian clock oscillation and its relevance to neuronal function].

    Science.gov (United States)

    Kon, Naohiro; Fukada, Yoshitaka

    2015-02-01

    Circadian clock generates a variety of biological rhythms such as sleep/wake cycles and blood hormone rhythms. The circadian clock also bolsters daily mental activities. In fact, abnormalities of the circadian rhythms are found in several neurological disorders. The circadian clock has two important functions: (i) a cell-autonomous oscillatory function and (ii) a phase-adjusting function that synchronizes the clock oscillation with environmental cycling conditions such as light/dark cycle. Behavioral rhythms are controlled by the central clock in hypothalamic suprachiasmatic nucleus (SCN). The central clock orchestrates peripheral clocks in the other tissues via neuronal connection and/or actions of humoral factors. The molecular mechanism of the cell-autonomous clock is based on transcriptional feedback regulation of clock genes by their encoded products. Ca2+ is essential for not only the light response of the clock but also the cell autonomous oscillation mechanism. This article provides an overview of recent progress in studies of Ca2+-dependent regulatory mechanism of the molecular clockwork. PMID:25634045

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

    Science.gov (United States)

    Zhu, Haisun; Sauman, Ivo; Yuan, Quan; Casselman, Amy; Emery-Le, Myai; Emery, Patrick; Reppert, Steven M

    2008-01-01

    The circadian clock plays a vital role in monarch butterfly (Danaus plexippus) migration by providing the timing component of time-compensated sun compass orientation, a process that is important for successful navigation. We therefore evaluated the monarch clockwork by focusing on the functions of a Drosophila-like cryptochrome (cry), designated cry1, and a vertebrate-like cry, designated cry2, that are both expressed in the butterfly and by placing these genes in the context of other relevant clock genes in vivo. We found that similar temporal patterns of clock gene expression and protein levels occur in the heads, as occur in DpN1 cells, of a monarch cell line that contains a light-driven clock. CRY1 mediates TIMELESS degradation by light in DpN1 cells, and a light-induced TIMELESS decrease occurs in putative clock cells in the pars lateralis (PL) in the brain. Moreover, monarch cry1 transgenes partially rescue both biochemical and behavioral light-input defects in cry(b) mutant Drosophila. CRY2 is the major transcriptional repressor of CLOCK:CYCLE-mediated transcription in DpN1 cells, and endogenous CRY2 potently inhibits transcription without involvement of PERIOD. CRY2 is co-localized with clock proteins in the PL, and there it translocates to the nucleus at the appropriate time for transcriptional repression. We also discovered CRY2-positive neural projections that oscillate in the central complex. The results define a novel, CRY-centric clock mechanism in the monarch in which CRY1 likely functions as a blue-light photoreceptor for entrainment, whereas CRY2 functions within the clockwork as the transcriptional repressor of a negative transcriptional feedback loop. Our data further suggest that CRY2 may have a dual role in the monarch butterfly's brain-as a core clock element and as an output that regulates circadian activity in the central complex, the likely site of the sun compass. PMID:18184036

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

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    Michael J McCarthy

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

  9. 生物钟的转录后与翻译后水平调控进展%Posttranscriptional and posttranslational regulation of circadian clock

    Institute of Scientific and Technical Information of China (English)

    俞波; 吴涛; 倪银华; 周静露; 诸葛芬; 孙璐; 傅正伟

    2011-01-01

    The circadian system in mammals is composed of a master pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and slave clocks in most peripheral cell types.The clock genes and their coding proteins compose the feedback loops ofthe circadian system.As for the regulating mechanism of circadian clock, the modification of core clock transcripts and proteins can significantly affect the phase of circadian clock in addition to the transcriptional regulation.This article briefly reviews the advances on some of the posttranseriptional and posttranslational modifications and their effects on the circadian clock, and also suggests the future research direction.%哺乳动物中的昼夜节律系统由位于下丘脑SCN核内的生物钟主钟和位于多数外周细胞中的子钟组成.在分子水平上,生物钟的节律振荡由生物钟基因及其编码蛋白的转录和翻译形成的自主的反馈环路组成,并接受外界因素的影响与环境周期保持同步.为此,就生物钟的调控机制而言,除了转录水平的基因表达调控外,生物钟转录产物和蛋白质的修饰也可以显著影响生物钟基因的表达时相.讨论了一些转录后与翻译后的修饰作用及其对生物钟的影响,并对其今后的研究方向作了展望.

  10. Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression.

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    Marina M Bellet

    Full Text Available Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.

  11. Cognitive dysfunction, elevated anxiety and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice

    Directory of Open Access Journals (Sweden)

    Emmanuel Valjent

    2013-10-01

    Full Text Available The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2. Mice lacking Cry1 and Cry2 (Cry1-/-Cry2-/- displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1-/-Cry2-/- mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK induced by a single cocaine administration are strongly reduced in Cry1-/-Cry2-/- mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Moreover, we further observed elevated anxiety in Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.

  12. Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice.

    Science.gov (United States)

    De Bundel, Dimitri; Gangarossa, Giuseppe; Biever, Anne; Bonnefont, Xavier; Valjent, Emmanuel

    2013-01-01

    The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1(-/-)Cry2(-/-) ) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1(-/-)Cry2(-/-) mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1(-/-)Cry2(-/-) mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1(-/-)Cry2(+/+) and Cry1(+/+)Cry2(-/-) mice. Moreover, we further observed elevated anxiety in Cry1(-/-)Cry2(+/+) and Cry1(+/+)Cry2(-/-) mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs. PMID:24187535

  13. A Novel Protein, CHRONO, Functions as a Core Component of the Mammalian Circadian Clock

    OpenAIRE

    Kavaklı, İbrahim Halil; Anafi, Ron C.; Lee, Yoo; Sato, Trey K.; Venkataraman, Anand; Ramanathan, Chidambaram; Hughes, Michael E.; Baggs, Julie E.; Growe, Jacqueline; Liu, Andrew C.; Kim, Junhyong; Hogenesch, John B.

    2014-01-01

    Machine Learning Helps Identify CHRONO as a Circadian Clock Component Ron C. Anafi1,2.*, Yool Lee3., Trey K. Sato3., Anand Venkataraman3, Chidambaram Ramanathan4, Ibrahim H. Kavakli5, Michael E. Hughes6, Julie E. Baggs7, Jacqueline Growe1,2, Andrew C. Liu4, Junhyong Kim8, John B. Hogenesch2,3* 1 Division of Sleep Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Center for Sleep and Circadian Neurobiology, Univer...

  14. Examining the Acute and Chronic Effects of Sepsis on the Circadian Clock in the Mouse

    OpenAIRE

    O'Callaghan, Emma

    2013-01-01

    Circadian rhythms are recurring patterns (~24hrs) in behaviour and physiology that are driven primarily by an endogenous biological timekeeping system, with the master pacemaker located in the suprachiasmatic nucleus. Studies have indicated bidirectional relationships between the circadian and the immune systems, however while there is much evidence regarding the regulation of immune function by the circadian system, information regarding the impact of immune processes on the timekeeping syst...

  15. Glaucoma alters the circadian timing system.

    Science.gov (United States)

    Drouyer, Elise; Dkhissi-Benyahya, Ouria; Chiquet, Christophe; WoldeMussie, Elizabeth; Ruiz, Guadalupe; Wheeler, Larry A; Denis, Philippe; Cooper, Howard M

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (approximately 50-70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system. PMID:19079596

  16. Glaucoma Alters the Circadian Timing System

    Science.gov (United States)

    Drouyer, Elise; Dkhissi-Benyahya, Ouria; Chiquet, Christophe; WoldeMussie, Elizabeth; Ruiz, Guadalupe; Wheeler, Larry A.; Denis, Philippe; Cooper, Howard M.

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (∼50–70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system. PMID:19079596

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-07-18

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

  19. 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 conserve

  20. Sleep disturbances and circadian CLOCK genes in borderline personality disorder

    OpenAIRE

    Fleischer, Monika; Schafer, Michael; Coogan, Andrew; Hassler, Frank; Thome, Johannes

    2012-01-01

    Borderline personality disorder (BPD) is characterised by a deep-reaching pattern of affective instability, incoherent identity, self-injury, suicide attempts, and disturbed interpersonal relations and lifestyle. The daily activities of BPD patients are often chaotic and disorganized, with patients often staying up late while sleeping during the day. These behavioural patterns suggest that altered circadian rhythms may be associated with BPD. Furthermore, BPD patients ...

  1. Insight Into the Circadian Clock Within Rat Colonic Epithelial Cells

    Czech Academy of Sciences Publication Activity Database

    Sládek, Martin; Rybová, Markéta; Jindráková, Zuzana; Zemanová, Zdeňka; Polidarová, Lenka; Mrnka, Libor; O´Neill, J.; Pácha, Jiří; Sumová, Alena

    2007-01-01

    Roč. 133, č. 4 (2007), s. 1240-1249. ISSN 0016-5085 R&D Projects: GA AV ČR(CZ) IAA500110605 Institutional research plan: CEZ:AV0Z50110509 Keywords : cirkadian clock * colon * NHE3 Subject RIV: FH - Neurology Impact factor: 11.673, year: 2007

  2. Photoperiodic entrainment of the circadian molecular clock in the mice

    Czech Academy of Sciences Publication Activity Database

    Sosniyenko, Serhiy; Hut, R.; Matějů, Kristýna; Sládek, Martin; Illnerová, Helena; Sumová, Alena

    Praha : The Czech Neuroscience Society, 2007. s. 92-92. [Conference of the Czech Neuroscience Society /6./. 19.11.2007-20.11.2007, Praha] Grant ostatní: 6th Framework project EUCLOCK(XE) 18741 Institutional research plan: CEZ:AV0Z50110509 Keywords : spo2 * photoperiod * clock genes * mice Subject RIV: FH - Neurology

  3. Photoperiodic entrainment of the circadian molecular clock in the mice

    Czech Academy of Sciences Publication Activity Database

    Sosniyenko, Serhiy; Laurinová, Kristýna; Sládek, Martin; Sumová, Alena

    Brno : Fyziologický ústav LF MU, 2007. [Fyziologické dny /83./. 06.02.2007-08.02.2007, Brno] Grant ostatní: 6th Framework project EUCLOCK(XE) 18741 Institutional research plan: CEZ:AV0Z50110509 Keywords : spo2 * photoperiod * clock genes * mice Subject RIV: FH - Neurology

  4. Time to Grow: Circadian Clock Controls Plant Hormone Signaling and Response

    OpenAIRE

    Covington, Michael F.; Harmer, Stacey L.

    2007-01-01

    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 circadia...

  5. Inferring bi-directional interactions between circadian clock genes and metabolism with model ensembles

    OpenAIRE

    Grzegorczyk, Marco; Aderhold, Andrej; Husmeier, Dirk

    2015-01-01

    There has been much interest in reconstructing bi-directional regulatory networks linking the circadian clock to metabolism in plants. A variety of reverse engineering methods from machine learning and computational statistics have been proposed and evaluated. The emphasis of the present paper is on combining models in a model ensemble to boost the network reconstruction accuracy, and to explore various model combination strategies to maximize the improvement. Our results demonstrate that a r...

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

    OpenAIRE

    Haisun Zhu; Ivo Sauman; Quan Yuan; Amy Casselman; Myai Emery-Le; Patrick Emery; Reppert, Steven M.

    2008-01-01

    The circadian clock plays a vital role in monarch butterfly (Danaus plexippus) migration by providing the timing component of time-compensated sun compass orientation, a process that is important for successful navigation. We therefore evaluated the monarch clockwork by focusing on the functions of a Drosophila-like cryptochrome (cry), designated cry1, and a vertebrate-like cry, designated cry2, that are both expressed in the butterfly and by placing these genes in the context of other releva...

  7. Antennal circadian clocks coordinate sun compass orientation in migratory monarch butterflies#

    OpenAIRE

    Merlin, Christine; Gegear, Robert J; Reppert, Steven M.

    2009-01-01

    During their fall migration, Eastern North American monarch butterflies (Danaus plexippus) use a time-compensated sun compass to aid navigation to their overwintering grounds in central Mexico. It has been assumed that the circadian clock that provides time compensation resides in the brain, although this assumption has never been examined directly. Here we show that the antennae are necessary for proper time-compensated sun compass orientation in migratory monarch butterflies, that antennal ...

  8. The Circadian Timing System and Environmental Circadian Disruption: From Follicles to Fertility.

    Science.gov (United States)

    Sen, Aritro; Sellix, Michael T

    2016-09-01

    The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility. PMID:27501186

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

    Directory of Open Access Journals (Sweden)

    Evangelia Charmandari

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

  10. CIRCADIAN CLOCK AND CELL CYCLE GENE EXPRESSION: IN MOUSE MAMMARY EPITHELIAL CELLS AND IN THE DEVELOPING MOUSE MAMMARY GLAND

    OpenAIRE

    Metz, Richard P.; Qu, Xiaoyu; Laffin, Brian; Earnest, David; Porter, Weston W.

    2006-01-01

    Mouse mammary epithelial cells (HC-11) and mammary tissues were analyzed for developmental changes in circadian clock, cellular proliferation and differentiation marker genes. Expression of the clock genes, Per1 and Bmal1, were elevated in differentiated HC-11 cells whereas Per2 mRNA levels were higher in undifferentiated cells. This differentiation-dependent profile of clock gene expression was consistent with that observed in mouse mammary glands as Per1 and Bmal1 mRNA levels were elevated ...

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

    Directory of Open Access Journals (Sweden)

    Maria Luisa eGuerriero

    2014-10-01

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

  12. Antennal circadian clocks coordinate sun compass orientation in migratory monarch butterflies.

    Science.gov (United States)

    Merlin, Christine; Gegear, Robert J; Reppert, Steven M

    2009-09-25

    During their fall migration, Eastern North American monarch butterflies (Danaus plexippus) use a time-compensated Sun compass to aid navigation to their overwintering grounds in central Mexico. It has been assumed that the circadian clock that provides time compensation resides in the brain, although this assumption has never been examined directly. Here, we show that the antennae are necessary for proper time-compensated Sun compass orientation in migratory monarch butterflies, that antennal clocks exist in monarchs, and that they likely provide the primary timing mechanism for Sun compass orientation. These unexpected findings pose a novel function for the antennae and open a new line of investigation into clock-compass connections that may extend widely to other insects that use this orientation mechanism. PMID:19779201

  13. Unproductive alternative splicing and nonsense mRNAs: A widespread phenomenon among plant circadian clock genes

    Directory of Open Access Journals (Sweden)

    Filichkin Sergei A

    2012-07-01

    Full Text Available Abstract Background Recent mapping of eukaryotic transcriptomes and spliceomes using massively parallel RNA sequencing (RNA-seq has revealed that the extent of alternative splicing has been considerably underestimated. Evidence also suggests that many pre-mRNAs undergo unproductive alternative splicing resulting in incorporation of in-frame premature termination codons (PTCs. The destinies and potential functions of the PTC-harboring mRNAs remain poorly understood. Unproductive alternative splicing in circadian clock genes presents a special case study because the daily oscillations of protein expression levels require rapid and steep adjustments in mRNA levels. Results We conducted a systematic survey of alternative splicing of plant circadian clock genes using RNA-seq and found that many Arabidopsis thaliana circadian clock-associated genes are alternatively spliced. Results were confirmed using reverse transcription polymerase chain reaction (RT-PCR, quantitative RT-PCR (qRT-PCR, and/or Sanger sequencing. Intron retention events were frequently observed in mRNAs of the CCA1/LHY-like subfamily of MYB transcription factors. In contrast, the REVEILLE2 (RVE2 transcript was alternatively spliced via inclusion of a "poison cassette exon" (PCE. The PCE type events introducing in-frame PTCs are conserved in some mammalian and plant serine/arginine-rich splicing factors. For some circadian genes such as CCA1 the ratio of the productive isoform (i.e., a representative splice variant encoding the full-length protein to its PTC counterpart shifted sharply under specific environmental stress conditions. Conclusions Our results demonstrate that unproductive alternative splicing is a widespread phenomenon among plant circadian clock genes that frequently generates mRNA isoforms harboring in-frame PTCs. Because LHY and CCA1 are core components of the plant central circadian oscillator, the conservation of alternatively spliced variants between CCA1 and LHY

  14. Temperature compensation model for the circadian clock of Neurospora crassa

    Science.gov (United States)

    Tang, Xiaojia; Schüttler, Heinz-Bernd; Arnold, Jonathan

    2008-03-01

    In the lowly bread mould, Neurospora crassa, biomolecular reactions involving the white-collar-1 (wc-1), white-colloar-2 (wc2), and frequency (frq) genes and their products constitute building blocks of the biological clock that would response to temperature as well as light. The period of the biological clock remains stable in response to variation in ambient temperature, which is called a compensation phenomenon. Recent experimental results show evidences that the temperature compensation could be explained by the temperature sensitive translational control of production of two isoforms of the main oscillator protein FRQ: a long form FRQ^1-989 which is more abundantly produced at higher temperature; and a short from FRQ^100-989, more abundantly produced at lower temperature. With our recently developed method of genetic network identification, we are now simulating the network's temperature response based on published experimental data. These will serve as the starting point for a simulation-prediction-experiment-simulation workflow cycle. In this cycle, the maximally informative next experiment (MINE) technology will be employed to select the best experimental control parameters specifying the temperature response to be used in the next step of the workflow cycle.

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

    Directory of Open Access Journals (Sweden)

    Haisun Zhu

    2008-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lucia Pagani

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

  17. Relationships between the circadian system and Alzheimer's disease-like symptoms in Drosophila.

    Directory of Open Access Journals (Sweden)

    Dani M Long

    Full Text Available Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD, are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01. No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism.

  18. 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.

  19. 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

    , 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 these...... genes, Per1, Per2, Per3, Cry1, Arntl, Nr1d1, and Dbp were found to exhibit circadian rhythms in a sequential temporal manner similar to that of the SCN, but with several hours of delay. The results of lesion studies indicate that the molecular oscillatory profiles of Per1, Per2, and Cry1 in the...

  20. Systemic PPARγ deletion impairs circadian rhythms of behavior and metabolism.

    Science.gov (United States)

    Yang, Guangrui; Jia, Zhanjun; Aoyagi, Toshinori; McClain, Donald; Mortensen, Richard M; Yang, Tianxin

    2012-01-01

    Compelling evidence from both human and animal studies suggests a physiological link between the circadian rhythm and metabolism but the underlying mechanism is still incompletely understood. We examined the role of PPARγ, a key regulator of energy metabolism, in the control of physiological and behavioral rhythms by analyzing two strains of whole-body PPARγ null mouse models. Systemic inactivation of PPARγ was generated constitutively by using Mox2-Cre mice (MoxCre/flox) or inducibly by using the tamoxifen system (EsrCre/flox/TM). Circadian variations in oxygen consumption, CO(2) production, food and water intake, locomotor activity, and cardiovascular parameters were all remarkably suppressed in MoxCre/flox mice. A similar phenotype was observed in EsrCre/flox/TM mice, accompanied by impaired rhythmicity of the canonical clock genes in adipose tissues and liver but not skeletal muscles or the kidney. PPARγ inactivation in isolated preadipocytes following exposure to tamoxifen led to a similar blockade of the rhythmicity of the clock gene expression. Together, these results support an essential role of PPARγ in the coordinated control of circadian clocks and metabolic pathways. PMID:22899986

  1. Circadian clocks and life-history related traits: is pupation height affected by circadian organization in Drosophila melanogaster?

    Indian Academy of Sciences (India)

    Dhanashree A. Paranjpe; D. Anitha; Vijay Kumar Sharma; Amitabh Joshi

    2004-04-01

    In D. melanogaster, the observation of greater pupation height under constant darkness than under constant light has been explained by the hypothesis that light has an inhibitory effect on larval wandering behaviour, preventing larvae from crawling higher up the walls of culture vials prior to pupation. If this is the only role of light in affecting pupation height, then various light : dark regimes would be predicted to yield pupation heights intermediate between those seen in constant light and constant darkness. We tested this hypothesis by measuring pupation height under various light : dark regimes in four laboratory populations of Drosophila melanogaster. Pupation height was the greatest in constant darkness, intermediate in constant light, and the least in a light / dark regime of LD 14:14 h. The results clearly suggest that there is more to light regime effects on pupation height than mere behavioural inhibition of wandering larvae, and that circadian organization may play some role in determining pupation height, although the details of this role are not yet clear. We briefly discuss these results in the context of the possible involvement of circadian clocks in life-history evolution.

  2. 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.

  3. Gravity and light effects on the circadian clock of a desert beetle, Trigonoscelis gigas.

    Science.gov (United States)

    Hoban-Higgins, T M; Alpatov, A M; Wassmer, G T; Rietveld, W J; Fuller, C A

    2003-07-01

    Circadian function is affected by exposure to altered ambient force environments. Under non-earth gravitational fields, both basic features of circadian rhythms and the expression of the clock responsible for these rhythms are altered. We examined the activity rhythm of the tenebrionid beetle, Trigonoscelis gigas, in conditions of microgravity (microG; spaceflight), earth's gravity (1 G) and 2 G (centrifugation). Data were recorded under a light-dark cycle (LD), constant light (LL), and constant darkness (DD). Free-running period (tau) was significantly affected by both the gravitational field and ambient light intensity. In DD, tau was longer under 2 G than under either 1 G or microG. In addition, tauLL was significantly different from tauDD under microG and 1 G, but not under 2 G. PMID:12837319

  4. Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position

    Science.gov (United States)

    Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this stu...

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

    International Nuclear Information System (INIS)

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

  6. Controllable clock circuit design in PEM system

    International Nuclear Information System (INIS)

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

  7. Circadian system from conception till adulthood

    Czech Academy of Sciences Publication Activity Database

    Sumová, Alena; Sládek, Martin; Polidarová, Lenka; Nováková, Marta; Houdek, Pavel

    2012-01-01

    Roč. 199, č. 2012 (2012), s. 83-103. ISSN 0079-6123 R&D Projects: GA ČR(CZ) GA305/09/0321; GA ČR(CZ) GAP303/11/0668; GA MŠk(CZ) LC554; GA MZd(CZ) NT11474; GA ČR(CZ) GAP303/12/1108 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : ontogenesis * suprachiasmatic nucleus * peripheral circadian clocks * clock gene Subject RIV: ED - Physiology Impact factor: 4.191, year: 2012

  8. Differential control of pre-invasive and post-invasive antibacterial defense by the Arabidopsis circadian clock.

    Science.gov (United States)

    Korneli, Christin; Danisman, Selahattin; Staiger, Dorothee

    2014-09-01

    Plants show a suite of inducible defense responses against bacterial pathogens. Here we investigate in detail the effect of the circadian clock on these reactions in Arabidopsis thaliana. The magnitude of immune responses elicited by flg22, by virulent and by avirulent Pseudomonas syringae strains depends on the time of day of inoculation. The oxidative burst is stronger when flg22 is infiltrated in the morning in wild-type plants but not in the arrhythmic clock mutant lux arrhythmo/phytoclock1 (pcl1), and thus is controlled by the endogenous clock. Similarly, when bacteria are syringe-infiltrated into the leaf, defense gene induction is higher and bacterial growth is suppressed more strongly after morning inoculation in wild-type but not in pcl1 plants. Furthermore, cell death associated with the hypersensitive response was found to be under clock control. Notably, the clock effect depends on the mode of infection: upon spray inoculation onto the leaf surface, defense gene induction is higher and bacterial growth is suppressed more strongly upon evening inoculation. This different phasing of pre-invasive and post-invasive defense relates to clock-regulated stomatal movement. In particular, TIME FOR COFFEE may impact pathogen defense via clock-regulated stomata movement apart from its known role in time-of-day-dependent jasmonate responses. Taken together, these data highlight the importance of the circadian clock for the control of different immune responses at distinct times of the day. PMID:24974385

  9. period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock

    Energy Technology Data Exchange (ETDEWEB)

    Emerson, Jillian M.; Bartholomai, Bradley M.; Ringelberg, Carol; Baker, Scott E.; Loros, Jennifer J.; Dunlap, Jay C.

    2015-12-22

    Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 and DDX17 in humans and Dbp2p in yeast, are implicated in various processes including transcriptional regulation, elongation, and termination, 23 ribosome biogenesis, and RNA decay. Although prdi-1smutantssiois an ATP-dependent RNA helicase, member of a sub-family display a long period (~25 hrs) circadian developmental cycle, they interestingly display a wild type period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator runs with a long period under glucose-sufficient conditions. Thus PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose PRD-1 is in the nucleus until glucose runs out which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd­-1 may be formally viewed as clock mutant with defective nutritional compensation of circadian period length.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  11. Intergeneric complementation of a circadian rhythmicity defect : phylogenetic conservation of structure and function of the clock gene frequency

    NARCIS (Netherlands)

    Merrow, Martha W.; Dunlap, Jay C.; Dover, G.

    1994-01-01

    The Neurospora crassa frequency locus encodes a 989 amino acid protein that is a central component, a state variable, of the circadian biological clock. We have determined the sequence of all or part of this protein and surrounding regulatory regions from additional fungi representing three genera a

  12. QUASIMODO, a novel GPI-anchored zona pellucida protein involved in light input to the Drosophila circadian clock

    Czech Academy of Sciences Publication Activity Database

    Chen, K. F.; Peschel, N.; Závodská, Radka; Sehadová, Hana; Stanewsky, R.

    2011-01-01

    Roč. 21, č. 9 (2011), s. 719-729. ISSN 0960-9822 R&D Projects: GA MŠk LC07032 Institutional research plan: CEZ:AV0Z50070508 Keywords : QUASIMODO * Drosophila * circadian clock Subject RIV: ED - Physiology Impact factor: 9.647, year: 2011

  13. Lego clocks : building a clock from parts

    NARCIS (Netherlands)

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

    2008-01-01

    A new finding opens up speculation that the molecular mechanism of circadian clocks in Synechococcus elongatus is composed of multiple oscillator systems (Kitayama and colleagues, this issue, pp. 1513-1521), as has been described in many eukaryotic clock model systems. However, an alternative intepr

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

    Science.gov (United States)

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

    2013-01-01

    Circadian clocks are endogenous approximately 24 h oscillators that temporally regulate many physiological and behavioural processes. In order to be beneficial for the organism, these clocks must be synchronized with the environmental cycles on a daily basis. Both light : dark and the concomitant daily temperature cycles (TCs) function as Zeitgeber (‘time giver’) and efficiently entrain circadian clocks. The temperature receptors mediating this synchronization have not been identified. Transient receptor potential (TRP) channels function as thermo-receptors in animals, and here we show that the Pyrexia (Pyx) TRP channel mediates temperature synchronization in Drosophila melanogaster. Pyx is expressed in peripheral sensory organs (chordotonal organs), which previously have been implicated in temperature synchronization. Flies deficient for Pyx function fail to synchronize their behaviour to TCs in the lower range (16–20°C), and this deficit can be partially rescued by introducing a wild-type copy of the pyx gene. Synchronization to higher TCs is not affected, demonstrating a specific role for Pyx at lower temperatures. In addition, pyx mutants speed up their clock after being exposed to TCs. Our results identify the first TRP channel involved in temperature synchronization of circadian clocks. PMID:23926145

  15. The Physiological Period Length of the Human Circadian Clock In Vivo Is Directly Proportional to Period in Human Fibroblasts

    Science.gov (United States)

    Moriggi, Ermanno; Revell, Victoria L.; Hack, Lisa M.; Lockley, Steven W.; Arendt, Josephine; Skene, Debra J.; Meier, Fides; Izakovic, Jan; Wirz-Justice, Anna; Cajochen, Christian; Sergeeva, Oksana J.; Cheresiz, Sergei V.; Danilenko, Konstantin V.; Eckert, Anne; Brown, Steven A.

    2010-01-01

    Background Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype (“larks” and “owls”), clock properties measured in human fibroblasts correlated with extreme diurnal behavior. Methodology/Principal Findings In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. Conclusions/Significance We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness. PMID:21042402

  16. Coupling of a core post-translational pacemaker to a slave transcription/translation feedback loop in a circadian system.

    Directory of Open Access Journals (Sweden)

    Ximing Qin

    Full Text Available Cyanobacteria are the only model circadian clock system in which a circadian oscillator can be reconstituted in vitro. The underlying circadian mechanism appears to comprise two subcomponents: a post-translational oscillator (PTO and a transcriptional/translational feedback loop (TTFL. The PTO and TTFL have been hypothesized to operate as dual oscillator systems in cyanobacteria. However, we find that they have a definite hierarchical interdependency-the PTO is the core pacemaker while the TTFL is a slave oscillator that quickly damps when the PTO stops. By analysis of overexpression experiments and mutant clock proteins, we find that the circadian system is dependent upon the PTO and that suppression of the PTO leads to damped TTFL-based oscillations whose temperature compensation is not stable under different metabolic conditions. Mathematical modeling indicates that the experimental data are compatible with a core PTO driving the TTFL; the combined PTO/TTFL system is resilient to noise. Moreover, the modeling indicates a mechanism by which the TTFL can feed into the PTO such that new synthesis of clock proteins can phase-shift or entrain the core PTO pacemaker. This prediction was experimentally tested and confirmed by entraining the in vivo circadian system with cycles of new clock protein synthesis that modulate the phosphorylation status of the clock proteins in the PTO. In cyanobacteria, the PTO is the self-sustained core pacemaker that can operate independently of the TTFL, but the TTFL damps when the phosphorylation status of the PTO is clamped. However, the TTFL can provide entraining input into the PTO. This study is the first to our knowledge to experimentally and theoretically investigate the dynamics of a circadian clock in which a PTO is coupled to a TTFL. These results have important implications for eukaryotic clock systems in that they can explain how a TTFL could appear to be a core circadian clockwork when in fact the true

  17. The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker

    OpenAIRE

    Triqueneaux, Gérard; Thenot, Sandrine; Kakizawa, Tomoko; Antoch, Marina P.; Safi, Rachid; Takahashi, Joseph S.; Delaunay, Franck; Laudet, Vincent

    2004-01-01

    Rev-erbα is a ubiquitously expressed orphan nuclear receptor which functions as a constitutive transcriptional repressor and is expressed in vertebrates according to a robust circadian rhythm. We report here that two Rev-erbα mRNA isoforms, namely Rev-erbα1 and Rev-erbα2, are generated through alternative promoter usage and that both show a circadian expression pattern in an in vitro system using serum-shocked fibroblasts. Both promoter regions P1 (Rev-erbα1) and P2 (Rev-erbα2) contain severa...

  18. Melatonin is a redundant entraining signal in the rat circadian system.

    Science.gov (United States)

    Houdek, Pavel; Nováková, Marta; Polidarová, Lenka; Sládek, Martin; Sumová, Alena

    2016-07-01

    The role of melatonin in maintaining proper function of the circadian system has been proposed but very little evidence for such an effect has been provided. To ascertain the role, the aim of the study was to investigate impact of long-term melatonin absence on regulation of circadian system. The parameters of behavior and circadian clocks of rats which were devoid of the melatonin signal due to pinealectomy (PINX) for more than one year were compared with those of intact age-matched controls. PINX led to a decrease in spontaneous locomotor activity and a shortening of the free-running period of the activity rhythm driven by the central clock in the suprachiasmatic nuclei (SCN) in constant darkness. However, the SCN-driven rhythms in activity and feeding were not affected and remained well entrained in the light/dark cycle. In contrast, in these conditions PINX had a significant effect on amplitudes of the clock gene expression rhythms in the duodenum and also partially in the liver. These results demonstrate the significant impact of long-term melatonin absence on period of the central clock in the SCN and the amplitudes of the peripheral clocks in duodenum and liver and suggest that melatonin might be a redundant but effective endocrine signal for these clocks. PMID:27167607

  19. Identifying Nonstationary Clock Noises in Navigation Systems

    OpenAIRE

    Patrizia Tavella; Lorenzo Galleani

    2008-01-01

    The stability of the atomic clocks on board the satellites of a navigation system should remain constant with time. In reality there are numerous physical phenomena that make the behavior of the clocks a function of time, and for this reason we have recently introduced the dynamic Allan variance (DAVAR), a measure of the time-varying stability of an atomic clock. In this paper we discuss the dynamic Allan variance for phase and frequency jumps, two common nonstationarities of atomic clocks. T...

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

    NARCIS (Netherlands)

    C. Feillet (Céline); G.T.J. van der Horst (Gijsbertus); F.A. Lévi (Francis); D.A. Rand (David); F. Delaunay (Franck)

    2015-01-01

    textabstractUncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift wor

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

    Directory of Open Access Journals (Sweden)

    Santiago A Plano

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

  2. The CK2 kinase stabilizes CLOCK and represses its activity in the Drosophila circadian oscillator.

    Directory of Open Access Journals (Sweden)

    Aron Szabó

    Full Text Available Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER and TIMELESS (TIM proteins, which inhibit CLOCK (CLK transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic α subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory β subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of CK2α activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2.

  3. The search for circadian clock components in humans: new perspectives for association studies

    Directory of Open Access Journals (Sweden)

    K.V. Allebrandt

    2008-08-01

    Full Text Available Individual circadian clocks entrain differently to environmental cycles (zeitgebers, e.g., light and darkness, earlier or later within the day, leading to different chronotypes. In human populations, the distribution of chronotypes forms a bell-shaped curve, with the extreme early and late types _ larks and owls, respectively _ at its ends. Human chronotype, which can be assessed by the timing of an individual's sleep-wake cycle, is partly influenced by genetic factors - known from animal experimentation. Here, we review population genetic studies which have used a questionnaire probing individual daily timing preference for associations with polymorphisms in clock genes. We discuss their inherent limitations and suggest an alternative approach combining a short questionnaire (Munich ChronoType Questionnaire, MCTQ, which assesses chronotype in a quantitative manner, with a genome-wide analysis (GWA. The advantages of these methods in comparison to assessing time-of-day preferences and single nucleotide polymorphism genotyping are discussed. In the future, global studies of chronotype using the MCTQ and GWA may also contribute to understanding the influence of seasons, latitude (e.g., different photoperiods, and climate on allele frequencies and chronotype distribution in different populations.

  4. Circadian expression of clock genes and angiotensin Ⅱ type 1 receptors in suprachiasmatic nuclei of sinoaortic-denervated rats

    Institute of Scientific and Technical Information of China (English)

    Hui LI; Ning-ling SUN; Jin WANG; Ai-jun LIU; Ding-feng SU

    2007-01-01

    Aim: To investigate whether the circadian expression of central clock genes and angiotensin Ⅱ type 1 (AT1) receptors was altered in sinoaortic-denervated (SAD)rats. Methods: Male Sprague-Dawley rats underwent sinoaortic denervation or a sham operation at the age of 12 weeks. Four weeks after the operation, blood pressure and heart period were measured in the conscious state in a group of sham-operated (n=10) and SAD rats (n=9). Rest SAD and sham-operated rats were divided into 6 groups (n=6 in each group). The suprachiasmatic nuclei (SCN)tissues were taken every 4 h throughout the day from each group for the determi-nation of the mRNA expression of clock genes (Per2 and Bmall) and the AT1receptor by RT-PCR; the protein expression of Per2 and Bmall was determined by Western blotting. Results: Blood pressure levels in the SAD rats were similar to those of the sham-operated rats. However, blood pressure variabilities signifi-cantly increased in the SAD rats compared with the sham-operated rats. The circadian variation of clock genes in the SCN of the sham-operated rats was char-acterized by a marked increase in the mRNA and protein expression during dark periods. Per2 and Bmall mRNA levels were significantly lower in the SAD rats,especially during dark periods. Western blot analysis confirmed an attenuation of the circadian rhythm of the 2 clock proteins in the SCN of the SAD rats. AT1 receptor mRNA expressions in the SCN were abnormally upregulated in the light phase, changed to a 12-h cycle in the SAD rats. Conclusion: The circadian varia-tion of the 2 central clock genes was attenuated in the SAD rats. Arterial baroreflex dysfunction also induced a disturbance in the expression of AT1 receptors in the SCN.

  5. Circadian Rhythm Management System Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The value of measuring sleep-wake cycles is significantly enhanced by measuring other physiological signals that depend on circadian rhythms (such as heart rate and...

  6. Circadian Organization of Behavior and Physiology in Drosophila

    Science.gov (United States)

    Allada, Ravi; Chung, Brian Y.

    2010-01-01

    Circadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks. We then describe the neural network important for circadian rhythms of locomotor activity, including how these molecular clocks might influence neuronal function. Finally, we address a range of behaviors and physiological systems regulated by circadian clocks, including discussion of specific peripheral oscillators and key molecular effectors where they have been described. These studies reveal a remarkable complexity to circadian pathways in this “simple” model organism. PMID:20148690

  7. Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock.

    Directory of Open Access Journals (Sweden)

    Erik Engelen

    Full Text Available The 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 conserved at the amino acid level through evolution. Within this evolutionary frame, TIM represents a fascinating puzzle. While Drosophila contains two paralogs, dTIM and dTIM2, acting in clock/photoreception and chromosome integrity/photoreception respectively, mammals contain only one TIM homolog. Whereas TIM has been shown to regulate replication termination and cell cycle progression, its functional link to the circadian clock is under debate. Here we show that RNAi-mediated knockdown of TIM in NIH3T3 and U2OS cells shortens the period by 1 hour and diminishes DNA damage-dependent phase advancing. Furthermore, we reveal that the N-terminus of TIM is sufficient for interaction with CRY1 and CHK1 as well for homodimerization, and the C-terminus is necessary for nuclear localization. Interestingly, the long TIM isoform (l-TIM, but not the short (s-TIM, interacts with CRY1 and both proteins can reciprocally regulate their nuclear translocation in transiently transfected COS7 cells. Finally, we demonstrate that co-expression of PER2 abolishes the formation of the TIM/CRY1 complex through affinity binding competition to the C-terminal tail of CRY1. Notably, the presence of the latter protein region evolutionarily and structurally distinguishes mammalian from insect CRYs. We propose that the dynamic interaction between these three proteins could represent a post-translational aspect of the mammalian circadian clock that is important for its pace and adaption to external stimuli, such as DNA damage and/or light.

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

    Science.gov (United States)

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

    2000-01-01

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

  9. Glaucoma Alters the Circadian Timing System

    OpenAIRE

    Drouyer, Elise; Dkhissi-Benyahya, Ouria; Chiquet, Christophe; WoldeMussie, Elizabeth; Ruiz, Guadalupe; Wheeler, Larry A.; Denis, Philippe; Cooper, Howard M.

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photi...

  10. Endocrine regulation of circadian physiology.

    Science.gov (United States)

    Tsang, Anthony H; Astiz, Mariana; Friedrichs, Maureen; Oster, Henrik

    2016-07-01

    Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis. PMID:27106109

  11. Does the clock make the poison? Circadian variation in response to pesticides.

    Directory of Open Access Journals (Sweden)

    Louisa A Hooven

    Full Text Available BACKGROUND: Circadian clocks govern daily physiological and molecular rhythms, and putative rhythms in expression of xenobiotic metabolizing (XM genes have been described in both insects and mammals. Such rhythms could have important consequences for outcomes of chemical exposures at different times of day. To determine whether reported XM gene expression rhythms result in functional rhythms, we examined daily profiles of enzyme activity and dose responses to the pesticides propoxur, deltamethrin, fipronil, and malathion. METHODOLOGY/PRINCIPAL FINDINGS: Published microarray expression data were examined for temporal patterns. Male Drosophila were collected for ethoxycoumarin-O-deethylase (ECOD, esterase, glutathione-S-transferase (GST, and, and uridine 5'-diphosphoglucosyltransferase (UGT enzyme activity assays, or subjected to dose-response tests at four hour intervals throughout the day in both light/dark and constant light conditions. Peak expression of several XM genes cluster in late afternoon. Significant diurnal variation was observed in ECOD and UGT enzyme activity, however, no significant daily variation was observed in esterase or GST activity. Daily profiles of susceptibility to lethality after acute exposure to propoxur and fipronil showed significantly increased resistance in midday, while susceptibility to deltamethrin and malathion varied little. In constant light, which interferes with clock function, the daily variation in susceptibility to propoxur and in ECOD and UGT enzyme activity was depressed. CONCLUSIONS/SIGNIFICANCE: Expression and activities of specific XM enzymes fluctuate during the day, and for specific insecticides, the concentration resulting in 50% mortality varies significantly during the day. Time of day of chemical exposure should be an important consideration in experimental design, use of pesticides, and human risk assessment.

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

    Directory of Open Access Journals (Sweden)

    Ingram Krista K

    2009-04-01

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

  13. Circadian Pacemaker – Temperature Compensation

    OpenAIRE

    Gerkema, Menno P.; Binder, Marc D.; Hirokawa, Nobutaka; Windhorst, Uwe

    2009-01-01

    One of the defining characteristics of circadian pacemakers and indicates the independence of the speed of circadian clock processes of environmental temperature. Mechanisms involved, so far not elucidated in full detail, entail at least two processes that are similarly affected by temperature changes, but with an opposing and counterbalancing effect on the periodicity of the clock system. As a result of temperature compensation, the increase in reaction velocity for every 10° rise in tempera...

  14. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis

    Science.gov (United States)

    Pekovic-Vaughan, Vanja; Gibbs, Julie; Yoshitane, Hikari; Yang, Nan; Pathiranage, Dharshika; Guo, Baoqiang; Sagami, Aya; Taguchi, Keiko; Bechtold, David; Loudon, Andrew; Yamamoto, Masayuki; Chan, Jefferson; van der Horst, Gijsbertus T.J.; Fukada, Yoshitaka; Meng, Qing-Jun

    2014-01-01

    The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock “gated” pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis. PMID:24637114

  15. Rev-erbalpha2 mRNA encodes a stable protein with a potential role in circadian clock regulation.

    Science.gov (United States)

    Rambaud, Juliette; Triqueneaux, Gérard; Masse, Ingrid; Staels, Bart; Laudet, Vincent; Benoit, Gérard

    2009-05-01

    Circadian rhythms are observed in nearly all aspects of physiology and behavior. In mammals, such biological rhythms are supported by a complex network of self-sustained transcriptional loops and posttranslational modifications, which regulate timely controlled production and degradation of critical factors on a 24-h basis. Among these factors, the orphan nuclear receptor rev-erbalpha plays an essential role by linking together positive and negative regulatory loops. As an essential part of the circadian core clock mechanism, REV-ERBalpha expression shows a precisely scheduled oscillation reflecting the tight control of its production and degradation. In previous studies, we identified two alternative transcripts encoding two protein variants referred to as REV-ERBalpha1 and -alpha2. Interestingly, recent work identified structural elements present only in REV-ERBalpha1 that controls its turnover and thereby influences circadian oscillations. In the present work, we comparatively analyze the two variants and show that REV-ERBalpha2 exhibits a half-life incompatible with a circadian function, suggesting that this variant exerts different biological functions. However, our comparative study clearly indicates undistinguishable DNA-binding properties and transcriptional repression activity as well as a similar regulation mechanism. The only consistent difference appears to be the relative expression level of the two transcripts, rev-erbalpha1 being one to 100 times more expressed than alpha2 depending on tissue and circadian time. Taking this finding into consideration, we reassessed REV-ERBalpha2 turnover and were able to show that this variant exhibits a reduced half-life when coexpressed with REV-ERBalpha1. We propose that the relative expression levels of the two REV-ERBalpha variants fine-tune the circadian period length by regulating REV-ERBalpha half-life. PMID:19228794

  16. Clock circadian regulator (CLOCK) gene network expression patterns in bovine adipose, liver, and mammary gland at 3 time points during the transition from pregnancy into lactation.

    Science.gov (United States)

    Wang, M; Zhou, Z; Khan, M J; Gao, J; Loor, J J

    2015-07-01

    The transition from late gestation to early lactation is the most critical phase of the lactation cycle for mammals. Research in rodents has revealed changes in the clock circadian regulator (CLOCK) gene network expression around parturition. However, their expression profiles and putative functions during the periparturient period in ruminants remain to be determined. The present study aimed to investigate the expression pattern of the CLOCK network and selected metabolic genes simultaneously in mammary gland (MG), liver (LIV), and subcutaneous adipose tissue (AT). Seven dairy cows were biopsied at -10 (±2), 7, and 21 d relative to parturition. A day × tissue interaction was observed for ARNTL, CRY1, and PER2 due to upregulation at 7 and 21 d postpartum, with their expression being greater in AT and MG compared with LIV. No interaction was detected for CLOCK, CRY2, PER1, and PER3. In general, the expression of NPAS2, NR1D1, NR2F2, ALAS1, FECH, FBXW11, CCRN4L, PPARA, PPARGC1A, and FGF21 was lower at -10 d but increased postpartum in all tissues. The interaction detected for CSNK1D was associated with increased expression postpartum in AT and MG but not LIV. The interaction detected for CPT1A was due to upregulation in AT and LIV postpartum without a change in MG. In contrast, the interaction for PPARG was due to upregulation in AT and MG postpartum but a downregulation in LIV. Leptin was barely detectable in LIV, but there was an interaction effect in AT and MG associated with upregulation postpartum in MG and downregulation in AT. Together, these results suggest that the control of metabolic adaptations in LIV, MG, and AT around parturition might be partly regulated through the CLOCK gene network. Although the present study did not specifically address rhythmic control of tissue metabolism via the CLOCK gene network, the difference in expression of genes studied among tissues confirms that the behavior of circadian-controlled metabolic genes around parturition

  17. A circadian clock in the olfactory bulb anticipates feeding during food anticipatory activity.

    Directory of Open Access Journals (Sweden)

    Nahum Nolasco

    Full Text Available Rabbit pups ingest food, in this case milk, once a day with circadian periodicity and are a natural model of food anticipatory activity. During nursing, several sensory systems receive information about properties of the food, one of them being the olfactory system, which has received little attention in relation to synchronization by food. In addition, the olfactory bulb has a circadian pacemaker that exhibits rhythms independently of the suprachiasmatic nucleus, but the biological functions of these rhythms are largely unknown. In the present contribution, we hypothesized that circadian suckling of milk synchronizes rhythms in the olfactory bulb. To this aim we explored by immunohistochemistry, rhythms of FOS and PER1 proteins, as indicators of activation and reporter of oscillations, respectively, through a complete 24-h cycle in periglomerular, mitral and granular cell layers of both the main and the accessory olfactory bulb. Subjects were 7-day-old rabbit pups scheduled to nurse during the night (02:00 h or day (10:00 h, and also fasted subjects, to explore the possible persistence of oscillations. In the three layers of the main olfactory bulb, FOS was high at time of nursing, then further increased 1.5 h afterward, and then decreased to increase again in advance of the next nursing bout. This pattern persisted, without the postprandial increase, in fasted subjects with a shift in subjects nursed at 02:00. PER1 was increased 2-8 h after nursing and this increase persisted in most cell layers, with a shift, in fasted subjects. In the accessory olfactory bulb we only observed a consistent pattern of FOS expression in the mitral cell layer of nursed subjects, similar to that of the main olfactory bulb. We conclude that the main olfactory bulb is synchronized during milk ingestion, but during fasting its oscillations perhaps are modulated by the suprachiasmatic nucleus, as proposed for rodents.

  18. Introduction: Finding new clock components; past and future

    OpenAIRE

    Takahashi, Joseph S.

    2004-01-01

    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. We are now in a position to consider what constitutes a clock component, whether we can establish criteria for clock components, and whether we have found most of the primary clock components? This perspective discusses clock genes and how genetics, molecular biology and biochemistry have been used to find clock gene...

  19. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  20. Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells.

    Science.gov (United States)

    Solocinski, Kristen; Richards, Jacob; All, Sean; Cheng, Kit-Yan; Khundmiri, Syed J; Gumz, Michelle L

    2015-12-01

    We have previously demonstrated that the circadian clock protein period (Per)1 coordinately regulates multiple genes involved in Na(+) reabsorption in renal collecting duct cells. Consistent with these results, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. The proximal tubule is responsible for a majority of Na(+) reabsorption. Previous work has demonstrated that expression of Na(+)/H(+) exchanger 3 (NHE3) oscillates with a circadian pattern and Na(+)-glucose cotransporter (SGLT)1 has been demonstrated to be a circadian target in the colon, but whether these target genes are regulated by Per1 has not been investigated in the kidney. The goal of the present study was to determine if Per1 regulates the expression of NHE3, SGLT1, and SGLT2 in the kidney. Pharmacological blockade of nuclear Per1 entry resulted in decreased mRNA expression of SGLT1 and NHE3 but not SGLT2 in the renal cortex of mice. Per1 small interfering RNA and pharmacological blockade of Per1 nuclear entry in human proximal tubule HK-2 cells yielded the same results. Examination of heterogeneous nuclear RNA suggested that the effects of Per1 on NHE3 and SGLT1 expression occurred at the level of transcription. Per1 and the circadian protein CLOCK were detected at promoters of NHE3 and SGLT1. Importantly, both membrane and intracellular protein levels of NHE3 and SGLT1 were decreased after blockade of nuclear Per1 entry. This effect was associated with reduced activity of Na(+)-K(+)-ATPase. These data demonstrate a role for Per1 in the transcriptional regulation of NHE3 and SGLT1 in the kidney. PMID:26377793

  1. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms.

    Science.gov (United States)

    Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu; Shan, Yongli; Fan, Junmei; Izumo, Mariko; Ikeda, Yuichi; Motoike, Toshiyuki; Dixon, Shelley; Seinfeld, Jeffrey E; Takahashi, Joseph S; Yanagisawa, Masashi

    2015-03-01

    Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. PMID:25741729

  2. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors.

    Directory of Open Access Journals (Sweden)

    Frank A J L Scheer

    Full Text Available BACKGROUND: Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (~9 AM, potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1 platelet function and (2 platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise. METHODOLOGY/PRINCIPAL FINDINGS: We studied 12 healthy adults (6 female who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p ≤ 0.01. These circadian peaks occurred at a circadian phase corresponding to 8-9 AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8 PM. The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors. CONCLUSIONS/SIGNIFICANCE: These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans--independent of the sleep/wake cycle, other behavioral influences and the environment. The 9 AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the

  3. CONSTANS LIKE 7 is Involved in Regulating Circadian Clock in Arabidopsis%CONSTANS LIKE 7参与调控拟南芥生物钟

    Institute of Scientific and Technical Information of China (English)

    王宏归; 姜雅; 唐冬英; 赵小英; 刘选明

    2015-01-01

    The circadian clock of plants can be trained by light/dark and cold /hot circles,and make it synchronized-with the environment.The circadian clock of plants is composed of input pathway,oscillator central and output pathway. The present study of circadian clock has revealed the basic composition of circadian clock,butthe operation mechanism and network of circadian clock need further research.CONSTANS LIKE 7(COL7)is one of the CONSTANS(CO)family genes.We used the real-time PCR,leaf movement to analyze the circadian clock of wild type (WT),col7 mutant and COL7 overexpression lines (COL7-OX-1 0 and COL7-OX-1 1 ).The results showed that COL7 is regulated by circadian clock and also involved in regulating circadian clock.%植物的生物钟节律可以被环境中的光/黑暗以及冷/热循环所诱导,并使其与环境同步。植物生物钟由输入途径、中央振荡器、输出途径组成。目前对植物生物钟的研究已经揭示生物钟最基本的组成,但是关于生物钟的运作机理及网络还需要进一步研究。CONSTANS LIKE 7(COL7)是 CONSTANS(CO)的家族基因。以拟南芥野生型(wild type,WT)、突变体 col7以及 COL7过量表达转基因株系 COL7-OX-10和 COL7-OX-11为材料,利用定量 PCR、叶片运动等方法,分析 COL7是否受生物钟调控以及 COL7是否参与调控生物。实验结果显示:COL7不仅受生物钟调控,同时也参与调控生物钟。

  4. Light and the circadian clock mediate time-specific changes in sensitivity to UV-B stress under light/dark cycles

    OpenAIRE

    Takeuchi, Tomomi; Newton, Linsey; Burkhardt, Alyssa; Mason, Saundra; Farré, Eva M.

    2014-01-01

    In Arabidopsis, the circadian clock regulates UV-B-mediated changes in gene expression. Here it is shown that circadian clock components are able to inhibit UV-B-induced gene expression in a gene-by-gene-specific manner and act downstream of the initial UV-B sensing by COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) and UVR8 (UV RESISTANCE LOCUS 8). For example, the UV-B induction of ELIP1 (EARLY LIGHT INDUCIBLE PROTEIN 1) and PRR9 (PSEUDO-RESPONSE REGULATOR 9) is directly regulated by LUX (LUX ARRYTH...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    -autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of...... to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the......The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell...

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

    Directory of Open Access Journals (Sweden)

    Daniel Pouly

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

  7. Progress in the Molecular Mechanism of Circadian Clock in Cyanobacterium%蓝藻生物节律性分子调控机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    李青雁; 庞羽彤; 李小龙; 周飞飞; 张芳; 霍宇鹏; 赵宇玮

    2013-01-01

    Circadian clocks are endogenous time-keeping mechanisms which are ubiquitous in a variety of o rganisms from bacteria to mammals. In order to coordinate with and adapt to the daily environmental changes which are driven by the self-rolling of the earth, the circadian clock controls various metabolic and biological activities with a circle period of 24 h. One of the cyanobacterial species, Synechococcus elongatus PCC7942 is a model organism for the circadian clock system. Three proteins encoded by the kaiA/B/C gene cluster, which is functional basis for the circadian rhythm, generate the basic timing loop of the circadian clock in Synechococcus. Circadian time clue is transmitted from the KaiABC-based central oscillator to the clock-controlled transcription factors. KaiC, an autokinase and autophosphatase, is the central component of the cyanobacterial circadian clock. The daily auto-phosphorylation and auto-dephosphorylation cycle of KaiC and the post-translational modification of the proteins, which consisted the inputing and output pathways of the circadian clock, have composed the transcriptional and translational feed-back loop (TTFL). In traditional theory of circadian clock model in cyanobacteria, TTFL regulation of clock genes are thought to be essential for sustaining and outputing of the basic circadian timing loop in Synechococcus. But surprisingly, KaiABC-based central oscillators are only found in cyanobacteria and very few prokaryotic species. It seems that this Kai-based clock is not an ubiquitous time-keeping mechanism that has been selected by organisms during natural evolution. Recently, some circadian clock research groups have demonstrated that non-transcriptional and translational oscillators could be the driving force of the generating and sustaining of biological circadian rhythm. The peroxiredoxins (PRX) are reported to be conserved markers of circadian rhythms, which are also thought to be a new focus of the researches on the molecular

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

    Czech Academy of Sciences Publication Activity Database

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

    2015-01-01

    Roč. 32, č. 4 (2015), s. 531-547. ISSN 0742-0528 R&D Projects: GA ČR(CZ) GAP303/12/1108 Grant ostatní: Program interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111202 Institutional support: RVO:67985823 Keywords : circadian clock * clock gene * colon * liver * SHR * supraciasmatic nucleus Subject RIV: ED - Physiology Impact factor: 3.343, year: 2014

  9. Hepatic, Duodenal, and Colonic Circadian Clocks Differ in their Persistence under Conditions of Constant Light and in their Entrainment by Restricted Feeding

    Czech Academy of Sciences Publication Activity Database

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

    2011-01-01

    Roč. 28, č. 3 (2011), s. 204-215. ISSN 0742-0528 R&D Projects: GA ČR(CZ) GA305/09/0321; GA MŠk(CZ) LC554 Grant ostatní: EC(XE) 018741 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * clock genes * constant light * gut * liver * restricted feeding Subject RIV: ED - Physiology Impact factor: 4.028, year: 2011

  10. Insight into a Physiological Role for the EC Night-Time Repressor in the Arabidopsis Circadian Clock.

    Science.gov (United States)

    Mizuno, Takeshi; Kitayama, Miki; Takayama, Chieko; Yamashino, Takafumi

    2015-09-01

    Life cycle adaptation to seasonal variation in photoperiod and temperature is a major determinant of ecological success of widespread domestication of Arabidopsis thaliana. The circadian clock plays a role in the underlying mechanism for adaptation. Nevertheless, the mechanism by which the circadian clock tracks seasonal changes in photoperiod and temperature is a longstanding subject of research in the field. We previously showed that a set of the target genes (i.e. GI, LNK1. PRR9 and PRR7) of the Evening Complex (EC) consisting of LUX-ELF3-ELF4 is synergistically induced in response to both warm-night and night-light signals. Here, we further show that the responses occur within a wide range of growth-compatible temperatures (16-28°C) in response to a small change in temperature (Δ4°C). A dim light pulse (tracking seasonal variation in photoperiod and temperature by conservatively double-checking both the light and temperature conditions. Another EC target output gene PIF4 regulating plant morphologies is also regulated by both the temperature and light stimuli during the night. Hence, the EC night-time repressor is also implicated in a physiological output of the PIF4-mediated regulation of morphologies in response to seasonal variation in photoperiod and ambient temperature. PMID:26108788

  11. Neural activity in the suprachiasmatic circadian clock of nocturnal mice anticipating a daytime meal.

    Science.gov (United States)

    Dattolo, T; Coomans, C P; van Diepen, H C; Patton, D F; Power, S; Antle, M C; Meijer, J H; Mistlberger, R E

    2016-02-19

    Circadian rhythms in mammals are regulated by a system of circadian oscillators that includes a light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) and food-entrainable oscillators (FEOs) elsewhere in the brain and body. In nocturnal rodents, the SCN promotes sleep in the day and wake at night, while FEOs promote an active state in anticipation of a predictable daily meal. For nocturnal animals to anticipate a daytime meal, wake-promoting signals from FEOs must compete with sleep-promoting signals from the SCN pacemaker. One hypothesis is that FEOs impose a daily rhythm of inhibition on SCN output that is timed to permit the expression of activity prior to a daytime meal. This hypothesis predicts that SCN activity should decrease prior to the onset of anticipatory activity and remain suppressed through the scheduled mealtime. To assess the hypothesis, neural activity in the SCN of mice anticipating a 4-5-h daily meal in the light period was measured using FOS immunohistochemistry and in vivo multiple unit electrophysiology. SCN FOS, quantified by optical density, was significantly reduced at the expected mealtime in food-anticipating mice with access to a running disk, compared to ad libitum-fed and acutely fasted controls. Group differences were not significant when FOS was quantified by other methods, or in mice without running disks. SCN electrical activity was markedly decreased during locomotion in some mice but increased in others. Changes in either direction were concurrent with locomotion, were not specific to food anticipation, and were not sustained during longer pauses. Reduced FOS indicates a net suppression of SCN activity that may depend on the intensity or duration of locomotion. The timing of changes in SCN activity relative to locomotion suggests that any effect of FEOs on SCN output is mediated indirectly, by feedback from neural or systemic correlates of locomotion. PMID:26701294

  12. Dynamical feedback between circadian clock and sucrose availability explains adaptive response of starch metabolism to various photoperiods

    Directory of Open Access Journals (Sweden)

    Francois Gabriel Feugier

    2013-01-01

    Full Text Available Plants deal with resource management during all their life. During the day they feed on photosynthetic carbon, sucrose, while storing a part into starch for night use. Careful control of carbon partitioning, starch degradation and sucrose export rates is crucial to avoid carbon starvation, insuring optimal growth whatever the photoperiod. Efficient regulation of these key metabolic rates can give an evolutionary advantage to plants. Here we propose a model of adaptive starch metabolism in response to various photoperiods. We assume the three key metabolic rates to be circadian regulated in leaves and that their phases of oscillations are shifted in response to sucrose starvation. We performed gradient descents for various photoperiod conditions to find the corresponding optimal sets of phase shifts that minimize starvation. Results at convergence were all consistent with experimental data: i diurnal starch profile showed linear increase during the day and linear decrease at night; ii shorter photoperiod tended to increase starch synthesis speed while decreasing its degradation speed during the longer night; iii sudden early dusk showed slower starch degradation during the longer night. Profiles that best explained observations corresponded to circadian regulation of all rates. This theoretical study would establish a framework for future research on feedback between starch metabolism and circadian clock as well as plant productivity.

  13. Circadian clock of Drosophila montana is adapted to high variation in summer day lengths and temperatures prevailing at high latitudes.

    Science.gov (United States)

    Kauranen, Hannele; Ala-Honkola, Outi; Kankare, Maaria; Hoikkala, Anneli

    2016-06-01

    Photoperiodic regulation of the circadian rhythms in insect locomotor activity has been studied in several species, but seasonal entrainment of these rhythms is still poorly understood. We have traced the entrainment of activity rhythm of northern Drosophila montana flies in a climate chamber mimicking the photoperiods and day and night temperatures that the flies encounter in northern Finland during the summer. The experiment was started by transferring freshly emerged females into the chamber in early and late summer conditions to obtain both non-diapausing and diapausing females for the studies. The locomotor activity of the females and daily changes in the expression levels of two core circadian clock genes, timeless and period, in their heads were measured at different times of summer. The study revealed several features in fly rhythmicity that are likely to help the flies to cope with high variation in the day length and temperature typical to northern summers. First, both the non-diapausing and the diapausing females showed evening activity, which decreased towards the short day length as observed in the autumn in nature. Second, timeless and period genes showed concordant daily oscillations and seasonal shifts in their expression level in both types of females. Contrary to Drosophila melanogaster, oscillation profiles of these genes were similar to each other in all conditions, including the extremely long days in early summer and the cool temperatures in late summer, and their peak expression levels were not locked to lights-off transition in any photoperiod. Third, the diapausing females were less active than the non-diapausing ones, in spite of their younger age. Overall, the study showed that D. montana clock functions well under long day conditions, and that both the photoperiod and the daily temperature cycles are important zeitgebers for seasonal changes in the circadian rhythm of this species. PMID:26993661

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

    Directory of Open Access Journals (Sweden)

    Peter S Podobed

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

  15. Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature.

    Science.gov (United States)

    Valenzuela, F J; Vera, J; Venegas, C; Muñoz, S; Oyarce, S; Muñoz, K; Lagunas, C

    2016-01-01

    The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1-3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined. PMID:27313610

  16. Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature

    Directory of Open Access Journals (Sweden)

    F. J. Valenzuela

    2016-01-01

    Full Text Available The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1–3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined.

  17. Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature

    Science.gov (United States)

    Valenzuela, F. J.; Vera, J.; Venegas, C.; Muñoz, S.; Oyarce, S.; Muñoz, K.; Lagunas, C.

    2016-01-01

    The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1–3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined. PMID:27313610

  18. Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Genzer, Yoni; Dadon, Maayan; Burg, Chen; Chapnik, Nava; Froy, Oren

    2016-07-15

    Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain and its decreased levels are associated with the development of obesity and neurodegeneration. Our aim was to test the effect of dietary fat, its timing and the circadian clock on the expression of BDNF and associated signaling pathways in mouse brain and liver. Bdnf mRNA oscillated robustly in brain and liver, but with a 12-h shift between the tissues. Brain and liver Bdnf mRNA showed a 12-h phase shift when fed ketogenic diet (KD) compared with high-fat diet (HFD) or low-fat diet (LFD). Brain or liver Bdnf mRNA did not show the typical phase advance usually seen under time-restricted feeding (RF). Clock knockdown in HT-4 hippocampal neurons led to 86% up-regulation of Bdnf mRNA, whereas it led to 60% down-regulation in AML-12 hepatocytes. Dietary fat in mice or cultured hepatocytes and hippocampal neurons led to increased Bdnf mRNA expression. At the protein level, HFD increased the ratio of the mature BDNF protein (mBDNF) to its precursor (proBDNF). In the liver, RF under LFD or HFD reduced the mBDNF/proBDNF ratio. In the brain, the two signaling pathways related to BDNF, mTOR and AMPK, showed reduced and increased levels, respectively, under timed HFD. In the liver, the reverse was achieved. In summary, Bdnf expression is mediated by the circadian clock and dietary fat. Although RF does not affect its expression phase, in the brain, when combined with high-fat diet, it leads to a unique metabolic state in which AMPK is activated, mTOR is down-regulated and the levels of mBDNF are high. PMID:27113028

  19. The Effects of Spaceflight on the Rat Circadian Timing System

    Science.gov (United States)

    Fuller, Charles A.; Murakami, Dean M.; Hoban-Higgins, Tana M.; Fuller, Patrick M.; Robinson, Edward L.; Tang, I.-Hsiung

    2003-01-01

    in one-G. Compared with control rats, the flight rats exhibited no change in HR. Finally, the LD FD2 flight rats demonstrated a reduced sensitivity to light as shown by significantly reduced c-fos expression in the SCN in comparison with controls. These findings constitute the first demonstration that microgravity affects the fundamental properties of the mammalian circadian timing system, specifically by influencing the clock's period, and its ability to maintain temporal organization and phase angle of synchronization to an external LD cycle.

  20. A baculovirus photolyase with DNA repair activity and circadian clock regulatory function

    NARCIS (Netherlands)

    Biernat, M.A.; Eker, A.P.M.; Oers, van M.M.; Vlak, J.M.; Horst, van der G.T.J.; Chaves, I.

    2012-01-01

    Cryptochromes and photolyases belong to the same family of flavoproteins but, despite being structurally conserved, display distinct functions. Photolyases use visible light to repair ultraviolet-induced DNA damage. Cryptochromes, however, function as blue-light receptors, circadian photoreceptors,

  1. Identification of proteins interacting with the circadian clock protein PER1 in tumors using bacterial two-hybrid system technique%细菌双杂交筛选肿瘤细胞中与人生物钟蛋白PER1相互作用的蛋白

    Institute of Scientific and Technical Information of China (English)

    张宇; 姚有林; 蒋思远; 卢亦路; 刘运强; 陶大昌; 张思仲; 马用信

    2015-01-01

    Objective To identify protein-protein interaction partners of PER1 (period circadian protein homolog 1),key component of the molecular oscillation system of the circadian rhythm in tumors using bacterial two-hybrid system technique.Methods Human cervical carcinoma cell Hela library was adopted.Recombinant bait plasmid pBT-PER1 and pTRG cDNA plasmid library were cotransformed into the two-hybrid system reporter strain cultured in a special selective medium.Target clones were screened.After isolating the positive clones,the target clones were sequenced and analyzed.Results Fourteen protein coding genes were identified,4 of which were found to contain whole coding regions of genes,which included optic atrophy 3 protein (OPA3) associated with mitochondrial dynamics and homo sapiens cutA divalent cation tolerance homolog of E.coli (CUTA) associated with copper metabolism.There were also cellular events related proteins and proteins which are involved in biochemical reaction and signal transduction-related proteins.Conclusion Identification of potential interacting proteins with PER1 in tumors may provide us new insights into the functions of the circadian clock protein PER1 during tumorigenesis.%目的 筛选肿瘤细胞中与生物钟分子振荡系统的重要组成部分PER1蛋白(period circadian protein homolog 1)相互作用的蛋白质分子,为生物钟基因在肿瘤发生发展过程中的功能研究提供条件.方法 应用细菌双杂交技术与人宫颈癌Hela细胞cDNA文库,以pBT为载体,构建pBT-PER1融合表达诱饵质粒,与pTRG连接的人宫颈癌Hela细胞cDNA文库质粒共转化双杂交系统报告菌株,利用培养基的特殊选择性,筛选出阳性克隆并测序分析.结果 筛选出14个蛋白编码基因,其中4个包含完整的蛋白编码序列,包括与线粒体动力学相关的OPA3蛋白,与铜代谢相关的CUTA蛋白,与细胞运动、定位等细胞事件相关的蛋白,与物质合成、代谢等生物化学反应相关

  2. Is the cell division cycle gated by a circadian clock? The case of Chlamydomonas reinhardtii

    OpenAIRE

    1995-01-01

    Circadian oscillators are known to regulate the timing of cell division in many organisms. In the case of Chlamydomonas reinhardtii, however, this conclusion has been challenged by several investigators. We have reexamined this issue and find that the division behavior of Chlamydomonas meets all the criteria for circadian rhythmicity: persistence of a cell division rhythm (a) with a period of approximately 24 h under free-running conditions, (b) that is temperature compensated, and (c) which ...

  3. Circadian organization of the mammalian retina: from gene regulation to physiology and diseases.

    Science.gov (United States)

    McMahon, Douglas G; Iuvone, P Michael; Tosini, Gianluca

    2014-03-01

    The retinal circadian system represents a unique structure. It contains a complete circadian system and thus the retina represents an ideal model to study fundamental questions of how neural circadian systems are organized and what signaling pathways are used to maintain synchrony of the different structures in the system. In addition, several studies have shown that multiple sites within the retina are capable of generating circadian oscillations. The strength of circadian clock gene expression and the emphasis of rhythmic expression are divergent across vertebrate retinas, with photoreceptors as the primary locus of rhythm generation in amphibians, while in mammals clock activity is most robust in the inner nuclear layer. Melatonin and dopamine serve as signaling molecules to entrain circadian rhythms in the retina and also in other ocular structures. Recent studies have also suggested GABA as an important component of the system that regulates retinal circadian rhythms. These transmitter-driven influences on clock molecules apparently reinforce the autonomous transcription-translation cycling of clock genes. The molecular organization of the retinal clock is similar to what has been reported for the SCN although inter-neural communication among retinal neurons that form the circadian network is apparently weaker than those present in the SCN, and it is more sensitive to genetic disruption than the central brain clock. The melatonin-dopamine system is the signaling pathway that allows the retinal circadian clock to reconfigure retinal circuits to enhance light-adapted cone-mediated visual function during the day and dark-adapted rod-mediated visual signaling at night. Additionally, the retinal circadian clock also controls circadian rhythms in disk shedding and phagocytosis, and possibly intraocular pressure. Emerging experimental data also indicate that circadian clock is also implicated in the pathogenesis of eye disease and compelling experimental data

  4. Rapid Adjustment of Circadian Clocks to Simulated Travel to Time Zones across the Globe.

    Science.gov (United States)

    Harrison, Elizabeth M; Gorman, Michael R

    2015-12-01

    Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure-based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules. PMID:26275871

  5. The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila.

    Directory of Open Access Journals (Sweden)

    Elizabeth F Stone

    2012-01-01

    Full Text Available Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim and Period (Per are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load or tolerance (endurance of the pathogenic effects of infection. Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim-independent; moreover, infection-induced AMP gene expression is not circadian-regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis can have significant effects on long-term survival of infection.

  6. OsELF3 Is Involved in Circadian Clock Regulation for Promoting Flowering under Long-Day Conditions in Rice

    Institute of Scientific and Technical Information of China (English)

    Ying Yang; Qiang Peng; Guo-Xing Chen; Xiang-Hua Li; Chang-Yin Wu

    2013-01-01

    Heading date is a critical trait that determines cropping seasons and regional adaptability in rice (Oryza sativa).Research efforts during the last decade have identified some important photoperiod pathway genes that are conserved between Arabidopsis and rice.In this study,we identified a novel gene,Oryza sativa ELF3 (OsELF3),which is a putative homolog of the ELF3 gene in Arabidopsis thaliana.OsELF3 was required for the control of heading date under long-day conditions.Its Tos17-tagging mutants exhibited a delayed heading date phenotype only under long-day,but not short-day,conditions.OsELF3 was highly expressed in leaf blades,and the OsELF3 protein was localized in the nucleolus.An obvious diurnal rhythm of OsELF3 transcript level was observed,with a trough in the early day and a peak in the late night in wild-type plants.However,this expression pattern was disrupted in oself3 mutants.Further investigations showed that the expression of OsGI and Ghd7 was up-regulated in the oself3 mutant,indicating that OsELF3 acts as a negative regulator upstream of OsGI and Ghd7 in the flowering-time control under long-day conditions.The rhythmic expression of circadian clock-related genes,including some OsPRR members,was obviously affected in oself3 mutants.Our results indicated that OsELF3 acts as a floral activator in the long-day photoperiodic pathway via its crosstalk with the circadian clock in rice.

  7. An In Vitro ES Cell-Based Clock Recapitulation Assay Model Identifies CK2α as an Endogenous Clock Regulator

    OpenAIRE

    Umemura, Yasuhiro; Yoshida, Junko; Wada, Masashi; Tsuchiya, Yoshiki; Minami, Yoichi; Watanabe, Hitomi; Kondoh, Gen; Takeda, Junji; Inokawa, Hitoshi; Horie, Kyoji; Yagita, Kazuhiro

    2013-01-01

    We previously reported emergence and disappearance of circadian molecular oscillations during differentiation of mouse embryonic stem (ES) cells and reprogramming of differentiated cells, respectively. Here we present a robust and stringent in vitro circadian clock formation assay that recapitulates in vivo circadian phenotypes. This assay system first confirmed that a mutant ES cell line lacking Casein Kinase I delta (CKIδ) induced ∼3 hours longer period-length of circadian rhythm than the w...

  8. Diurnal variation in myocardial ischemia/reperfusion tolerance; mediation by the circadian clock within the cardiomyocyte

    Science.gov (United States)

    Circadian rhythms in cardiovascular physiology (e.g. blood pressure and heart rate) and pathophysiology (e.g. myocardial infarction (MI)) exist. Humans exhibit a marked increase in MI frequency during the early hours of the morning. However, MIs occurring during the evening are more likely to result...

  9. Die circadiane Uhr im Immunsystem

    OpenAIRE

    Keller, Maren

    2010-01-01

    Daily rhythms of a variety of immunological phenomena and functions are well known, but so far they have largely been neglected. Examples of daily rhythms in the immune system are: circadian differences in susceptibility to bacterial infection and daily variations in the symptoms of diseases such as rheumatoid arthritis or asthma. Therefore, it is very important for clinical diagnosis and pharmacological therapies to elucidate the connections between the circadian clock and the immune system....

  10. Circadian and wakefulness-sleep modulation of cognition in humans.

    Science.gov (United States)

    Wright, Kenneth P; Lowry, Christopher A; Lebourgeois, Monique K

    2012-01-01

    Cognitive and affective processes vary over the course of the 24 h day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24 h period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain (BF) and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety. PMID:22529774

  11. Circadian and Wakefulness-Sleep Modulation of Cognition in Humans

    Directory of Open Access Journals (Sweden)

    Kenneth P Wright

    2012-04-01

    Full Text Available Cognitive and affective processes vary over the course of the 24 hour day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24-hour period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei, to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety.

  12. Constitutive, light-responsive and circadian clock-responsive factors compete for the different l box elements in plant light-regulated promoters.

    Science.gov (United States)

    Borello, U; Ceccarelli, E; Giuliano, G

    1993-10-01

    The l box is a conserved regulatory motif which is found upstream of plant genes (rbcS, cab and nia) whose transcription is regulated by light and the circadian clock. Gel retardation and UV cross-linking assays were used to resolve two different groups of I box binding factors (IBFs) in tomato nuclear extracts. Active components of the first group (IBF-1) recognize the l box of the light-responsive rbcS promoter; one factor within this group, IBF-1a, also recognizes the adjacent G box, which has been shown previously to bind a different class of plant transcription factors, the G box binding factors (GBFs). To the limit of experimental resolution, IBF-1a and GBF compete for the same nucleotides on the G box. Nevertheless, these two activities are biochemically and immunologically distinct. The relative abundance of IBF-1a shows a vast decrease in dark-adapted plants. Factors in the second group (IBF-2), recognize the l box of the nia promoter, which is regulated both by light and the circadian clock; one factor within this group, IBF-2a, also binds the l box of a second promoter showing similar regulation, the cab promoter. The IBF-2a binding sites on the cab and nia promoters show extensive homology to a circadian clock-responsive promoter element from wheat. The abundance of IBF-2a is diurnally regulated and shows a dramatic induction around the onset of the light period. Transfer of the plants in continuous darkness demonstrates that this induction is under the control of a circadian clock.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8252065

  13. Pathophysiology and pathogenesis of circadian rhythm sleep disorders

    Directory of Open Access Journals (Sweden)

    Hida Akiko

    2012-03-01

    Full Text Available Abstract Metabolic, physiological and behavioral processes exhibit 24-hour rhythms in most organisms, including humans. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues. The transcription and translation feedback loops of multiple clock genes are involved in the molecular mechanism of the circadian system. Disturbed circadian rhythms are known to be closely related to many diseases, including sleep disorders. Advanced sleep phase type, delayed sleep phase type and nonentrained type of circadian rhythm sleep disorders (CRSDs are thought to result from disorganization of the circadian system. Evaluation of circadian phenotypes is indispensable to understanding the pathophysiology of CRSD. It is laborious and costly to assess an individual's circadian properties precisely, however, because the subject is usually required to stay in a laboratory environment free from external cues and masking effects for a minimum of several weeks. More convenient measurements of circadian rhythms are therefore needed to reduce patients' burden. In this review, we discuss the pathophysiology and pathogenesis of CRSD as well as surrogate measurements for assessing an individual's circadian phenotype.

  14. Immunity’s fourth dimension: approaching the circadian-immune connection

    OpenAIRE

    Arjona, Alvaro; Adam C Silver; Walker, Wendy E; Fikrig, Erol

    2012-01-01

    The circadian system ensures the generation and maintenance of self-sustained ~24 h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related di...

  15. Clock distribution system for large high altitude air shower observatory

    International Nuclear Information System (INIS)

    In this paper, we report a clock distribution system for Water Cherenkov Detector Arrays (WCDAs) in Large High Altitude Air Shower Observatory (LHAASO) project. The designed electronics system is of high performance in implementing the clock distribution among detectors of a large scale of dimension. Based on Serializer/Deserializer (SerDes) and fiber transmission, the clock distribution system is the modules of central back end to distributed front end. The clock distribution system has been evaluated with a two modules system. While all the four SerDes candidates for clock transmission with jitters below 17 ps, the DS92LV16 has a fixed phase relationship between transmission clock and recovered clock, hence its use in LHAASO WCDAs. (authors)

  16. Time-of-day- and light-dependent expression of ubiquitin protein ligase E3 component N-recognin 4 (UBR4 in the suprachiasmatic nucleus circadian clock.

    Directory of Open Access Journals (Sweden)

    Harrod H Ling

    Full Text Available Circadian rhythms of behavior and physiology are driven by the biological clock that operates endogenously but can also be entrained to the light-dark cycle of the environment. In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN, which is composed of individual cellular oscillators that are driven by a set of core clock genes interacting in transcriptional/translational feedback loops. Light signals can trigger molecular events in the SCN that ultimately impact on the phase of expression of core clock genes to reset the master pacemaker. While transcriptional regulation has received much attention in the field of circadian biology in the past, other mechanisms including targeted protein degradation likely contribute to the clock timing and entrainment process. In the present study, proteome-wide screens of the murine SCN led to the identification of ubiquitin protein ligase E3 component N-recognin 4 (UBR4, a novel E3 ubiquitin ligase component of the N-end rule pathway, as a time-of-day-dependent and light-inducible protein. The spatial and temporal expression pattern of UBR4 in the SCN was subsequently characterized by immunofluorescence microscopy. UBR4 is expressed across the entire rostrocaudal extent of the SCN in a time-of-day-dependent fashion. UBR4 is localized exclusively to arginine vasopressin (AVP-expressing neurons of the SCN shell. Upon photic stimulation in the early subjective night, the number of UBR4-expressing cells within the SCN increases. This study is the first to identify a novel E3 ubiquitin ligase component, UBR4, in the murine SCN and to implicate the N-end rule degradation pathway as a potential player in regulating core clock mechanisms and photic entrainment.

  17. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks.

    Science.gov (United States)

    Wolff, Gretchen; Duncan, Marilyn J; Esser, Karyn A

    2013-08-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  18. Flight Schedule and the Circadian Clock Influence on Sleep Loss During Overnight Cargo Operations

    Science.gov (United States)

    Gander, Philippa H.; Gregory, Kevin B.; Rosekind, Mark R.; Shafto, Michael G. (Technical Monitor)

    1995-01-01

    Thirty-four flight crew members were monitored before, during, and after two 8-day overnight cargo duty patterns which involved multiple flights at night crossing no more than one time zone per 24 h. Rectal temperature, heart rate, and wrist activity were recorded every 2 min. Sleep quantity and quality, and nap timing, were noted in a logbook. To reduce the masking effects of physical activity on temperature, 0.28 C was added to each subject's raw temperature data whenever he reported being asleep. For both masked and unmasked data, daily temperature minima were estimated from the multiple complex demodulated waveform. The temperature minima did not show a progressive adaptation to night duty, which was interrupted by a night off after 5 nights on one trip pattern and after 3 nights on the other. On duty days, the average temperature minimum delayed by about 3 h, occurring near the end of the duty period. Daytime sleep episodes averaged 2.9 h shorter than nighttime sleep episodes, and were rated as lighter, less restorative, and poorer overall. Fifty-three percent of subjects slept more than once per 24 h while they were on night duty, compared to 17% when able to sleep at night. The total sleep per 24 h on duty days averaged 1.2 h less than pretrip. Twenty-nine percent of subjects lost more than 2 h of sleep per 24 h across the 8-day duty patterns. After night duty, subjects awoke around 1400 local time, even when they had slept 2-3 h less than a normal nocturnal sleep episode. Consequently, the duration of morning sleep episodes was correlated with the off-duty time (multiple r(sup 2)=0.44, F=37.23, p less than 0.0001). Anecdotally, crew members complained of being unable to sleep longer and not feeling well-rested. These wakeups were clustered 6 h after the temperature minimum, which suggests that they may have been a response to the circadian wakeup signal. Daytime layovers in which crew members were able to sleep again in the evening ended later (0200

  19. Cnot2 is a Negative Factor in the Signaling Pathway of Circadian Clock%cnot2基因是生物钟信号通路中的一个负向因子

    Institute of Scientific and Technical Information of China (English)

    张云峰; 秦海棠; 张双艳; 胡孟娜; 冯永杰

    2015-01-01

    Objective To clone and investigate the role of the cnot2 gene in the circadian clock signal path, providing a theoretical basis for further study of the circadian clock signaling pathway. To extract RNA from the B6 mice in vitro, inverting it to cDNA. Based on mouse gene sequence to synthesis a pair of specifi c primers, then to amplify DNA fragment of the cnot2 gene by using mouse cDNA as a template. The fragment was cloned into the expression vector, and to detect whether the gene was successfully expressed in vitro, we transfect it to HEK293T cell line, obtaining the total protein and analysed by Western blot, then design experimental system and collect the cells by using Dual-Luciferase Reporter Assay System kit to detect the activity of the per1-luc, fi nally through co-precipitation technique to prove the interaction between cnot2 and the main clock gene.Result cnot2 could inhibit the transcriptional activity of clock and bmal1, which is mammalian circadian clock genes. The possible mechanism is that cnot2 could competitive bind to bmal1 and clock.Conclusion In circadian clock signaling pathway, cnot2 is a negative factor.%目的:克隆表达并研究cnot2(CCR4-NOT转录复合体亚基2)基因在哺乳动物生物钟信号通路中的作用,为进一步研究生物钟信号通路提供理论依据。方法提取B6小鼠的总RNA进行体外反转得到cDNA。依据小鼠的基因序列设计合成一对特异性引物,以反转录的小鼠cDNA为模板,扩增得到cnot2的基因片段。将基因克隆到表达载体,转染HEK293T细胞系,获得总蛋白后通过Western blot检测该基因在体外是否成功表达。然后设计实验体系,收集细胞利用报告基因检测试剂盒检测per1-luc的活性,最后通过免疫共沉淀技术证明cnot2与主要生物钟基因之间的相互作用。结果 cnot2基因能够抑制哺乳动物生物钟基因bmal1和clock的转录活性,其可能的机制是cnot2

  20. The Circadian System: A Regulatory Feedback Network of Periphery and Brain.

    Science.gov (United States)

    Buijs, Frederik N; León-Mercado, Luis; Guzmán-Ruiz, Mara; Guerrero-Vargas, Natali N; Romo-Nava, Francisco; Buijs, Ruud M

    2016-05-01

    Circadian rhythms are generated by the autonomous circadian clock, the suprachiasmatic nucleus (SCN), and clock genes that are present in all tissues. The SCN times these peripheral clocks, as well as behavioral and physiological processes. Recent studies show that frequent violations of conditions set by our biological clock, such as shift work, jet lag, sleep deprivation, or simply eating at the wrong time of the day, may have deleterious effects on health. This infringement, also known as circadian desynchronization, is associated with chronic diseases like diabetes, hypertension, cancer, and psychiatric disorders. In this review, we will evaluate evidence that these diseases stem from the need of the SCN for peripheral feedback to fine-tune its output and adjust physiological processes to the requirements of the moment. This feedback can vary from neuronal or hormonal signals from the liver to changes in blood pressure. Desynchronization renders the circadian network dysfunctional, resulting in a breakdown of many functions driven by the SCN, disrupting core clock rhythms in the periphery and disorganizing cellular processes that are normally driven by the synchrony between behavior and peripheral signals with neuronal and humoral output of the hypothalamus. Consequently, we propose that the loss of synchrony between the different elements of this circadian network as may occur during shiftwork and jet lag is the reason for the occurrence of health problems. PMID:27053731

  1. Phase resetting of the mammalian circadian clock relies on a rapid shift of a small population of pacemaker neurons.

    Directory of Open Access Journals (Sweden)

    Jos H T Rohling

    Full Text Available The circadian pacemaker of the suprachiasmatic nuclei (SCN contains a major pacemaker for 24 h rhythms that is synchronized to the external light-dark cycle. In response to a shift in the external cycle, neurons of the SCN resynchronize with different pace. We performed electrical activity recordings of the SCN of rats in vitro following a 6 hour delay of the light-dark cycle and observed a bimodal electrical activity pattern with a shifted and an unshifted component. The shifted component was relatively narrow as compared to the unshifted component (2.2 h and 5.7 h, respectively. Curve fitting and simulations predicted that less than 30% of the neurons contribute to the shifted component and that their phase distribution is small. This prediction was confirmed by electrophysiological recordings of neuronal subpopulations. Only 25% of the neurons exhibited an immediate shift in the phase of the electrical activity rhythms, and the phases of the shifted subpopulations appeared significantly more synchronized as compared to the phases of the unshifted subpopulations (p<0.05. We also performed electrical activity recordings of the SCN following a 9 hour advance of the light-dark cycle. The phase advances induced a large desynchrony among the neurons, but consistent with the delays, only 19% of the neurons peaked at the mid of the new light phase. The data suggest that resetting of the central circadian pacemaker to both delays and advances is brought about by an initial shift of a relatively small group of neurons that becomes highly synchronized following a shift in the external cycle. The high degree of synchronization of the shifted neurons may add to the ability of this group to reset the pacemaker. The large desynchronization observed following advances may contribute to the relative difficulty of the circadian system to respond to advanced light cycles.

  2. Effect of melatonin on endogenous circadian rhythm

    Institute of Scientific and Technical Information of China (English)

    XU Feng; WANG Min; ZANG Ling-he

    2008-01-01

    Objective To further authenticate the role of melatonin on endogenous biologic clock system. Methods Pinealectomized mice were used in the experiments, a series of circadian rhythm of physiology index, such as glucocorticoid, amino acid neurotransmitter, immune function, sensitivity of algesia and body temperature were measured. Results Effects of melatonin on endogenous circadian rhythm roughly appeared four forms: 1) The model of inherent rhythm was invariant, but midvalue was removed. 2) Pacing function: pinealectomy and melatonin administration changed amplitude of the circadian vibration of aspartate, peripheral blood WBC and serum hemolysin. 3) Phase of rhythm changed, such as the effects on percentage of lymphocyte and sensitivity of algesia. 4) No effect, the circadian rhythm of body temperature belong to this form Conclusions Melatonin has effects some circadian rhythm, and it can adjust endogenous inherent rhythm and make the rhythm keep step with environmental cycle. Melatonin may be a kind of Zeitgeber, Pineal gland might being a rhythm bearing organ to some circadian rhythm.

  3. A circadian clock-regulated toggle switch explains AtGRP7 and AtGRP8 oscillations in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Christoph Schmal

    Full Text Available The circadian clock controls many physiological processes in higher plants and causes a large fraction of the genome to be expressed with a 24h rhythm. The transcripts encoding the RNA-binding proteins AtGRP7 (Arabidopsis thaliana Glycine Rich Protein 7 and AtGRP8 oscillate with evening peaks. The circadian clock components CCA1 and LHY negatively affect AtGRP7 expression at the level of transcription. AtGRP7 and AtGRP8, in turn, negatively auto-regulate and reciprocally cross-regulate post-transcriptionally: high protein levels promote the generation of an alternative splice form that is rapidly degraded. This clock-regulated feedback loop has been proposed to act as a molecular slave oscillator in clock output. While mathematical models describing the circadian core oscillator in Arabidopsis thaliana were introduced recently, we propose here the first model of a circadian slave oscillator. We define the slave oscillator in terms of ordinary differential equations and identify the model's parameters by an optimization procedure based on experimental results. The model successfully reproduces the pertinent experimental findings such as waveforms, phases, and half-lives of the time-dependent concentrations. Furthermore, we obtain insights into possible mechanisms underlying the observed experimental dynamics: the negative auto-regulation and reciprocal cross-regulation via alternative splicing could be responsible for the sharply peaking waveforms of the AtGRP7 and AtGRP8 mRNA. Moreover, our results suggest that the AtGRP8 transcript oscillations are subordinated to those of AtGRP7 due to a higher impact of AtGRP7 protein on alternative splicing of its own and of the AtGRP8 pre-mRNA compared to the impact of AtGRP8 protein. Importantly, a bifurcation analysis provides theoretical evidence that the slave oscillator could be a toggle switch, arising from the reciprocal cross-regulation at the post-transcriptional level. In view of this

  4. Development of the circadian clockwork in the kidney

    DEFF Research Database (Denmark)

    Mészáros, Krisztina; Pruess, Linda; Szabó, Attila J.; Gondan, Matthias; Ritz, Eberhard; Schaefer, Franz

    2014-01-01

    The circadian molecular clock is an internal time-keeping system composed of centrally synchronized tissue-level pacemakers. Here, we explored the ontogeny of the clock machinery in the developing kidney. Pregnant rats were housed at 12-12 h light-dark cycles. Offsprings were killed at 4-h...

  5. Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders

    OpenAIRE

    De Forni, D; Pozzoli, U; R. Cagliani; C. Tresoldi; G. Menozzi; Riva, S; F. Guerini; Comi, G; Bolognesi, E; Bresolin, N.; Clerici, M.; Sironi, M.

    2014-01-01

    Background The temporal coordination of biological processes into daily cycles is a common feature of most living organisms. In humans, disruption of circadian rhythms is commonly observed in psychiatric diseases, including schizophrenia, bipolar disorder, depression and autism. Light therapy is the most effective treatment for seasonal affective disorder and circadian-related treatments sustain antidepressant response in bipolar disorder patients. Day/night cycles represent a major circadian...

  6. A Novel Method of Clock Synchronization in Distributed System

    Science.gov (United States)

    Li, G.; Niu, M. J.; Cai, Y. S.; Chen, X.; Ren, Y. Q.

    2016-03-01

    Time synchronization plays an important role in application of aircraft flying formation and constellation autonomous navigation, etc. In application of clock synchronization in the network system, it is not always true that each observed node may be interconnected, therefore, it is difficult to achieve time synchronization of network system with high precision in the condition that a certain node can only obtain the measurement information of clock from one of its corresponding neighbors, and cannot obtain from other nodes. According to this special problem, a novel method of high precision time synchronization of network system has been proposed. In this paper, we regard each clock as a node in the network system, and based on different distributed topology definition, the following three control algorithms of time synchronization under three circumstances have been designed: without a master clock (reference clock), with a master clock (reference clock), and with a fixed communication delay in the network system. The validity of the designed clock synchronization protocol has been proved both theoretically and through numerical simulation.

  7. Analysis and Simulation of Circadian Multi-Oscillator Systems in a Crassulacean Acid Metabolism Plant

    OpenAIRE

    Bohn, Andreas

    2003-01-01

    Crassulacean acid metabolism (CAM) is an adaptation of photosynthetic organisms to drought stress: improved water-use efficiency is achieved by an optimized temporal arrangement of photosynthetic subprocesses, which are driven by an endogenous pacemaker, i.e. a circadian clock. The present work deals with the hypothesis that the circadian rhythm of gas-exchange of entire leaves of the CAM plant Kalanchoë daigremontiana has to be understood as the collective signal of the population of cells i...

  8. Circadian Rhythms and Obesity in Mammals

    OpenAIRE

    Oren Froy

    2012-01-01

    Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabol...

  9. Functional analysis of Casein Kinase 1 in a minimal circadian system.

    Directory of Open Access Journals (Sweden)

    Gerben van Ooijen

    Full Text Available The Earth's rotation has driven the evolution of cellular circadian clocks to facilitate anticipation of the solar cycle. Some evidence for timekeeping mechanism conserved from early unicellular life through to modern organisms was recently identified, but the components of this oscillator are currently unknown. Although very few clock components appear to be shared across higher species, Casein Kinase 1 (CK1 is known to affect timekeeping across metazoans and fungi, but has not previously been implicated in the circadian clock in the plant kingdom. We now show that modulation of CK1 function lengthens circadian rhythms in Ostreococcustauri, a unicellular marine algal species at the base of the green lineage, separated from humans by ~1.5 billion years of evolution. CK1 contributes to timekeeping in a phase-dependent manner, indicating clock-mediated gating of CK1 activity. Label-free proteomic analyses upon overexpression as well as inhibition revealed CK1-responsive phosphorylation events on a set of target proteins, including highly conserved potentially clock-relevant cellular regulator proteins. These results have major implications for our understanding of cellular timekeeping and can inform future studies in any circadian organism.

  10. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice.

    Directory of Open Access Journals (Sweden)

    Susie Lee

    Full Text Available BACKGROUND: Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per or Cryptochrome1 and 2 (Cry are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. CONCLUSIONS/SIGNIFICANCE: Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.

  11. The relationship between circadian disruption and the development of metabolic syndrome and type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Karatsoreos IN

    2014-12-01

    Full Text Available Ilia N Karatsoreos Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Abstract: Circadian (daily rhythms are pervasive in nature, and expressed in nearly every behavioral and physiological process. In mammals, circadian rhythms are regulated by the master brain clock in the suprachiasmatic nucleus of the hypothalamus that coordinates the activity of “peripheral” oscillators throughout the brain and body. While much progress has been made in understanding the basic functioning of the circadian clock at the level of genes, molecules, and cells, our understanding of how these clocks interact with complex systems is still in its infancy. Much recent work has focused on the role of circadian clocks in the etiology of disorders as diverse as cancer, diabetes, and obesity. Given the rapid rise in obesity, and the economic costs involved in treating its associated cardiometabolic disorders such as heart disease and diabetes mellitus, understanding the development of obesity and metabolic dysregulation is crucial. Significant epidemiological data indicate a role for circadian rhythms in metabolic disorders. Shift workers have a higher incidence of obesity and diabetes, and laboratory studies in humans show misaligning sleep and the circadian clock leads to hyperinsulinemia. In animal models, body-wide “clock gene” knockout mice are prone to obesity. Further, disrupting the circadian clock by manipulating the light–dark cycle can result in metabolic dysregulation and development of obesity. At the molecular level, elegant studies have shown that targeted disruption of the genetic circadian clock in the pancreas leads to diabetes, highlighting the fact that the circadian clock is directly coupled to metabolism at the cellular level. Keywords: glucose, metabolism, sleep, rhythms, obesity

  12. Role of the circadian clock gene Per2 in adaptation to cold temperature

    OpenAIRE

    Chappuis, Sylvie; Ripperger, Jürgen Alexander; Schnell, Anna; Rando, Gianpaolo; Jud, Corinne; Wahli, Walter; Albrecht, Urs

    2013-01-01

    Adaptive thermogenesis allows mammals to resist to cold. For instance, in brown adipose tissue (BAT) the facultative uncoupling of the proton gradient from ATP synthesis in mitochondria is used to generate systemic heat. However, this system necessitates an increase of the Uncoupling protein 1 (Ucp1) and its activation by free fatty acids. Here we show that mice without functional Period2 (Per2) were cold sensitive because their adaptive thermogenesis system was less efficient. Upon cold-expo...

  13. CCL2 mediates the circadian response to low dose endotoxin.

    Science.gov (United States)

    Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A

    2016-09-01

    The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation. PMID:27178133

  14. Clock and clock-controlled genes are differently expressed in the retina, lamina and in selected cells of the visual system of Drosophila melanogaster

    OpenAIRE

    Milena eDamulewicz; Agnieszka eLoboda; Karolina eBukowska-Strakova; Alicja eJozkowicz; Jozef eDulak; Elzbieta M Pyza

    2015-01-01

    The retina and the first optic neuropil (lamina) of Drosophila show circadian rhythms in various processes. To learn about the regulation of circadian rhythms in the retina and lamina and in two cell types, glial and the lamina L2 interneurons, we examined expression of the following clock genes; per, tim, clk, and cry and clock-controlled genes; Atp, nrv2, brp, Pdfr. We found that the expression of gene studied is specific for the retina and lamina. The rhythms of per and tim expression in...

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

    Science.gov (United States)

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

    2016-05-01

    Plant circadian clocks control the timing of a variety of genetic, metabolic and physiological processes. Recent studies revealed a possible molecular mechanism for circadian clock regulation. Arabidopsis thaliana (Arabidopsis) PSEUDO-RESPONSE REGULATOR (PRR) genes, including TIMING OF CAB EXPRESSION 1 (TOC1), encode clock-associated transcriptional repressors that act redundantly. Disruption of multiple PRR genes results in drastic phenotypes, including increased biomass and abiotic stress tolerance, whereas PRR single mutants show subtle phenotypic differences due to genetic redundancy. In this study, we demonstrate that constitutive expression of engineered PRR5 (PRR5-VP), which functions as a transcriptional activator, can increase biomass and abiotic stress tolerance, similar to prr multiple mutants. Concomitant analyses of relative growth rate, flowering time and photosynthetic activity suggested that increased biomass of PRR5-VP plants is mostly due to late flowering, rather than to alterations in photosynthetic activity or growth rate. In addition, genome-wide gene expression profiling revealed that genes related to cold stress and water deprivation responses were up-regulated in PRR5-VP plants. PRR5-VP plants were more resistant to cold, drought and salinity stress than the wild type, whereas ft tsf and gi, well-known late flowering and increased biomass mutants, were not. These findings suggest that attenuation of PRR function by a single transformation of PRR-VP is a valuable method for increasing biomass as well as abiotic stress tolerance in Arabidopsis. Because the PRR gene family is conserved in vascular plants, PRR-VP may regulate biomass and stress responses in many plants, but especially in long-day annual plants. PMID:27012548

  16. Bmal1 and Beta cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced Beta cell failure in mice

    Science.gov (United States)

    Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in Beta cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in Beta cells. To address this, we generated mice with Beta cell ...

  17. USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Protein Stability Paces the Oscillation of the Mammalian Circadian Clock.

    Directory of Open Access Journals (Sweden)

    Arisa Hirano

    Full Text Available Mammalian Cryptochromes, CRY1 and CRY2, function as principal regulators of a transcription-translation-based negative feedback loop underlying the mammalian circadian clockwork. An F-box protein, FBXL3, promotes ubiquitination and degradation of CRYs, while FBXL21, the closest paralog of FBXL3, ubiquitinates CRYs but leads to stabilization of CRYs. Fbxl3 knockout extremely lengthened the circadian period, and deletion of Fbxl21 gene in Fbxl3-deficient mice partially rescued the period-lengthening phenotype, suggesting a key role of CRY protein stability for maintenance of the circadian periodicity. Here, we employed a proteomics strategy to explore regulators for the protein stability of CRYs. We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP associates with CRY1 and CRY2 and stabilizes CRYs through deubiquitination. Treatment with USP7-specific inhibitor or Usp7 knockdown shortened the circadian period of the cellular rhythm. We identified another CRYs-interacting protein, TAR DNA binding protein 43 (TDP-43, an RNA-binding protein. TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. The present study identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process of CRY proteins for period determination in the mammalian circadian clockwork.

  18. Moderate Changes in the Circadian System of Alzheimer's Disease Patients Detected in Their Home Environment

    Czech Academy of Sciences Publication Activity Database

    Weissová, Kamila; Bartoš, A.; Sládek, Martin; Nováková, Marta; Sumová, Alena

    Roč. 11, č. 1 ( 2016 ), e0146200. E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : circadian * melatonin * clock gene * Alzheimer's disease Subject RIV: FH - Neurology Impact factor: 3.234, year: 2014

  19. The circadian system of patients with bipolar disorder differs in episodes of mania and depression

    Czech Academy of Sciences Publication Activity Database

    Nováková, Marta; Praško, J.; Látalová, K.; Sládek, Martin; Sumová, Alena

    2015-01-01

    Roč. 17, č. 3 (2015), s. 303-314. ISSN 1398-5647 R&D Projects: GA MZd(CZ) NT11474 Institutional support: RVO:67985823 Keywords : bipolar disorder * circadian * clock gene * melatonin * Nr1d1 * Per1 Subject RIV: FH - Neurology Impact factor: 4.965, year: 2014

  20. Consistency Models in Distributed Systems with Physical Clocks

    OpenAIRE

    Du, Jiaqing

    2014-01-01

    Most existing distributed systems use logical clocks to order events in the implementation of various consistency models. Although logical clocks are straightforward to implement and maintain, they may affect the scalability, availability, and latency of the system when being used to totally order events in strong consistency models. They can also incur considerable overhead when being used to track and check the causal relationships among events in some weak consistency models. In this thesi...

  1. Master Clock and Time-Signal-Distribution System

    Science.gov (United States)

    Tjoelker, Robert; Calhoun, Malcolm; Kuhnle, Paul; Sydnor, Richard; Lauf, John

    2007-01-01

    A timing system comprising an electronic master clock and a subsystem for distributing time signals from the master clock to end users is undergoing development to satisfy anticipated timing requirements of NASA s Deep Space Network (DSN) for the next 20 to 30 years. This system has a modular, flexible, expandable architecture that is easier to operate and maintain than the present frequency and timing subsystem (FTS).

  2. An in vitro ES cell-based clock recapitulation assay model identifies CK2α as an endogenous clock regulator.

    Science.gov (United States)

    Umemura, Yasuhiro; Yoshida, Junko; Wada, Masashi; Tsuchiya, Yoshiki; Minami, Yoichi; Watanabe, Hitomi; Kondoh, Gen; Takeda, Junji; Inokawa, Hitoshi; Horie, Kyoji; Yagita, Kazuhiro

    2013-01-01

    We previously reported emergence and disappearance of circadian molecular oscillations during differentiation of mouse embryonic stem (ES) cells and reprogramming of differentiated cells, respectively. Here we present a robust and stringent in vitro circadian clock formation assay that recapitulates in vivo circadian phenotypes. This assay system first confirmed that a mutant ES cell line lacking Casein Kinase I delta (CKIδ) induced ∼3 hours longer period-length of circadian rhythm than the wild type, which was compatible with recently reported results using CKIδ null mice. In addition, this assay system also revealed that a Casein Kinase 2 alpha subunit (CK2α) homozygous mutant ES cell line developed significantly longer (about 2.5 hours) periods of circadian clock oscillations after in vitro or in vivo differentiation. Moreover, revertant ES cell lines in which mutagenic vector sequences were deleted showed nearly wild type periods after differentiation, indicating that the abnormal circadian period of the mutant ES cell line originated from the mutation in the CK2α gene. Since CK2α deficient mice are embryonic lethal, this in vitro assay system represents the genetic evidence showing an essential role of CK2α in the mammalian circadian clock. This assay was successfully applied for the phenotype analysis of homozygous mutant ES cells, demonstrating that an ES cell-based in vitro assay is available for circadian genetic screening. PMID:23840637

  3. A Circadian Clock in Neurospora: How Genes and Proteins Cooperate to Produce a Sustained, Entrainable, and Compensated Biological Oscillator with a Period of about a Day

    OpenAIRE

    Dunlap, J C; Loros, J.J.; Colot, H V; Mehra, A.; Belden, W J; Shi, M.; Hong, C.I.; Larrondo, L. F.; Baker, C.L.; Chen, C. -H.; Schwerdtfeger, C.; Collopy, P.D.; Gamsby, J.J.; Lambreghts, R.

    2007-01-01

    Neurospora has proven to be a tractable model system for understanding the molecular bases of circadian rhythms in eukary-otes. At the core of the circadian oscillatory system is a negative feedback loop in which two transcription factors, WC-1 and WC-2, act together to drive expression of the frq gene. WC-2 enters the promoter region of frq coincident with increases in frq expression and then exits when the cycle of transcription is over, whereas WC-1 can always be found there. FRQ promotes ...

  4. Effects of Ovarian Hormones on Internal Circadian Organization in Rats1

    OpenAIRE

    Murphy, Zachary C.; Pezuk, Pinar; Menaker, Michael; Sellix, Michael T

    2013-01-01

    The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is the central pacemaker driving rhythms in endocrine physiology. Gonadal steroid hormones affect behavioral rhythms and clock gene expression. However, the impact of fluctuating ovarian steroid levels during the estrous cycle on internal circadian organization remains to be determined. Further, it is not known if steroid hormone depletion, as in menopause, affects the timing system. To determine the influence of est...

  5. Synergistic interactions between the molecular and neuronal circadian networks drive robust behavioral circadian rhythms in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Ron Weiss

    2014-04-01

    Full Text Available Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK and CYCLE (CYC initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for circadian timekeeping. In order to address this issue, we generated flies in which the amplitude of CLK-driven transcription can be reduced partially (approx. 60% or strongly (90% without affecting the average levels of CLK-target genes. The impaired transcriptional oscillations lead to low amplitude protein oscillations that were not sufficient to drive outputs of peripheral oscillators. However, circadian rhythms in locomotor activity were resistant to partial reduction in transcriptional and protein oscillations. We found that the resilience of the brain oscillator is depending on the neuronal communication among circadian neurons in the brain. Indeed, the capacity of the brain oscillator to overcome low amplitude transcriptional oscillations depends on the action of the neuropeptide PDF and on the pdf-expressing cells having equal or higher amplitude of molecular rhythms than the rest of the circadian neuronal groups in the fly brain. Therefore, our work reveals the importance of high amplitude transcriptional oscillations for cell-autonomous circadian timekeeping. Moreover, we demonstrate that the circadian neuronal network is an essential buffering system that protects against changes in circadian transcription in the brain.

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

    OpenAIRE

    Anwer, M.; Boikoglou, E.; E. Herrero; Hallstein, M.; Davis, A; James, G.; Nagy, F; Davis, S.

    2014-01-01

    eLife digest Life on Earth tends to follow a daily rhythm: some animals are awake during the day and asleep at night, whilst others are more active at night, or during the twilight around dawn and dusk. For many living things, these cycles of activity are driven by an internal body clock that helps the organism to adapt to the daily cycle of light and dark—and similar internal clocks also exist in plants. These internal clocks define daily—or circadian—cycles whereby multiple genes are switch...

  7. Final Report [Regulated mRNA Decay in Arabidopsis: A global analysis of differential control by hormones and the circadian clock

    Energy Technology Data Exchange (ETDEWEB)

    Green, Pamela J.

    2010-03-18

    The long-term goal of this research was to better understand the influence of mRNA stability on gene regulation, particularly in response to hormones and the circadian clock. The primary aim of this project was to examine this using DNA microarrays, small RNA analysis and other approaches. We accomplished these objectives, although we were only able to detect small changes in mRNA stability in response to these stimuli. However, the work also contributed to a major breakthrough allowing the identification of small RNAs on a genomic scale in eukaryotes. Moreover, the project prompted us to develop a new way to analyze mRNA decay genome wide. Thus, the research was hugely successful beyond our objectives.

  8. The Retina and Other Light-sensitive Ocular Clocks.

    Science.gov (United States)

    Besharse, Joseph C; McMahon, Douglas G

    2016-06-01

    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 nonmammalian 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 nonmammalian 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 nonmammalian 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 nonmammalian 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 affect diseases such as glaucoma or retinal degeneration syndromes. PMID:27095816

  9. The role of circadian rhythm in breast cancer

    Science.gov (United States)

    Li, Shujing; Ao, Xiang

    2013-01-01

    The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer. PMID:23997531

  10. Experience-Independent Development of the Hamster Circadian Visual System

    OpenAIRE

    Kampf-Lassin, August; Wei, Jenny; Galang, Jerome; Prendergast, Brian J

    2011-01-01

    Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduc...

  11. Fault-tolerant clock synchronization validation methodology. [in computer systems

    Science.gov (United States)

    Butler, Ricky W.; Palumbo, Daniel L.; Johnson, Sally C.

    1987-01-01

    A validation method for the synchronization subsystem of a fault-tolerant computer system is presented. The high reliability requirement of flight-crucial systems precludes the use of most traditional validation methods. The method presented utilizes formal design proof to uncover design and coding errors and experimentation to validate the assumptions of the design proof. The experimental method is described and illustrated by validating the clock synchronization system of the Software Implemented Fault Tolerance computer. The design proof of the algorithm includes a theorem that defines the maximum skew between any two nonfaulty clocks in the system in terms of specific system parameters. Most of these parameters are deterministic. One crucial parameter is the upper bound on the clock read error, which is stochastic. The probability that this upper bound is exceeded is calculated from data obtained by the measurement of system parameters. This probability is then included in a detailed reliability analysis of the system.

  12. Clock and clock-controlled genes are differently expressed in the retina, lamina and in selected cells of the visual system of Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Milena eDamulewicz

    2015-09-01

    Full Text Available The retina and the first optic neuropil (lamina of Drosophila show circadian rhythms in various processes. To learn about the regulation of circadian rhythms in the retina and lamina and in two cell types, glial and the lamina L2 interneurons, we examined expression of the following clock genes; per, tim, clk, and cry and clock-controlled genes; Atp, nrv2, brp, Pdfr. We found that the expression of gene studied is specific for the retina and lamina. The rhythms of per and tim expression in the retina and glial cells are similar to that observed in the whole head and in clock neurons, while they differ in the lamina and L2 cells. In both the retina and lamina, CRY seems to be a repressor of clk expression. In L2 interneurons per expression is not cyclic indicating the other function of PER in those cells than in the circadian molecular clock. In contrast to per and tim, the pattern of clk and cry expression is similar in both the retina and lamina. The retina holds the autonomous oscillators but the expression of cry and clock-controlled genes, Atp and nrv2, is also regulated by inputs from the pacemaker transmitted by PDF and ITP neuropeptides.

  13. Selection during crop diversification involves correlated evolution of the circadian clock and ecophysiological traits in Brassica rapa.

    Science.gov (United States)

    Yarkhunova, Yulia; Edwards, Christine E; Ewers, Brent E; Baker, Robert L; Aston, Timothy Llewellyn; McClung, C Robertson; Lou, Ping; Weinig, Cynthia

    2016-04-01

    Crop selection often leads to dramatic morphological diversification, in which allocation to the harvestable component increases. Shifts in allocation are predicted to impact (as well as rely on) physiological traits; yet, little is known about the evolution of gas exchange and related anatomical features during crop diversification. In Brassica rapa, we tested for physiological differentiation among three crop morphotypes (leaf, turnip, and oilseed) and for correlated evolution of circadian, gas exchange, and phenological traits. We also examined internal and surficial leaf anatomical features and biochemical limits to photosynthesis. Crop types differed in gas exchange; oilseed varieties had higher net carbon assimilation and stomatal conductance relative to vegetable types. Phylogenetically independent contrasts indicated correlated evolution between circadian traits and both gas exchange and biomass accumulation; shifts to shorter circadian period (closer to 24 h) between phylogenetic nodes are associated with higher stomatal conductance, lower photosynthetic rate (when CO2 supply is factored out), and lower biomass accumulation. Crop type differences in gas exchange are also associated with stomatal density, epidermal thickness, numbers of palisade layers, and biochemical limits to photosynthesis. Brassica crop diversification involves correlated evolution of circadian and physiological traits, which is potentially relevant to understanding mechanistic targets for crop improvement. PMID:26618783

  14. Structural model of the circadian clock KaiB-KaiC complex and mechanism for modulation of KaiC phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Pattanayek, Rekha; Williams, Dewight R; Pattanayek, Sabuj; Mori, Tetsuya; Johnson, Carl H; Stewart, Phoebe L; Egli, Martin [Vanderbilt

    2010-03-08

    The circadian clock of the cyanobacterium Synechococcus elongatus can be reconstituted in vitro by the KaiA, KaiB and KaiC proteins in the presence of ATP. The principal clock component, KaiC, undergoes regular cycles between hyper- and hypo-phosphorylated states with a period of ca. 24 h that is temperature compensated. KaiA enhances KaiC phosphorylation and this enhancement is antagonized by KaiB. Throughout the cycle Kai proteins interact in a dynamic manner to form complexes of different composition. We present a three-dimensional model of the S. elongatus KaiB-KaiC complex based on X-ray crystallography, negative-stain and cryo-electron microscopy, native gel electrophoresis and modelling techniques. We provide experimental evidence that KaiB dimers interact with KaiC from the same side as KaiA and for a conformational rearrangement of the C-terminal regions of KaiC subunits. The enlarged central channel and thus KaiC subunit separation in the C-terminal ring of the hexamer is consistent with KaiC subunit exchange during the dephosphorylation phase. The proposed binding mode of KaiB explains the observation of simultaneous binding of KaiA and KaiB to KaiC, and provides insight into the mechanism of KaiB's antagonism of KaiA.

  15. Reference clock parameters for digital communications systems applications

    Science.gov (United States)

    Kartaschoff, P.

    1981-01-01

    The basic parameters relevant to the design of network timing systems describe the random and systematic time departures of the system elements, i.e., master (or reference) clocks, transmission links, and other clocks controlled over the links. The quantitative relations between these parameters were established and illustrated by means of numerical examples based on available measured data. The examples were limited to a simple PLL control system but the analysis can eventually be applied to more sophisticated systems at the cost of increased computational effort.

  16. Gravitational biology and the mammalian circadian timing system.

    Science.gov (United States)

    Fuller, C A; Murakami, D M; Sulzman, F M

    1989-01-01

    Mammals have evolved under the influence of many selective pressures. Two of these pressures have been the static force of gravity and the daily variations in the environment due to the rotation of the earth. It is now clear that each of these pressures has led to specific adaptations which influence how organisms respond to changes in either gravity or daily time cues. However, several unpredicted responses to altered gravitational environments occur within the homeostatic and circadian control systems. These results may be particularly relevant to biological and medical issues related to spaceflight. This paper demonstrates that the homeostatic regulation of rat body temperature, heart rate, and activity become depressed following exposure to a 2 G hyperdynamic field, and recovers within 5-6 days. In addition, the circadian rhythms of these same variables exhibit a depression of rhythm amplitude; however, recovery required a minimum of 7 days. PMID:11537343

  17. Chromatin Dynamics of Circadian Transcription

    OpenAIRE

    Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

    2015-01-01

    The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Disruption of this transcriptional program leads to a variety of pathologies, including insomnia, depression and metabolic disorders. Circadian rhythms in gene expression rely on specific chromatin transitions which are ultimately coordinated by the molecular clock. As a consequence, a highly plastic and dynamic circadian epigenome can be delineated across different tissues and cell types. Intrigui...

  18. The Kitaev–Feynman clock for open quantum systems

    International Nuclear Information System (INIS)

    We show that Kitaev's construction of Feynman's clock, in which the time-evolution of a closed quantum system is encoded as a ground state problem, can be extended to open quantum systems. In our formalism, the ground states of an ensemble of non-Hermitian Kitaev–Feynman clock Hamiltonians yield stochastic trajectories, which unravel the evolution of a Lindblad master equation. In this way, one can use the Kitaev–Feynman clock not only to simulate the evolution of a quantum system, but also its interaction with an environment such as a heat bath or measuring apparatus. A simple numerical example of a two-level atom undergoing spontaneous emission is presented and analyzed. (paper)

  19. Circadian metabolism in the light of evolution.

    Science.gov (United States)

    Gerhart-Hines, Zachary; Lazar, Mitchell A

    2015-06-01

    Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health. PMID:25927923

  20. Temperature compensation and entrainment in circadian rhythms

    International Nuclear Information System (INIS)

    To anticipate daily variations in the environment and coordinate biological activities into a daily cycle many organisms possess a circadian clock. In the absence of external time cues the circadian rhythm persists with a period of approximately 24 h. The clock phase can be shifted by single pulses of light, darkness, chemicals, or temperature and this allows entrainment of the clock to exactly 24 h by cycles of these zeitgebers. On the other hand, the period of the circadian rhythm is kept relatively constant within a physiological range of constant temperatures, which means that the oscillator is temperature compensated. The mechanisms behind temperature compensation and temperature entrainment are not fully understood, neither biochemically nor mathematically. Here, we theoretically investigate the interplay of temperature compensation and entrainment in general oscillatory systems. We first give an analytical treatment for small temperature shifts and derive that every temperature-compensated oscillator is entrainable to external small-amplitude temperature cycles. Temperature compensation ensures that this entrainment region is always centered at the endogenous period regardless of possible seasonal temperature differences. Moreover, for small temperature cycles the entrainment region of the oscillator is potentially larger for rectangular pulses. For large temperature shifts we numerically analyze different circadian clock models proposed in the literature with respect to these properties. We observe that for such large temperature shifts sinusoidal or gradual temperature cycles allow a larger entrainment region than rectangular cycles. (paper)

  1. Modelling and analysis of the feeding regimen induced entrainment of hepatocyte circadian oscillators using petri nets.

    Directory of Open Access Journals (Sweden)

    Samar Hayat Khan Tareen

    Full Text Available Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.

  2. Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey.

    Science.gov (United States)

    Landgraf, Dominic; Long, Jaimie E; Welsh, David K

    2016-05-01

    An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined. PMID:26414405

  3. Influence of gravity on the circadian timing system.

    Science.gov (United States)

    Fuller, C A; Hoban-Higgins, T M; Griffin, D W; Murakami, D M

    1994-01-01

    The circadian timing system (CTS) is responsible for daily temporal coordination of physiological and behavioral functions both internally and with the external environment. Experiments in altered gravitational environments have revealed changes in circadian rhythms of species ranging from fungi to primates. The altered gravitational environments examined included both the microgravity environment of spaceflight and hyperdynamic environments produced by centrifugation. Acute exposure to altered gravitational environments changed homeostatic parameters such as body temperature. These changes were time of day dependent. Exposure to gravitational alterations of relatively short duration produced changes in both the homeostatic level and the amplitude of circadian rhythms. Chronic exposure to a non-earth level of gravity resulted in changes in the period of the expressed rhythms as well as in the phase relationships between the rhythms and between the rhythms and the external environment. In addition, alterations in gravity appeared to act as a time cue for the CTS. Altered gravity also affected the sensitivity of the pacemaker to other aspects of the environment (i.e., light) and to shifts of time cues. Taken together, these studies lead to the conclusion that the CTS is indeed sensitive to gravity and its alterations. This finding has implications for both basic biology and space medicine. PMID:11537948

  4. The Internal Circadian Clock Increases Hunger and Appetite in the Evening Independent of Food Intake and Other Behaviors

    OpenAIRE

    Scheer, Frank A. J. L.; Morris, Christopher J.; Shea, Steven A.

    2013-01-01

    Objective Despite the extended overnight fast, paradoxically, people are typically not ravenous in the morning and breakfast is typically the smallest meal of the day. Here we assessed whether this paradox could be explained by an endogenous circadian influence on appetite with a morning trough, while controlling for sleep/wake and fasting/feeding effects. Design and Methods We studied 12 healthy non-obese adults (6 male; age, 20–42 year) throughout a 13-day laboratory protocol that balanced ...

  5. The Internal Circadian Clock Increases Hunger and Appetite in the Evening Independent of Food Intake and Other Behaviors

    OpenAIRE

    Scheer, Frank A. J. L.; Morris, Christopher J.; Shea, Steven A.

    2013-01-01

    Objective: Despite the extended overnight fast, paradoxically, people are typically not ravenous in the morning and breakfast is typically the smallest meal of the day. Here we assessed whether this paradox could be explained by an endogenous circadian influence on appetite with a morning trough, while controlling for sleep/wake and fasting/feeding effects. Design and Methods We studied 12 healthy non-obese adults (6 male; age, 20–42 year) throughout a 13-day laboratory protocol that balanced...

  6. Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors

    Science.gov (United States)

    Despite the importance of total energy intake in circadian system regulation, no study has related human CLOCK gene polymorphisms and food intake measures. The aim of this study was to investigate associations of five CLOCK single-nucleotide-polymorphisms (SNPs) with food-intake and to explore the p...

  7. Temperature as a universal resetting cue for mammalian circadian oscillators

    OpenAIRE

    Buhr, Ethan D.; Yoo, Seung-Hee; Takahashi, Joseph S.

    2010-01-01

    Environmental temperature cycles are a universal entraining cue for all circadian systems at the organismal level with the exception of homeothermic vertebrates. We report here that resistance to temperature entrainment is a property of the suprachiasmatic nucleus (SCN) network and is not a cell autonomous property of mammalian clocks. This differential sensitivity to temperature allows the SCN to drive circadian rhythms in body temperature which can then act as a universal cue for the entrai...

  8. General flat four-dimensional world pictures and clock systems

    Science.gov (United States)

    Hsu, J. P.; Underwood, J. A.

    1978-01-01

    We explore the mathematical structure and the physical implications of a general four-dimensional symmetry framework which is consistent with the Poincare-Einstein principle of relativity for physical laws and with experiments. In particular, we discuss a four-dimensional framework in which all observers in different frames use one and the same grid of clocks. The general framework includes special relativity and a recently proposed new four-dimensional symmetry with a nonuniversal light speed as two special simple cases. The connection between the properties of light propagation and the convention concerning clock systems is also discussed, and is seen to be nonunique within the four-dimensional framework.

  9. Long-Lasting Effect of Perinatal Exposure to L-tryptophan on Circadian Clock of Primary Cell Lines Established from Male Offspring Born from Mothers Fed on Dietary Protein Restriction

    OpenAIRE

    Elizabeth Nascimento; Omar Guzman-Quevedo; Nellie Delacourt; Raquel da Silva Aragão; Georgina Perez-Garcia; Sandra Lopes de Souza; Raul Manhães-de-Castro; Francisco Bolaños-Jiménez; Bertrand Kaeffer

    2013-01-01

    Background & Aims: Maternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation. [br/] Methods: Male rat pups from mothers fed on low protein (8%, LP) or control (18%, CP) diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg) between Da...

  10. Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.

    Directory of Open Access Journals (Sweden)

    Jorien Laermans

    Full Text Available BACKGROUND: In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF, a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS: Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD. Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test. Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS: The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. CONCLUSIONS: This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and

  11. The Circadian System Is a Target and Modulator of Prenatal Cocaine Effects

    OpenAIRE

    Shang, Eva H.; Zhdanova, Irina V.

    2007-01-01

    Background Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. Methodology and Principle Findings Here we introduce a new high-throughput gene...

  12. The circadian system is a target and modulator of prenatal cocaine effects.

    Directory of Open Access Journals (Sweden)

    Eva H Shang

    Full Text Available BACKGROUND: Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. METHODOLOGY AND PRINCIPLE FINDINGS: Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH and neurotransmission (dopamine transporter, zDAT. Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR, demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1 and genes encoding melatonin receptors (zMelR that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily

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

    Science.gov (United States)

    Martins, Rute S. T.; Gomez, Ana; Zanuy, Silvia; Carrillo, Manuel; Canário, Adelino V. M.

    2015-01-01

    The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG) axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL) alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP) accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis. PMID:26641263

  14. Adrenergic regulation of clock gene expression in mouse liver

    OpenAIRE

    Terazono, Hideyuki; Mutoh, Tatsushi; Yamaguchi, Shun; Kobayashi, Masaki; Akiyama, Masashi; Udo, Rhyuta; Ohdo, Shigehiro; Okamura, Hitoshi; Shibata, Shigenobu

    2003-01-01

    A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether inj...

  15. The Bird of Time: Cognition and the Avian Biological Clock

    Directory of Open Access Journals (Sweden)

    Vincent Michael Cassone

    2012-03-01

    Full Text Available Avian behavior and physiology are embedded in time at many levels of biological organization. Biological clock function in birds is critical for sleep/wake cycles, but may also regulate the acquisition of place memory, learning of song from tutors, social integration and time-compensated navigation. This relationship has two major implications. First, mechanisms of the circadian clock should be linked in some way to the mechanisms of all these behaviors. How is not yet clear, and evidence that the central clock has effects is piecemeal. Second, selection acting on characters that are linked to the circadian clock should influence aspects of the clock mechanism itself. Little evidence exists for this in birds, but there have been few attempts to assess this idea. At its core, the avian circadian clock is a multi-oscillator system comprising the pineal gland, the retinae and the avian homologues of the suprachiasmatic nuclei, whose mutual interactions ensure coordinated physiological functions, which are in turn synchronized to ambient light cycles via encephalic, pineal and retinal photoreceptors. At the molecular level, avian biological clocks comprise a genetic network of positive elements clock and bmal1 whose interactions with the negative elements period2, period3 and the cryptochromes form an oscillatory feedback loop that circumnavigates the 24 hrs of the day. We assess the possibilities for dual integration of the clock with time-dependent cognitive processes. Closer examination of the molecular, physiological, and behavioral elements of the circadian system would place birds at a very interesting fulcrum in the neurobiology of time in learning, memory and navigation. 

  16. A bi-directional fixed-latency clock distribution system

    International Nuclear Information System (INIS)

    The Askar'yan Radio Array (ARA) Collaboration is constructing a giant array of radio-frequency antennas deployed in the ice near the geographic South Pole. This experiment aims at detecting the extremely weak signal of neutrinos with energies in excess of 100 PeV from ultrahigh-energy cosmic ray interactions with the cosmic microwave background radiation. The antennas are located in shallow holes drilled to depths of 200 m and need high fidelity RF signal transmission over extended lengths to the data acquisition logic at the surface. We report on a transmission scheme whereby signals are digitized in the ice and the waveforms are digitally sent via high-speed serial links. Reconstruction algorithms require distribution of a low-jitter clock from the surface down to the digitization boards in the holes with knowledge of the overall time delay between the two clock domains. Previously, we designed a clock synchronization system using electrical signaling over CAT5. This year we have updated our solution to optical fibers using high speed transceiver blocks in Spartan-6 FPGAs. This note describes our improvements on the latter solution: technical details as well as methods of maintaining a fixed phase between two clocks after power cycles and resets

  17. Circadian Oscillation of the Lettuce Transcriptome under Constant Light and Light–Dark Conditions

    Science.gov (United States)

    Higashi, Takanobu; Aoki, Koh; Nagano, Atsushi J.; Honjo, Mie N.; Fukuda, Hirokazu

    2016-01-01

    Although, the circadian clock is a universal biological system in plants and it orchestrates important role of plant production such as photosynthesis, floral induction and growth, there are few such studies on cultivated species. Lettuce is one major cultivated species for both open culture and plant factories and there is little information concerning its circadian clock system. In addition, most of the relevant genes have not been identified. In this study, we detected circadian oscillation in the lettuce transcriptome using time-course RNA sequencing (RNA-Seq) data. Constant light (LL) and light–dark (LD) conditions were used to detect circadian oscillation because the circadian clock has some basic properties: one is self-sustaining oscillation under constant light and another is entrainment to environmental cycles such as light and temperature. In the results, 215 contigs were detected as common oscillating contigs under both LL and LD conditions. The 215 common oscillating contigs included clock gene-like contigs CCA1 (CIRCADIAN CLOCK ASSOCIATED 1)-like, TOC1 (TIMING OF CAB EXPRESSION 1)-like and LHY (LATE ELONGATED HYPOCOTYL)-like, and their expression patterns were similar to those of Arabidopsis. Functional enrichment analysis by GO (gene ontology) Slim and GO Fat showed that the GO terms of response to light stimulus, response to stress, photosynthesis and circadian rhythms were enriched in the 215 common oscillating contigs and these terms were actually regulated by circadian clocks in plants. The 215 common oscillating contigs can be used to evaluate whether the gene expression pattern related to photosynthesis and optical response performs normally in lettuce. PMID:27512400

  18. Circadian Oscillation of the Lettuce Transcriptome under Constant Light and Light-Dark Conditions.

    Science.gov (United States)

    Higashi, Takanobu; Aoki, Koh; Nagano, Atsushi J; Honjo, Mie N; Fukuda, Hirokazu

    2016-01-01

    Although, the circadian clock is a universal biological system in plants and it orchestrates important role of plant production such as photosynthesis, floral induction and growth, there are few such studies on cultivated species. Lettuce is one major cultivated species for both open culture and plant factories and there is little information concerning its circadian clock system. In addition, most of the relevant genes have not been identified. In this study, we detected circadian oscillation in the lettuce transcriptome using time-course RNA sequencing (RNA-Seq) data. Constant light (LL) and light-dark (LD) conditions were used to detect circadian oscillation because the circadian clock has some basic properties: one is self-sustaining oscillation under constant light and another is entrainment to environmental cycles such as light and temperature. In the results, 215 contigs were detected as common oscillating contigs under both LL and LD conditions. The 215 common oscillating contigs included clock gene-like contigs CCA1 (CIRCADIAN CLOCK ASSOCIATED 1)-like, TOC1 (TIMING OF CAB EXPRESSION 1)-like and LHY (LATE ELONGATED HYPOCOTYL)-like, and their expression patterns were similar to those of Arabidopsis. Functional enrichment analysis by GO (gene ontology) Slim and GO Fat showed that the GO terms of response to light stimulus, response to stress, photosynthesis and circadian rhythms were enriched in the 215 common oscillating contigs and these terms were actually regulated by circadian clocks in plants. The 215 common oscillating contigs can be used to evaluate whether the gene expression pattern related to photosynthesis and optical response performs normally in lettuce. PMID:27512400

  19. Plasticity of the intrinsic period of the human circadian timing system.

    Directory of Open Access Journals (Sweden)

    Frank A J L Scheer

    Full Text Available Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol, which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2 for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.

  20. Circadian Organization of Behavior and Physiology in Drosophila

    OpenAIRE

    Allada, Ravi; Chung, Brian Y.

    2010-01-01

    Circadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks....

  1. Development of a Configurable Growth Chamber with a Computer Vision System to Study Circadian Rhythm in Plants

    Directory of Open Access Journals (Sweden)

    Marcos Egea-Cortines

    2012-11-01

    Full Text Available Plant development is the result of an endogenous morphogenetic program that integrates environmental signals. The so-called circadian clock is a set of genes that integrates environmental inputs into an internal pacing system that gates growth and other outputs. Study of circadian growth responses requires high sampling rates to detect changes in growth and avoid aliasing. We have developed a flexible configurable growth chamber comprising a computer vision system that allows sampling rates ranging between one image per 30 s to hours/days. The vision system has a controlled illumination system, which allows the user to set up different configurations. The illumination system used emits a combination of wavelengths ensuring the optimal growth of species under analysis. In order to obtain high contrast of captured images, the capture system is composed of two CCD cameras, for day and night periods. Depending on the sample type, a flexible image processing software calculates different parameters based on geometric calculations. As a proof of concept we tested the system in three different plant tissues, growth of petunia- and snapdragon (Antirrhinum majus flowers and of cladodes from the cactus Opuntia ficus-indica. We found that petunia flowers grow at a steady pace and display a strong growth increase in the early morning, whereas Opuntia cladode growth turned out not to follow a circadian growth pattern under the growth conditions imposed. Furthermore we were able to identify a decoupling of increase in area and length indicating that two independent growth processes are responsible for the final size and shape of the cladode.

  2. The clock distribution system for the ATLAS Liquid Argon Calorimeter Phase-I Upgrade Demonstrator

    International Nuclear Information System (INIS)

    A prototype Liquid-argon Trigger Digitizer Board (LTDB), called the LTDB Demonstrator, has been developed to demonstrate the functions of the ATLAS Liquid Argon Calorimeter Phase-I trigger electronics upgrade. Forty Analog-to-Digital converters and four FPGAs with embedded multi-gigabit-transceivers on each Demonstrator need high quality clocks. A clock distribution system based on commercial components has been developed for the Demonstrator. The design of the clock distribution system is presented. The performance of the clock distribution system has been evaluated. The components used in the clock distribution system have been qualified to meet radiation tolerance requirements of the Demonstrator

  3. System and method for clock synchronization and position determination using entangled photon pairs

    Science.gov (United States)

    Shih, Yanhua (Inventor)

    2010-01-01

    A system and method for clock synchronization and position determination using entangled photon pairs is provided. The present invention relies on the measurement of the second order correlation function of entangled states. Photons from an entangled photon source travel one-way to the clocks to be synchronized. By analyzing photon registration time histories generated at each clock location, the entangled states allow for high accuracy clock synchronization as well as high accuracy position determination.

  4. Short-term influence of cataract surgery on circadian biological rhythm and related health outcomes (CLOCK-IOL trial): study protocol for a randomized controlled trial

    OpenAIRE

    Saeki, Keigo; Obayashi, Kenji; Nishi, Tomo; Miyata, Kimie; Maruoka, Shinji; Ueda, Tetsuo; OKAMOTO, Masahiro; Hasegawa, Taiji; Matsuura, Toyoaki; Tone, Nobuhiro; Ogata, Nahoko; Kurumatani, Norio

    2014-01-01

    Background Light information is the most important cue of circadian rhythm which synchronizes biological rhythm with external environment. Circadian misalignment of biological rhythm and external environment is associated with increased risk of depression, insomnia, obesity, diabetes, cardiovascular disease, and cancer. Increased light transmission by cataract surgery may improve circadian misalignment and related health outcomes. Although some observational studies have shown improvement of ...

  5. Research of a long distance clock distribution system

    International Nuclear Information System (INIS)

    Ultrahigh-energy neutrinos with energies in excess of 100 PeV from the GZK effect will be studied using a new detector at the South Pole called the Askaryan Radio Array (ARA). The radiofrequency emission which occurs when these particles interact in the glacial ice is detected by an array of antennas spread out over an enormous area, over 100 km2 and embedded in the ice at depths of 200 m to increase sensitivity. Signals from the antennas are digitized by specialized electronics and must be time synchronized with accuracies of order 50 ps or less for event reconstruction to function properly. A system has been proposed which digitizes the impulse waveforms in situ in the ice and sends the data to the surface using high-speed serial links. This requires distribution of a low-jitter clock to each hole but has substantial advantages in cost and power which drive our development effort to realize this technology. Last year we implemented a first version of a long distance clock synchronization system using electrical signaling over CAT5. This year we have updated our solution to optical fiber using high speed transceiver blocks in Spartan 6 FPGAs. The master clock is embedded into the data stream and distributed to the various holes where a phase-locked derivative is recovered. In this way, we have implemented a 1.25 Gbps data link over a bi-directional communication system fulfilling the requirements of the project. This note describes our efforts on the latter solution: technical details as well as methods of maintaining fixed phase difference between two clocks after power cycle and reset.

  6. Design and Analysis of Sequential Elements for Low Power Clocking System with Low Power Techniques

    Directory of Open Access Journals (Sweden)

    S.Sasidhar Reddy

    2014-09-01

    Full Text Available This paper proposed the design of sequential elements for low power clocking system with low low power techniques for saving the power. Power consumption is a major bottleneck of system performance and is listed as one of the top three challenges in International Technology Roadmap for Semiconductor 2008. In practice, a large portion of the on chip power is consumed by the clock system which is made of the clock distribution network and flop-flops. In this paper, various design techniques for a low power clocking system are surveyed. Among them is an effective way to reduce capacity of the clock load by minimizing number of clocked transistors. To approach this, proposed a novel clocked pair shared flip-flop which reduces the number of local clocked transistors by approximately 40%. A 24% reduction of clock driving power is achieved. In addition, low swing and double edge clocking, can be easily incorporated into the new flip-flop to build clocking systems. As the feature size becomes smaller, shorter channel lengths result in increased sub-threshold leakage current through a transistor when it is off. Dual sleep and sleepy stack methods are proposed to avoid static power consumption; the flip flops are simulated using HSPICE.

  7. Dephosphorylation of the Core Clock Protein KaiC in the Cyanobacterial KaiABC Circadian Oscillator Proceeds via an ATP Synthase Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Egli, Martin; Mori, Tetsuya; Pattanayek, Rekha; Xu, Yao; Qin, Ximing; Johnson, Carl H. (Vanderbilt)

    2014-10-02

    The circadian clock of the cyanobacterium Synechococcus elongatus can be reconstituted in vitro from three proteins, KaiA, KaiB, and KaiC in the presence of ATP, to tick in a temperature-compensated manner. KaiC, the central cog of this oscillator, forms a homohexamer with 12 ATP molecules bound between its N- and C-terminal domains and exhibits unusual properties. Both the N-terminal (CI) and C-terminal (CII) domains harbor ATPase activity, and the subunit interfaces between CII domains are the sites of autokinase and autophosphatase activities. Hydrolysis of ATP correlates with phosphorylation at threonine and serine sites across subunits in an orchestrated manner, such that first T432 and then S431 are phosphorylated, followed by dephosphorylation of these residues in the same order. Although structural work has provided insight into the mechanisms of ATPase and kinase, the location and mechanism of the phosphatase have remained enigmatic. From the available experimental data based on a range of approaches, including KaiC crystal structures and small-angle X-ray scattering models, metal ion dependence, site-directed mutagenesis (i.e., E318, the general base), and measurements of the associated clock periods, phosphorylation patterns, and dephosphorylation courses as well as a lack of sequence motifs in KaiC that are typically associated with known phosphatases, we hypothesized that KaiCII makes use of the same active site for phosphorylation and dephosphorlyation. We observed that wild-type KaiC (wt-KaiC) exhibits an ATP synthase activity that is significantly reduced in the T432A/S431A mutant. We interpret the first observation as evidence that KaiCII is a phosphotransferase instead of a phosphatase and the second that the enzyme is capable of generating ATP, both from ADP and P{sub i} (in a reversal of the ATPase reaction) and from ADP and P-T432/P-S431 (dephosphorylation). This new concept regarding the mechanism of dephosphorylation is also supported by the

  8. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome

    Science.gov (United States)

    Genetic variation at the Circadian Locomotor Output Cycles Kaput (CLOCK) locus has been associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular diseases. In fact, it has been suggested that the disruption of the circadian system may play a causal ro...

  9. Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature

    OpenAIRE

    Valenzuela, F. J.; Vera, J.; Venegas, C.; S Muñoz; Oyarce, S.; K. Muñoz; Lagunas, C.

    2016-01-01

    The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized b...

  10. A New Method to Minimize the Clock Skew to Enhance Performance of Digital System

    OpenAIRE

    N. Suresh Kumar,; J. Anitha; M.S.S. Praveen,; N. Asok Kumar,; R. Ajay Suresh Babu

    2010-01-01

    A Pipe line technology is used in any digital system to perform multiple tasks simultaneously and to reduce the data losses in data transactions. But the conventional pipeline system is facing problems due to improper synchronization of clock pulses. This is a universal problem in all the digital systems mostly called jitter or skew. Inmost of the digital systems the propagation of information mainly controlled on the basis of clock pulses. In most of the digital systems the clock skew decrea...

  11. Byzantine-fault tolerant self-stabilizing protocol for distributed clock synchronization systems

    Science.gov (United States)

    Malekpour, Mahyar R. (Inventor)

    2010-01-01

    A rapid Byzantine self-stabilizing clock synchronization protocol that self-stabilizes from any state, tolerates bursts of transient failures, and deterministically converges within a linear convergence time with respect to the self-stabilization period. Upon self-stabilization, all good clocks proceed synchronously. The Byzantine self-stabilizing clock synchronization protocol does not rely on any assumptions about the initial state of the clocks. Furthermore, there is neither a central clock nor an externally generated pulse system. The protocol converges deterministically, is scalable, and self-stabilizes in a short amount of time. The convergence time is linear with respect to the self-stabilization period.

  12. 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

  13. The promoter activities of sucrose phosphate synthase genes in rice, OsSPS1 and OsSPS11, are controlled by light and circadian clock, but not by sucrose

    Directory of Open Access Journals (Sweden)

    Madoka eYonekura

    2013-03-01

    Full Text Available Although sucrose plays a role in sugar sensing and its signaling pathway, little is known about the regulatory mechanisms of the expressions of plant sucrose-related genes. Our previous study on the expression of the sucrose phosphate synthase gene family in rice (OsSPSs suggested the involvement of sucrose sensing and/or circadian rhythm in the transcriptional regulation of OsSPS. To examine whether the promoters of OsSPSs can be controlled by sugars and circadian clock, we produced transgenic rice plants harboring a promoter–luciferase construct for OsSPS1 or OsSPS11 and analyzed the changes in the promoter activities by monitoring bioluminescence from intact transgenic plants in real time. Transgenic plants fed sucrose, glucose, or mannitol under continuous light conditions showed no changes in bioluminescence intensity; meanwhile, the addition of sucrose increased the concentration of sucrose in the plants, and the mRNA levels of OsSPS remained constant. These results suggest that these OsSPS promoters may not be regulated by sucrose levels in the tissues. Next, we investigated the changes in the promoter activities under 12-h light/12-h dark cycles and continuous light conditions. Under the light–dark cycle, both OsSPS1 and OsSPS11 promoter activities were low in the dark and increased rapidly after the beginning of the light period. When the transgenic rice plants were moved to the continuous light condition, both POsSPS1::LUC and POsSPS11::LUC reporter plants exhibited circadian bioluminescence rhythms; bioluminescence peaked during the subjective day with a 27-h period: in the early morning as for OsSPS1 promoter and midday for OsSPS11 promoter. These results indicate that these OsSPS promoters are controlled by both light illumination and circadian clock and that the regulatory mechanism of promoter activity differs between the 2 OsSPS genes.

  14. Molecular Mechanisms of Circadian Regulation During Spaceflight

    Science.gov (United States)

    Zanello, Susana; Boyle, Richard

    2011-01-01

    Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4

  15. 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: 2.774, year: 2014

  16. Neuroimaging, cognition, light and circadian rhythms

    Directory of Open Access Journals (Sweden)

    Giulia eGaggioni

    2014-07-01

    Full Text Available In humans, sleep and wakefulness and the associated cognitive processes are regulated through interactions between sleep homeostasis and the circadian system. Chronic disruption of sleep and circadian rhythmicity is common in our society and there is a need for a better understanding of the brain mechanisms regulating sleep, wakefulness and associated cognitive processes. This review summarizes recent investigations which provide first neural correlates of the combined influence of sleep homeostasis and circadian rhythmicity on cognitive brain activity. Markers of interindividual variations in sleep-wake regulation, such as chronotype and polymorphisms in sleep and clock genes, are associated with changes in cognitive brain responses in subcortical and cortical areas in response to manipulations of the sleep-wake cycle. This review also includes recent data showing that cognitive brain activity is regulated by light, which is a powerful modulator of cognition and alertness and also directly impacts sleep and circadian rhythmicity. The effect of light varied with age, psychiatric status, PERIOD3 genotype and changes in sleep homeostasis and circadian phase. These data provide new insights into the contribution of demographic characteristics, the sleep-wake cycle, circadian rhythmicity and light to brain functioning.

  17. Crystal Structure of the Redox-Active Cofactor Dibromothymoquinone Bound to Circadian Clock Protein KaiA and Structural Basis for Dibromothymoquinone's Ability to Prevent Stimulation of KaiC Phosphorylation by KaiA

    Energy Technology Data Exchange (ETDEWEB)

    Pattanayek, Rekha; Sidiqi, Said K.; Egli, Martin [Vanderbilt-MED

    2013-09-19

    KaiA protein that stimulates KaiC phosphorylation in the cyanobacterial circadian clock was recently shown to be destabilized by dibromothymoquinone (DBMIB), thus revealing KaiA as a sensor of the plastoquinone (PQ) redox state and suggesting an indirect control of the clock by light through PQ redox changes. Here we show using X-ray crystallography that several DBMIBs are bound to KaiA dimer. Some binding modes are consistent with oligomerization of N-terminal KaiA pseudoreceiver domains and/or reduced interdomain flexibility. DBMIB bound to the C-terminal KaiA (C-KaiA) domain and limited stimulation of KaiC kinase activity by C-KaiA in the presence of DBMIB demonstrate that the cofactor may weakly inhibit KaiA-KaiC binding.

  18. Central Circadian Control of Female Reproductive Function

    Directory of Open Access Journals (Sweden)

    BrookeHMiller

    2014-01-01

    Full Text Available Over the past two decades, it has become clear just how much of our physiology is under the control of the suprachiasmatic nucleus (SCN and the cell-intrinsic molecular clock that ticks with a periodicity of approximately 24 hours. The SCN prepares our digestive system for meals, our adrenal axis for the stress of waking up in the morning, and the genes expressed in our muscles when we prepare to exercise, Long before molecular studies of genes such as Clock, Bmal1, and the Per homologs were possible, it was obvious that female reproductive function was under strict circadian control at every level of the hypothalamic-pituitary-gonadal (HPG axis, and in the establishment and successful maintenance of pregnancy. This review highlights our current understanding of the role that the SCN plays in regulating female reproductive physiology, with a special emphasis on the advances made possible through the use of circadian mutant mice.

  19. The effects of gravity on the circadian timing system

    Science.gov (United States)

    Fuller, C. A.

    1994-01-01

    The physiological system responsible for the temporal coordination of an organism is the circadian timing system (CTS). This system provides two forms of temporal coordination. First, the CTS provides for synchronization of the organism with the 24 hour period of the external environment. This synchronization of the organism with the environment is termed entrainment. Second, this system also provides for internal coordination of the various physiological, behavioral, and biochemical events within the organism. When either of these two temporal relationships are disturbed, various dysfunctions can be manifest within the organism. Homeostatic capacity of other physiological systems may be reduced. Performance is decreased and sleep disorders, mental health impairment (e.g., depression), jet lag syndrome, and shift work maladaptation frequently occur. Over the last several years, several studies have evaluated the potential influence of gravity on this physiological control system by examining changes in rhythmic characteristics of organisms exposed to altered gravitational environments. The altered gravitational environments have included the microgravity of spaceflight as well as hyperdynamic fields produced via centrifugation.

  20. Analysis of a clock-aided global navigation satellite system (GNSS)

    International Nuclear Information System (INIS)

    This paper presents a dilution of precision (DOP) analysis of a clock-aided global navigation satellite system (GNSS). Firstly, the analysis shows that a best linear unbiased estimator should be used in the clock-aided GNSS to get the best improvements in accuracy. Secondly, the influence of the clock on vertical DOP (VDOP) and horizontal DOP (HDOP) is analysed by using the clock characteristics as a weighting matrix. The analysis highlights quantitative improvements in the VDOP and HDOP and explains why improvements in the VDOP are superior to those of the HDOP in the clock-aided GNSS. Finally, the paper analyses how incorrectly known a priori clock variances degrade the level of accuracy and offers guidelines for determining a weighting matrix in the cases where the clock characteristics are not clearly known

  1. A circadian oscillator in the fungus Botrytis cinerea regulates virulence when infecting Arabidopsis thaliana.

    Science.gov (United States)

    Hevia, Montserrat A; Canessa, Paulo; Müller-Esparza, Hanna; Larrondo, Luis F

    2015-07-14

    The circadian clock of the plant model Arabidopsis thaliana modulates defense mechanisms impacting plant-pathogen interactions. Nevertheless, the effect of clock regulation on pathogenic traits has not been explored in detail. Moreover, molecular description of clocks in pathogenic fungi--or fungi in general other than the model ascomycete Neurospora crassa--has been neglected, leaving this type of question largely unaddressed. We sought to characterize, therefore, the circadian system of the plant pathogen Botrytis cinerea to assess if such oscillatory machinery can modulate its virulence potential. Herein, we show the existence of a functional clock in B. cinerea, which shares similar components and circuitry with the Neurospora circadian system, although we found that its core negative clock element FREQUENCY (BcFRQ1) serves additional roles, suggesting extracircadian functions for this protein. We observe that the lesions produced by this necrotrophic fungus on Arabidopsis leaves are smaller when the interaction between these two organisms occurs at dawn. Remarkably, this effect does not depend solely on the plant clock, but instead largely relies on the pathogen circadian system. Genetic disruption of the B. cinerea oscillator by mutation, overexpression of BcFRQ1, or by suppression of its rhythmicity by constant light, abrogates circadian regulation of fungal virulence. By conducting experiments with out-of-phase light:dark cycles, we confirm that indeed, it is the fungal clock that plays the main role in defining the outcome of the Arabidopsis-Botrytis interaction, providing to our knowledge the first evidence of a microbial clock modulating pathogenic traits at specific times of the day. PMID:26124115

  2. Clock synchronization design and evaluation for trigger-less data acquisition system

    International Nuclear Information System (INIS)

    For modern particle physics experiments, trigger-less data acquisition (DAQ) system has been put into practice because of the need of reaction multiplicity and trigger flexibility. In such new DAQ systems, global synchronized clock plays an important role because it affects the granularity of time slice and precision of reference clock. In this paper, a novel synchronized clock distribution method is proposed. With the help of modulation technique, master clock module distributes system clock to each slave module. To synchronize slave clocks, the propagation delay is adjusted and the clock phase is aligned by an FPGA chip automatically. Furthermore, an ADC- based method is proposed to evaluate the performance of multi-module clock synchronization simultaneously. The experiments of a prototype system show that slave clocks can be synchronized less than 100 ps over 150 m range. The proposed method is simple and flexible, and it can be used in trigger-less DAQ system and other applications of clock distribution preciously. (authors)

  3. The clock and control system for the ATLAS Liquid Argon Calorimeter Phase-I upgrade

    International Nuclear Information System (INIS)

    A Liquid-argon Trigger Digitizer Board (LTDB) is being developed to upgrade the ATLAS Liquid Argon Calorimeter Phase-I trigger electronics. The LTDB located at the front end needs to obtain the clock signals and be configured and monitored remotely from the back end. A clock and control system is being developed for the LTDB and the major functions of the system have been evaluated. The design and evaluation of the clock and control system are presented in this paper

  4. The functional interplay between protein kinase CK2 and CCA1 transcriptional activity is essential for clock temperature compensation in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Sergi Portolés

    2010-11-01

    Full Text Available Circadian rhythms are daily biological oscillations driven by an endogenous mechanism known as circadian clock. The protein kinase CK2 is one of the few clock components that is evolutionary conserved among different taxonomic groups. CK2 regulates the stability and nuclear localization of essential clock proteins in mammals, fungi, and insects. Two CK2 regulatory subunits, CKB3 and CKB4, have been also linked with the Arabidopsis thaliana circadian system. However, the biological relevance and the precise mechanisms of CK2 function within the plant clockwork are not known. By using ChIP and Double-ChIP experiments together with in vivo luminescence assays at different temperatures, we were able to identify a temperature-dependent function for CK2 modulating circadian period length. Our study uncovers a previously unpredicted mechanism for CK2 antagonizing the key clock regulator CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1. CK2 activity does not alter protein accumulation or subcellular localization but interferes with CCA1 binding affinity to the promoters of the oscillator genes. High temperatures enhance the CCA1 binding activity, which is precisely counterbalanced by the CK2 opposing function. Altering this balance by over-expression, mutation, or pharmacological inhibition affects the temperature compensation profile, providing a mechanism by which plants regulate circadian period at changing temperatures. Therefore, our study establishes a new model demonstrating that two opposing and temperature-dependent activities (CCA1-CK2 are essential for clock temperature compensation in Arabidopsis.

  5. Circadian gating of neuronal functionality: a basis for iterative metaplasticity.

    Science.gov (United States)

    Iyer, Rajashekar; Wang, Tongfei A; Gillette, Martha U

    2014-01-01

    Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory. PMID:25285070

  6. Expression of Clock Proteins in Developing Tooth

    OpenAIRE

    Zheng, Li; Papagerakis, Silvana; Schnell, Santiago D.; Hoogerwerf, Willemijntje A; Papagerakis, Petros

    2010-01-01

    Morphological and functional changes during ameloblast and odontoblast differentiation suggest that enamel and dentin formation is under circadian control. Circadian rhythms are endogenous self-sustained oscillations with periods of 24 hours that control diverse physiological and metabolic processes. Mammalian clock genes play a key role in synchronizing circadian functions in many organs. However, close to nothing is known on clock genes expression during tooth development. In this work, we ...

  7. Time maintenance of user clocks via the tracking and data relay satellite system

    Science.gov (United States)

    Whitworth, G.; Mcintyre, J. W.; Downs, R. E.

    1983-01-01

    A system is described which uses the Tracking and Data Relay Satellite System (TDRSS) itself to compare the user satellite clock with a clock at the White Sands station that is referenced to Universal Time Coordinated (UTC). No command of the spacecraft by the system is required, and actual on-board clock corrections are made by the spacecraft control center at its discretion. Computer models were constructed using basic orbital parameters for user and TDRS satellites. With only first-order corrections and simple averaging techniques for constant clock rates, error measurement precision of better than one microsecond was obtained. More sophisticated computations should allow considerable improvement over this.

  8. The hormonal Zeitgeber melatonin: Role as a circadian modulator in memory processing

    Directory of Open Access Journals (Sweden)

    Oliver eRawashdeh

    2012-03-01

    Full Text Available The neuroendocrine substance melatonin is a hormone synthesized rhythmically by the pineal gland under the influence of the circadian system and alternating light/dark cycles. Melatonin has been shown to have broad applications, and consequently becoming a molecule of great controversy. Undoubtedly, however, melatonin plays an important role as a time cue for the endogenous circadian system. This review focuses on melatonin as a regulator in the circadian modulation of memory processing. Memory processes (acquisition, consolidation and retrieval are modulated by the circadian system. However, the mechanism by which the biological clock is rhythmically influencing cognitive processes remains unknown. We also discuss, how the circadian system by generating cycling melatonin levels can implant information about daytime into memory processing, depicted as day and nighttime differences in acquisition, memory consolidation and/or retrieval.

  9. Links between circadian rhythms and psychiatric disease

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    Ilia N Karatsoreos

    2014-05-01

    Full Text Available Determining the cause of psychiatric disorders is a goal of modern neuroscience, and will hopefully lead to the discovery of treatments to either prevent or alleviate the suffering caused by these diseases. One roadblock to attaining this goal is the realization that neuropsychiatric diseases are rarely due to a single gene polymorphism, environmental exposure, or developmental insult. Rather, it is a complex interaction between these various influences that likely leads to the development of clinically relevant syndromes. Our lab is exploring the links between environmental exposures and neurobehavioral function by investigating how disruption of the circadian (daily clock alters the structure and function of neural circuits, with the hypothesis that disrupting this crucial homeostatic system can directly contribute to altered vulnerability of the organism to other factors that interact to produce psychiatric illness. This review explores some historical and more recent findings that link disrupted circadian clocks to neuropsychiatric disorders, particularly depression, mania, and schizophrenia. We take a comparative approach by exploring the effects observed in human populations, as well as some experimental models used in the laboratory to unravel mechanistic and causal relationships between disruption of the circadian clock and behavioral abnormalities. This is a rich area of research that we predict will contribute greatly to our understanding of how genes, environment, and development interact to modulate an individual’s vulnerability to psychiatric disorders.

  10. Long-lasting effect of perinatal exposure to L-tryptophan on circadian clock of primary cell lines established from male offspring born from mothers fed on dietary protein restriction.

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    Elizabeth Nascimento

    Full Text Available BACKGROUND AIMS: Maternal undernutrition programs metabolic adaptations which are ultimately detrimental to adult. L-tryptophan supplementation was given to manipulate the long-term sequelae of early-life programming by undernutrition and explore whether cultured cells retain circadian clock dysregulation. METHODS: Male rat pups from mothers fed on low protein (8%, LP or control (18%, CP diet were given, one hour before light off, an oral bolus of L-tryptophan (125 mg/kg between Day-12 and Day-21 of age. Body weight, food intake, blood glucose along with the capacity of colonization of primary cells from biopsies were measured during the young (45-55 days and adult (110-130 days phases. Circadian clock oscillations were re-induced by a serum shock over 30 hours on near-confluent cell monolayers to follow PERIOD1 and CLOCK proteins by Fluorescent Linked ImmunoSorbent Assay (FLISA and period1 and bmal1 mRNA by RT-PCR. Cell survival in amino acid-free conditions were used to measure circadian expression of MAP-LC3B, MAP-LC3B-FP and Survivin. RESULTS: Tryptophan supplementation did not alter body weight gain nor feeding pattern. By three-way ANOVA of blood glucose, sampling time was found significant during all phases. A significant interaction between daily bolus (Tryptophan, saline and diets (LP, CP were found during young (p = 0.0291 and adult (p = 0.0285 phases. In adult phase, the capacity of colonization at seeding of primary cells was twice lower for LP rats. By three-way ANOVA of PERIOD1 perinuclear/nuclear immunoreactivity during young phase, we found a significant effect of diets (p = 0.049, daily bolus (p<0.0001 and synchronizer hours (p = 0.0002. All factors were significantly interacting (p = 0.0148. MAP-LC3B, MAP-LC3B-FP and Survivin were altered according to diets in young phase. CONCLUSIONS: Sequelae of early-life undernutrition and the effects of L-tryptophan supplementation can be monitored non-invasively by

  11. The clock modules in TOF readout system for heavy ion experiments at IMP

    International Nuclear Information System (INIS)

    This paper describes two clock modules in the time-of-flight readout systems, which are applied in the Cold Target Recoil Ion Momentum Spectrometer(COLTRIMS) system and the Cooler Storage Ring (CSRm) at Institute of Modern Physics, Chinese Academy of Sciences.The two clock modules are designed on 3U PXI module and 6U PXI module. With high precision crystal oscillators and clock distribution, these two modules offer clock signal to the TOF readout electronics modules with low jitter less than 11 ps(RMS) and 12 ps(RMS). (authors)

  12. Circadian Control of Global Transcription

    Science.gov (United States)

    Li, Shujing; Zhang, Luoying

    2015-01-01

    Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs). CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. PMID:26682214

  13. Circadian Control of Global Transcription

    Directory of Open Access Journals (Sweden)

    Shujing Li

    2015-01-01

    Full Text Available Circadian rhythms exist in most if not all organisms on the Earth and manifest in various aspects of physiology and behavior. These rhythmic processes are believed to be driven by endogenous molecular clocks that regulate rhythmic expression of clock-controlled genes (CCGs. CCGs consist of a significant portion of the genome and are involved in diverse biological pathways. The transcription of CCGs is tuned by rhythmic actions of transcription factors and circadian alterations in chromatin. Here, we review the circadian control of CCG transcription in five model organisms that are widely used, including cyanobacterium, fungus, plant, fruit fly, and mouse. Comparing the similarity and differences in the five organisms could help us better understand the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions.

  14. System and method for adaptively deskewing parallel data signals relative to a clock

    Science.gov (United States)

    Jenkins, Philip Nord; Cornett, Frank N.

    2011-10-04

    A system and method of reducing skew between a plurality of signals transmitted with a transmit clock is described. Skew is detected between the received transmit clock and each of received data signals. Delay is added to the clock or to one or more of the plurality of data signals to compensate for the detected skew. The delay added to each of the plurality of delayed signals is updated to adapt to changes in detected skew.

  15. In vivo imaging of clock gene expression in multiple tissues of freely moving mice.

    Science.gov (United States)

    Hamada, Toshiyuki; Sutherland, Kenneth; Ishikawa, Masayori; Miyamoto, Naoki; Honma, Sato; Shirato, Hiroki; Honma, Ken-Ichi

    2016-01-01

    Clock genes are expressed throughout the body, although how they oscillate in unrestrained animals is not known. Here, we show an in vivo imaging technique that enables long-term simultaneous imaging of multiple tissues. We use dual-focal 3D tracking and signal-intensity calibration to follow gene expression in a target area. We measure circadian rhythms of clock genes in the olfactory bulb, right and left ears and cortices, and the skin. In addition, the kinetic relationship between gene expression and physiological responses to experimental cues is monitored. Under stable conditions gene expression is in phase in all tissues. In response to a long-duration light pulse, the olfactory bulb shifts faster than other tissues. In Cry1(-/-) Cry2(-/-) arrhythmic mice circadian oscillation is absent in all tissues. Thus, our system successfully tracks circadian rhythms in clock genes in multiple tissues in unrestrained mice. PMID:27285820

  16. Gravitational biology and the mammalian circadian timing system

    Science.gov (United States)

    Fuller, Charles A.; Murakami, Dean M.; Sulzman, Frank M.

    1989-01-01

    Using published reports, this paper compares and contrasts results on the effects of altered gravitational fields on the regulation in mammals of several physiological and behavioral variables with the circadian regulation of the same variables. The variables considered include the temperature regulation, heart rate, activity, food intake, and calcium balance. It is shown that, in rats, the homeostatic regulation of the body temperature, heart rate, and activity becomes depressed following exposure to a 2 G hyperdynamic field, and recovers within 6 days of 1 G condition. In addition, the circadian rhythms of these variables exhibit a depression of the rhythm amplitude; a recovery of this condition requires a minimum of 7 days.

  17. The Effects of Gravity on the Circadian Timing System

    Science.gov (United States)

    Fuller, Charles A.

    1999-01-01

    All vertebrates have a physiological control system that regulates the timing of the rhythms of their daily life. Dysfunction of this system, the circadian timing system (CTS), adversely affects an organism's ability to respond to environmental challenges and has been linked to physiological and psychological disorders. Exposure to altered gravitational environments (the microgravity of space and hyperdynamic environments produced via centrifugation) produces changes in both the functioning of the CTS and the rhythmic variables it controls. The earliest record of primate rhythms in a spaceflight environment come from Biosatellite III. The subject, a pig-tailed macaque, showed a loss of synchronization of the body temperature rhythm and a fragmented sleep-wake cycle. Alterations in the rhythm of body temperature were also seen in rhesus macaques flown on COSMOS 1514. Squirrel monkeys exposed to chronic centrifugation showed an initial decrease in the amplitude and mean of their body temperature and activity rhythms. In a microgravity environment, Squirrel monkeys on Spacelab-3 showed a reduction in the mean and amplitude of their feeding rhythms. Since 1992 we have had the opportunity to participate on three US/Russian sponsored biosatellite missions on which a total of six juvenile male rhesus macaques were flown. These animals uniformly exhibited delays in the phasing of their temperature rhythms, but not their heart rate or activity rhythms during spaceflight. There was also a tendency for changes in waveform mean and amplitude. These data suggest that the spaceflight environment may have a differential effect on the different oscillators controlling different rhythmic variables. Ongoing studies are examining the effects of +G on the CTS. The long-term presence of humans in space highlights the need for effective countermeasures to gravitational effects on the CTS.

  18. Manipulating the circadian and sleep cycles to protect against metabolic disease

    Directory of Open Access Journals (Sweden)

    Kazunari eNohara

    2015-03-01

    Full Text Available Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g. obesity involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude enhancing small molecules (CEMs identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep and metabolism will also have far-reaching implications for various chronic human diseases and aging.

  19. Time-Specific Fear Acts as a Non-Photic Entraining Stimulus of Circadian Rhythms in Rats.

    Science.gov (United States)

    Pellman, Blake A; Kim, Earnest; Reilly, Melissa; Kashima, James; Motch, Oleksiy; de la Iglesia, Horacio O; Kim, Jeansok J

    2015-01-01

    Virtually all animals have endogenous clock mechanisms that "entrain" to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms "entrained" to the LD cycle can be overridden by entrainment to daily recurring threats. We show that unsignaled nocturnal footshock caused rats living in an "ethological" apparatus to switch their natural foraging behavior from the dark to the light phase and that this switch was maintained as a free-running circadian rhythm upon removal of light cues and footshocks. Furthermore, this fear-entrained circadian behavior was dependent on an intact amygdala and suprachiasmatic nucleus. Thus, time-specific fear can act as a non-photic entraining stimulus for the circadian system, and limbic centers encoding aversive information are likely part of the circadian oscillator network that temporally organizes behavior. PMID:26468624

  20. Protein phosphatase dependent circadian regulation of intermediate-term associative memory

    OpenAIRE

    Michel, Maximilian; Gardner, Jacob S.; Green, Charity L.; Organ, Chelsea L.; Lyons, Lisa C.

    2013-01-01

    The endogenous circadian clock is a principal factor modulating memory across species. Determining the processes through which the circadian clock modulates memory formation is a key issue in understanding and identifying mechanisms to improve memory. We used the marine mollusk Aplysia californica to investigate circadian modulation of intermediate-term memory (ITM) and the mechanisms through which the circadian clock phase specifically suppresses memory using the operant learning paradigm, l...

  1. 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…

  2. Systematic identification of rhythmic genes reveals camk1gb as a new element in the circadian clockwork.

    Directory of Open Access Journals (Sweden)

    Adi Tovin

    Full Text Available A wide variety of biochemical, physiological, and molecular processes are known to have daily rhythms driven by an endogenous circadian clock. While extensive research has greatly improved our understanding of the molecular mechanisms that constitute the circadian clock, the links between this clock and dependent processes have remained elusive. To address this gap in our knowledge, we have used RNA sequencing (RNA-seq and DNA microarrays to systematically identify clock-controlled genes in the zebrafish pineal gland. In addition to a comprehensive view of the expression pattern of known clock components within this master clock tissue, this approach has revealed novel potential elements of the circadian timing system. We have implicated one rhythmically expressed gene, camk1gb, in connecting the clock with downstream physiology of the pineal gland. Remarkably, knockdown of camk1gb disrupts locomotor activity in the whole larva, even though it is predominantly expressed within the pineal gland. Therefore, it appears that camk1gb plays a role in linking the pineal master clock with the periphery.

  3. Dynamic circadian protein-protein interaction networks predict temporal organization of cellular functions.

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    Thomas Wallach

    2013-03-01

    Full Text Available Essentially all biological processes depend on protein-protein interactions (PPIs. Timing of such interactions is crucial for regulatory function. Although circadian (~24-hour clocks constitute fundamental cellular timing mechanisms regulating important physiological processes, PPI dynamics on this timescale are largely unknown. Here, we identified 109 novel PPIs among circadian clock proteins via a yeast-two-hybrid approach. Among them, the interaction of protein phosphatase 1 and CLOCK/BMAL1 was found to result in BMAL1 destabilization. We constructed a dynamic circadian PPI network predicting the PPI timing using circadian expression data. Systematic circadian phenotyping (RNAi and overexpression suggests a crucial role for components involved in dynamic interactions. Systems analysis of a global dynamic network in liver revealed that interacting proteins are expressed at similar times likely to restrict regulatory interactions to specific phases. Moreover, we predict that circadian PPIs dynamically connect many important cellular processes (signal transduction, cell cycle, etc. contributing to temporal organization of cellular physiology in an unprecedented manner.

  4. A Novel Bmal1 Mutant Mouse Reveals Essential Roles of the C-Terminal Domain on Circadian Rhythms.

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    Noheon Park

    Full Text Available The mammalian circadian clock is an endogenous biological timer comprised of transcriptional/translational feedback loops of clock genes. Bmal1 encodes an indispensable transcription factor for the generation of circadian rhythms. Here, we report a new circadian mutant mouse from gene-trapped embryonic stem cells harboring a C-terminus truncated Bmal1 (Bmal1GTΔC allele. The homozygous mutant (Bmal1GTΔC/GTΔC mice immediately lost circadian behavioral rhythms under constant darkness. The heterozygous (Bmal1+/GTΔC mice displayed a gradual loss of rhythms, in contrast to Bmal1+/- mice where rhythms were sustained. Bmal1GTΔC/GTΔC mice also showed arrhythmic mRNA and protein expression in the SCN and liver. Lack of circadian reporter oscillation was also observed in cultured fibroblast cells, indicating that the arrhythmicity of Bmal1GTΔC/GTΔC mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in Bmal1+/GTΔC and Bmal1GTΔC/GTΔC mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1GTΔC was unable to activate transcription of Per1 promoter and BMAL1-dependent CLOCK degradation. These results indicate that the C-terminal region of Bmal1 has pivotal roles in the regulation of circadian rhythms and the Bmal1GTΔC mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1.

  5. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity

    OpenAIRE

    Franken, Paulus; Lopez Molina, Luis; Marcacci, Lysiane; Schibler, Ulrich; Tafti, Mehdi

    2000-01-01

    Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeosta...

  6. Reciprocal regulation between C/EBP-a and the cellular circadian clock%C/EBP-a与细胞生物钟之间的相互调节作用

    Institute of Scientific and Technical Information of China (English)

    张海东; 张峰; 张继国

    2013-01-01

    目的 探讨CCAAT/增强子结合蛋白(C/EBPs)与生物钟基因表达之间的关系.方法 构建C/EBP-a 240,280,650,1300和Rev erb-a启动子-荧光素酶报告基因表达载体,并建立相应报告基因稳定转染细胞株.通过检测生物荧光观察相应报告基因表达强度及节律.结果 CLOCK/BMAL1二聚体可通过E-box元件激活C/EBP-a;C/EBP-a呈现E-box依赖的节律性表达;C/EBP-a过表达可抑制Rev erb-a转录;地塞米松(Dex)可抑制C/EBP-a转录.结论 C/EBP-a作为一个关键转录因子与细胞内的定时机制存在相互的反馈调节.%Objective To study the relationship between CCAAT/enhancer-binding proteins (C/EBPs) and circadian genes expression in mammals.Methods C/EBP-a 240,280,650,1300 and Rev erb-a promoter-luciferase reporter gene expression vectors were set up,as well as the corresponding report gene stable transfection cell lines were established.The intensity and/or rhythm of report gene expression were observed by testing the biological fluorescent.Results The transcription factor CLOCK/BMAL1 heterodimer activated C/EBP-a via a conserved E-box element in its promoter,and the latter showed circadian oscillation which was E-box dependent.On the other hand,C/EBP-a suppressed Rev-erba transcription.Moreover,GR signaling,a known resetting signal for circadian clock,suppressed C/EBP-a transcription.Conclusion The data highlight the reciprocal feedback regulation between a key transcription factor C/EBP-a and the timing mechanism in cells.

  7. Circadian remodeling of neuronal circuits involved in rhythmic behavior.

    Directory of Open Access Journals (Sweden)

    María Paz Fernández

    2008-03-01

    Full Text Available Clock output pathways are central to convey timing information from the circadian clock to a diversity of physiological systems, ranging from cell-autonomous processes to behavior. While the molecular mechanisms that generate and sustain rhythmicity at the cellular level are well understood, it is unclear how this information is further structured to control specific behavioral outputs. Rhythmic release of pigment dispersing factor (PDF has been proposed to propagate the time of day information from core pacemaker cells to downstream targets underlying rhythmic locomotor activity. Indeed, such circadian changes in PDF intensity represent the only known mechanism through which the PDF circuit could communicate with its output. Here we describe a novel circadian phenomenon involving extensive remodeling in the axonal terminals of the PDF circuit, which display higher complexity during the day and significantly lower complexity at nighttime, both under daily cycles and constant conditions. In support to its circadian nature, cycling is lost in bona fide clockless mutants. We propose this clock-controlled structural plasticity as a candidate mechanism contributing to the transmission of the information downstream of pacemaker cells.

  8. Circadian rhythms of clock gene expression in Nile tilapia (Oreochromis niloticus) central and peripheral tissues: influence of different lighting and feeding conditions.

    Science.gov (United States)

    Costa, Leandro S; Serrano, Ignacio; Sánchez-Vázquez, Francisco J; López-Olmeda, Jose F

    2016-08-01

    The present research aimed to investigate the existence of clock gene expression rhythms in tilapia, their endogenous origin, and how light and feeding cycles synchronize these rhythms. In the first experiment, two groups of fish were kept under an LD cycle and fed at two different time points: in the middle of the light (ML) or in the middle of the dark (MD) phase. In the second experiment, fish fed at ML was fasted and kept under constant lighting (LL) conditions for 1 day. In both experiments, the samples from central (optic tectum and hypothalamus) and peripheral (liver) tissues were collected every 3 h throughout a 24 h cycle. The expression levels of clock genes bmal1a, clock1, per1b, cry2a, and cry5 were analyzed by quantitative PCR. All the clock genes analyzed in brain regions showed daily rhythms: clock1, bmal1a, and cry2a showed the acrophase approximately at the end of the light phase (ZT 8:43-11:22 h), whereas per1b and cry5 did so between the end of the dark phase and the beginning of the light phase, respectively (ZT 21:16-4:00 h). These rhythms persisted under constant conditions. No effect of the feeding time was observed in the brain. In the liver, however, the rhythms of clock1 and cry5 were influenced by feeding, and a shift was observed in the MD fish group (ZT 3:58 h for clock1 and 11:20 h for cry5). This study provides the first insights into the molecular clock of tilapia, a very important fish species for aquaculture. It also reveals the endogenous origin of clock gene rhythms and the ability of feeding time to shift the phase in some clock genes in the peripheral, but not the central, oscillator. PMID:27085855

  9. Analysis of Circadian Leaf Movements.

    Science.gov (United States)

    Müller, Niels A; Jiménez-Gómez, José M

    2016-01-01

    The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato. PMID:26867616

  10. Determination of global positioning system (GPS) receiver clock errors: impact on positioning accuracy

    International Nuclear Information System (INIS)

    Enhancing the positioning precision is the primary pursuit of global positioning system (GPS) users. To achieve this goal, most studies have focused on the relationship between GPS receiver clock errors and GPS positioning precision. This study utilizes undifferentiated phase data to calculate GPS clock errors and to compare with the frequency of cesium clock directly, to verify estimated clock errors by the method used in this paper. The frequency stability calculated from this paper (the indirect method) and measured from the National Standard Time and Frequency Laboratory (NSTFL) of Taiwan (the direct method) match to 1.5 × 10−12 (the value from this study was smaller than that from NSTFL), suggesting that the proposed technique has reached a certain level of quality. The built-in quartz clocks in the GPS receivers yield relative frequency offsets that are 3–4 orders higher than those of rubidium clocks. The frequency stability of the quartz clocks is on average two orders worse than that of the rubidium clock. Using the rubidium clock instead of the quartz clock, the horizontal and vertical positioning accuracies were improved by 26–78% (0.6–3.6 mm) and 20–34% (1.3–3.0 mm), respectively, for a short baseline. These improvements are 7–25% (0.3–1.7 mm) and 11% (1.7 mm) for a long baseline. Our experiments show that the frequency stability of the clock, rather than relative frequency offset, is the governing factor of positioning accuracy

  11. Identification of Soybean Genes Involved in Circadian Clock Mechanism and Photoperiodic Control of Flowering Time by In Silico Analyses Flowering Time by In Silico Analyses

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Glycine max is a photoperiodic short-day plant and the practical consequence of the response is latitude and sowing period limitations to commercial crops.Genetic and physiological studies using the model plants Arabidopsis thaliana and rice (Oryza sativa)have uncovered several genes and genetic pathways controlling the process,however information about the corresponding pathways in legumes is scarce.Data mining prediction methodologies,Including multiple sequence alignment,phylogenetic analysis,bioinformatics expression and sequence motif pattern identification were used to identify soybean genes involved In day length perception and photoperiodic flowering induction.We have investigated approximately 330 000 sequences from open-access databases and have identified all bona fide central oscillator genes and circadian photoreceptors from A.thaliana in soybean sequence databases.We propose e working model for the photoperiodic control of flowering time in G.max,based on the identified key components.These results demonstrate the power of comparative genomics between model systems and crop species to elucidate the several aspects of plant physiology and metabolism.

  12. The effects of hydrogen peroxide on the circadian rhythms of Microcystis aeruginosa.

    Directory of Open Access Journals (Sweden)

    Haifeng Qian

    Full Text Available BACKGROUND: The cyanobacterium Microcystis aeruginosa is one of the principal bloom-forming cyanobacteria present in a wide range of freshwater ecosystems. M. aeruginosa produces cyanotoxins, which can harm human and animal health. Many metabolic pathways in M. aeruginosa, including photosynthesis and microcystin synthesis, are controlled by its circadian rhythms. However, whether xenobiotics affect the cyanobacterial circadian system and change its growth, physiology and biochemistry is unknown. We used real-time PCR to study the effect of hydrogen peroxide (H(2O(2 on the expression of clock genes and some circadian genes in M. aeruginosa during the light/dark (LD cycle. RESULTS: The results revealed that H(2O(2 changes the expression patterns of clock genes (kaiA, kaiB, kaiC and sasA and significantly decreases the transcript levels of kaiB, kaiC and sasA. H(2O(2 treatment also decreased the transcription of circadian genes, such as photosynthesis-related genes (psaB, psbD1 and rbcL and microcystin-related genes (mcyA, mcyD and mcyH, and changed their circadian expression patterns. Moreover, the physiological functions of M. aeruginosa, including its growth and microcystin synthesis, were greatly influenced by H(2O(2 treatment during LD. These results indicate that changes in the cyanobacterial circadian system can affect its physiological and metabolic pathways. CONCLUSION: Our findings show that a xenobiotic can change the circadian expression patterns of its clock genes to influence clock-controlled gene regulation, and these influences are evident at the level of cellular physiology.

  13. What time is it? Deep learning approaches for circadian rhythms

    Science.gov (United States)

    Agostinelli, Forest; Ceglia, Nicholas; Shahbaba, Babak; Sassone-Corsi, Paolo; Baldi, Pierre

    2016-01-01

    Motivation: Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. Results: We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. Availability and Implementation: All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/. Contacts: fagostin@uci.edu or pfbaldi@uci.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307647

  14. Diurnal Oscillation of Amygdala Clock Gene Expression and Loss of Synchrony in a Mouse Model of Depression

    OpenAIRE

    Savalli, Giorgia; Diao, Weifei; Schulz, Stefan; Todtova, Kristina; Pollak, Daniela D.

    2015-01-01

    Background: Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as risk factors for the development of mood disorders. However, the particular involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface is incompletely understood. Methods: A naturalistic animal model of depression based upon exposure to chronic mild stress w...

  15. Sympathetic Activation Induces Skeletal Fgf23 Expression in a Circadian Rhythm-dependent Manner*

    Science.gov (United States)

    Kawai, Masanobu; Kinoshita, Saori; Shimba, Shigeki; Ozono, Keiichi; Michigami, Toshimi

    2014-01-01

    The circadian clock network is well known to link food intake and metabolic outputs. Phosphorus is a pivotal nutritional factor involved in energy and skeletal metabolisms and possesses a circadian profile in the circulation; however, the precise mechanisms whereby phosphate metabolism is regulated by the circadian clock network remain largely unknown. Because sympathetic tone, which displays a circadian profile, is activated by food intake, we tested the hypothesis that phosphate metabolism was regulated by the circadian clock network through the modification of food intake-associated sympathetic activation. Skeletal Fgf23 expression showed higher expression during the dark phase (DP) associated with elevated circulating FGF23 levels and enhanced phosphate excretion in the urine. The peaks in skeletal Fgf23 expression and urine epinephrine levels, a marker for sympathetic tone, shifted from DP to the light phase (LP) when mice were fed during LP. Interestingly, β-adrenergic agonist, isoproterenol (ISO), induced skeletal Fgf23 expression when administered at ZT12, but this was not observed in Bmal1-deficient mice. In vitro reporter assays revealed that ISO trans-activated Fgf23 promoter through a cAMP responsive element in osteoblastic UMR-106 cells. The mechanism of circadian regulation of Fgf23 induction by ISO in vivo was partly explained by the suppressive effect of Cryptochrome1 (Cry1) on ISO signaling. These results indicate that the regulation of skeletal Fgf23 expression by sympathetic activity is dependent on the circadian clock system and may shed light on new regulatory networks of FGF23 that could be important for understanding the physiology of phosphate metabolism. PMID:24302726

  16. Heritable circadian period length in a wild bird population

    NARCIS (Netherlands)

    Helm, B.; Visser, M.E.

    2010-01-01

    Timing is essential, but circadian clocks, which play a crucial role in timekeeping, are almost unaddressed in evolutionary ecology. A key property of circadian clocks is their free-running period length (τ), i.e. the time taken for a full cycle under constant conditions. Under laboratory conditions

  17. Heritable circadian period length in a wild bird population

    NARCIS (Netherlands)

    Helm, Barbara; Visser, Marcel E.

    2010-01-01

    Timing is essential, but circadian clocks, which play a crucial role in timekeeping, are almost unaddressed in evolutionary ecology. A key property of circadian clocks is their free-running period length (tau), i.e. the time taken for a full cycle under constant conditions. Under laboratory conditio

  18. 大麦(Hordeum vulgare)昼夜节律钟基因CCA1的克隆及表达分析%Cloning and Expression Analysis of Circadian Clock Gene CCA1 in Barley (Hordeum vulgare)

    Institute of Scientific and Technical Information of China (English)

    邢国芳; 宋萌; 姚涵; 韩渊怀

    2012-01-01

    CCA 1 gene plays an important role in circadian clock sensitivity in rice (Oryza sativa L. ) and Arabidopsis thaliana. In this study, CCAl gene in barley was cloned by RT-PCR using homological primers based on the highly conserved region of the multiple alignments of the rice and Arabidopsis. The similarities of this sequence were up to 72% and 69%, respectively, to corresponding mRNA sequences of rice and maize in BLASTx of GenBank database. Using ORF Finder software, a 2157 bp open reading frame was found to code 718 amino acids. Using Compute pI/Mw tool, the amino acid sequence was analyzed, and it revealed that the molecular weight of this protein was about 77 769. 4 Da, and isoelectric point was about 6. 55. We established fluorescence quantitative RT-PCR system with barley inbred lines HUADAMAI 1 and HUADAMAI 2, and studied the expression of CCAl in leaf under 16h/8h (light/ dark) conditions. Expression analysis showed that the gene expression peaked at dawn (ZTO) then gradually declined from ZTO to ZT15, bottomed at ZT15, then increased and returned to the initial level at ZT24. This study will provide information of barley CCAl gene for further studying the function in regulating photoperiod sensitivity in barley, and provide scientific basis for clarifying the mechanism of the circadian synchronization in barley.%昼夜节律钟基因CCA1在调解水稻和拟南芥的光周期反应中起着重要作用.利用BLAST手段以玉米中的CCA1基因序列作为靶序列,调取Genbank数据库信息,并结合RT-PCR方法获得了大麦的cDNA同源序列.BLASTx分析发现其与水稻和玉米的序列相似性分别达到72%和69%.通过ORF Finder软件分析发现,该序列包含一个2157 bp的开放阅读框,编码一个由718个氨基酸残基组成的蛋白序列,其分子量为77769.4 Da,等电点为6.55.采用实时荧光定量PCR分析发现,随光照时间的变化,该基因在大麦叶片中的表达量呈现出白天不断降低而夜晚逐渐

  19. Cloning and Expression Analysis of Circadian Clock Gene CCA1 in Maize%玉米昼夜节律钟基因CCA1的克隆及表达分析

    Institute of Scientific and Technical Information of China (English)

    邢国芳; 杜伟建; 张雁明; 韩浩坤; 韩渊怀

    2011-01-01

    昼夜节律钟基因CCA1在调解水稻和拟南芥的光周期反应中起着重要作用.本研究利用从水稻和拟南芥中分离到的CCA1基因序列作为靶序列BLAST获取Genbank中的信息,通过RT-PCR方法克隆获得了一条2326bp的玉米CCA1基因cDNA序列.BLAST比对发现其与水稻、大麦和拟南芥的序列相似性分别达73.7%、69.4%和39.8%.利用NCBI中的ORF Finder软件分析,发现该序列包含一个2163bp的开放阅读框,编码720个氨基酸残基,蛋白的分子量约为78819.17Da,等电点为6.468.推测其含有3个myb-DNA结合域、7个N-豆蔻酰化位点、1个G-box蛋白结合域以及1个蛋白跨膜结合域.采用实时荧光定量PCR分析发现,随光照时间的变化,该基因在玉米叶片中的表达量呈现出白天不断降低而夜晚逐渐升高的昼夜变化趋势.本研究为进一步研究玉米CCA1基因在调控玉米光周期敏感现象中的功能,阐明玉米光周期敏感机制提供了科学依据.%CCA 1 gene plays an important role in circadian clock sensitivity in rice (Oryza sative L. ) and Arabidopsis thaliana. In this study, CCA1 (2326 bp) was cloned by RT-PCR using homological primers based on the highly conserved region of the multiple alignment of the rice and Arabidopsis. CCA1 from GenBank of NCBI. The similarities of these sequences were up to 73. 7% ,69. 4 and 39. 8% , respectively, to corresponding mRNA sequences of rice, barley and Arabidopsis in BLAST/nr of GenBank database. Using ORF Finder software, a 2163 bp open reading frame was found to code 720 amino acids. Analyzing this ami no acid sequence by Compute pI/Mw tool revealed that the molecular weight of this protein was about 78819.17 Da , and isoelectric point was about 6. 468. The amino acid sequence contained three myb-DNA binding domains, seven N-myristoylation sites, one G-box binding domain and one putative transmembrane spanning region. We established fluorescence quantitative RT-PCR system with maize

  20. Imaging Multidimensional Therapeutically Relevant Circadian Relationships

    Directory of Open Access Journals (Sweden)

    Jamil Singletary

    2009-01-01

    Full Text Available Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies.

  1. Automatic Clock and Time Signal System of the Astronomical Agency in East Asia Area

    Science.gov (United States)

    Lee, Yong Sam

    2009-09-01

    We analysed the old automatic clock and time signal system that was used by the national astronomical agency in East Asian Area. Jagyeongnu is a kind of water clock that was operated by the flowing water in Joseon Dynasty. Seowoongwan managed the water clock so as to keep the standard time system in the dynasty from the 16th year (1434) of King Sejong's reign. In 1438 the Okru that was invented in the period. Such kind of clock system already was used in China, which was Shui yun i hsiang t'ai (?) in 1092. During the period Joseon Dynasty, China and Japan had been kept the time system that one day is divided into 12 shin (?2?) or 100 gak (?). However detailed part of the system had a little difference among the three countries. Though the whole system of water clock in Joseon had manufactured on the basis of Chinese, it had been gradually developed by own method and idea. In this study we show the historical records of the standard time keeping system in East Asian history. And then we can inform materials on the structure and functional devises for the purpose of new restoration models about the automatic clock and time system.

  2. Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Depression

    Directory of Open Access Journals (Sweden)

    Roberto Salgado-Delgado

    2011-01-01

    Full Text Available Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.

  3. Implications of circadian rhythm and stress in addiction vulnerability.

    Science.gov (United States)

    Becker-Krail, Darius; McClung, Colleen

    2016-01-01

    In the face of chronic stress, some individuals can maintain normal function while others go on to develop mental illness. Addiction, affecting one in every twelve people in America, is a substance use disorder long associated with stressful life events and disruptions in the sleep/wake cycle. The circadian and stress response systems have evolved to afford adaptability to environmental changes and allow for maintenance of functional stability, or homeostasis. This mini-review will discuss how circadian rhythms and stress individually affect drug response, affect each other, and how their interactions may regulate reward-related behavior. In particular, we will focus on the interactions between the circadian clock and the regulation of glucocorticoids by the hypothalamic-pituitary-adrenal (HPA) axis. Determining how these two systems act on dopaminergic reward circuitry may not only reveal the basis for vulnerability to addiction, but may also illuminate potential therapeutic targets for future investigation. PMID:26913197

  4. Regulation of clock-controlled genes in mammals.

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    Full Text Available The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs.Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCKratioBMAL1, DBP, HLF, E4BP4, CREB, RORalpha and the recently described regulators HSF1, STAT3, SP1 and HNF-4alpha. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1 and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1 are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including

  5. Increased Sensitivity of the Circadian System to Temporal Changes in the Feeding Regime of Spontaneously Hypertensive Rats - A Potential Role for Bmal2 in the Liver

    Czech Academy of Sciences Publication Activity Database

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

    2013-01-01

    Roč. 8, č. 9 (2013), e75690. E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP303/11/0668 Institutional support: RVO:67985823 Keywords : circadian * clock gene * metabolism * liver * feeding regime * Bmal2 * spontaneously hypertensive rat Subject RIV: ED - Physiology Impact factor: 3.534, year: 2013

  6. Adaptation of sleep and circadian rhythms to the Antarctic summer - A question of zeitgeber strength

    Science.gov (United States)

    Gander, Philippa H.; Macdonald, John A.; Montgomery, John C.; Paulin, Michael G.

    1991-01-01

    Adaptation of sleep and circadian rhythms was examined in three temperate zone dwellers arriving in Antarctica during summer. Rectal temperature, wrist activity, and heart rate were monitored continuously, sleep timing and quality noted on awakening, and mood and fatigue rated every 2 h while awake. Sleep was poorer in 2/3 subjects in Antarctica, where all subjects reported more difficulty rising. Sleep occurred at the same clock times in New Zealand and Antarctica, however, the rhythms of temperature, activity, and heart rate underwent a delay of about of 2 h. The subject with the most Antarctic experience had the least difficulty adapting to sleeping during constant daylight. The subject with the most delayed circadian rhythms had the most difficulty. The delay in the circadian system with respect to sleep and clock time is hypothesized to be due to differences in zeitgeber strength and/or zeitgeber exposure between Antarctica and New Zealand.

  7. Shift work and circadian dysregulation of reproduction

    Directory of Open Access Journals (Sweden)

    Karen L. Gamble

    2013-08-01

    Full Text Available Health impairments, including reproductive issues, are associated with working nights or rotating shifts. For example, shift work has been associated with an increased risk of irregular menstrual cycles, endometriosis, infertility, miscarriage, low birth weight or pre-term delivery, and reduced incidence of breastfeeding. Based on what is known about circadian regulation of endocrine rhythms in rodents (and much less in humans, the circadian clock is an integral regulatory part of the reproductive system. When this 24-h program is disordered by environmental perturbation (such as shift work or genetic alterations, the endocrine system can be impaired. The purpose of this review is to explore the hypothesis that misalignment of reproductive hormones with the environmental light-dark cycle and/or sleep wake rhythms can disrupt menstrual cycles, pregnancy, and parturition. We highlight the role of the circadian clock in regulating human reproductive physiology and shift work-induced pathology within each step of the reproductive axis while exploring potential mechanisms from the animal model literature. In addition to documenting the reproductive hazards of shift work, we also point out important gaps in our knowledge as critical areas for future investigation. For example, future studies should examine whether forced desynchronization disrupts gonadotropin secretion rhythms and whether there are sleep/wake schedules that are better or worse for the adaptation of the reproductive system to shift work. These studies are necessary in order to define not only whether or not shift-work induced circadian misalignment impairs reproductive capacity, but also to identify strategies for the future that can minimize this desynchronization.

  8. Shift work and circadian dysregulation of reproduction.

    Science.gov (United States)

    Gamble, Karen L; Resuehr, David; Johnson, Carl Hirschie

    2013-01-01

    Health impairments, including reproductive issues, are associated with working nights or rotating shifts. For example, shift work has been associated with an increased risk of irregular menstrual cycles, endometriosis, infertility, miscarriage, low birth weight or pre-term delivery, and reduced incidence of breastfeeding. Based on what is known about circadian regulation of endocrine rhythms in rodents (and much less in humans), the circadian clock is an integral regulatory part of the reproductive system. When this 24-h program is disordered by environmental perturbation (such as shift work) or genetic alterations, the endocrine system can be impaired. The purpose of this review is to explore the hypothesis that misalignment of reproductive hormones with the environmental light-dark cycle and/or sleep-wake rhythms can disrupt menstrual cycles, pregnancy, and parturition. We highlight the role of the circadian clock in regulating human reproductive physiology and shift work-induced pathology within each step of the reproductive axis while exploring potential mechanisms from the animal model literature. In addition to documenting the reproductive hazards of shift work, we also point out important gaps in our knowledge as critical areas for future investigation. For example, future studies should examine whether forced desynchronization disrupts gonadotropin secretion rhythms and whether there are sleep/wake schedules that are better or worse for the adaptation of the reproductive system to shift work. These studies are necessary in order to define not only whether or not shift work-induced circadian misalignment impairs reproductive capacity, but also to identify strategies for the future that can minimize this desynchronization. PMID:23966978

  9. High-fat medium and circadian transcription factors (cryptochrome and clock) contribute to the regulation of cholesterogenic Cyp51 and Hmgcr genes in mouse embryonic fibroblasts

    OpenAIRE

    Rozman, Damjana; Španinger, Klemen; Fink, Martina; Prosenc, Uršula

    2015-01-01

    The aim of our research was to investigate how cholesterol, unsaturated fatty acids and circadian genes affect the expression of cholesterogenic genes, Cyp51 and Hmgcr, in somatic and in embryonic fibroblast cell lines. We found that in immortal Hepa1-6 cells cholesterol represses the transcription of Hmgcr and Cyp51 for 80%, while unsaturated fatty acids have different effects: Hmgcr was repressed for 50%, but Cyp51 was unaffected by the presence of linoloeic acid. In embryonic fibroblasts t...

  10. Clock genes, hair growth and aging

    OpenAIRE

    Geyfman, Mikhail; Andersen, Bogi

    2010-01-01

    Hair follicles undergo continuous cycles of growth, involution and rest. This process, referred to as the hair growth cycle, has a periodicity of weeks to months. At the same time, skin and hair follicles harbor a functional circadian clock that regulates gene expression with a periodicity of approximately twenty four hours. In our recent study we found that circadian clock genes play a role in regulation of the hair growth cycle during synchronized hair follicle cycling, uncovering an unexpe...

  11. Daily rhythmicity of clock gene transcripts in atlantic cod fast skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Carlo C Lazado

    Full Text Available 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.

  12. A Byzantine-Fault Tolerant Self-Stabilizing Protocol for Distributed Clock Synchronization Systems

    Science.gov (United States)

    Malekpour, Mahyar R.

    2006-01-01

    Embedded distributed systems have become an integral part of safety-critical computing applications, necessitating system designs that incorporate fault tolerant clock synchronization in order to achieve ultra-reliable assurance levels. Many efficient clock synchronization protocols do not, however, address Byzantine failures, and most protocols that do tolerate Byzantine failures do not self-stabilize. Of the Byzantine self-stabilizing clock synchronization algorithms that exist in the literature, they are based on either unjustifiably strong assumptions about initial synchrony of the nodes or on the existence of a common pulse at the nodes. The Byzantine self-stabilizing clock synchronization protocol presented here does not rely on any assumptions about the initial state of the clocks. Furthermore, there is neither a central clock nor an externally generated pulse system. The proposed protocol converges deterministically, is scalable, and self-stabilizes in a short amount of time. The convergence time is linear with respect to the self-stabilization period. Proofs of the correctness of the protocol as well as the results of formal verification efforts are reported.

  13. The clock system for LHAASO WCDA based on reduced White Rabbit

    International Nuclear Information System (INIS)

    Due to the large scale of Water Cherenkov Detector Array in Large High Altitude Air Shower Observatory, the front-end digitization is imperative. Thus a clock distribution system is desired, which broadcasts the synchronous clock signals with low jitter to the front-end electronics distributed in the field of 90000 m2. The White Rabbit protocol provides an option, which has been approved to achieve sub-ns accuracy and ps jitter in the synchronization of around 1000 nodes in the order of 10 km. But the hierarchy of the original is too complex for Large High Altitude Air Shower Observatory application. Thus we proposed a reduced scheme based on the White Rabbit protocol. The validation circuit shows that the clock skew due to the fiber length difference can be adjusted to less than 25 ps and the clock jitter is less than 62 ps. (authors)

  14. Development of circadian oscillators in neurosphere cultures during adult neurogenesis.

    Directory of Open Access Journals (Sweden)

    Astha Malik

    Full Text Available Circadian rhythms are common in many cell types but are reported to be lacking in embryonic stem cells. Recent studies have described possible interactions between the molecular mechanism of circadian clocks and the signaling pathways that regulate stem cell differentiation. Circadian rhythms have not been examined well in neural stem cells and progenitor cells that produce new neurons and glial cells during adult neurogenesis. To evaluate circadian timing abilities of cells undergoing neural differentiation, neurospheres were prepared from the mouse subventricular zone (SVZ, a rich source of adult neural stem cells. Circadian rhythms in mPer1 gene expression were recorded in individual spheres, and cell types were characterized by confocal immunofluorescence microscopy at early and late developmental stages in vitro. Circadian rhythms were observed in neurospheres induced to differentiate into neurons or glia, and rhythms emerged within 3-4 days as differentiation proceeded, suggesting that the neural stem cell state suppresses the functioning of the circadian clock. Evidence was also provided that neural stem progenitor cells derived from the SVZ of adult mice are self-sufficient clock cells capable of producing a circadian rhythm without input from known circadian pacemakers of the organism. Expression of mPer1 occurred in high frequency oscillations before circadian rhythms were detected, which may represent a role for this circadian clock gene in the fast cycling of gene expression responsible for early cell differentiation.

  15. How Temperature Changes Reset a Circadian Oscillator

    NARCIS (Netherlands)

    Merrow, Martha; Loros, Jennifer J.; Dunlap, Jay C.

    1998-01-01

    Circadian rhythms control many physiological activities. The environmental entrainment of rhythms involves the immediate responses of clock components. Levels of the clock protein FRQ were measured in Neurospora at various temperatures; at higher temperatures, the amount of FRQ oscillated around hig

  16. Daily methylphenidate and atomoxetine treatment impacts on clock gene protein expression in the mouse brain.

    Science.gov (United States)

    Baird, Alison L; Coogan, Andrew N; Kaufling, Jennifer; Barrot, Michel; Thome, Johannes

    2013-06-01

    Circadian rhythms are repeating patterns of physiological and other parameters that recur with periods of approximately 24h, and are generated by an endogenous circadian timekeeping mechanism. Such circadian rhythms, and their underlying molecular mechanisms, are known to be altered by a number of central nervous system acting pharmacological compounds, as well as becoming perturbed in a number of common psychiatric and neurological conditions. The psychostimulant methylphenidate and the non-stimulant atomoxetine are used in the pharmacotherapy of attention deficit hyperactivity disorder, a common condition in which circadian rhythms have been reported to be altered. In the present study we have examined the effects of daily methylphenidate or atomoxetine treatment across 7 days on circadian clock gene product expression across numerous brain regions in the male mouse to test the potential impact of such compounds on circadian timing. We report drug, brain region and molecular specific effects of such treatments, including alterations in expression profiles in the suprachiasmatic nucleus, the master circadian pacemaker. These results indicate that drugs used in the clinical management of attention deficit hyperactivity disorder can alter molecular factors that are believed to underpin circadian timekeeping, and such effects may be of importance in both the therapeutic and side effect profiles of such drugs. PMID:23566813

  17. Variation in circadian rhythms is maintained among and within populations in Boechera stricta.

    Science.gov (United States)

    Salmela, Matti J; Greenham, Kathleen; Lou, Ping; McClung, C Robertson; Ewers, Brent E; Weinig, Cynthia

    2016-06-01

    Circadian clocks have evolved independently in all three domains of life, and fitness benefits of a functional clock have been demonstrated in experimental genotypes in controlled conditions. Still, little is known about genetic variation in the clock and its fitness consequences in natural populations from heterogeneous environments. Using Wyoming populations of the Arabidopsis relative Boechera stricta as our study system, we demonstrate that genetic variation in the clock can occur at multiple levels: means of circadian period among populations sampled at different elevations differed by less than 1 h, but means among families sampled within populations varied by as much as 3.5 h. Growth traits also varied among and within populations. Within the population with the most circadian variation, we observed evidence for a positive correlation between period and growth and a negative correlation between period and root-to-shoot ratio. We then tested whether performance tradeoffs existed among families of this population across simulated seasonal settings. Growth rankings of families were similar across seasonal environments, but for root-to-shoot ratio, genotype × environment interactions contributed significantly to total variation. Therefore, further experiments are needed to identify evolutionary mechanisms that preserve substantial quantitative genetic diversity in the clock in this and other species. PMID:26514754

  18. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms.

    OpenAIRE

    Landgraf, D; Joiner, WJ; McCarthy, MJ; Kiessling, S.; Barandas, R; Young, JW; Cermakian, N; Welsh, DK

    2016-01-01

    Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to distu...

  19. Circadian Rhythms of Crawling and Swimming in the Nudibranch Mollusc Melibe leonina

    OpenAIRE

    Newcomb, James M; Kirouac, Lauren E.; NAIMIE, AMANDA A.; BIXBY, KIMBERLY A.; Lee, Colin; MALANGA, STEPHANIE; RAUBACH, MAUREEN; Watson, Winsor H.

    2014-01-01

    Daily rhythms of activity driven by circadian clocks are expressed by many organisms, including molluscs. We initiated this study, with the nudibranch Melibe leonina, with four goals in mind: (1) determine which behaviors are expressed with a daily rhythm; (2) investigate which of these rhythmic behaviors are controlled by a circadian clock; (3) determine if a circadian clock is associated with the eyes or optic ganglia of Melibe, as it is in several other gastropods; and (4) test the hypothe...

  20. Profiling molecular and behavioral circadian rhythms in the non-symbiotic sea anemone Nematostella vectensis

    OpenAIRE

    Oren, Matan; Tarrant, Ann M.; Alon, Shahar; Simon-Blecher, Noa; Elbaz, Idan; Appelbaum, Lior; Levy, Oren

    2015-01-01

    Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have characterized circadian behavioral patterns and identified potential components of the circadian clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal symbionts. Using automatic video tracking we showed that Nematostella exhibits rhythmic circadian locomotor activity, which is persistent in constant dark, shifted or disrupted by external dark/light cues and...

  1. Circadian rhythm sleep disorders

    Directory of Open Access Journals (Sweden)

    Morgenthaler TI

    2012-05-01

    Full Text Available Bhanu P Kolla,1,2 R Robert Auger,1,2 Timothy I Morgenthaler11Mayo Center for Sleep Medicine, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Misalignment between endogenous circadian rhythms and the light/dark cycle can result in pathological disturbances in the form of erratic sleep timing (irregular sleep–wake rhythm, complete dissociation from the light/dark cycle (circadian rhythm sleep disorder, free-running type, delayed sleep timing (delayed sleep phase disorder, or advanced sleep timing (advanced sleep phase disorder. Whereas these four conditions are thought to involve predominantly intrinsic mechanisms, circadian dysrhythmias can also be induced by exogenous challenges, such as those imposed by extreme work schedules or rapid transmeridian travel, which overwhelm the ability of the master clock to entrain with commensurate rapidity, and in turn impair approximation to a desired sleep schedule, as evidenced by the shift work and jet lag sleep disorders. This review will focus on etiological underpinnings, clinical assessments, and evidence-based treatment options for circadian rhythm sleep disorders. Topics are subcategorized when applicable, and if sufficient data exist. The length of text associated with each disorder reflects the abundance of associated literature, complexity of management, overlap of methods for assessment and treatment, and the expected prevalence of each condition within general medical practice.Keywords: circadian rhythm sleep disorders, assessment, treatment

  2. The harmala alkaloid harmine is a modulator of circadian Bmal1 transcription.

    Science.gov (United States)

    Onishi, Yoshiaki; Oishi, Katsutaka; Kawano, Yasuhiro; Yamazaki, Yoshimitsu

    2012-02-01

    Biological rhythms are orchestrated by a cell-autonomous clock system that drives the rhythmic cascade of clock genes. We established an assay system using NIH 3T3 cells stably expressing the Bmal1 promoter-driven luciferase reporter gene and used it to analyse circadian oscillation of the gene. Modulators of PKC (protein kinase C) revealed that an activator and an inhibitor represented short- and long-period phenotypes respectively which were consistent with reported effects of PKC on the circadian clock and validated the assay system. We examined the effects of the alkaloid harmine, contained in Hoasca, which has a wide spectrum of pharmacological actions, on circadian rhythms using the validated assay system. Harmine dose dependently elongated the period. Furthermore, EMSA (electrophoretic mobility-shift assay) and Western-blot analysis showed that harmine enhanced the transactivating function of RORα (retinoid-related orphan receptor α), probably by increasing its nuclear translocation. Exogenous expression of RORα also caused a long period, confirming the phenotype indicated by harmine. These results suggest that harmine extends the circadian period by enhancing RORα function and that harmine is a new candidate that contributes to the control of period length in mammalian cells. PMID:21401525

  3. RighTime: A real time clock correcting program for MS-DOS-based computer systems

    Science.gov (United States)

    Becker, G. Thomas

    1993-01-01

    A computer program is described which effectively eliminates the misgivings of the DOS system clock in PC/AT-class computers. RighTime is a small, sophisticated memory-resident program that automatically corrects both the DOS system clock and the hardware 'CMOS' real time clock (RTC) in real time. RighTime learns what corrections are required without operator interaction beyond the occasional accurate time set. Both warm (power on) and cool (power off) errors are corrected, usually yielding better than one part per million accuracy in the typical desktop computer with no additional hardware, and RighTime increases the system clock resolution from approximately 0.0549 second to 0.01 second. Program tools are also available which allow visualization of RighTime's actions, verification of its performance, display of its history log, and which provide data for graphing of the system clock behavior. The program has found application in a wide variety of industries, including astronomy, satellite tracking, communications, broadcasting, transportation, public utilities, manufacturing, medicine, and the military.

  4. Circadian oscillators in the mouse brain

    DEFF Research Database (Denmark)

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-01-01

    The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators...... residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice with...... conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje and...

  5. The CDF TESTCLK module - Providing system level clocking and triggering for Run 2 prototyping crates

    International Nuclear Information System (INIS)

    The TESTCLK module was specifically designed for use in prototyping crates for the Colliding Detector Facility (CDF) Run 2 Experiment at Fermi National Accelerator Laboratory. The TESTCLK Module allows the user to supply system clocks and trigger signals to stand-alone crates. This module has allowed designers of the CDF Run 2 electronics to thoroughly test their modules, despite the lack of a DAQ system supplied clock and trigger interface. This paper will explore the features that were found important to incorporate into the TESTCLK, and describe how they were implemented. The paper will also describe how the TESTCLK module has been used to support the initial implementation of the DAQ system at CDF. This has allowed data taking and testing of CDF Electronic modules before production clock and trigger modules became available

  6. Circadian polymorphisms associated with affective disorders

    OpenAIRE

    Kripke, Daniel F; Nievergelt, Caroline M; Joo, EJ; Shekhtman, Tatyana; Kelsoe, John R.

    2009-01-01

    Background: Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies.Methods:...

  7. Circadian Rhythms

    Science.gov (United States)

    ... body function and health? Circadian rhythms can influence sleep-wake cycles, hormone release, body temperature and other important bodily functions. They have been linked to various sleep disorders, such as insomnia. Abnormal circadian rhythms have also ...

  8. A Long Noncoding RNA Perturbs the Circadian Rhythm of Hepatoma Cells to Facilitate Hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Ming Cui

    2015-01-01

    Full Text Available Clock circadian regulator (CLOCK/brain and muscle arnt-like protein-1 (BMAL1 complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC remains unclear. Here, we report that a long noncoding RNA (lncRNA, highly upregulated in liver cancer (HULC, contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC.

  9. 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

  10. Later endogenous circadian temperature nadir relative to an earlier wake time in older people

    Science.gov (United States)

    Duffy, J. F.; Dijk, D. J.; Klerman, E. B.; Czeisler, C. A.

    1998-01-01

    The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.

  11. Postnatal constant light compensates Cryptochrome1 and 2 double deficiency for disruption of circadian behavioral rhythms in mice under constant dark.

    Directory of Open Access Journals (Sweden)

    Daisuke Ono

    Full Text Available Clock genes Cryptochrome (Cry1 and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD. However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN of neonatal Cry1 and Cry2 double deficient (Cry1 (-/-/Cry2 (-/- mice. A lack of circadian rhythms in adult Cry1 (-/-/Cry2 (-/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1 (-/-/Cry2 (-/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1 (-/-/Cry2 (-/- mice, but failed to detect the rhythms in Cry1 (-/-/Cry2 (-/- mice raised under light-dark cycles (LD. By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1 (-/-/Cry2 (-/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1(-/-/Cry2(-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1(-/-/Cry2(-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in

  12. Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork.

    Directory of Open Access Journals (Sweden)

    Johanna L Barclay

    Full Text Available Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.

  13. Using light to tell the time of day: sensory coding in the mammalian circadian visual network

    Science.gov (United States)

    2016-01-01

    ABSTRACT Circadian clocks are a near-ubiquitous feature of biology, allowing organisms to optimise their physiology to make the most efficient use of resources and adjust behaviour to maximise survival over the solar day. To fulfil this role, circadian clocks require information about time in the external world. This is most reliably obtained by measuring the pronounced changes in illumination associated with the earth's rotation. In mammals, these changes are exclusively detected in the retina and are relayed by direct and indirect neural pathways to the master circadian clock in the hypothalamic suprachiasmatic nuclei. Recent work reveals a surprising level of complexity in this sensory control of the circadian system, including the participation of multiple photoreceptive pathways conveying distinct aspects of visual and/or time-of-day information. In this Review, I summarise these important recent advances, present hypotheses as to the functions and neural origins of these sensory signals, highlight key challenges for future research and discuss the implications of our current knowledge for animals and humans in the modern world. PMID:27307539

  14. Electromagnetic synchronisation of clocks with finite separation in a rotating system

    International Nuclear Information System (INIS)

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

  15. Feeding Period Restriction Alters the Expression of Peripheral Circadian Rhythm Genes without Changing Body Weight in Mice

    OpenAIRE

    Jang, Hagoon; Lee, Gung; Kong, Jinuk; Choi, Goun; Park, Yoon Jeong; Kim, Jae Bum

    2012-01-01

    Accumulating evidence suggests that the circadian clock is closely associated with metabolic regulation. However, whether an impaired circadian clock is a direct cause of metabolic dysregulation such as body weight gain is not clearly understood. In this study, we demonstrate that body weight gain in mice is not significantly changed by restricting feeding period to daytime or nighttime. The expression of peripheral circadian clock genes was altered by feeding period restriction, while the ex...

  16. Animal clocks: when science meets nature.

    Science.gov (United States)

    Kronfeld-Schor, Noga; Bloch, Guy; Schwartz, William J

    2013-08-22

    Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian 'clock'), with the alternation of environmental light and darkness synchronizing (entraining) these rhythms to the natural day-night cycle. Our knowledge of the circadian system of animals at the molecular, cellular, tissue and organismal levels is remarkable, and we are beginning to understand how each of these levels contributes to the emergent properties and increased complexity of the system as a whole. For the most part, these analyses have been carried out using model organisms in standard laboratory housing, but to begin to understand the adaptive significance of the clock, we must expand our scope to study diverse animal species from different taxonomic groups, showing diverse activity patterns, in their natural environments. The seven papers in this Special Feature of Proceedings of the Royal Society B take on this challenge, reviewing the influences of moonlight, latitudinal clines, evolutionary history, social interactions, specialized temporal niches, annual variation and recently appreciated post-transcriptional molecular mechanisms. The papers emphasize that the complexity and diversity of the natural world represent a powerful experimental resource. PMID:23825215

  17. Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy.

    Science.gov (United States)

    Lahouaoui, Hasna; Coutanson, Christine; Cooper, Howard M; Bennis, Mohamed; Dkhissi-Benyahya, Ouria

    2014-01-01

    There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges. PMID:25006976

  18. Quantification of circadian rhythms in single cells.

    Directory of Open Access Journals (Sweden)

    Pål O Westermark

    2009-11-01

    Full Text Available Bioluminescence techniques allow accurate monitoring of the circadian clock in single cells. We have analyzed bioluminescence data of Per gene expression in mouse SCN neurons and fibroblasts. From these data, we extracted parameters such as damping rate and noise intensity using two simple mathematical models, one describing a damped oscillator driven by noise, and one describing a self-sustained noisy oscillator. Both models describe the data well and enabled us to quantitatively characterize both wild-type cells and several mutants. It has been suggested that the circadian clock is self-sustained at the single cell level, but we conclude that present data are not sufficient to determine whether the circadian clock of single SCN neurons and fibroblasts is a damped or a self-sustained oscillator. We show how to settle this question, however, by testing the models' predictions of different phases and amplitudes in response to a periodic entrainment signal (zeitgeber.

  19. A high stability semiconductor laser system for a $^{88}$Sr-based optical lattice clock

    CERN Document Server

    Tarallo, Marco G; Schioppo, Marco; Tino, Guglielmo M

    2010-01-01

    We describe a frequency stabilized diode laser at 698 nm used for high resolution spectroscopy of the 1S0-3P0 strontium clock transition. For the laser stabilization we use state-of-the-art symmetrically suspended optical cavities optimized for very low thermal noise at room temperature. Two-stage frequency stabilization to high finesse optical cavities results in measured laser frequency noise about a factor of three above the cavity thermal noise between 2 Hz and 11 Hz. With this system, we demonstrate high resolution remote spectroscopy on the 88Sr clock transition by transferring the laser output over a phase-noise-compensated 200 m-long fiber link between two separated laboratories. Our dedicated fiber link ensures a transfer of the optical carrier with frequency stability of 7 \\cdot 10^{-18} after 100 s integration time, which could enable the observation of the strontium clock transition with an atomic Q of 10^{14}. Furthermore, with an eye towards the development of transportable optical clocks, we in...

  20. Stable clocks and general relativity

    CERN Document Server

    Will, C M

    1995-01-01

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

  1. Heritable circadian period length in a wild bird population

    OpenAIRE

    Helm, Barbara; Visser, Marcel E

    2010-01-01

    Timing is essential, but circadian clocks, which play a crucial role in timekeeping, are almost unaddressed in evolutionary ecology. A key property of circadian clocks is their free-running period length (τ), i.e. the time taken for a full cycle under constant conditions. Under laboratory conditions, concordance of τ with the ambient light–dark cycle confers major fitness benefits, but little is known about period length and its implications in natural populations. We therefore studied natura...

  2. CIRCADIAN GENES AND REGULATION OF DIAPAUSE IN INSECT

    OpenAIRE

    Bajgar, Adam

    2013-01-01

    This thesis considers various roles of circadian clock genes in insect physiology. Application of molecular-biology methods in Pyrrhocoris apterus, non-model insect species, enable us to investigate involvement of circadian clock genes in photoperiod induced physiological responses. We discover involvement of neuroendocrine cells, and a role of Juvenile hormone (JH) signalization in transduction of photoperiodic signalization to peripheral tissues. We found new principles of JH signal diversi...

  3. Measurement and simulation of clock errors from resource-constrained embedded systems

    International Nuclear Information System (INIS)

    Resource-constrained embedded systems such as wireless sensor networks are becoming increasingly sought-after in a range of critical sensing applications. Hardware for such systems is typically developed as a general tool, intended for research and flexibility. These systems often have unexpected limitations and sources of error when being implemented for specific applications. We investigate via measurement and simulation the output of the onboard clock of a Crossbow MICAz testbed, comprising a quartz oscillator accessed via a combination of hardware and software. We show that the clock output available to the user suffers a number of instabilities and errors. Using a simple software simulation of the system based on a series of nested loops, we identify the source of each component of the error, finding that there is a 7.5 × 10−6 probability that a given oscillation from the governing crystal will be miscounted, resulting in frequency jitter over a 60 µHz range

  4. Circadian Control of the Estrogenic Circuits Regulating GnRH Secretion and the Preovulatory Luteinizing Hormone Surge

    Directory of Open Access Journals (Sweden)

    Lance J Kriegsfeld

    2012-05-01

    Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

  5. 大鼠视交叉上核与松果体中Clock基因转录的昼夜节律性及不同光反应性%Circadian rhythms and different photoresponses of Clock gene transcription in the rat suprachiasmatic nucleus and pineal gland

    Institute of Scientific and Technical Information of China (English)

    王国卿; 傅春玲; 李建祥; 杜玉珍; 童建

    2006-01-01

    The aim of this study was to observe and compare the endogenous circadian rhythm and photoresponse of Clock gene transcription in the suprachiasmatic nucleus (SCN) and pineal gland (PG) of rats. With free access to food and water in special darkrooms, Sprague-Dawley rats were housed under the light regime of constant darkness (DD) for 8 weeks (n=36) or 12 hour-light:12 hour-dark cycle (LD) for 4 weeks (n=36), respectively. Then, their SCN and PG were dissected out every 4 h in a circadian day, 6rats at each time (n=6). All animal treatments and sampling during the dark phases were conducted under red dim light (<0.1 lux). The total RNA was extracted from each sample and the semi-quantitative RT-PCR was used to determine the temporal mRNA changes of Clock gene in the SCN and PG at different circadian times (CT) or zeitgeber times (ZT). The grayness ratio of Clock/H3.3 bands was served as the relative estimation of Clock gene expression. The experimental data were analyzed by the Cosine method and the Clock Lab software to fit original results measured at 6 time points and to simulate a circadian rhythmic curve which was then examined for statistical difference by the amplitude F test. The main results are as follows: (1) The mRNA levels of Clock gene in the SCN under DD regime displayed the circadian oscillation (P<0.05). The endogenous rhythmic profiles of Clock gene transcription in the PG were similar to those in the SCN (P>0.05) throughout the day with the peak at the subjective night (CT15 in the SCN or CT18 in the PG)and the trough during the subjective day (CT3 in the SCN or CT6 in the PG). (2) Clock gene transcription in the SCN under LD cycle also showed the circadian oscillation (P<0.05), and the rhythmic profile was anti-phasic to that under DD condition (P<0.05). The amplitude and the mRNA level at the peak of Clock gene transcription in the SCN under LD were significantly increased compared with that under DD (P<0.05), while the value of

  6. An empirical clock to measure the dynamical age of stellar systems

    CERN Document Server

    Dalessandro, Emanuele

    2013-01-01

    Blue Straggler Stars (BSS) are among the brightest and more massive stars in globular clusters (GCs). For this reason they represent an ideal tool to probe the dynamical evolution of these stellar systems. Here I show, following the results by Ferraro et al. (2012), that the BSS radial distribution can be used as a powerful indicator of the cluster dynamical age. In fact on the basis of their BSS radial distribution shape, GCs can be efficiently grouped in different families corresponding to the different dynamical stages reached by the stellar systems. This allows to define a first empirical clock, the dynamical clock, able to measure the dynamical age of a stellar system from pure observational quantities.

  7. The Evolution of the Cyanobacterial Posttranslational Clock from a Primitive "Phoscillator"

    NARCIS (Netherlands)

    Simons, Mirre J. P.

    2009-01-01

    Cyanobacteria were among the 1st organisms to evolve on earth. The molecular circadian clock proteins of cyanobacteria and their phylogenetics have recently been elucidated. This allows for a conjecture on the evolution of 1 of the 1st circadian clocks. A scenario has now been created by combining k

  8. Influence of Electric, Magnetic, and Electromagnetic Fields on the Circadian System: Current Stage of Knowledge

    Directory of Open Access Journals (Sweden)

    Bogdan Lewczuk

    2014-01-01

    Full Text Available One of the side effects of each electrical device work is the electromagnetic field generated near its workplace. All organisms, including humans, are exposed daily to the influence of different types of this field, characterized by various physical parameters. Therefore, it is important to accurately determine the effects of an electromagnetic field on the physiological and pathological processes occurring in cells, tissues, and organs. Numerous epidemiological and experimental data suggest that the extremely low frequency magnetic field generated by electrical transmission lines and electrically powered devices and the high frequencies electromagnetic radiation emitted by electronic devices have a potentially negative impact on the circadian system. On the other hand, several studies have found no influence of these fields on chronobiological parameters. According to the current state of knowledge, some previously proposed hypotheses, including one concerning the key role of melatonin secretion disruption in pathogenesis of electromagnetic field induced diseases, need to be revised. This paper reviews the data on the effect of electric, magnetic, and electromagnetic fields on melatonin and cortisol rhythms—two major markers of the circadian system as well as on sleep. It also provides the basic information about the nature, classification, parameters, and sources of these fields.

  9. Projections from the subparaventricular zone define four channels of output from the circadian timing system.

    Science.gov (United States)

    Vujovic, Nina; Gooley, Joshua J; Jhou, Thomas C; Saper, Clifford B

    2015-12-15

    The subparaventricular zone of the hypothalamus (SPZ) is the main efferent target of neural projections from the suprachiasmatic nucleus (SCN) and an important relay for the circadian timing system. Although the SPZ is fairly homogeneous cytoarchitecturally and neurochemically, it has been divided into distinct functional and connectional subdivisions. The dorsal subdivision of the SPZ (dSPZ) plays an important role in relaying signals from the SCN controlling body temperature rhythms, while the ventral subdivision (vSPZ) is critical for rhythms of sleep and locomotor activity (Lu et al. [] J Neurosci 21:4864-4874). On the other hand, the medial part of the SPZ receives input mainly from the dorsomedial SCN, whereas the lateral SPZ receives input from the ventrolateral SCN and the retinohypothalamic tract (Leak and Moore [] J Comp Neurol 433:312-334). We therefore investigated whether there are corresponding differences in efferent outputs from these four quadrants of the SPZ (dorsolateral, ventrolateral, dorsomedial, and ventromedial) by a combination of anterograde and retrograde tracing. We found that, while all four subdivisions of the SPZ share a similar backbone of major projection pathways to the septal region, thalamus, hypothalamus, and brainstem, each segment of the SPZ has a specific set of targets where its projections dominate. Furthermore, we observed intra-SPZ projections of varying densities between the four subdivisions. Taken together, this pattern of organization suggests that the circadian timing system may have several parallel neural outflow pathways that provide a road map for understanding how they subserve different functions. PMID:26010698

  10. An automated tracking system for Caenorhabditis elegans locomotor behavior and circadian studies application.

    Science.gov (United States)

    Simonetta, Sergio H; Golombek, Diego A

    2007-04-15

    Automation of simple behavioral patterns, such as locomotor activity, is fundamental for pharmacological and genetic screening studies. Recently, circadian behaviors in locomotor activity and stress responses were reported in the nematode Caenorhabditis elegans, a well-known model in genetics and developmental studies. Here we present a new method for long-term recordings of C. elegans (as well as other similar-sized animals) locomotor activity based on an infrared microbeam scattering. Individual nematodes were cultured in a 96-well microtiter plate; we tested L15, CeMM and E. coli liquid cultures in long-term activity tracking experiments, and found CeMM to be the optimal medium. Treatment with 0.2% azide caused an immediate decrease in locomotor activity as recorded with our system. In addition to the validation of the method (including hardware and software details), we report its application in chronobiological studies. Circadian rhythms in animals entrained to light-dark and constant dark conditions (n=48 and 96 worms, respectively) at 16 degrees C, were analyzed by LS periodograms. We obtained a 24.2+/-0.44 h period (52% of significantly rhythmic animals) in LD, and a 23.1+/-0.40 h period (37.5% of significantly rhythmic animals) under DD. The system is automateable using microcontrollers, of low-cost construction and highly reproducible. PMID:17207862

  11. Circadian genes differentially affect tolerance to ethanol in Drosophila

    Science.gov (United States)

    Pohl, Jascha B.; Ghezzi, Alfredo; Lew, Linda K.; Robles, Roseanna B.; Cormack, Lawrence; Atkinson, Nigel S.

    2016-01-01

    Background There is a strong relationship between circadian rhythms and ethanol responses. Ethanol consumption has been shown to disrupt physiological and behavioral circadian rhythms in mammals (Spanagel et al., 2005b). The Drosophila central circadian pacemaker is composed of proteins encoded by the per, tim, cyc, and Clk genes. Using Drosophila mutant analysis we asked whether these central components of the circadian clock make the equivalent contribution towards ethanol tolerance and whether rhythmicity itself is necessary for tolerance. Methods We tested flies carrying mutations in core clock genes for the capacity to acquire ethanol tolerance. Tolerance was assayed by comparing the sedation curves of populations during their first and second sedation. Animals that had acquired tolerance sedated more slowly. Movement was also monitored as the flies breathe the ethanol vapor to determine if other facets of the ethanol response were affected by the mutations. Gas chromatography was used to measure internal ethanol concentration. Constant light was used to non-genetically destabilize the PER and TIM proteins. Results A group of circadian mutations, all of which eliminate circadian rhythms, do not disrupt tolerance identically. Mutations in per, tim, and cyc completely block tolerance. However, a mutation in Clk does not interfere with tolerance. Constant light also disrupts the capacity to acquire tolerance. These lines did not differ in ethanol absorption. Conclusions Mutations affecting different parts of the intracellular circadian clock can block the capacity to acquire rapid ethanol tolerance. However, the role of circadian genes in ethanol tolerance is independent of their role in producing circadian rhythmicity. The interference in the capacity to acquire ethanol tolerance by some circadian mutations is not merely a downstream effect of a nonfunctional circadian clock, instead these circadian genes play an independent role in ethanol tolerance. PMID

  12. Oscillation of Clock and Clock Controlled Genes Induced by Serum Shock in Human Breast Epithelial and Breast Cancer Cells: Regulation by Melatonin

    OpenAIRE

    S. Xiang; Mao, L; T. Duplessis; Yuan, L.; R. Dauchy; Dauchy, E.; D.E. Blask,; T. Frasch; Hill, S M

    2012-01-01

    This study investigates differences in expression of clock and clock-controlled genes (CCGs) between human breast epithelial and breast cancer cells and breast tumor xenografts in circadian intact rats and examines if the pineal hormone melatonin influences clock gene and CCG expression. Oscillation of clock gene expression was not observed under standard growth conditions in vitro, however, serum shock (50% horse serum for 2 h) induced oscillation of clock gene and CCG expression in MCF-10A ...

  13. Clocks underneath: the role of peripheral clocks in the timing of female reproductive physiology

    Directory of Open Access Journals (Sweden)

    MichaelTSellix

    2013-07-01

    Full Text Available The central circadian pacemaker in the suprachiasmatic nucleus (SCN is a critical component of the neuroendocrine circuit controlling gonadotropin secretion from the pituitary gland. The SCN conveys photic information to hypothalamic targets including the gonadotropin releasing hormone (GnRH neurons. Many of these target cells are also cell autonomous clocks. It has been suggested that, rather then being singularly driven by the SCN, the timing of gonadotropin secretion depends on the activity of multiple hypothalamic oscillators. While this view provides a novel twist to an old story, it does little to diminish the central role of rhythmic hypothalamic output in this system. It is now clear that the pituitary, ovary, uterus and oviduct have functional molecular clocks. Evidence supports the notion that the clocks in these tissues contribute to the timing of events in reproductive physiology. The goal of this review is to highlight the current evidence for molecular clock function in the peripheral components of the female hypothalamo-pituitary-gonadal (HPG axis as it relates to the timing of gonadotropin secretion, ovulation and parturition.

  14. The role of microRNAs (miRNA) in circadian rhythmicity

    Indian Academy of Sciences (India)

    Mirko Pegoraro; Eran Tauber

    2008-12-01

    MicroRNA (miRNA) is a recently discovered new class of small RNA molecules that have a significant role in regulating gene and protein expression. These small RNAs (∼22 nt) bind to 3′ untranslated regions (3′UTRs) and induce degradation or repression of translation of their mRNA targets. Hundreds of miRNAs have been identified in various organisms and have been shown to play a significant role in development and normal cell functioning. Recently, a few studies have suggested that miRNAs may be an important regulators of circadian rhythmicity, providing a new dimension (posttranscriptional) of our understanding of biological clocks. Here, we describe the mechanisms of miRNA regulation, and recent studies attempting to identify clock miRNAs and their function in the circadian system.

  15. A compact ultranarrow high-power laser system for experiments with 578nm Ytterbium clock transition

    CERN Document Server

    Cappellini, Giacomo; Mancini, Marco; Pagano, Guido; Pizzocaro, Marco; Fallani, Leonardo; Catani, Jacopo

    2015-01-01

    In this paper we present the realization of a compact, high-power laser system able to excite the Ytterbium clock transition at 578 nm. Starting from an external-cavity laser based on a quantum dot chip at 1156 nm with an intra-cavity electro-optic modulator, we were able to obtain up to 60 mW of visible light at 578 nm via frequency doubling. The laser is locked with a 500 kHz bandwidth to a ultra-low-expansion glass cavity stabilized at its zero coefficient of thermal expansion temperature through an original thermal insulation and correction system. This laser allowed the observation of the clock transition in fermionic $^{173}$Yb with a < 50 Hz linewidth over 5 minutes, limited only by a residual frequency drift of some 0.1 Hz/s.

  16. A compact ultranarrow high-power laser system for experiments with 578 nm ytterbium clock transition

    International Nuclear Information System (INIS)

    In this paper, we present the realization of a compact, high-power laser system able to excite the ytterbium clock transition at 578 nm. Starting from an external-cavity laser based on a quantum dot chip at 1156 nm with an intra-cavity electro-optic modulator, we were able to obtain up to 60 mW of visible light at 578 nm via frequency doubling. The laser is locked with a 500 kHz bandwidth to an ultra-low-expansion glass cavity stabilized at its zero coefficient of thermal expansion temperature through an original thermal insulation and correction system. This laser allowed the observation of the clock transition in fermionic 173Y b with a <50 Hz linewidth over 5 min, limited only by a residual frequency drift of some 0.1 Hz/s

  17. A quantum many-body spin system in an optical lattice clock

    CERN Document Server

    Martin, M J; Swallows, M D; Zhang, X; Benko, C; von-Stecher, J; Gorshkov, A V; Rey, A M; Ye, Jun

    2013-01-01

    Strongly interacting quantum many-body systems are fundamentally compelling and ubiquitous in science. However, their complexity generally prevents exact solutions of their dynamics. Precisely engineered ultracold atomic gases are emerging as a powerful tool to unravel these challenging physical problems. Here we present a new laboratory for the study of many-body effects: strongly interacting two-level systems formed by the clock states in ${}^{87}$Sr, which are used to realize a neutral atom optical clock that performs at the highest level of optical-atomic coherence and with precision near the limit set by quantum fluctuations. Our measurements of the collective spin evolution reveal signatures of many-body dynamics, including beyond-mean-field effects. We derive a many-body Hamiltonian that describes the experimental observation of severely distorted lineshapes, atomic spin coherence decay, density-dependent frequency shifts, and correlated quantum spin noise. These investigations open the door to explori...

  18. Circadian influences on myocardial infarction

    OpenAIRE

    Virag, Jitka A. I.; Lust, Robert M.

    2014-01-01

    Components of circadian rhythm maintenance, or “clock genes,” are endogenous entrainable oscillations of about 24 h that regulate biological processes and are found in the suprachaismatic nucleus (SCN) and many peripheral tissues, including the heart. They are influenced by external cues, or Zeitgebers, such as light and heat, and can influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial...

  19. Complex bird clocks.

    OpenAIRE

    Gwinner, E.; Brandstätter, R

    2001-01-01

    The circadian pacemaking system of birds comprises three major components: (i) the pineal gland, which rhythmically synthesizes and secretes melatonin; (ii) a hypothalamic region, possibly equivalent to the mammalian suprachiasmatic nuclei; and (iii) the retinae of the eyes. These components jointly interact, stabilize and amplify each other to produce a highly self-sustained circadian output. Their relative contribution to overt rhythmicity appears to differ between species and the system ma...

  20. Heterogeneity induces rhythms of weakly coupled circadian neurons.

    Science.gov (United States)

    Gu, Changgui; Liang, Xiaoming; Yang, Huijie; Rohling, Jos H T

    2016-01-01

    The main clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms in mammals. The SCN is composed of approximately twenty thousand heterogeneous self-oscillating neurons, that have intrinsic periods varying from 22 h to 28 h. They are coupled through neurotransmitters and neuropeptides to form a network and output a uniform periodic rhythm. Previous studies found that the heterogeneity of the neurons leads to attenuation of the circadian rhythm with strong cellular coupling. In the present study, we investigate the heterogeneity of the neurons and of the network in the condition of constant darkness. Interestingly, we found that the heterogeneity of weakly coupled neurons enables them to oscillate and strengthen the circadian rhythm. In addition, we found that the period of the SCN network increases with the increase of the degree of heterogeneity. As the network heterogeneity does not change the dynamics of the rhythm, our study shows that the heterogeneity of the neurons is vitally important for rhythm generation in weakly coupled systems, such as the SCN, and it provides a new method to strengthen the circadian rhythm, as well as an alternative explanation for differences in free running periods between species in the absence of the daily cycle. PMID:26898574