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Sample records for feeding uncouples circadian

  1. Circadian clocks, feeding time, and metabolic homeostasis

    PubMed Central

    Paschos, Georgios K.

    2015-01-01

    Metabolic processes exhibit diurnal variation from cyanobacteria to humans. The circadian clock is thought to have evolved as a time keeping system for the cell to optimize the timing of metabolic events according to physiological needs and environmental conditions. Circadian rhythms temporally separate incompatible cellular processes and optimize cellular and organismal fitness. A modern 24 h lifestyle can run at odds with the circadian rhythm dictated by our molecular clocks and create desynchrony between internal and external timing. It has been suggested that this desynchrony compromises metabolic homeostasis and may promote the development of obesity (Morris et al., 2012). Here we review the evidence supporting the association between circadian misalignment and metabolic homeostasis and discuss the role of feeding time. PMID:26082718

  2. Adult-specific electrical silencing of pacemaker neurons uncouples the molecular oscillator from circadian outputs

    PubMed Central

    Depetris-Chauvin, Ana; Berni, Jimena; Aranovich, Ezequiel J.; Muraro, Nara I.; Beckwith, Esteban J.; Ceriani, María Fernanda

    2011-01-01

    Summary Background Circadian rhythms regulate physiology and behavior through transcriptional feedback loops of clock genes running within specific pacemaker cells. In Drosophila, molecular oscillations in the small ventral Lateral Neurons (sLNvs) command rhythmic behavior under free-running conditions releasing the neuropeptide PIGMENT DISPERSING FACTOR (PDF) in a circadian fashion. Electrical activity in the sLNvs is also required for behavioral rhythmicity. Yet, how temporal information is transduced into behavior remains unclear. Results Here we developed a new tool for temporal control of gene expression to obtain adult-restricted electrical silencing of the PDF circuit, which led to reversible behavioral arrhythmicity. Remarkably, PER oscillations during the silenced phase remained unaltered, indicating that arrhythmicity is a direct consequence of the silenced activity. Accordingly, circadian axonal remodeling and PDF accumulation were severely affected during the silenced phase. Conclusions Although electrical activity of the sLNvs is not a clock component it coordinates circuit outputs leading to rhythmic behavior. PMID:22018542

  3. Renal electrolyte circadian rhythms - Independence from feeding and activity patterns

    NASA Technical Reports Server (NTRS)

    Moore-Ede, M. C.; Herd, J. A.

    1977-01-01

    Experiments were conducted on six unanesthetized chair-acclimatized adult male squirrel monkeys (Saimiri sciureus) weighing 600-900 g to determine whether internal synchronization is the result of simple passive dependence of renal excretory rhythms on endogenous rhythms of those variable that influence electrolyte excretion such as dietary intake and muscular activity. Independence of the urinary rhythms from diurnal variations in feeding, drinking, and activity was secured by depriving the animals of food, water, and training them to perform a two-hourly schedule of feeding, drinking, and activity throughout day and night. Results indicate that the internal synchronization which is normally observed between the behavioral and urinary rhythms cannot be explained by any direct dependence of renal function on behavioral patterns. The most probable mechanism for circadian internal synchronization is that the various behavioral and renal rhythms are controlled by potentially independent separate oscillators which are normally kept in synchrony with one another.

  4. Ultrasonic vocalizations in rats anticipating circadian feeding schedules.

    PubMed

    Opiol, Hanna; Pavlovski, Ilya; Michalik, Mateusz; Mistlberger, Ralph E

    2015-05-01

    Rats readily learn to anticipate a reward signaled by an external stimulus. Anticipatory behaviors evoked by conditioned stimuli include 50 kHz ultrasonic vocalizations (USVs), a proposed behavioral correlate of positive affect and activation of midbrain dopamine pathways. Rats can also anticipate a reward, such as food, provided once daily, without external cueing. Anticipation of a daily reward exhibits formal properties of a circadian rhythm. The neural circuits that regulate the timing and amplitude of these rhythms remain an open question, but evidence suggests a role for dopamine. To gain further insight into the neural and affective correlates of circadian food anticipatory rhythms, we made 2h and 24h USV recordings in rats fed 2h/day in the light period, a procedure that induces robust anticipation 2-3h before mealtime. Potential interactions between internal and external time cues in USV production were evaluated by inclusion of a 3 kHz tone 15 min before mealtime. Prior to scheduled feeding, spontaneous 50 kHz USVs were rare during the light period. During scheduled feeding, flat and frequency modulated (FM) 50kHz USVs occurred prior to and during mealtime. FM USVs were more closely related to anticipation, while flat USVs were more dependent on food access. USVs also occurred during spontaneous waking at other times of day. The tone did not evoke USVs but did modulate activity. Behavioral anticipation of a daily meal is accompanied by USVs consistent with a positive affective state and elevated dopamine transmission. PMID:25677650

  5. Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression.

    PubMed

    Wang, C; Billington, C J; Levine, A S; Kotz, C M

    2000-09-28

    Cocaine and amphetamine regulated transcript (CART) decreases feeding and body weight after ventricular injection. CART mRNA and peptide are found in the paraventricular nucleus of the hypothalamus (PVN). The purpose of the present study was to determine effects of PVN-injected CART on feeding and thermogenic capacity. PVN-injected CART (55-102, 100 pmol) significantly decreased NPY-induced feeding at 1, 2 and 4 h, but did not significantly affect deprivation-induced feeding. CART induced gene expression of uncoupling protein 1 (UCP1), UCP2, and UCP3 in brown and white adipose tissue and biceps femoris muscle respectively. These results indicate the PVN as a specific site of CART action, and suggest that CART in the PVN may have an important influence on energy metabolism. PMID:11043558

  6. Modelling and Analysis of the Feeding Regimen Induced Entrainment of Hepatocyte Circadian Oscillators Using Petri Nets

    PubMed Central

    Tareen, Samar Hayat Khan; Ahmad, Jamil

    2015-01-01

    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. PMID:25789928

  7. Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

    PubMed Central

    Atger, Florian; Gobet, Cédric; Marquis, Julien; Martin, Eva; Wang, Jingkui; Weger, Benjamin; Lefebvre, Grégory; Descombes, Patrick; Naef, Felix; Gachon, Frédéric

    2015-01-01

    Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light–dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5′-Terminal Oligo Pyrimidine tract (5′-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5′-UTR (TISU) motif. The increased translation efficiency of 5′-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation. PMID:26554015

  8. Effects of restricted feeding schedules on circadian organization in squirrel monkeys

    NASA Technical Reports Server (NTRS)

    Boulos, Z.; Frim, D. M.; Dewey, L. K.; Moore-Ede, M. C.

    1989-01-01

    Free running circadian rhythms of motor activity, food-motivated lever-pressing, and either drinking (N = 7) or body temperature (N = 3) were recorded from 10 squirrel monkeys maintained in constant illumination with unlimited access to food. Food availability was then restricted to a single unsignaled 3-hour interval each day. The feeding schedule failed to entrain the activity rhythms of 8 monkeys, which continued to free-run. Drinking was almost completely synchronized by the schedule, while body temperature showed a feeding-induced rise superimposed on a free-running rhythm. Nonreinforced lever-pressing showed both a free-running component and a 24-hour component that anticipated the time of feeding. At the termination of the schedule, all recorded variables showed free-running rhythms, but in 3 animals the initial phase of the postschedule rhythms was advanced by several hours, suggesting relative coordination. Of the remaining 2 animals, one exhibited stable entrainment of all 3 recorded rhythms, while the other appeared to entrain temporarily to the feeding schedule. These results indicate that restricted feeding schedules are only a weak zeitgeber for the circadian pacemaker generating free-running rhythms in the squirrel monkey. Such schedules, however, may entrain a separate circadian system responsible for the timing of food-anticipatory changes in behavior and physiology.

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

    PubMed

    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

  10. Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight

    NASA Technical Reports Server (NTRS)

    Cassone, Vincent M.; Stephan, Friedrich K.

    2002-01-01

    Circadian clocks have evolved to predict and coordinate physiologic processes with the rhythmic environment on Earth. Space studies in non-human primates and humans have suggested that this clock persists in its rhythmicity in space but that its function is altered significantly in long-term space flight. Under normal circumstances, the clock is synchronized by the light-dark cycle via the retinohypothalamic tract and the suprachiasmatic nucleus. It is also entrained by restricted feeding regimes via a suprachiasmatic nucleus-independent circadian oscillator. The site of this suboscillator (or oscillators) is not known, but new evidence has suggested that peripheral tissues in the liver and viscera may express circadian clock function when forced to do so by restricted feeding schedules or other homeostatic disruptions. New research on the role of the circadian clock in the control of feeding on Earth and in space is warranted.

  11. Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats.

    PubMed

    Reznick, Jane; Preston, Elaine; Wilks, Donna L; Beale, Susan M; Turner, Nigel; Cooney, Gregory J

    2013-01-01

    Energy metabolism follows a diurnal pattern responding to the light/dark cycle and food availability. This study investigated the impact of restricting feeding to the daylight hours and feeding a high fat diet on circadian clock (bmal1, dbp, tef and e4bp4) and metabolic (pepck, fas, ucp3, pdk4) gene expression and markers of energy metabolism in muscle and liver of rats. The results show that in chow-fed rats switched to daylight feeding, the peak diurnal expression of genes in liver was shifted by 6-12h while expression of these genes in muscle remained in a similar phase to rats feeding ad libitum. High fat feeding during the daylight hours had limited effect on clock gene expression in liver or muscle but shifted the peak expression of metabolic genes (pepck, fas) in liver by 6-12h. The differential effects of daylight feeding on gene and protein expression in muscle and liver were accompanied by an 8% reduction in whole body energy expenditure, a 20-30% increased glycogen content during the light phase in muscle of day-fed rats and increased adipose tissue deposition per gram food consumed. These data demonstrate that a mismatch of feeding and light/dark cycle disrupts tissue metabolism in muscle with significant consequences for whole body energy homeostasis. PMID:22952003

  12. Effect of feeding and temperature on the circadian rhythms of cortisol, thyroxine and triiodothyronine in pigs

    SciTech Connect

    Becker, B.A.; Nienaber, J.A.; Ford, J.J.; Hahn, G.L.

    1986-03-05

    An experiment was conducted to evaluate the circadian rhythms of cortisol, thyroxine (T/sub 4/) and triiodothyronine (T/sub 3/) in pigs under two temperature and feeding regimes. Twenty-eight barrows were randomly assigned to one of the following: 1) ad-libitum fed at 5/sup 0/C(AL-5); 2) ad-libitum fed at 20/sup 0/C(AL-20); 3) meal fed at 5/sup 0/C(M-5); and 4) meal fed at 20/sup 0/C(M-20). M-5 and M-20 animals were fed at 0730 and 1400 hrs. Lights were on from 0600 to 2000 hrs. After 5 wks, blood samples were collected for 27 hrs. Serum cortisol, T/sub 4/ and T/sub 3/ concentrations were determined by RIA. No significant differences were found in the mesors, amplitudes or acrophases for cortisol. The mesors for T/sub 4/ (p<.01) were 60.6 +/- 5.6, 40.2 +/- 5.6, 61.2 +/- 5.6 and 49.1 +/- 5.0 ng/ml for AL-5, AL-20, M-5, and M-20, respectively. The mesors for T/sub 3/ (p<.01) were .85 +/- .06, .69 +/- .06, .92 +/- .06 and .66 +/- .05 ng/ml for AL-5, AL-20, M-5, and M-20 respectively. No differences in the amplitudes or acrophases for T/sub 3/ or T/sub 4/ were found. These data show that temperature and feeding regimes do not entrain the circadian rhythm of cortisol in pigs. The circadian rhythms of T/sub 4/ and T/sub 3/ are also not altered by feeding regimes but are affected by temperature.

  13. Shift of Circadian Feeding Pattern by High-Fat Diets Is Coincident with Reward Deficits in Obese Mice

    PubMed Central

    Valladolid-Acebes, Ismael; Fole, Alberto; Cano, Victoria; Merino, Beatriz; Stucchi, Paula; Ruggieri, Daniela; López, Laura; Alguacil, Luis Fernando; Ruiz-Gayo, Mariano

    2012-01-01

    Recent studies provide evidence that high-fat diets (HF) trigger both i) a deficit of reward responses linked to a decrease of mesolimbic dopaminergic activity, and ii) a disorganization of circadian feeding behavior that switch from a structured meal-based schedule to a continuous snacking, even during periods normally devoted to rest. This feeding pattern has been shown to be a cause of HF-induced overweight and obesity. Our hypothesis deals with the eventual link between the rewarding properties of food and the circadian distribution of meals. We have investigated the effect of circadian feeding pattern on reward circuits by means of the conditioned-place preference (CPP) paradigm and we have characterized the rewarding properties of natural (food) and artificial (cocaine) reinforcers both in free-feeding ad libitum HF mice and in HF animals submitted to a re-organized feeding schedule based on the standard feeding behavior displayed by mice feeding normal chow (“forced synchronization”). We demonstrate that i) ad libitum HF diet attenuates cocaine and food reward in the CPP protocol, and ii) forced synchronization of feeding prevents this reward deficit. Our study provides further evidence that the rewarding impact of food with low palatability is diminished in mice exposed to a high-fat diet and strongly suggest that the decreased sensitivity to chow as a positive reinforcer triggers a disorganized feeding pattern which might account for metabolic disorders leading to obesity. PMID:22570696

  14. Scheduled Feeding Alters the Timing of the Suprachiasmatic Nucleus Circadian Clock in Dexras 1-Deficient Mice

    PubMed Central

    Bouchard-Cannon, Pascale; Cheng, Hai-Ying M.

    2013-01-01

    Restricted feeding (RF) schedules are potent zeitgebers capable of entraining metabolic and hormonal rhythms in peripheral oscillators in anticipation of food. Behaviorally, this manifests in the form of food anticipatory activity (FAA) in the hours preceding food availability. Circadian rhythms of FAA are thought to be controlled by a food-entrainable oscillator (FEO) outside of the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. Although evidence suggests that the FEO and the SCN are capable of interacting functionally under RF conditions, the genetic basis of these interactions remains to be defined. In this study, using dexras1-deficient (dexras1−/−) mice, the authors examined whether Dexras1, a modulator of multiple inputs to the SCN, plays a role in regulating the effects of RF on activity rhythms and gene expression in the SCN. Daytime RF under 12L:12D or constant darkness (DD) resulted in potentiated (but less stable) FAA expression in dexras1−/− mice compared with wild-type (WT) controls. Under these conditions, the magnitude and phase of the SCN-driven activity component were greatly perturbed in the mutants. Restoration to ad libitum (AL) feeding revealed a stable phase displacement of the SCN-driven activity component of dexras1−/− mice by ~2 h in advance of the expected time. RF in the late night/early morning induced a long-lasting increase in the period of the SCN-driven activity component in the mutants but not the WT. At the molecular level, daytime RF advanced the rhythm of PER1, PER2, and pERK expression in the mutant SCN without having any effect in the WT. Collectively, these results indicate that the absence of Dexras1 sensitizes the SCN to perturbations resulting from restricted feeding. PMID:22928915

  15. The Comparison between Circadian Oscillators in Mouse Liver and Pituitary Gland Reveals Different Integration of Feeding and Light Schedules

    PubMed Central

    Bur, Isabelle M.; Zouaoui, Sonia; Fontanaud, Pierre; Coutry, Nathalie; Molino, François; Martin, Agnès O.; Mollard, Patrice; Bonnefont, Xavier

    2010-01-01

    The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues. PMID:21179516

  16. Constant light induces alterations in melatonin levels, food intake, feed efficiency, visceral adiposity, and circadian rhythms in rats.

    PubMed

    Wideman, Cyrilla H; Murphy, Helen M

    2009-10-01

    Melatonin levels, metabolic parameters, circadian rhythm activity patterns, and behavior were observed in rats subjected to a 12-h/12-h light/dark cycle (LD) compared to animals exposed to continuous dark (DD) or continuous light (LL). LD and DD animals were similar in melatonin levels, food intake, relative food intake, feed efficiency, water intake, circadian activity levels, and behavior. LL animals had lower melatonin levels in the subjective dark compared to LD and DD animals. Food intake, relative food intake, and water intake values were lower and feed efficiency was more positive in LL animals compared to LD and DD animals. In addition, LL animals exhibited greater visceral adiposity than the other two groups. The circadian rhythmicity of activity became free-running in LL animals and there was a decrease in overall activity. Notable behavioral changes in LL animals were an increase in irritability and excitability. Results indicate that a decrease in melatonin levels and concomitant changes in metabolism, circadian rhythms, and behavior are consequences of exposure to constant light. PMID:19761654

  17. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant

    PubMed Central

    Izumo, Mariko; Pejchal, Martina; Schook, Andrew C; Lange, Ryan P; Walisser, Jacqueline A; Sato, Takashi R; Wang, Xiaozhong; Bradfield, Christopher A; Takahashi, Joseph S

    2014-01-01

    In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks, and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain. DOI: http://dx.doi.org/10.7554/eLife.04617.001 PMID:25525750

  18. Impact of nutrients on circadian rhythmicity

    PubMed Central

    Oosterman, Johanneke E.; Kalsbeek, Andries; la Fleur, Susanne E.

    2014-01-01

    The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock. PMID:25519730

  19. Effects of short-term feed deprivation and melatonin implants on circadian patterns of leptin in the horse.

    PubMed

    Buff, P R; Morrison, C D; Ganjam, V K; Keisler, D H

    2005-05-01

    Leptin is a protein hormone produced by adipose tissue that influences hypothalamic mechanisms regulating appetite and energy balance. In species tested thus far, including horses, concentrations of leptin increase as animal fat mass increases. The variables and mechanisms that influence the secretion of leptin are not well known, nor is it known in equine species how the secretion of leptin is influenced by acute alterations in energy balance, circadian patterns, and/or reproductive competence. Our objectives were to determine in horses: 1) whether plasma concentrations of leptin are secreted in a circadian and/or a pulsatile pattern; 2) whether a 48-h period of feed restriction would alter plasma concentrations of leptin, growth hormone, or insulin; and 3) whether ovariectomy and/or a melatonin implant would affect leptin. In Exp. 1, mares exposed to ambient photoperiod of visible light (11 h, 33 min to 11 h, 38 min), received treatments consisting of a 48-h feed restriction (RES) or 48 h of alfalfa hay fed ad libitum (FED). Mares were maintained in a dry lot before sampling and were tethered to a rail during sampling. Analyses revealed that leptin was not secreted in a pulsatile manner, and that mean leptin concentrations were greater (P < 0.001) in FED vs. RES mares (17.20 +/- 0.41 vs. 7.29 +/- 0.41 ng/mL). Plasma growth hormone was pulsatile, and mean concentrations were greater in RES than FED mares (2.15 +/- 0.31 vs. 1.08 +/- 0.31 ng/mL; P = 0.05). Circadian patterns of leptin secretion were observed, but only in FED mares (15.39 +/- 0.58 ng/mL for morning vs. 19.00 +/- 0.58 ng/mL for evening; P < 0.001). In Exp. 2, mares that were ovariectomized or intact received either a s.c. melatonin implant or a sham implant. Thereafter, blood was sampled at weekly intervals at 1000 and 1700. Concentrations of leptin in samples collected at 1700 were greater (P < 0.001) than in those collected at 1000 (28.24 +/- 1.7 vs. 22.07 +/- 1.7 ng/mL). Neither ovariectomy nor

  20. Circadian feeding entrains anticipatory metabolic activity in piriform cortex and olfactory tubercle, but not in suprachiasmatic nucleus.

    PubMed

    Olivo, Diana; Caba, Mario; Gonzalez-Lima, F; Vázquez, Araceli; Corona-Morales, Aleph

    2014-12-10

    Animals maintained under conditions of food-availability restricted to a specific period of the day show molecular and physiological circadian rhythms and increase their locomotor activity 2-3h prior to the next scheduled feeding, called food anticipatory activity (FAA). Although the anatomical substrates and underlying mechanisms of the food-entrainable oscillator are not well understood, experimental evidence indicates that it involves multiple structures and systems. Using rabbit pups entrained to circadian nursing as a natural model of food restriction, we hypothesized that the anterior piriform cortex (APCx) and the olfactory tubercle (OTu) are activated during nursing-associated FAA. Two groups of litters were entrained to one of two different nursing times. At postnatal day 7, when litters showed clear FAA, pups from each litter were euthanized at nursing time, or 1, 2, 4, 8, 12, 16 or 20h later. Neural metabolic activities of the APCx, OTu, olfactory bulb (OB) and suprachiasmatic nucleus (SCN) were assessed by cytochrome oxidase histochemistry. Additionally, two fasted groups were nurse-deprived for two cycles before being euthanized at postnatal day 9. In nursed pups, metabolic activity of APCx, OTu and OB increased during FAA and after feeding, independently of the geographical time. Metabolic activity in SCN was not affected by nursing schedule. Given that APCx and OTu are in a key network position to integrate temporal odor signals with body energetic state, brain arousal and reward mechanisms, we suggest that these structures could be an important part of the conditioned oscillatory mechanism that leads to food entrainment. PMID:25281805

  1. A Circadian Clock in the Olfactory Bulb Anticipates Feeding during Food Anticipatory Activity

    PubMed Central

    Nolasco, Nahum; Juárez, Claudia; Morgado, Elvira; Meza, Enrique; Caba, Mario

    2012-01-01

    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. PMID:23094084

  2. Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding.

    PubMed

    Tong, Xin; Muchnik, Marina; Chen, Zheng; Patel, Manish; Wu, Nan; Joshi, Shree; Rui, Liangyou; Lazar, Mitchell A; Yin, Lei

    2010-11-19

    Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding. PMID:20851878

  3. Entrainment of mouse peripheral circadian clocks to <24 h feeding/fasting cycles under 24 h light/dark conditions

    PubMed Central

    Hamaguchi, Yutaro; Tahara, Yu; Kuroda, Hiroaki; Haraguchi, Atsushi; Shibata, Shigenobu

    2015-01-01

    The circadian clock system in peripheral tissues can endogenously oscillate and is entrained by the light-dark and fasting-feeding cycles in mammals. Although the system’s range of entrainment to light-dark cycles with a non-24 h (<24 h) interval has been studied, the range of entrainment to fasting-feeding cycles with shorter periods (<24 h) has not been investigated in peripheral molecular clocks. In the present study, we measured this range by monitoring the mouse peripheral PER2::LUCIFERASE rhythm in vivo at different periods under each feeding cycle (Tau (T) = 15–24 h) under normal light-dark conditions. Peripheral clocks could be entrained to the feeding cycle with T = 22–24 h, but not to that with T = 15–21 h. Under the feeding cycle with T = 15–18 h, the peripheral clocks oscillated at near the 24-h period, suggesting that they were entrained to the light-dark cycle. Thus, for the first time, we demonstrated the range of entrainment to the non-24 h feeding cycle, and that the circadian range (T = 22–24 h) of feeding stimulus is necessary for peripheral molecular clock entrainment under light-dark cycles. PMID:26395309

  4. Restricted daytime feeding attenuates reentrainment of the circadian melatonin rhythm after an 8-h phase advance of the light-dark cycle.

    PubMed

    Kalsbeek, A; Barassin, S; van Heerikhuize, J J; van der Vliet, J; Buijs, R M

    2000-02-01

    It is well established that in the absence of photic cues, the circadian rhythms of rodents can be readily phase-shifted and entrained by various nonphotic stimuli that induce increased levels of locomotor activity (i.e., benzodiazepines, a new running wheel, and limited food access). In the presence of an entraining light-dark (LD) cycle, however, the entraining effects of nonphotic stimuli on (parts of) the circadian oscillator are far less clear. Yet, an interesting finding is that appropriately timed exercise after a phase shift can accelerate the entrainment of circadian rhythms to the new LD cycle in both rodents and humans. The present study investigated whether restricted daytime feeding (RF) (1) induces a phase shift of the melatonin rhythm under entrained LD conditions and (2) accelerates resynchronization of circadian rhythms after an 8-h phase advance. Animals were adapted to RF with 2-h food access at the projected time of the new dark onset. Before and at several time points after the 8-h phase advance, nocturnal melatonin profiles were measured in RF animals and animals on ad libitum feeding (AL). In LD-entrained conditions, RF did not cause any significant changes in the nocturnal melatonin profile as compared to AL. Unexpectedly, after the 8-h phase advance, RF animals resynchronized more slowly to the new LD cycle than AL animals. These results indicate that prior entrainment to a nonphotic stimulus such as RF may "phase lock" the circadian oscillator and in that way hinder resynchronization after a phase shift. PMID:10677017

  5. Circadian serum concentrations of tylosin in broilers after feed or water medication.

    PubMed

    Lilia, G; Aguilera, R; Cortés-Cuevas, A; Rosario, C; Sumano, H

    2008-09-01

    1. Because tylosin is a time-dependent antibacterial agent, and because feeding and drinking of broilers decreases in late afternoon and ceases in the dark, it was hypothesised that serum concentrations of this drug are greatly reduced during the dark period. 2. The trial was carried out in a commercial poultry house, under standard broiler husbandry conditions, with food and water withdrawn from 22:00 until 07:00 h next morning and exposed to a natural light cycle of 13L:11D. 3. Broilers were given tylosin tartrate, in either feed or water, for 5 d as follows: 100, 200 and 300 ppm in feed, equivalent to 12.6, 25.2 and 37.8 mg/kg/d, respectively; and 200 and 400 mg/l in drinking water, equivalent to 51 to 102 mg/kg/d, respectively. 4. At 07:00 h on d 4, and for the next 40 h, hourly serum samples were obtained and analysed for tylosin by means of a microbiological assay. 5. Day vs night concentrations of tylosin expressed as area under the curve (AUC) in all groups revealed greater values during the day. The highest AUC and AUC(24)/minimal inhibitory concentration (MIC) ratio were obtained in the group medicated with 400 mg/l and the corresponding lowest values were found in the group medicated with 100 ppm in feed. 6. In conclusion, tylosin did not reach therapeutic serum concentrations during the dark period, at all dose rates tested when administered in feed or water. A sustained release form of this drug is needed to solve this inadequacy of tylosin medication in broilers. PMID:18836909

  6. Synchronization to light and mealtime of the circadian rhythms of self-feeding behavior and locomotor activity of white shrimps (Litopenaeus vannamei).

    PubMed

    Santos, Aline Dos Anjos; López-Olmeda, José Fernando; Sánchez-Vázquez, Francisco Javier; Fortes-Silva, Rodrigo

    2016-09-01

    The role of light and feeding cycles in synchronizing self-feeding and locomotor activity rhythms was studied in white shrimps using a new self-feeding system activated by photocell trigger. In experiment 1, shrimps maintained under a 12:12h light/dark (LD) photoperiod were allowed to self-feed using feeders connected to a photoelectric cell, while locomotor activity was recorded with a second photocell. On day 30, animals were subjected to constant darkness (DD) for 12days to check the existence of endogenous circadian rhythms. In the experiment 2, shrimps were exposed to both a 12:12h LD photoperiod and a fixed meal schedule in the middle of the dark period (MD, 01:00h). On day 20, shrimps were exposed to DD conditions and the same fixed feeding. On day 30, they were maintained under DD and fasted for 7days. The results revealed that under LD, shrimps showed a clear nocturnal feeding pattern and locomotor activity (81.9% and 67.7% of total daily food-demands and locomotor activity, respectively, at nighttime). Both feeding and locomotor rhythms were endogenously driven and persisted under DD with an average period length (τ) close to 24h (circadian) (τ=24.18±0.13 and 23.87±0.14h for locomotor and feeding, respectively). Moreover, Shrimp showed a daily food intake under LD condition (1.1±0.2gday(-1) in the night phase vs. 0.2±0.1gday(-1) in the light phase). Our findings might be relevant for some important shrimp aquaculture aspects, such as developing suitable feeding management on shrimp farms. PMID:27155052

  7. Increased neuropeptide Y concentrations in the lateral hypothalamic area of the rat after the onset of darkness: Possible relevance to the circadian periodicity of feeding behavior

    SciTech Connect

    McKibbin, P.E.; Robers, P.; Williams, G. )

    1991-01-01

    Neuropeptide Y (NPY) is a major hypothalamic peptide which powerfully stimulates feeding when injected into the hypothalamus and is implicated in circadian rhythmicity. To investigate whether NPY is involved in the increased feeding that follows the onset of darkness in rats, NPY levels were measured in discrete hypothalamic areas before and after darkness. Four groups of eight adult female Wistar rats were habituated to a 12:12 hour light:dark cycle, with food presented at the onset of darkness (19.00 hours). Seven hypothalamic regions were microdissected from slices of fresh brain and acid-extracted for radioimmunoassay of NPY. NPY levels ((fmol/{mu}g) protein) were significantly higher in the lateral hypothalamic area (LHA) of the dark-phase group in both studies. In the other six regions, NPY levels did not differ between light and dark phases. The LHA regulates the circadian rhythmicity of feeding and NPY injection here stimulates feeding. Alterations in NPY in the LHA around the onset of darkness may be related to the initiation of dark-phase feeding.

  8. Synchronizing an aging brain: can entraining circadian clocks by food slow Alzheimer’s disease?

    PubMed Central

    Kent, Brianne A.

    2014-01-01

    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 behavior 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. PMID:25225484

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

    PubMed

    Kent, Brianne A

    2014-01-01

    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 behavior 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. PMID:25225484

  10. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan.

    PubMed

    Longo, Valter D; Panda, Satchidananda

    2016-06-14

    Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interventions into feasible, effective, and inexpensive treatments with the potential to improve healthspan. PMID:27304506

  11. Circadian Rhythms

    MedlinePlus

    ... chronobiology. Are circadian rhythms the same thing as biological clocks? No, but they are related. Our biological clocks drive our circadian rhythms. What are biological clocks? The biological clocks that control circadian rhythms ...

  12. Uncouplers of oxidative phosphorylation.

    PubMed

    Terada, H

    1990-07-01

    Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound. PMID:2176586

  13. Bacterial resistance to uncouplers.

    PubMed

    Lewis, K; Naroditskaya, V; Ferrante, A; Fokina, I

    1994-12-01

    Uncoupler resistance presents a potential challenge to the conventional chemiosmotic coupling mechanism. In E. coli, an adaptive response to uncouplers was found in cell growing under conditions requiring oxidative phosphorylation. It is suggested that uncoupler-resistant mutants described in the earlier literature might represent a constitutive state of expression of this "low energy shock" adaptive response. In the environment, bacteria are confronted by nonclassical uncoupling factors such as organic solvents, heat, and extremes of pH. It is suggested that the low energy shock response will aid the cell in coping with the effects of natural uncoupling factors. The genetic analysis of uncoupler resistance has only recently began, and is yielding interesting and largely unexpected results. In Bacillus subtilis, a mutation in fatty acid desaturase causes an increased content of saturated fatty acids in the membrane and increased uncoupler resistance. The protonophoric efficiency of uncouplers remains unchanged in the mutants, inviting nonorthodox interpretations of the mechanism of resistance. In E. coli, two loci conferring resistance to CCCP and TSA were cloned and were found to encode multidrug resistance pumps. Resistance to one of the uncouplers, TTFB, remained unchanged in strains mutated for the MDRs, suggesting a resistance mechanism different from uncoupler extrusion. PMID:7721726

  14. Uncouplers of oxidative phosphorylation.

    PubMed Central

    Terada, H

    1990-01-01

    Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound. PMID:2176586

  15. Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

    PubMed Central

    Mukherji, Atish; Kobiita, Ahmad; Chambon, Pierre

    2015-01-01

    The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα–RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs. PMID:26627259

  16. The relationship between feed efficiency and the circadian profile of blood plasma analytes measured in beef heifers at different physiological stages.

    PubMed

    Gonano, C V; Montanholi, Y R; Schenkel, F S; Smith, B A; Cant, J P; Miller, S P

    2014-10-01

    The characterization of blood metabolite concentrations over the circadian period and across physiological stages is important for understanding the biological basis of feed efficiency, and may culminate in indirect methods for assessing feed efficiency. Hematological analyses for albumin, urea, creatine kinase, glutamate dehydrogenase, aspartate aminotransferase, carbon dioxide, and acetate were carried out in growing and gestating heifers. These measures were carried out in a sample of 36 Bos taurus crossed beef heifers held under the same husbandry conditions. Hourly blood samples were collected over a 24-h period on three separate sampling occasions, corresponding approximately to the yearling (and open), early-gestation and late-gestation stages. This design was used to determine variation throughout the day, effects due to physiological status and any associations with feed efficiency, as measured by residual feed intake. Blood analyte levels varied with time of day, with the most variation occurring between 0800 and 1600 h. There were also considerable differences in analyte levels across the three physiological stages; for example, creatine kinase was higher (P<0.05) in open heifers, followed by early- and late-gestation heifers. Feed efficiency was also associated with analyte abundance. In more feed-efficient open heifers, there were higher activities of creatine kinase (P<0.05) and aspartate aminotransferase (P<0.05), and lower concentrations of carbon dioxide (P<0.05). Furthermore, in late gestation, more efficient heifers had lower urea concentrations (P<0.05) and lower creatine kinase levels (P<0.05). Over the whole experimental period, carbon dioxide concentrations were numerically lower in more feed efficient heifers (P=0.079). Differences were also observed across physiological stages. For instance, open heifers had increased levels (P<0.05) of creatine kinase, aspartate aminotransferase, carbon dioxide than early and late pregnancy heifers. In

  17. Effect of acetic acid feeding on the circadian changes in glycogen and metabolites of glucose and lipid in liver and skeletal muscle of rats.

    PubMed

    Fushimi, Takashi; Sato, Yuzo

    2005-11-01

    The aim of the present study is to investigate the effect of acetic acid feeding on the circadian changes in glycogen concentration in liver and skeletal muscle. Rats were provided meal once daily (09.00-13.00 hours) for 10 d. On the 11th day, they were either killed immediately or given 9 g diet containing either 0 (control) or 0.7 g/kg-diet acetic acid beginning at 09.00 hours for 4 h, as in the previous regimen. Rats in the fed group were killed at 4, 8 or 24 h after the start of feeding. At 4 h after the start of feeding, the acetic acid group had significantly greater liver and gastrocnemius muscle glycogen concentrations (P<0.05). Also, at this same point, liver xylulose-5-phosphate, a key stimulator of glycolysis, the ratio of fructose-1,6-bisphosphate to fructose-6-phosphate in skeletal muscle, which reflects phosphofructokinase-1 activity, and liver malonyl-CoA, an allosteric inhibitor of carnitine palmitoyl-transferase, were significantly lower in the acetic acid group than in the control group (P<0.05). In addition, the acetic acid group had a significantly lower serum lactate concentration and lower ratio of insulin to glucagon than the control group at the same point (P<0.05). We conclude that a diet containing acetic acid may enhance glycogen repletion but not induce supercompensation, a large increase in the glycogen level that is beneficial in improving performance, in liver and skeletal muscle by transitory inhibition of glycolysis. Further, we indicate the possibility of a transient enhancement of fatty acid oxidation in liver by acetic acid feeding. PMID:16277773

  18. Nutrition and the Circadian System

    PubMed Central

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

    2016-01-01

    The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partition 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 hour 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’ (HFDs) 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 HFDs 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

  19. Nutrition and the circadian system.

    PubMed

    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

  20. Phenotyping Circadian Rhythms in Mice.

    PubMed

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    Circadian rhythms take place with a periodicity of 24 hr, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the "central pacemaker" of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hr as manifest when an animal is placed into constant dark or "free-running" conditions. Simple measurements of an organism's activity in free-running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their homecage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are presented here including the process of entrainment, determination of tau (period length) in free-running conditions, determination of circadian periodicity in response to light disruption (e.g., jet lag studies), and evaluation of clock plasticity in non-24-hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of environmental surroundings. PMID:26331760

  1. Transient Uncoupling Induces Synchronization

    NASA Astrophysics Data System (ADS)

    Schröder, Malte; Mannattil, Manu; Dutta, Debabrata; Chakraborty, Sagar; Timme, Marc

    2015-07-01

    Finding conditions that support synchronization is a fertile and active area of research with applications across multiple disciplines. Here we present and analyze a scheme for synchronizing chaotic dynamical systems by transiently uncoupling them. Specifically, systems coupled only in a fraction of their state space may synchronize even if fully coupled they do not. While for many standard systems coupling strengths need to be bounded to ensure synchrony, transient uncoupling removes this bound and thus enables synchronization in an infinite range of effective coupling strengths. The presented coupling scheme therefore opens up the possibility to induce synchrony in (biological or technical) systems whose parameters are fixed and cannot be modified continuously.

  2. Transient Uncoupling Induces Synchronization.

    PubMed

    Schröder, Malte; Mannattil, Manu; Dutta, Debabrata; Chakraborty, Sagar; Timme, Marc

    2015-07-31

    Finding conditions that support synchronization is a fertile and active area of research with applications across multiple disciplines. Here we present and analyze a scheme for synchronizing chaotic dynamical systems by transiently uncoupling them. Specifically, systems coupled only in a fraction of their state space may synchronize even if fully coupled they do not. While for many standard systems coupling strengths need to be bounded to ensure synchrony, transient uncoupling removes this bound and thus enables synchronization in an infinite range of effective coupling strengths. The presented coupling scheme therefore opens up the possibility to induce synchrony in (biological or technical) systems whose parameters are fixed and cannot be modified continuously. PMID:26274420

  3. Uncouplers and the molecular mechanism of uncoupling in mitochondria.

    PubMed Central

    Kessler, R J; Vande Zande, H; Tyson, C A; Blondin, G A; Fairfield, J; Glasser, P; Green, D E

    1977-01-01

    Uncouplers are molecules with protonophoric and ionophoric capabilities that mediate coupled cyclical transport of cations--a transport that takes precedence over all other coupled processes. Uncouplers form cation-containing complexes with electrogenic ionophores that potentiate cyclical transport of cations. The molecular mechanism of uncoupling sheds strong light on the mechanism of coupling. PMID:142250

  4. CIRCADIAN REGULATION OF METABOLISM

    PubMed Central

    Bailey, Shannon M.; Udoh, Uduak S.; Young, Martin E.

    2014-01-01

    In association with sleep/wake and fasting/feeding cycles, organisms experience dramatic oscillations in energetic demands and nutrient supply. It is therefore not surprising that various metabolic parameters, ranging from the activity status of molecular energy sensors to circulating nutrient levels, oscillate in time-of-day-dependent manners. It has become increasingly clear that rhythms in metabolic processes are not simply in response to daily environmental/behavioral influences, but are driven in part by cell autonomous circadian clocks. By synchronizing the cell with its environment, clocks modulate a host of metabolic processes in a temporally appropriate manner. The purpose of this article is to review current understanding of the interplay between circadian clocks and metabolism, in addition to the pathophysiologic consequences of disruption of this molecular mechanism, in terms of cardiometabolic disease development. PMID:24928941

  5. Ablation of the Id2 Gene Results in Altered Circadian Feeding Behavior, and Sex-Specific Enhancement of Insulin Sensitivity and Elevated Glucose Uptake in Skeletal Muscle and Brown Adipose Tissue

    PubMed Central

    Mathew, Deepa; Zhou, Peng; Pywell, Cameron M.; van der Veen, Daan R.; Shao, Jinping; Xi, Yang; Bonar, Nicolle A.; Hummel, Alyssa D.; Chapman, Sarah; Leevy, W. Matthew; Duffield, Giles E.

    2013-01-01

    Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our earlier studies have demonstrated a role for ID2 in the input pathway, core clock function and output pathways of the mouse circadian system. We have also reported that Id2 null (Id2−/−) mice are lean with low gonadal white adipose tissue deposits and lower lipid content in the liver. These results coincided with altered or disrupted circadian expression profiles of liver genes including those involved in lipid metabolism. In the present phenotypic study we intended to decipher, on a sex-specific basis, the role of ID2 in glucose metabolism and in the circadian regulation of activity, important components of energy balance. We find that Id2−/− mice exhibited altered daily and circadian rhythms of feeding and locomotor activity; activity profiles extended further into the late night/dark phase of the 24-hr cycle, despite mice showing reduced total locomotor activity. Also, male Id2−/− mice consumed a greater amount of food relative to body mass, and displayed less weight gain. Id2−/− females had smaller adipocytes, suggesting sexual-dimorphic programing of adipogenesis. We observed increased glucose tolerance and insulin sensitivity in male Id2−/− mice, which was exacerbated in older animals. FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue of male Id2−/− mice, suggesting increased glucose metabolism and thermogenesis in these tissues. Reductions in intramuscular triacylglycerol and diacylglycerol were detected in male Id2−/− mice, highlighting its possible mechanistic role in enhanced insulin sensitivity in these mice. Our findings indicate a role for ID2 as a regulator of glucose and lipid metabolism, and in the circadian control of feeding/locomotor behavior; and contribute to the understanding of the development of obesity and diabetes, particularly in shift

  6. Central and peripheral circadian clocks in mammals.

    PubMed

    Mohawk, Jennifer A; Green, Carla B; Takahashi, Joseph S

    2012-01-01

    The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism. PMID:22483041

  7. Phenotyping Circadian Rhythms in Mice

    PubMed Central

    Eckel-Mahan, Kristin; Sassone-Corsi, Paolo

    2015-01-01

    Circadian rhythms take place with a periodicity of twenty-four hours, temporally following the rotation of the earth around its axis. Examples of circadian rhythms are the sleep/wake cycle, feeding, and hormone secretion. Light powerfully entrains the mammalian clock and assists in keeping animals synchronized to the 24-hour cycle of the earth by activating specific neurons in the “central pacemaker” of the brain, the suprachiasmatic nucleus. Absolute periodicity of an animal can deviate slightly from 24 hours as manifest when an animal is placed into constant dark- or “free running”- conditions. Simple measurements of an organism's activity in free running conditions reveal its intrinsic circadian period. Mice are a particularly useful model for studying circadian rhythmicity due to the ease of genetic manipulation, thus identifying molecular contributors to rhythmicity. Furthermore, their small size allows for monitoring locomotion or activity in their home cage environment with relative ease. Several tasks commonly used to analyze circadian periodicity and plasticity in mice are outlined here including the process of entrainment, determination of tau (period length) in free running conditions, determination of circadian periodicity in response to light disruption (i.e. jet lag studies), and evaluation of clock plasticity in non-twenty-four hour conditions (T-cycles). Studying the properties of circadian periods such as their phase, amplitude, and length in response to photic perturbation, can be particularly useful in understanding how humans respond to jet lag, night shifts, rotating shifts, or other transient or chronic disruption of one's environmental surroundings. PMID:26331760

  8. Circadian regulation of renal function.

    PubMed

    Firsov, Dmitri; Bonny, Olivier

    2010-10-01

    Urinary excretion of water and all major electrolytes exhibit robust circadian oscillations. The 24-h periodicity has been well documented for several important determinants of urine formation, including renal blood flow, glomerular filtration, tubular reabsorption, and tubular secretion. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids that are entrained by rest/activity and feeding/fasting cycles. However, numerous studies have shown that most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock made of a system of autoregulatory transcriptional/translational feedback loops, which have been found in all tissues studied, including the kidney. Here, we present a review of the growing evidence showing the involvement of the molecular clock in the generation of renal excretory rhythms. PMID:20664559

  9. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans.

    PubMed

    Morris, Christopher J; Yang, Jessica N; Garcia, Joanna I; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M; Shea, Steven A; Scheer, Frank A J L

    2015-04-28

    Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers. PMID:25870289

  10. Circadian rhythms, alcohol and gut interactions

    PubMed Central

    Forsyth, Christopher B.; Voigt, Rbin M.; Burgess, Helen J.; Swanson, Garth R.; Keshavarzian, Ali

    2015-01-01

    The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20–30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyper-permeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in ClockΔ19 mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our

  11. Achromatic and Uncoupled Medical Gantry

    NASA Astrophysics Data System (ADS)

    Tsoupas, N.; Kayran, D.; Litvinenko, V.

    One of the functions of a medical gantry is to irradiate a tumor from different angles to reduce the dose received by the healthy tissue which surrounds the tumor. The rotation of the gantry rotates also its quadrupoles that focus the beam, as a result the beam is "coupled" in the sense that the horizontal motion of the beam particles is affected by the vertical motion and vice-versa therefore the beam spot size at the tumor may vary with the angular orientation of the gantry. Although such a beam-coupling is inevitable in a rotated gantry in which the horizontal plane is not the symmetry plane of the quadrupoles, it is possible to find a solution that the optics of the gantry"appears uncoupled" at any angular orientation of the gantry. As we show in the paper, the condition of an uncoupled gantry is equivalent to an uncoupled linear-beam-transport-matrix which is independent of the angular orientation of the gantry, therefore the beam spot size at the location of the tumor is independent of the orientation of the gantry. In this paper we present the theoretical basis to generate the beam optics for a gantry which is constrained to provide uncoupled and also achromatic beamtransport to the location of the tumor. In addition we present the layout of the magnetic elements and the optics of a medical gantrywhich satisfies the achromaticity and uncoupled conditions.

  12. [The kidney and circadian rhythms: a whole new world?].

    PubMed

    Manfredini, Roberto; Sasso, Ferdinando Carlo; Pala, Marco; De Giorgi, Alfredo; Fabbian, Fabio

    2013-01-01

    Chronobiology is a branch of biomedical sciences devoted to the study of biological rhythms. Biological rhythms exist at any level of living organisms and, according to their cycle length, may be divided into three main types: circadian, ultradian, and infradian rhythms. Circadian rhythms are the most commonly and widely studied. The principal circadian clock is located in the suprachiasmatic nucleus of the hypothalamus, and is supposed to regulate peripheral clocks via neurohumoral modulation. Circadian clocks have been identified within almost all mammalian cell types, and circadian clock genes seem to be essential for cardiovascular health. Disturbance of the renal circadian rhythms is increasingly recognized as a risk factor for hypertension, polyuria, and other diseases and may contribute to renal fibrosis. The origin of these rhythms has been attributed to the reactive response of the kidney to circadian changes in volume and/or in the composition of extracellular fluids regulated by rest/activity and feeding/fasting cycles. However, most of the renal excretory rhythms persist for long periods of time, even in the absence of periodic environmental cues. These observations led to the hypothesis of the existence of a self-sustained mechanism, enabling the kidney to anticipate various predictable circadian challenges to homeostasis. The molecular basis of this mechanism remained unknown until the recent discovery of the mammalian circadian clock, comprising a system of autoregulatory transcriptional/translational feedback loops, which have also been found in the kidney. PMID:24403200

  13. Uncoupling Mitochondrial Respiration for Diabesity.

    PubMed

    Larrick, James W; Larrick, Jasmine W; Mendelsohn, Andrew R

    2016-08-01

    Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway to uncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibits catalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act as endogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration of PM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance by increasing energy expenditure. In short-term studies, treated animals exhibit no toxicity while experiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway may identify novel therapies for diabesity, the disease state associated with diabetes and obesity. PMID:27378359

  14. Circadian rhythms of clock gene expression in Nile tilapia (Oreochromis niloticus) central and peripheral tissues: influence of different lighting and feeding conditions.

    PubMed

    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

  15. Synchronizing noisy nonidentical oscillators by transient uncoupling

    NASA Astrophysics Data System (ADS)

    Tandon, Aditya; Schröder, Malte; Mannattil, Manu; Timme, Marc; Chakraborty, Sagar

    2016-09-01

    Synchronization is the process of achieving identical dynamics among coupled identical units. If the units are different from each other, their dynamics cannot become identical; yet, after transients, there may emerge a functional relationship between them—a phenomenon termed "generalized synchronization." Here, we show that the concept of transient uncoupling, recently introduced for synchronizing identical units, also supports generalized synchronization among nonidentical chaotic units. Generalized synchronization can be achieved by transient uncoupling even when it is impossible by regular coupling. We furthermore demonstrate that transient uncoupling stabilizes synchronization in the presence of common noise. Transient uncoupling works best if the units stay uncoupled whenever the driven orbit visits regions that are locally diverging in its phase space. Thus, to select a favorable uncoupling region, we propose an intuitive method that measures the local divergence at the phase points of the driven unit's trajectory by linearizing the flow and subsequently suppresses the divergence by uncoupling.

  16. Molecular components of the circadian clock in mammals.

    PubMed

    Takahashi, J S

    2015-09-01

    The circadian clock mechanism in animals involves a transcriptional feedback loop in which the bHLH-PAS proteins CLOCK and BMAL1 form a transcriptional activator complex to activate the transcription of the Period and Cryptochrome genes, which in turn feed back to repress their own transcription. In the mouse liver, CLOCK and BMAL1 interact with the regulatory regions of thousands of genes, which are both cyclically and constitutively expressed. The circadian transcription in the liver is clustered in phase and this is accompanied by circadian occupancy of RNA polymerase II recruitment and initiation. These changes also lead to circadian fluctuations in histone H3 lysine4 trimethylation (H3K4me3) as well as H3 lysine9 acetylation (H3K9ac) and H3 lysine27 acetylation (H3K27ac). Thus, the circadian clock regulates global transcriptional poise and chromatin state by regulation of RNA polymerase II. PMID:26332962

  17. Nutrient Sensing and the Circadian Clock

    PubMed Central

    Peek, Clara B.; Ramsey, Kathryn M.; Marcheva, Biliana; Bass, Joseph

    2012-01-01

    The circadian system synchronizes behavioral and physiologic 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 hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24hr oscillations of energy storage and utilization. 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. Here, we highlight the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems. PMID:22424658

  18. Klf15 orchestrates circadian nitrogen homeostasis

    PubMed Central

    Jeyaraj, Darwin; Scheer, Frank A.J.L.; Ripperger, Jürgen A.; Haldar, Saptarsi M.; Lu, Yuan; Prosdocimo, Domenick A.; Eapen, Sam J.; Eapen, Betty L.; Cui, Yingjie; Mahabeleshwar, Ganapathi H.; Lee, Hyoung-gon; Smith, Mark A.; Casadesus, Gemma; Mintz, Eric M.; Sun, Haipeng; Wang, Yibin; Ramsey, Kathryn M.; Bass, Joseph; Shea, Steven A.; Albrecht, Urs; Jain, Mukesh K.

    2012-01-01

    SUMMARY Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis still expressed endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor15. PMID:22405069

  19. Circadian Clocks and Metabolism

    PubMed Central

    Marcheva, Biliana; Ramsey, Kathryn M.; Peek, Clara B.; Affinati, Alison; Maury, Eleonore; Bass, Joseph

    2014-01-01

    Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health. PMID:23604478

  20. Achromatic and uncoupled medical gantry

    DOEpatents

    Tsoupas, Nicholaos; Kayran, Dmitry; Litvinenko, Vladimir; MacKay, William W.

    2011-11-22

    A medical gantry that focus the beam from the beginning of the gantry to the exit of the gantry independent of the rotation angle of the gantry by keeping the beam achromatic and uncoupled, thus, avoiding the use of collimators or rotators, or additional equipment to control the beam divergence, which may cause beam intensity loss or additional time in irradiation of the patient, or disadvantageously increase the overall gantry size inapplicable for the use in the medical treatment facility.

  1. Lactating performance, water and feed consumption of rabbit does reared under a Mediterranean summer circadian cycle of temperature v. comfort temperature conditions.

    PubMed

    Bakr, M H; Tusell, L; Rafel, O; Terré, M; Sánchez, J P; Piles, M

    2015-07-01

    The general aim of this research was to study the effect of high ambient temperature on the performance of does during lactation, specifically the following factors: average daily feed (ADFI) and water (ADWI) intakes, daily milk yield (DMY); milk composition: dry matter (DM), CP and gross energy (GE); doe BW (DW); individual kit weaning weight (IWW) and litter survival rate during lactation (SR). The study was undertaken comparing the performance of two groups of contemporary does reared under the same management, feeding regime and environmental conditions, except the environmental temperature and humidity. A total of 80 females were randomly allocated, at 60 days of age, into two identical and continuous rooms. In one room, the temperature was maintained permanently within the thermo-neutral zone (between 18°C to 22°C); thus, environmental conditions in this room were considered as comfort conditions. In the second room, the environmental temperature pattern simulated the daily temperature cycles that were characteristic of the summer in Mediterranean countries (24°C at 0800 h, increasing up to 29°C until 1100 h; maintenance at 29°C to 31°C for 4 h and decreasing to about 24°C to 26°C around 1700 h until 0800 h of the following day), which were considered as thermal stress conditions. Females followed a semi-intensive reproductive rhythm, first artificial insemination at 4.5 months of age, with subsequent 42-day reproductive cycles. Traits were recorded from a total of 138 lactations. Does were controlled up to the 5th lactation. Data were analyzed using linear and linear mixed models. High ambient temperature led to a lower ADFI (-9.4%), DW (-6.2%) and IWW (-8%), but it did not affect ADWI. No significant difference was found either for DMY, milk composition (DM, CP and GE) and SR during the lactation period. Heat stress was moderate, and does were able to adapt to it behaviorally by decreasing feed intake (to reduce heat production), but also live

  2. Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice

    PubMed Central

    Peek, Clara Bien; Affinati, Alison H.; Ramsey, Kathryn Moynihan; Kuo, Hsin-Yu; Yu, Wei; Sena, Laura A.; Ilkayeva, Olga; Marcheva, Biliana; Kobayashi, Yumiko; Omura, Chiaki; Levine, Daniel C.; Bacsik, David J.; Gius, David; Newgard, Christopher B.; Goetzman, Eric; Chandel, Navdeep S.; Denu, John M.; Mrksich, Milan; Bass, Joseph

    2014-01-01

    Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD+) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD+ supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD+ bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding. PMID:24051248

  3. Circadian Disruption Leads to Loss of Homeostasis and Disease

    PubMed Central

    Escobar, Carolina; Salgado-Delgado, Roberto; Gonzalez-Guerra, Eduardo; Tapia Osorio, Araceli; Angeles-Castellanos, Manuel; Buijs, Ruud M.

    2011-01-01

    The relevance of a synchronized temporal order for adaptation and homeostasis is discussed in this review. We present evidence suggesting that an altered temporal order between the biological clock and external temporal signals leads to disease. Evidence mainly based on a rodent model of “night work” using forced activity during the sleep phase suggests that altered activity and feeding schedules, out of phase from the light/dark cycle, may be the main cause for the loss of circadian synchrony and disease. It is proposed that by avoiding food intake during sleep hours the circadian misalignment and adverse consequences can be prevented. This review does not attempt to present a thorough revision of the literature, but instead it aims to highlight the association between circadian disruption and disease with special emphasis on the contribution of feeding schedules in circadian synchrony. PMID:23471148

  4. Metabolic Effects of Bariatric Surgery in Mouse Models of Circadian Disruption

    PubMed Central

    Arble, Deanna M.; Sandoval, Darleen A.; Turek, Fred W.; Woods, Stephen C.; Seeley, Randy J.

    2015-01-01

    Background/Objectives Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (e.g., night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared to the non-disrupted population. However, it is unclear if the obesity and obesity-related disorders associated with circadian disruption respond to therapeutic treatments as well as individuals with other types of obesity. Subjects/Methods Here, we test the effectiveness of the commonly used bariatric surgical procedure, Vertical Sleeve Gastrectomy (VSG) in mouse models of genetic and environmental circadian disruption. Results VSG led to a reduction in body weight and fat mass in both ClockΔ19 mutant and constant-light mouse models (P < .05), resulting in an overall metabolic improvement independent of circadian disruption. Interestingly, the decrease in body weight occurred without altering diurnal feeding or activity patterns (P > .05). Within circadian-disrupted models, VSG also led to improved glucose tolerance and lipid handling (P < .05). Conclusions Together these data demonstrate that VSG is an effective treatment for the obesity associated with circadian disruption, and that the potent effects of bariatric surgery are orthogonal to circadian biology. However, since the effects of bariatric surgery are independent of circadian disruption, VSG cannot be considered a cure for circadian disruption. These data have important implications for circadian-disrupted obese patients. Moreover, these results reveal new information about the metabolic pathways governing the effects of bariatric surgery as well as of circadian disruption. PMID:25869599

  5. Mitochondrial uncouplers with an extraordinary dynamic range.

    PubMed

    Lou, Phing-How; Hansen, Birgit S; Olsen, Preben H; Tullin, Søren; Murphy, Michael P; Brand, Martin D

    2007-10-01

    We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 10(6) in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate. Covalent attachment of the uncoupler to a mitochondrially targeted hydrophobic cation sensitizes it to membrane potential, giving a small additional effect. The wide dynamic range of these uncouplers in isolated mitochondria and intact cells reveals a novel allosteric activation of proton transport through the adenine nucleotide translocase and provides a promising starting point for designing safer uncouplers for obesity therapy. PMID:17608618

  6. Mitochondrial uncouplers with an extraordinary dynamic range

    PubMed Central

    Lou, Phing-How; Hansen, Birgit S.; Olsen, Preben H.; Tullin, Søren; Murphy, Michael P.; Brand, Martin D.

    2007-01-01

    We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 106 in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate. Covalent attachment of the uncoupler to a mitochondrially targeted hydrophobic cation sensitizes it to membrane potential, giving a small additional effect. The wide dynamic range of these uncouplers in isolated mitochondria and intact cells reveals a novel allosteric activation of proton transport through the adenine nucleotide translocase and provides a promising starting point for designing safer uncouplers for obesity therapy. PMID:17608618

  7. Characterization of peripheral circadian clocks in adipose tissues.

    PubMed

    Zvonic, Sanjin; Ptitsyn, Andrey A; Conrad, Steven A; Scott, L Keith; Floyd, Z Elizabeth; Kilroy, Gail; Wu, Xiying; Goh, Brian C; Mynatt, Randall L; Gimble, Jeffrey M

    2006-04-01

    First described in the suprachiasmatic nucleus, circadian clocks have since been found in several peripheral tissues. Although obesity has been associated with dysregulated circadian expression profiles of leptin, adiponectin, and other fat-derived cytokines, there have been no comprehensive analyses of the circadian clock machinery in adipose depots. In this study, we show robust and coordinated expression of circadian oscillator genes (Npas2, Bmal1, Per1-3, and Cry1-2) and clock-controlled downstream genes (Rev-erb alpha, Rev-erb beta, Dbp, E4bp4, Stra13, and Id2) in murine brown, inguinal, and epididymal (BAT, iWAT, and eWAT) adipose tissues. These results correlated with respective gene expression in liver and the serum markers of circadian function. Through Affymetrix microarray analysis, we identified 650 genes that shared circadian expression profiles in BAT, iWAT, and liver. Furthermore, we have demonstrated that temporally restricted feeding causes a coordinated phase-shift in circadian expression of the major oscillator genes and their downstream targets in adipose tissues. The presence of circadian oscillator genes in fat has significant metabolic implications, and their characterization may have potential therapeutic relevance with respect to the pathogenesis and treatment of diseases such as obesity, type 2 diabetes, and the metabolic syndrome. PMID:16567517

  8. Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators

    PubMed Central

    Malloy, Jaclyn N.; Paulose, Jiffin K.; Li, Ye

    2012-01-01

    Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the β-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system. PMID:22723262

  9. The Arabidopsis Circadian System

    PubMed Central

    McClung, C. Robertson; Salomé, Patrice A.; Michael, Todd P.

    2002-01-01

    Rhythms with periods of approximately 24 hr are widespread in nature. Those that persist in constant conditions are termed circadian rhythms and reflect the activity of an endogenous biological clock. Plants, including Arabidopsis, are richly rhythmic. Expression analysis, most recently on a genomic scale, indicates that the Arabidopsis circadian clock regulates a number of key metabolic pathways and stress responses. A number of sensitive and high-throughput assays have been developed to monitor the Arabidopsis clock. These assays have facilitated the identification of components of plant circadian systems through genetic and molecular biological studies. Although much remains to be learned, the framework of the Arabidopsis circadian system is coming into focus. Dedication This review is dedicated to the memory of DeLill Nasser, a wonderful mentor and an unwavering advocate of both Arabidopsis and circadian rhythms research. PMID:22303209

  10. Mechanism of uncoupling in mitochondria: uncouplers as ionophores for cycling cations and protons.

    PubMed Central

    Kessler, R J; Tyson, C A; Green, D E

    1976-01-01

    Classical uncouplers such as 2,4-dinitrophenol have been shown to be ionophores with the capability for transporting monovalent or divalent cations with equal efficiency. The conditions appropriate for the maximal expression of this ionophoric capability have been explored. Two critical factors are the polarity of the organic phase and the pH of the aqueous phase that is equilibrated with the organic phase. The demonstrated cationic ionophoric capability of uncouplers, taken in conjunction with the known ability of uncouplers to cycle protons across a membrane phase, provides the experimental basis for the thesis that uncoupling of electron flow from ATP synthesis via classical uncouplers involves the substitution of one coupled process by another. Uncoupling thus reduces to the replacement of one driven reaction (ATP synthesis) by the driven reaction (cyclical transport) mediated by the uncoupler. PMID:9641

  11. Oxyntomodulin regulates resetting of the liver circadian clock by food.

    PubMed

    Landgraf, Dominic; Tsang, Anthony H; Leliavski, Alexei; Koch, Christiane E; Barclay, Johanna L; Drucker, Daniel J; Oster, Henrik

    2015-01-01

    Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues. PMID:25821984

  12. Biophotonics: Circadian photonics

    NASA Astrophysics Data System (ADS)

    Rea, Mark S.

    2011-05-01

    A growing body of medical evidence suggests that disrupting the body's biological clock can have adverse effects on health. Researchers are now creating the photonic tools to monitor, predict and influence the circadian rhythm.

  13. Nuclear receptors linking circadian rhythms and cardiometabolic control

    PubMed Central

    Duez, Hélène; Staels, Bart

    2010-01-01

    Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep(fasting)/wake(feeding) cycles as well as metabolic regulation display diurnal rhythms. The biological clock ensures proper metabolic alignment of energy substrate availability and processing. Studies in animals and humans highlight a strong link between circadian disorders and altered metabolic responses and cardiovascular events. Shiftwork, for instance, increases the risk to develop metabolic abnormalities resembling the Metabolic Syndrome. Nuclear receptors have long been known as metabolic regulators. Several of them (ie. Rev-erbα, RORα, PPARs) are subjected to circadian variations and are integral components of the molecular clock machinery. In turn, these nuclear receptors regulate downstream target genes in a circadian manner, acting to properly gate metabolic events to the appropriate circadian time window. PMID:20631353

  14. Physiology of circadian entrainment.

    PubMed

    Golombek, Diego A; Rosenstein, Ruth E

    2010-07-01

    Mammalian circadian rhythms are controlled by endogenous biological oscillators, including a master clock located in the hypothalamic suprachiasmatic nuclei (SCN). Since the period of this oscillation is of approximately 24 h, to keep synchrony with the environment, circadian rhythms need to be entrained daily by means of Zeitgeber ("time giver") signals, such as the light-dark cycle. Recent advances in the neurophysiology and molecular biology of circadian rhythmicity allow a better understanding of synchronization. In this review we cover several aspects of the mechanisms for photic entrainment of mammalian circadian rhythms, including retinal sensitivity to light by means of novel photopigments as well as circadian variations in the retina that contribute to the regulation of retinal physiology. Downstream from the retina, we examine retinohypothalamic communication through neurotransmitter (glutamate, aspartate, pituitary adenylate cyclase-activating polypeptide) interaction with SCN receptors and the resulting signal transduction pathways in suprachiasmatic neurons, as well as putative neuron-glia interactions. Finally, we describe and analyze clock gene expression and its importance in entrainment mechanisms, as well as circadian disorders or retinal diseases related to entrainment deficits, including experimental and clinical treatments. PMID:20664079

  15. Circadian clocks and breast cancer.

    PubMed

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

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome. PMID:27590298

  16. Trifluoromethanesulfonamide anthelmintics. Protonophoric uncouplers of oxidative phosphorylation.

    PubMed

    McCracken, R O; Carr, A W; Stillwell, W H; Lipkowitz, K B; Boisvenue, R; O'Doherty, G O; Wickiser, D I

    1993-05-01

    A series of trifluoromethanesulfonamides (TFMS) was synthesized and tested for uncoupling activity in rat liver mitochondria. With succinate as the mitochondrial substrate, and the respiratory control index (RCI) as an indicator of their uncoupling ability, we found that all of the TFMS tested were uncouplers of oxidative phosphorylation; the effective concentration (RCI I50) ranged from less than 1 microM to greater than 1000 microM. Correlation techniques were used to assess the strength of the relationship between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower the electrical resistance of planar bimolecular lipid membranes. There was a highly significant (P < 0.001) positive linear relationship (r = 0.97) between the ability of a TFMS to uncouple oxidative phosphorylation and its ability to lower electrical resistance. These findings are consistent with the view that the TFMS are lipophilic protonophoric uncouplers of mitochondrial oxidative phosphorylation. Quantitative structure-activity relationship studies using experiment and semiempirical molecular orbital theory revealed that the hydrophobicity of a TFMS and its molecular dipole moment were the principal determinants of mitochondrial uncoupling activity within the pKa range examined. PMID:8388210

  17. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock

    PubMed Central

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

    2015-01-01

    In mammals, multiple physiological, metabolic, and behavioral processes are subject to circadian rhythms, adapting to changing light in the environment. Here we analyzed circadian rhythms in the fecal microbiota of mice using deep sequencing, and found that the absolute amount of fecal bacteria and the abundance of Bacteroidetes exhibited circadian rhythmicity, which was more pronounced in female mice. Disruption of the host circadian clock by deletion of Bmal1, a gene encoding a core molecular clock component, abolished rhythmicity in the fecal microbiota composition in both genders. Bmal1 deletion also induced alterations in bacterial abundances in feces, with differential effects based on sex. Thus, although host behavior, such as time of feeding, is of recognized importance, here we show that sex interacts with the host circadian clock, and they collectively shape the circadian rhythmicity and composition of the fecal microbiota in mice. PMID:26240359

  18. Circadian Rhythms in Cyanobacteria.

    PubMed

    Cohen, Susan E; Golden, Susan S

    2015-12-01

    Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718

  19. Socially synchronized circadian oscillators

    PubMed Central

    Bloch, Guy; Herzog, Erik D.; Levine, Joel D.; Schwartz, William J.

    2013-01-01

    Daily rhythms of physiology and behaviour are governed by an endogenous timekeeping mechanism (a circadian ‘clock’). The alternation of environmental light and darkness synchronizes (entrains) these rhythms to the natural day–night cycle, and underlying mechanisms have been investigated using singly housed animals in the laboratory. But, most species ordinarily would not live out their lives in such seclusion; in their natural habitats, they interact with other individuals, and some live in colonies with highly developed social structures requiring temporal synchronization. Social cues may thus be critical to the adaptive function of the circadian system, but elucidating their role and the responsible mechanisms has proven elusive. Here, we highlight three model systems that are now being applied to understanding the biology of socially synchronized circadian oscillators: the fruitfly, with its powerful array of molecular genetic tools; the honeybee, with its complex natural society and clear division of labour; and, at a different level of biological organization, the rodent suprachiasmatic nucleus, site of the brain's circadian clock, with its network of mutually coupled single-cell oscillators. Analyses at the ‘group’ level of circadian organization will likely generate a more complex, but ultimately more comprehensive, view of clocks and rhythms and their contribution to fitness in nature. PMID:23825203

  20. Circadian Rhythm Sleep Disorders

    PubMed Central

    Kim, Min Ju; Lee, Jung Hie; Duffy, Jeanne F.

    2014-01-01

    Objective To review circadian rhythm sleep disorders, including underlying causes, diagnostic considerations, and typical treatments. Methods Literature review and discussion of specific cases. Results Survey studies 1,2 suggest that up to 3% of the adult population suffers from a circadian rhythm sleep disorder (CRSD). However, these sleep disorders are often confused with insomnia, and an estimated 10% of adult and 16% of adolescent sleep disorders patients may have a CRSD 3-6. While some CRSD (such as jet lag) can be self-limiting, others when untreated can lead to adverse medical, psychological, and social consequences. The International Classification of Sleep Disorders classifies CRSD as dyssomnias, with six subtypes: Advanced Sleep Phase Type, Delayed Sleep Phase Type, Irregular Sleep Wake Type, Free Running Type, Jet Lag Type, and Shift Work Type. The primary clinical characteristic of all CRSD is an inability to fall asleep and wake at the desired time. It is believed that CRSD arise from a problem with the internal biological clock (circadian timing system) and/or misalignment between the circadian timing system and the external 24-hour environment. This misalignment can be the result of biological and/or behavioral factors. CRSD can be confused with other sleep or medical disorders. Conclusions Circadian rhythm sleep disorders are a distinct class of sleep disorders characterized by a mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep. If untreated, CRSD can lead to insomnia and excessive daytime sleepiness, with negative medical, psychological, and social consequences. It is important for physicians to recognize potential circadian rhythm sleep disorders so that appropriate diagnosis, treatment, and referral can be made. PMID:25368503

  1. Circadian Disruption in Psychiatric Disorders.

    PubMed

    Jones, Stephanie G; Benca, Ruth M

    2015-12-01

    Evidence suggests that abnormalities in circadian rhythms might prove causally or pathophysiologically significant in psychiatric illness. The circadian regulation of hormonal and behavioral timekeeping processes is often altered in patients with major depression, bipolar disorder, and schizophrenia, and a susceptibility to rhythm instability may contribute to the functional impairment. For some patients, interventions that stabilize or resynchronize circadian rhythms prove therapeutically effective. Circadian disruption in the clinical profiles of most psychiatric illnesses and the treatment efficacy of chronobiological interventions suggest that attention to circadian phenotypes in a range of psychiatric disorders may help to uncover shared pathophysiologic mechanisms. PMID:26568124

  2. Circadian Clocks, Stress, and Immunity

    PubMed Central

    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

  3. Mitochondrial uncouplers inhibit hepatic stellate cell activation

    PubMed Central

    2012-01-01

    Background Mitochondrial dysfunction participates in the progression of several pathologies. Although there is increasing evidence for a mitochondrial role in liver disease, little is known about its contribution to hepatic stellate cell (HSC) activation. In this study we investigated the role of mitochondrial activity through mild uncoupling during in vitro activation of HSCs. Methods Cultured primary human and mouse HSCs were treated with the chemical uncouplers FCCP and Valinomycin. ATP levels were measured by luciferase assay and production of reactive oxygen species was determined using the fluorescent probe DCFH-DA. Possible cytotoxicity by uncoupler treatment was evaluated by caspase 3/7 activity and cytoplasmic protease leakage. Activation of HSCs and their response to the pro-fibrogenic cytokine TGF-β was evaluated by gene expression of activation markers and signal mediators using RT-qPCR. Proliferation was measured by incorporation of EdU and protein expression of α-smooth muscle actin was analyzed by immunocytochemistry and western blot. Results FCCP and Valinomycin treatment mildly decreased ATP and reactive oxygen species levels. Both uncouplers increased the expression of mitochondrial genes such as Tfam and COXIV while inducing morphological features of quiescent mouse HSCs and abrogating TGF-β signal transduction. Mild uncoupling reduced HSC proliferation and expression of pro-fibrogenic markers of mouse and human HSCs. Conclusions Mild mitochondrial uncoupling inhibits culture-induced HSC activation and their response to pro-fibrogenic cytokines like TGF-β. These results therefore suggest mitochondrial uncoupling of HSCs as a strategy to reduce progression of liver fibrosis. PMID:22686625

  4. Biological Clocks & Circadian Rhythms

    ERIC Educational Resources Information Center

    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…

  5. The systemic control of circadian gene expression.

    PubMed

    Gerber, A; Saini, C; Curie, T; Emmenegger, Y; Rando, G; Gosselin, P; Gotic, I; Gos, P; Franken, P; Schibler, U

    2015-09-01

    The mammalian circadian timing system consists of a central pacemaker in the brain's suprachiasmatic nucleus (SCN) and subsidiary oscillators in nearly all body cells. The SCN clock, which is adjusted to geophysical time by the photoperiod, synchronizes peripheral clocks through a wide variety of systemic cues. The latter include signals depending on feeding cycles, glucocorticoid hormones, rhythmic blood-borne signals eliciting daily changes in actin dynamics and serum response factor (SRF) activity, and sensors of body temperature rhythms, such as heat shock transcription factors and the cold-inducible RNA-binding protein CIRP. To study these systemic signalling pathways, we designed and engineered a novel, highly photosensitive apparatus, dubbed RT-Biolumicorder. This device enables us to record circadian luciferase reporter gene expression in the liver and other organs of freely moving mice over months in real time. Owing to the multitude of systemic signalling pathway involved in the phase resetting of peripheral clocks the disruption of any particular one has only minor effects on the steady state phase of circadian gene expression in organs such as the liver. Nonetheless, the implication of specific pathways in the synchronization of clock gene expression can readily be assessed by monitoring the phase-shifting kinetics using the RT-Biolumicorder. PMID:26332965

  6. Circadian Clock Control of Endocrine Factors

    PubMed Central

    Gamble, Karen L.; Berry, Ryan; Frank, Stuart J.; Young, Martin E.

    2015-01-01

    Organisms experience dramatic fluctuations in demands/stresses over the course of the day. In order to maintain biological processes within physiologic boundaries, it is imperative that mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors undoubtedly play an integral role in homeostasis. Not only do circulating levels of various endocrine factors oscillate over the 24 period, but so too does responsiveness of target tissues to these signals/stimuli. Emerging evidence suggests that these daily oscillations do not occur solely in response to behavioral fluctuations associated with sleep/wake and feeding/fasting cycles, but are orchestrated in part by an intrinsic timekeeping mechanism known as the circadian clock. Disruption of circadian clocks, through genetic and/or environmental means, appears to precipitate numerous common disorders, including cardiometabolic diseases and cancer. Collectively, these observations, which are reviewed within the current article, have led to suggestion that strategies designed to realign normal circadian rhythmicities hold a therapeutic potential for the treatment of various endocrine-related disorders. PMID:24863387

  7. Circadian clocks and cell division

    PubMed Central

    2010-01-01

    Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription and translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO). PMID:20890114

  8. A mitochondrial uncoupling artifact can be caused by expression of uncoupling protein 1 in yeast.

    PubMed Central

    Stuart, J A; Harper, J A; Brindle, K M; Jekabsons, M B; Brand, M D

    2001-01-01

    Uncoupling protein 1 (UCP1) from mouse was expressed in yeast and the specific (GDP-inhibitable) and artifactual (GDP-insensitive) effects on mitochondrial uncoupling were assessed. UCP1 provides a GDP-inhibitable model system to help interpret the uncoupling effects of high expression in yeast of other members of the mitochondrial carrier protein family, such as the UCP1 homologues UCP2 and UCP3. Yeast expressing UCP1 at modest levels (approx. 1 microg/mg of mitochondrial protein) showed no growth defect, normal rates of chemically uncoupled respiration and an increased non-phosphorylating proton conductance that was completely GDP-sensitive. The catalytic-centre activity of UCP1 in these yeast mitochondria was similar to that in mammalian brown-adipose-tissue mitochondria. However, yeast expressing UCP1 at higher levels (approx. 11 microg/mg of mitochondrial protein) showed a growth defect. Their mitochondria had depressed chemically uncoupled respiration rates and an increased proton conductance that was partly GDP-insensitive. Thus, although UCP1 shows native behaviour at modest levels of expression in yeast, higher levels (or rates) of expression can lead to an uncoupling that is not a physiological property of the native protein and is therefore artifactual. This observation might be important in the interpretation of results from experiments in which the functions of UCP1 homologues are verified by their ability to uncouple yeast mitochondria. PMID:11389685

  9. Role of Uncoupling Proteins in Cancer

    PubMed Central

    Valle, Adamo; Oliver, Jordi; Roca, Pilar

    2010-01-01

    Uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins whose function is to allow the re-entry of protons to the mitochondrial matrix, by dissipating the proton gradient and, subsequently, decreasing membrane potential and production of reactive oxygen species (ROS). Due to their pivotal role in the intersection between energy efficiency and oxidative stress, UCPs are being investigated for a potential role in cancer. In this review we compile the latest evidence showing a link between uncoupling and the carcinogenic process, paying special attention to their involvement in cancer initiation, progression and drug chemoresistance. PMID:24281083

  10. Inositols affect the mating circadian rhythm of Drosophila melanogaster

    PubMed Central

    Sakata, Kazuki; Kawasaki, Haruhisa; Suzuki, Takahiro; Ito, Kumpei; Negishi, Osamu; Tsuno, Takuo; Tsuno, Hiromi; Yamazaki, Youta; Ishida, Norio

    2015-01-01

    Accumulating evidence indicates that the molecular circadian clock underlies the mating behavior of Drosophila melanogaster. However, information about which food components affect circadian mating behavior is scant. The ice plant, Mesembryanthemum crystallinum has recently become a popular functional food. Here, we showed that the close-proximity (CP) rhythm of D. melanogaster courtship behavior was damped under low-nutrient conditions, but significantly enhanced by feeding the flies with powdered ice plant. Among various components of ice plants, we found that myo-inositol increased the amplitude and slightly shortened the period of the CP rhythm. Real-time reporter assays showed that myo-inositol and D-pinitol shortened the period of the circadian reporter gene Per2-luc in NIH 3T3 cells. These data suggest that the ice plant is a useful functional food and that the ability of inositols to shorten rhythms is a general phenomenon in insects as well as mammals. PMID:26097456

  11. Aging signaling pathways and circadian clock-dependent metabolic derangements

    PubMed Central

    Tevy, Maria Florencia; Giebultowicz, Jadwiga; Pincus, Zachary; Mazzoccoli, Gianluigi; Vinciguerra, Manlio

    2013-01-01

    The circadian clock machinery orchestrates organism metabolism in order to ensure that development, survival and reproduction are attuned to diurnal environmental variations. For unknown reasons, there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissues homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient sensing networks might underlie age-related diseases; overall, greater knowledge of the molecular mediators of and variations in clock networks during lifespan may shed light on the aging process and how it may be delayed. In this review we address the complex links between the circadian clock, metabolic (dys)functions and aging in different model organisms. PMID:23299029

  12. Circadian Regulation of Synaptic Plasticity.

    PubMed

    Frank, Marcos G

    2016-01-01

    Circadian rhythms refer to oscillations in biological processes with a period of approximately 24 h. In addition to the sleep/wake cycle, there are circadian rhythms in metabolism, body temperature, hormone output, organ function and gene expression. There is also evidence of circadian rhythms in synaptic plasticity, in some cases driven by a master central clock and in other cases by peripheral clocks. In this article, I review the evidence for circadian influences on synaptic plasticity. I also discuss ways to disentangle the effects of brain state and rhythms on synaptic plasticity. PMID:27420105

  13. Postoperative circadian disturbances.

    PubMed

    Gögenur, Ismail

    2010-12-01

    An increasing number of studies have shown that circadian variation in the excretion of hormones, the sleep wake circle, the core body temperature rhythm, the tone of the autonomic nervous system and the activity rhythm are important both in health and in disease processes. An increasing attention has also been directed towards the circadian variation in endogenous rhythms in relation to surgery. The attention has been directed to the question whether the circadian variation in endogenous rhythms can affect postoperative recovery, morbidity and mortality. Based on the lack of studies where these endogenous rhythms have been investigated in relation to surgery we performed a series of studies exploring different endogenous rhythms and factors affecting these rhythms. We also wanted to examine whether the disturbances in the postoperative circadian rhythms could be correlated to postoperative recovery parameters, and if pharmacological administration of chronobiotics could improve postoperative recovery. Circadian rhythm disturbances were found in all the examined endogenous rhythms. A delay was found in the endogenous rhythm of plasma melatonin and excretion of the metabolite of melatonin (AMT6s) in urine the first night after both minor and major surgery. This delay after major surgery was correlated to the duration of surgery. The amplitude in the melatonin rhythm was unchanged the first night but increased in the second night after major surgery. The amplitude in AMT6s was reduced the first night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively. There was also a shift in the autonomic nervous balance after major surgery with a significantly increased number of myocardial ischaemic episodes during the nighttime period. The

  14. Sleep and circadian rhythms

    NASA Technical Reports Server (NTRS)

    Monk, Timothy H.

    1991-01-01

    Three interacting processes are involved in the preservation of circadian rhythms: (1) endogenous rhythm generation mechanisms, (2) entrainment mechanisms to keep these rhythms 'on track', and (3) exogenous masking processes stemming from changes in environment and bahavior. These processes, particularly the latter two, can be dramatically affected in individuals of advanced age and in space travelers, with a consequent disruption in sleep and daytime functioning. This paper presents results of a phase-shift experiment investigating the age-related effects of the exogeneous component of circadian rhythms in various physiological and psychological functions by comparing these functions in middle aged and old subjects. Dramatic differences were found between the two age groups in measures of sleep, mood, activation, and performance efficiency.

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

    PubMed Central

    Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S. I.; Hau, Michaela

    2016-01-01

    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

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

    PubMed

    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

  17. Emerging Models for the Molecular Basis of Mammalian Circadian Timing

    PubMed Central

    2015-01-01

    Mammalian circadian timekeeping arises from a transcription-based feedback loop driven by a set of dedicated clock proteins. At its core, the heterodimeric transcription factor CLOCK:BMAL1 activates expression of Period, Cryptochrome, and Rev-Erb genes, which feed back to repress transcription and create oscillations in gene expression that confer circadian timing cues to cellular processes. The formation of different clock protein complexes throughout this transcriptional cycle helps to establish the intrinsic ∼24 h periodicity of the clock; however, current models of circadian timekeeping lack the explanatory power to fully describe this process. Recent studies confirm the presence of at least three distinct regulatory complexes: a transcriptionally active state comprising the CLOCK:BMAL1 heterodimer with its coactivator CBP/p300, an early repressive state containing PER:CRY complexes, and a late repressive state marked by a poised but inactive, DNA-bound CLOCK:BMAL1:CRY1 complex. In this review, we analyze high-resolution structures of core circadian transcriptional regulators and integrate biochemical data to suggest how remodeling of clock protein complexes may be achieved throughout the 24 h cycle. Defining these detailed mechanisms will provide a foundation for understanding the molecular basis of circadian timing and help to establish new platforms for the discovery of therapeutics to manipulate the clock. PMID:25303119

  18. Metabolism as an Integral Cog in the Mammalian Circadian Clockwork

    PubMed Central

    Gamble, Karen L.; Young, Martin E.

    2013-01-01

    Circadian rhythms are an integral part of life. These rhythms are apparent in virtually all biological processes studies to date, ranging from the individual cell (e.g., DNA synthesis) to the whole organism (e.g., behaviors such as physical activity). Oscillations in metabolism have been characterized extensively in various organisms, including mammals. These metabolic rhythms often parallel behaviors such as sleep/wake and fasting/feeding cycles that occur on a daily basis. What has become increasingly clear over the past several decades is that many metabolic oscillations are driven by cell autonomous circadian clocks, which orchestrate metabolic processes in a temporally appropriate manner. During the process of identifying the mechanisms by which clocks influence metabolism, molecular-based studies have revealed that metabolism should be considered an integral circadian clock component. The implications of such an interrelationship include the establishment of a vicious cycle during cardiometabolic disease states, wherein metabolism-induced perturbations in the circadian clock exacerbate metabolic dysfunction. The purpose of this review is therefore to highlight recent insights gained regarding links between cell autonomous circadian clocks and metabolism, and the implications of clock dysfunction in the pathogenesis of cardiometabolic diseases. PMID:23594144

  19. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  20. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  1. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  2. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  3. 49 CFR 215.125 - Defective uncoupling device.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Defective uncoupling device. 215.125 Section 215... System § 215.125 Defective uncoupling device. A railroad may not place or continue in service a car, if the car has an uncoupling device without sufficient vertical and lateral clearance to prevent—...

  4. 30 CFR 56.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Coupling or uncoupling cars. 56.14215 Section... Equipment Safety Practices and Operational Procedures § 56.14215 Coupling or uncoupling cars. Prior to coupling or uncoupling cars manually, trains shall be brought to a complete stop, and then moved at...

  5. Mitochondrial uncoupling proteins in mammals and plants.

    PubMed

    Borecký, J; Maia, I G; Arruda, P

    2001-04-01

    Uncoupling proteins (UCPs) belong to a distinct cluster of the mitochondrial anion carrier family. Up to five different uncoupling protein types were found in mitochondria of mammals and plants, and recently in fishes, fungi and protozoa. They exhibit a significantly conserved structure with several motifs specific to either the whole cluster or protein type. Uncoupling proteins, as well as the whole mitochondrial anion carrier gene family, probably emerged in evolution before the separation of animal, fungi, and plant kingdoms and originate from an anion/nucleotide or anion/anion transporter ancestor. Mammalian UCP1, UCP2, UCP3, and plant uncoupling proteins pUCP1 and pUCP2 are similar and seem to form one subgroup, whereas UCP4 and BMCP1 belong to a different group. Molecular, biochemical, and phylogenic data suggest that UCP2 could be considered as an UCP-prototype. UCP1 plays its biological role mainly in the non-shivering thermogenesis while the role of the other types is unknown. However, hypotheses have suggested that they are involved in the general balance of basic energy expenditure, protection from reactive oxygen species, and, in plants, in fruit ripening and seed ontogeny. PMID:11725869

  6. Circadian rhythms of temperature and activity in obese and lean Zucker rats

    NASA Technical Reports Server (NTRS)

    Murakami, D. M.; Horwitz, B. A.; Fuller, C. A.

    1995-01-01

    The circadian timing system is important in the regulation of feeding and metabolism, both of which are aberrant in the obese Zucker rat. This study tested the hypothesis that these abnormalities involve a deficit in circadian regulation by examining the circadian rhythms of body temperature and activity in lean and obese Zucker rats exposed to normal light-dark cycles, constant light, and constant dark. Significant deficits in both daily mean and circadian amplitude of temperature and activity were found in obese Zucker female rats relative to lean controls in all lighting conditions. However, the circadian period of obese Zucker rats did not exhibit differences relative to lean controls in either of the constant lighting conditions. These results indicate that although the circadian regulation of temperature and activity in obese Zucker female rats is in fact depressed, obese rats do exhibit normal entrainment and pacemaker functions in the circadian timing system. The results suggest a deficit in the process that generates the amplitude of the circadian rhythm.

  7. A novel circadianly expressed Drosophila melanogaster gene dependent on the period gene for its rhythmic expression.

    PubMed Central

    Van Gelder, R N; Krasnow, M A

    1996-01-01

    The Drosophila melanogaster period (per) gene is required for expression of endogenous circadian rhythms of locomotion and eclosion. per mRNA is expressed with a circadian rhythm that is dependent on Per protein; this feedback loop has been proposed to be essential to the central circadian pacemaker. This model would suggest the Per protein also controls the circadian expression of other genetic loci to generate circadian behavior and physiology. In this paper we describe Dreg-5, a gene whose mRNA is expressed in fly heads with a circadian rhythm nearly identical to that of the per gene. Dreg-5 mRNA continues to cycle in phase with that of per mRNA in conditions of total darkness and also when the daily feeding time is altered. Like per mRNA, Dreg-5 mRNA is not expressed rhythmically in per null mutant flies. Dreg-5 encodes a novel 298 residue protein and Dreg-5 protein isoforms also oscillate in abundance with a circadian rhythm. The phase of Dreg-5 protein oscillation, however, is different from that of Per protein expression, suggesting that Dreg-5 and per have common translational but different post-translational control mechanisms. These results demonstrate that the per gene is capable of modulating the rhythmic expression of other genes; this activity may form the basis of the output of circadian rhythmicity in Drosophila. Images PMID:8612586

  8. Circadian gene variants in cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostas...

  9. Circadian Disorganization Alters Intestinal Microbiota

    PubMed Central

    Voigt, Robin M.; Forsyth, Christopher B.; Green, Stefan J.; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H.; Turek, Fred W.; Keshavarzian, Ali

    2014-01-01

    Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases. PMID:24848969

  10. Circadian rhythms in the short-tailed shrew, Blarina brevicauda.

    PubMed

    Antipas, A J; Madison, D M; Ferraro, J S

    1990-08-01

    Circadian rhythms of wheel running and feeding were measured in the short-tailed shrew. Shrews were strongly nocturnal, and their activity rhythms entrained to both long-day (LD 16:8) and short-day (LD 6:18) photocycles. Under conditions of continuous light (LL) or darkness (DD), the activity rhythms free-ran with average periodicities of 25.1 hours and 24.1 hours, respectively. In LL the level of activity was depressed, and in some cases wheel running was completely inhibited. No significant sex differences were observed in the period or amplitude of the monitored circadian rhythms. All shrews fed throughout the day and night; however, unlike in previous reports, ultradian periods of feeding behavior were not found. The results are related to Aschoff's four observations for the effect of light on activity rhythms in nocturnal rodents. PMID:2255728

  11. Thermoregulatory uncoupling in heart muscle mitochondria: involvement of the ATP/ADP antiporter and uncoupling protein.

    PubMed

    Simonyan, R A; Skulachev, V P

    1998-09-25

    Possible involvement of the ATP/ADP antiporter and uncoupling protein (UCP) in thermoregulatory uncoupling of oxidative phosphorylation in heart muscle has been studied. To this end, effects of carboxyatractylate (cAtr) and GDP, specific inhibitors of the antiporter and UCP, on the membrane potential of the oligomycin-treated mitochondria from cold-exposed (6 degrees C, 48 h) and control rats have been measured. It is found that cAtr increases the membrane potential level in both cold-exposed and non-exposed groups, the effect being strongly enhanced by cooling. As for GDP, it is effective only in mitochondria from the cold-exposed rats. In these mitochondria, the coupling effect of GDP is smaller than that of cAtr. CDP, which does not interact with UCP, is without any influence on membrane potential. The cold exposure is found to increase the uncoupling efficiency of added natural (palmitate) or artificial (SF6847) uncouplers, the increase being cAtr- and GDP-sensitive in the case of palmitate. The fatty acid-free bovine serum albumin enhances delta psi in both cold-exposed and control groups, the effect being much larger in the former case. It is concluded that in heart muscle mitochondria the ATP/ADP antiporter is responsible for the 'mild uncoupling' under normal conditions and for major portion of the thermoregulatory uncoupling in the cold whereas the rest of thermoregulatory uncoupling is served by UCP (presumably by UCP2 since the UCP2 mRNA level is shown to strongly increase in rat heart muscle under the cold exposure conditions used). PMID:9771898

  12. Circadian gene variants in cancer

    PubMed Central

    Kettner, Nicole M.; Katchy, Chinenye A.; Fu, Loning

    2014-01-01

    Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356

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

    PubMed

    Harfmann, Brianna D; Schroder, Elizabeth A; Esser, Karyn A

    2015-04-01

    Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle. PMID:25512305

  14. A New Uncoupled Viscoplastic Constitutive Model

    NASA Technical Reports Server (NTRS)

    Bradley, W. L.; Yuen, S.

    1983-01-01

    A new uncoupled viscoplastic model has been proposed along with experiments and analysis to define the various material constraints. Distinguishing between rate sensitive and rate insensitive strain allows the rate sensitive strain to be modelled over a wide range of temperatures with very little variation in the stress component 'n'. Furthermore, it allows the rounded corners on stress-strain hysteresis loops to be achieved very naturally.

  15. Endocrine Effects of Circadian Disruption.

    PubMed

    Bedrosian, Tracy A; Fonken, Laura K; Nelson, Randy J

    2016-01-01

    Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems. PMID:26208951

  16. Nocturia: The circadian voiding disorder

    PubMed Central

    Moon, Young Tae; Kim, Kyung Do

    2016-01-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  17. Nocturia: The circadian voiding disorder.

    PubMed

    Kim, Jin Wook; Moon, Young Tae; Kim, Kyung Do

    2016-05-01

    Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology. PMID:27195315

  18. Neurobiology of Circadian Rhythm Regulation.

    PubMed

    Rosenwasser, Alan M; Turek, Fred W

    2015-12-01

    Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes. The maintenance of proper coordination within this network of cellular- and tissue-level clocks is essential for health and well-being. PMID:26568118

  19. Role of cardiomyocyte circadian clock in myocardial metabolic adaptation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential f...

  20. Effects of exercise on circadian rhythms and mobility in aging Drosophila melanogaster.

    PubMed

    Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M; Giebultowicz, Jadwiga M

    2013-11-01

    Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging-related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exercise via stimulation of upward climbing movement could improve circadian rest/activity rhythms in aging Drosophila melanogaster. We found that repeated exercise regimen did not strengthen circadian locomotor activity rhythms in aging flies and had no effect on their lifespan. We also tested the effects of exercise on mobility and determined that regular exercise lowered age-specific climbing ability in both wild type and clock mutant flies. Interestingly, the climbing ability was most significantly reduced in flies carrying a null mutation in the core clock gene period, while rescue of this gene significantly improved climbing to wild type levels. Our work highlights the importance of period in sustaining endurance in aging flies exposed to physical challenge. PMID:23916842

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

    PubMed

    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

  2. Endocrine regulation of circadian physiology.

    PubMed

    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

  3. Circadian Control of Global Transcription

    PubMed Central

    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

  4. Misaligned feeding impairs memories

    PubMed Central

    Loh, Dawn H; Jami, Shekib A; Flores, Richard E; Truong, Danny; Ghiani, Cristina A; O’Dell, Thomas J; Colwell, Christopher S

    2015-01-01

    Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour. DOI: http://dx.doi.org/10.7554/eLife.09460.001 PMID:26652002

  5. Circadian organization is governed by extra-SCN pacemakers.

    PubMed

    Pezuk, Pinar; Mohawk, Jennifer A; Yoshikawa, Tomoko; Sellix, Michael T; Menaker, Michael

    2010-12-01

    In mammals, a pacemaker in the suprachiasmatic nucleus (SCN) is thought to be required for behavioral, physiological, and molecular circadian rhythms. However, there is considerable evidence that temporal food restriction (restricted feedisng [RF]) and chronic methamphetamine (MA) can drive circadian rhythms of locomotor activity, body temperature, and endocrine function in the absence of SCN. This indicates the existence of extra-SCN pacemakers: the Food Entrainable Oscillator (FEO) and Methamphetamine Sensitive Circadian Oscillator (MASCO). Here, we show that these extra-SCN pacemakers control the phases of peripheral oscillators in intact as well as in SCN-ablated PER2::LUC mice. MA administration shifted the phases of SCN, cornea, pineal, pituitary, kidney, and salivary glands in intact animals. When the SCN was ablated, disrupted phase relationships among peripheral oscillators were reinstated by MA treatment. When intact animals were subjected to restricted feeding, the phases of cornea, pineal, kidney, salivary gland, lung, and liver were shifted. In SCN-lesioned restricted-fed mice, phases of all of the tissues shifted such that they aligned with the time of the meal. Taken together, these data show that FEO and MASCO are strong circadian pacemakers able to regulate the phases of peripheral oscillators. PMID:21135159

  6. The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

    PubMed Central

    Kim, Tae Won; Jeong, Jong-Hyun; Hong, Seung-Chul

    2015-01-01

    The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity. PMID:25861266

  7. Time-restricted feeding of a high-fat diet reduces adiposity and inflammatory cytokine production in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Disruption of the circadian rhythms contributes to obesity. Restricting feeding to particular times of the day may reset the circadian rhythms and reduce obesity and resulting complications. The present study investigated the effects of time-restricted feeding (TRF) of a high-fat diet on adiposity...

  8. The regulation and turnover of mitochondrial uncoupling proteins

    PubMed Central

    Azzu, Vian; Jastroch, Martin; Divakaruni, Ajit S; Brand, Martin D

    2010-01-01

    Uncoupling proteins (UCP1, UCP2 and UCP3) are important in regulating cellular fuel metabolism and as attenuators of reactive oxygen species production, through strong or mild uncoupling. The generic function and broad tissue distribution of the uncoupling protein family means that they are increasingly implicated in a range of pathophysiological processes including obesity, insulin resistance and diabetes mellitus, neurodegeneration, cardiovascular disease, immunity and cancer. The significant recent progress describing the turnover of novel uncoupling proteins, as well as current views on the physiological roles and regulation of UCPs, is outlined. PMID:20211596

  9. Uncoupling proteins of invertebrates: A review.

    PubMed

    Slocinska, Malgorzata; Barylski, Jakub; Jarmuszkiewicz, Wieslawa

    2016-09-01

    Uncoupling proteins (UCPs) mediate inducible proton conductance in the mitochondrial inner membrane. Herein, we summarize our knowledge regarding UCPs in invertebrates. Since 2001, the presence of UCPs has been demonstrated in nematodes, mollusks, amphioxi, and insects. We discuss the following important issues concerning invertebrate UCPs: their evolutionary relationships, molecular and functional properties, and physiological impact. Evolutionary analysis indicates that the branch of vertebrate and invertebrate UCP4-5 diverged early in the evolutionary process prior to the divergence of the animal groups. Several proposed physiological roles of invertebrate UCPs are energy control, metabolic balance, and preventive action against oxidative stress. © 2016 IUBMB Life, 68(9):691-699, 2016. PMID:27385510

  10. Effect of hypergravity on the circadian rhythms of white rats.

    NASA Technical Reports Server (NTRS)

    Lafferty, J. F.

    1972-01-01

    The effects of artificial gravity on the circadian rhythm of white rats was observed by comparing feeding activity at 1.0 and 1.75 g. The feeding cycle data were obtained by observing the number of feeding switch responses, as well as the amount of food obtained, as a function of time. One of the three subjects clearly established a free-running cycle with a period of 24.742 hr. During a 40-day exposure to the 1.75 g environment, the subjects maintained the same feeding cycle period which was established at 1.0 g. While the results of this study indicate that the activity rhythms of rats are insensitive to gravity levels between 1.0 and 1.75 g, the effects of gravity levels below 1.0 g are yet to be determined.

  11. Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice.

    PubMed

    Wu, Nan; Kim, Kang Ho; Zhou, Ying; Lee, Jae Man; Kettner, Nicole M; Mamrosh, Jennifer L; Choi, Sungwoo; Fu, Loning; Moore, David D

    2016-09-01

    Circadian rhythm regulates multiple metabolic processes and in turn is readily entrained by feeding-fasting cycles. However, the molecular mechanisms by which the peripheral clock senses nutrition availability remain largely unknown. Bile acids are under circadian control and also increase postprandially, serving as regulators of the fed state in the liver. Here, we show that nuclear receptor Small Heterodimer Partner (SHP), a regulator of bile acid metabolism, impacts the endogenous peripheral clock by directly regulating Bmal1. Bmal1-dependent gene expression is altered in Shp knockout mice, and liver clock adaptation is delayed in Shp knockout mice upon restricted feeding. These results identify SHP as a potential mediator connecting nutrient signaling with the circadian clock. PMID:27427832

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

    PubMed Central

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

    2015-01-01

    Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1−/− and ClockΔ19 mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle. PMID:21621073

  13. Analysis of Circadian Leaf Movements.

    PubMed

    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

  14. Circadian Transcription from Beta Cell Function to Diabetes Pathophysiology.

    PubMed

    Perelis, Mark; Ramsey, Kathryn Moynihan; Marcheva, Biliana; Bass, Joseph

    2016-08-01

    The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease. PMID:27440914

  15. Glucocorticosteroid injection is a circadian zeitgeber in the laboratory rat

    SciTech Connect

    Horseman, N.D.; Ehret, C.F.

    1982-09-01

    Intraperitoneal temperatures were monitored by radiotelemetry to observe the thermoregulatory rhythm of male laboratory rats (Rattus norvegicus albinus). Rats received single injections of dexamethasone (as dexamethasone sodium phosphate) during constant darkness (0.1 lx) with food freely available or no food available. No phase shifts occurred following saline injection or dexamethasone at 1 mg/kg body wt. Depending on the phase of injection relative to the circadian cycle, dexamethasone at 10 mg/kg caused thermoregulatory peaks to be either delayed or advanced on the 4th and 5th days after injection. There was an insensitive interval which corresponded to subjective day. Phase shifts induced by dexamethasone during ad libitum feeding were of less magnitude than those induced during starvation. The determination of phase-shifting parameters (i.e., a phase-response curve) for hormonal substances represents a rigorous and broadly applicable technique for determining endogenous mechanisms for circadian phase control and entrainment.

  16. Circadian regulation of metabolic homeostasis: causes and consequences

    PubMed Central

    McGinnis, Graham R; Young, Martin E

    2016-01-01

    Robust circadian rhythms in metabolic processes have been described in both humans and animal models, at the whole body, individual organ, and even cellular level. Classically, these time-of-day-dependent rhythms have been considered secondary to fluctuations in energy/nutrient supply/demand associated with feeding/fasting and wake/sleep cycles. Renewed interest in this field has been fueled by studies revealing that these rhythms are driven, at least in part, by intrinsic mechanisms and that disruption of metabolic synchrony invariably increases the risk of cardiometabolic disease. The objectives of this paper are to provide a comprehensive review regarding rhythms in glucose, lipid, and protein/amino acid metabolism, the relative influence of extrinsic (eg, neurohumoral factors) versus intrinsic (eg, cell autonomous circadian clocks) mediators, the physiologic roles of these rhythms in terms of daily fluctuations in nutrient availability and activity status, as well as the pathologic consequences of dyssynchrony. PMID:27313482

  17. QSAR studies of hydrazone uncouplers of oxidative phosphorylation.

    PubMed

    Winkler, D A; Holan, G; Smith, D R; Middleton, E J; Hart, N K; Rihs, K; Smith, K W

    1988-07-01

    Semiempirical molecular orbital calculations have been performed on a series of hydrazone uncouplers of mitochondrial oxidative phosphorylation which show insecticidal activity. Regression analysis yielded significant correlations between uncoupling activity, insecticidal potency and such physicochemical or theoretically-derived parameters as lipophilicity, pKa and atom charges. PMID:3255329

  18. 49 CFR 215.125 - Defective uncoupling device.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Draft System § 215.125 Defective uncoupling device. A railroad may not place or continue in service a car, if the car has an uncoupling device without sufficient vertical and lateral clearance to prevent—...

  19. 49 CFR 215.125 - Defective uncoupling device.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Draft System § 215.125 Defective uncoupling device. A railroad may not place or continue in service a car, if the car has an uncoupling device without sufficient vertical and lateral clearance to prevent—...

  20. 49 CFR 215.125 - Defective uncoupling device.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Draft System § 215.125 Defective uncoupling device. A railroad may not place or continue in service a car, if the car has an uncoupling device without sufficient vertical and lateral clearance to prevent—...

  1. 49 CFR 215.125 - Defective uncoupling device.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Draft System § 215.125 Defective uncoupling device. A railroad may not place or continue in service a car, if the car has an uncoupling device without sufficient vertical and lateral clearance to prevent—...

  2. Smith-Magenis Syndrome Results in Disruption of CLOCK Gene Transcription and Reveals an Integral Role for RAI1 in the Maintenance of Circadian Rhythmicity

    PubMed Central

    Williams, Stephen R.; Zies, Deborah; Mullegama, Sureni V.; Grotewiel, Michael S.; Elsea, Sarah H.

    2012-01-01

    Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of Rai1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and Rai1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator. PMID:22578325

  3. Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase.

    PubMed

    Klaus, Susanne; Keipert, Susanne; Rossmeisl, Martin; Kopecky, Jan

    2012-07-01

    Strategies to prevent and treat obesity aim to decrease energy intake and/or increase energy expenditure. Regarding the increase of energy expenditure, two key intracellular targets may be considered (1) mitochondrial oxidative phosphorylation, the major site of ATP production, and (2) AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. Experiments performed mainly in transgenic mice revealed a possibility to ameliorate obesity and associated disorders by mitochondrial uncoupling in metabolically relevant tissues, especially in white adipose tissue (WAT), skeletal muscle (SM), and liver. Thus, ectopic expression of brown fat-specific mitochondrial uncoupling protein 1 (UCP1) elicited major metabolic effects both at the cellular/tissue level and at the whole-body level. In addition to expected increases in energy expenditure, surprisingly complex phenotypic effects were detected. The consequences of mitochondrial uncoupling in WAT and SM are not identical, showing robust and stable obesity resistance accompanied by improvement of lipid metabolism in the case of ectopic UCP1 in WAT, while preservation of insulin sensitivity in the context of high-fat feeding represents the major outcome of muscle UCP1 expression. These complex responses could be largely explained by tissue-specific activation of AMPK, triggered by a depression of cellular energy charge. Experimental data support the idea that (1) while being always activated in response to mitochondrial uncoupling and compromised intracellular energy status in general, AMPK could augment energy expenditure and mediate local as well as whole-body effects; and (2) activation of AMPK alone does not lead to induction of energy expenditure and weight reduction. PMID:22139637

  4. Circadian Clock, Cancer, and Chemotherapy

    PubMed Central

    2015-01-01

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

  5. Circadian Insights into Motivated Behavior.

    PubMed

    Antle, Michael C; Silver, Rae

    2016-01-01

    For an organism to be successful in an evolutionary sense, it and its offspring must survive. Such survival depends on satisfying a number of needs that are driven by motivated behaviors, such as eating, sleeping, and mating. An individual can usually only pursue one motivated behavior at a time. The circadian system provides temporal structure to the organism's 24 hour day, partitioning specific behaviors to particular times of the day. The circadian system also allows anticipation of opportunities to engage in motivated behaviors that occur at predictable times of the day. Such anticipation enhances fitness by ensuring that the organism is physiologically ready to make use of a time-limited resource as soon as it becomes available. This could include activation of the sympathetic nervous system to transition from sleep to wake, or to engage in mating, or to activate of the parasympathetic nervous system to facilitate transitions to sleep, or to prepare the body to digest a meal. In addition to enabling temporal partitioning of motivated behaviors, the circadian system may also regulate the amplitude of the drive state motivating the behavior. For example, the circadian clock modulates not only when it is time to eat, but also how hungry we are. In this chapter we explore the physiology of our circadian clock and its involvement in a number of motivated behaviors such as sleeping, eating, exercise, sexual behavior, and maternal behavior. We also examine ways in which dysfunction of circadian timing can contribute to disease states, particularly in psychiatric conditions that include adherent motivational states. PMID:26419240

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

    PubMed Central

    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, these attributes make members of this phylum attractive as models for testing hypotheses on roles for circadian clocks in regulating behavior, physiology, and reproduction as well as those regarding the deep evolutionary conservation of circadian regulatory pathways in animal evolution. Here, we review and synthesize the field of cnidarian circadian biology by discussing the diverse effects of daily light cycles on cnidarians, summarizing the molecular evidence for the conservation of a bilaterian-like circadian clock in anthozoan cnidarians, and presenting new empirical data supporting the presence of a conserved feed-forward loop in the starlet sea anemone, Nematostella vectensis. Furthermore, we discuss critical gaps in our current knowledge about the cnidarian clock, including the functions directly regulated by the clock and the precise molecular interactions that drive the oscillating gene-expression patterns. We conclude that the field of cnidarian circadian biology is moving rapidly toward linking molecular mechanisms with physiology and behavior. PMID:23620252

  7. In vitro circadian rhythms: imaging and electrophysiology.

    PubMed

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D

    2011-06-30

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  8. In vitro circadian rhythms: imaging and electrophysiology

    PubMed Central

    Beaulé, Christian; Granados-Fuentes, Daniel; Marpegan, Luciano; Herzog, Erik D.

    2013-01-01

    In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell-cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID:21819387

  9. Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: A Historical Perspective

    PubMed Central

    Ricquier, Daniel

    2011-01-01

    Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas the family of mitochondrial metabolite carriers comprises ∼40 members, UCP1 is the only memberable to translocate protons through the inner membrane of brown adipocyte mitochondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore provokes energy dissipation in the form of heat while, also stimulating high levels of fatty acid oxidation. UCP1 homologs were identified but they are biochemically and physiologically different from UCP1. Thirty five years after its identification, UCP1 still appears as a fascinating component. The recent renewal of the interest in human brown adipose tissue makes UCP1 as a potential target for strategies of treatment of metabolic disorders. PMID:22649389

  10. Seismic coupling and uncoupling at subduction zones

    NASA Technical Reports Server (NTRS)

    Ruff, L.; Kanamori, H.

    1983-01-01

    Some of the correlations concerning the properties of subduction zones are reviewed. A quantitative global comparison of many subduction zones reveals that the largest earthquakes occur in zones with young lithosphere and fast convergence rates. Maximum earthquake size is directly related to the asperity distribution on the fault plane. This observation can be translated into a simple model of seismic coupling where the horizontal compressive stress between two plates is proportional to the ratio of the summed asperity area to the total area of the contact surface. Plate age and rate can control asperity distribution directly through the horizontal compressive stress associated with the vertical and horizontal velocities of subducting slabs. The basalt to eclogite phase change in the down-going oceanic crust may be largely responsible for the uncoupling of subduction zones below a depth of about 40 km.

  11. Uncoupled achromatic tilted S-bend

    SciTech Connect

    Tsoupas,N.; Kayran, D.; Litvinenko, V.; MacKay, W.W.

    2008-06-23

    A particular section of the electron beam transport line, to be used in the e-cooling project [l] of the Relativistic Heavy Ion Collider (RHIC), is constrained to displace the trajectory with both horizontal and vertical offsets so that the outgoing beamline is parallel to the incoming beamline. We also require that section be achromatic in both planes. This mixed horizontal and vertical achromatic Sbend is accomplished by rotating the two dipoles and the quadrupoles of the line, about the longitudinal axis of the incoming beam. However such a rotation of the magnetic elements may couple the transported beam through the first order beam transfer matrix (linear coupling). In this paper we study a sufficient condition, that the first order transport matrix (R-matrix) can satisfy, so that this section of beam transfer line is both achromatic and linearly uncoupled. We provide a complete solution for the beam optics which satisfies both conditions.

  12. Circadian rhythm and its role in malignancy

    PubMed Central

    2010-01-01

    Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer. PMID:20353609

  13. Circadian rhythms: basic neurobiology and clinical applications.

    PubMed

    Moore, R Y

    1997-01-01

    Circadian rhythms are major features of adaptation to our environment. In mammals, circadian rhythms are generated and regulated by a circadian timing system. This system consists of entertainment pathways, pacemakers, and pace-maker output to effector systems that are under circadian control. The primary entertainment pathway is the retinohypothalamic tract, which terminates in the circadian pacemakers, the suprachiasmatic nuclei of the hypothalamus. The output of the suprachiasmatic nuclei is principally to the hypothalamus, the midline thalamus, and the basal forebrain. This provides a temporal organization to the sleep-wake cycle, to many physiological and endocrine functions, and to psychomotor performance functions. Disorders of circadian timing primarily affect entertainment and pacemaker functions. The pineal hormone, melatonin, appears to be promising agent for therapy of some circadian timing disorders. PMID:9046960

  14. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    PubMed

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-01

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. PMID:27476975

  15. Metabolism and the Circadian Clock Converge

    PubMed Central

    Eckel-Mahan, Kristin

    2013-01-01

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

  16. Prokineticin 2 and circadian clock output

    PubMed Central

    Zhou, Qun-Yong; Cheng, Michelle Y.

    2009-01-01

    Circadian timing from the suprachiasmatic nucleus (SCN) is a critical component of sleep regulation. Animal lesion and genetic studies have indicated an essential interaction between the circadian signals and the homeostatic processes that regulate sleep. Here we summarize the biological functions of prokineticins, a pair of newly discovered regulatory proteins, with focus on the circadian function of prokineticin 2 (PK2) and its potential role in sleep-wake regulation. PK2 has been shown as a candidate SCN output molecule that regulates circadian locomotor behavior. The PK2 molecular rhythm in the SCN is predominantly controlled by the circadian transcriptional/translational loops, but also regulated directly by light. The receptor for PK2 is expressed in the primary SCN output targets that regulate circadian behavior including sleep-wake. The depolarizing effect of PK2 on neurons that express PK2 receptor may represent a possible mechanism for the regulatory role of PK2 in circadian rhythms. PMID:16279936

  17. Escherichia coli mutants resistant to uncouplers of oxidative phosphorylation.

    PubMed

    Jones, M R; Beechey, R B

    1987-10-01

    Two mutant strains of Escherichia coli K 12 Doc-S resistant to the uncoupling agents 4,5,6,7-tetrachloro-2-trifluoromethyl benzimidazole and carbonyl cyanide m-chlorophenylhydrazone were isolated. These strains, designated TUV and CUV, were capable of (a) growth, (b) the transport of succinate and L-proline and (c) electron-transport-linked oxidative synthesis of ATP in the presence of titres of uncoupler which inhibited these processes in strain Doc-S. The inhibition of transport of L-proline by a fixed titre of uncoupler was sharply pH dependent in strain Doc-S: uptake was unaffected at pH 7.6 but completely inhibited at pH 5.6. This pH dependence was not shown by the resistant strains. We believe that uncouplers were equally accessible to their site(s) of action in the energy-conserving membrane of the sensitive and resistant strains. We conclude that uncoupler resistance in these strains of E. coli has arisen as a consequence of mutations which directly affect a specific site of uncoupler action within the cytoplasmic membrane, rather than as a consequence of a decrease in the permeability of cells to uncoupler. PMID:3329677

  18. Circadian influences on myocardial infarction.

    PubMed

    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 cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

  19. Circadian influences on myocardial infarction

    PubMed Central

    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 cells. While it is known that the central master clock in the SCN synchronizes peripheral physiologic rhythms, the mechanisms by which the information is transmitted are complex and may include hormonal, metabolic, and neuronal inputs. Whether circadian patterns are causally related to the observed periodicity of events, or whether they are simply epi-phenomena is not well established, but a few studies suggest that the circadian effects likely are real in their impact on myocardial infarct incidence. Cycle disturbances may be harbingers of predisposition and subsequent response to acute and chronic cardiac injury, and identifying the complex interactions of circadian rhythms and myocardial infarction may provide insights into possible preventative and therapeutic strategies for susceptible populations. PMID:25400588

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

    PubMed Central

    Ribas-Latre, Aleix; Eckel-Mahan, Kristin

    2016-01-01

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

  1. Glucocorticoids as entraining signals for peripheral circadian oscillators.

    PubMed

    Pezük, Pinar; Mohawk, Jennifer A; Wang, Laura A; Menaker, Michael

    2012-10-01

    Mammalian circadian organization is governed by pacemaker neurons in the brain that communicate with oscillators in peripheral tissues. Adrenal glucocorticoids are important time-giving signals to peripheral circadian oscillators. We investigated the rhythm of Per1-luc expression in pineal, pituitary, salivary glands, liver, lung, kidney, cornea as well as suprachiasmatic nucleus from adrenalectomized and sham-operated rats kept under light-dark cycles, or exposed to single 6-h phase delays or advances of their light cycles. Adrenalectomy shifted the phases of Per1-luc in liver, kidney, and cornea and caused phase desynchrony and significant dampening in the rhythmicity of cornea. Treatment with hydrocortisone shifted the phases of Per1-luc in most of the tissues examined, even those that were not affected by adrenalectomy. The rhythm in cornea recovered in animals given hydrocortisone in vivo or when corneas were treated with dexamethasone in vitro. Adrenalectomy increased the rate of reentrainment after phase shifts in liver, kidney, cornea, pineal, lung, and suprachiasmatic nucleus but not in pituitary and salivary glands. Our data show that glucocorticoids act as strong entraining signals for peripheral circadian oscillators and may feed back on central oscillators as well. PMID:22893723

  2. Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*

    PubMed Central

    Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

    2014-01-01

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

  3. 30 CFR 57.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Machinery... uncoupling shall not be attempted from the inside of curves unless the railroad and cars are designed...

  4. 30 CFR 57.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Machinery... uncoupling shall not be attempted from the inside of curves unless the railroad and cars are designed...

  5. 30 CFR 57.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Machinery... uncoupling shall not be attempted from the inside of curves unless the railroad and cars are designed...

  6. 30 CFR 57.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Machinery... uncoupling shall not be attempted from the inside of curves unless the railroad and cars are designed...

  7. 30 CFR 57.14215 - Coupling or uncoupling cars.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... NONMETAL MINE SAFETY AND HEALTH SAFETY AND HEALTH STANDARDS-UNDERGROUND METAL AND NONMETAL MINES Machinery... uncoupling shall not be attempted from the inside of curves unless the railroad and cars are designed...

  8. Inhibition of photosynthetic oxygen evolution by protonophoric uncouplers.

    PubMed

    Samuilov, V D; Renger, G; Paschenko, V Z; Oleskin, A V; Gusev, M V; Gubanova, O N; Vasil'ev, S S; Barsky, E L

    1995-01-01

    The protonophoric uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), 2,3,4,5,6-pentachlorophenol (PCP) and 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole (TTFB) inhibited the Hill reaction with K3[Fe(CN)6] (but not with SiMo) in chloroplast and cyanobacterial membranes (the I50 values were approx. 1-2, 4-6 and 0.04-0.10 μM, respectively). The inhibition is due to oxidation of the uncouplers on the Photosystem II donor side (ADRY effect) and their subsequent reduction on the acceptor side, ie. to the formation of a cyclic electron transfer chain around Photosystem II involving the uncouplers as redox carriers. The relative amplitude of nanosecond chlorophyll fluorescence in chloroplasts was increased by DCMU or HQNO and did not change upon addition of uncouplers, DBMIB or DNP-INT; the HQNO effect was not removed by the uncouplers. The uncouplers did not inhibit the electron transfer from reduced TMPD or duroquinol to methylviologen which is driven by Photosystem I. These data show that CCCP, PCP and TTFB oxidized on the Photosystem II donor side are reduced by the membrane pool of plastoquinone (Qp) which is also the electron donor for K3 [Fe(CN)6] in the Hill reaction as deduced from the data obtained in the presence of inhibitors. Inhibition of the Hill reaction by the uncouplers was maximum at the pH values corresponding to the pK of these compounds. It is suggested that the tested uncouplers serve as proton donors, and not merely as electron donors on the oxidizing side of Photosystem II. PMID:24301640

  9. Dexamethasone, tetrahydrobiopterin and uncoupling of endothelial nitric oxide synthase

    PubMed Central

    Tobias, Silke; Habermeier, Alice; Siuda, Daniel; Reifenberg, Gisela; Xia, Ning; Closs, Ellen I; Förstermann, Ulrich; Li, Huige

    2015-01-01

    Objective To find out whether dexamethasone induces an uncoupling of the endothelial nitric oxide synthase (eNOS). Methods & Results A major cause of eNOS uncoupling is a deficiency of its cofactor tetrahydrobiopterin (BH4). Treatment of human EA.hy 926 endothelial cells with dexamethasone decreased mRNA and protein expression of both BH4-synthesizing enzymes: GTP cyclohydrolase I and dihydrofolate reductase. Consistently, a concentration- and time-dependent reduction of BH4, dihydrobiopterin (BH2) as well as BH4: BH2 ratio was observed in dexamethasone-treated cells. Surprisingly, no evidence for eNOS uncoupling was found. We then analyzed the expression and phosphorylation of the eNOS enzyme. Dexamethasone treatment led to a down-regulation of eNOS protein and a reduction of eNOS phosphorylation at serine 1177. A reduction of eNOS expression may lead to a relatively normal BH4: eNOS molar ratio in dexamethasone-treated cells. Because the BH4-eNOS stoichiometry rather than the absolute BH4 amount is the key determinant of eNOS functionality (i.e., coupled or uncoupled), the down-regulation of eNOS may represent an explanation for the absence of eNOS uncoupling. Phosphorylation of eNOS at serine 1177 is needed for both the NO-producing activity of the coupled eNOS and the superoxide-producing activity of the uncoupled eNOS. Thus, a reduction of serine 1177 phosphorylation may render a potentially uncoupled eNOS hardly detectable. Conclusions Although dexamethasone reduces BH4 levels in endothelial cells, eNOS uncoupling is not evident. The reduction of NO production in dexamethasone-treated endothelial cells is mainly attributable to reduced eNOS expression and decreased eNOS phosphorylation at serine 1177. PMID:26512245

  10. Circadian Cycles of Gene Expression in the Coral, Acropora millepora

    PubMed Central

    Brady, Aisling K.; Snyder, Kevin A.; Vize, Peter D.

    2011-01-01

    Background Circadian rhythms regulate many physiological, behavioral and reproductive processes. These rhythms are often controlled by light, and daily cycles of solar illumination entrain many clock regulated processes. In scleractinian corals a number of different processes and behaviors are associated with specific periods of solar illumination or non-illumination—for example, skeletal deposition, feeding and both brooding and broadcast spawning. Methodology/Principal Findings We have undertaken an analysis of diurnal expression of the whole transcriptome and more focused studies on a number of candidate circadian genes in the coral Acropora millepora using deep RNA sequencing and quantitative PCR. Many examples of diurnal cycles of RNA abundance were identified, some of which are light responsive and damped quickly under constant darkness, for example, cryptochrome 1 and timeless, but others that continue to cycle in a robust manner when kept in constant darkness, for example, clock, cryptochrome 2, cycle and eyes absent, indicating that their transcription is regulated by an endogenous clock entrained to the light-dark cycle. Many other biological processes that varied between day and night were also identified by a clustering analysis of gene ontology annotations. Conclusions/Significance Corals exhibit diurnal patterns of gene expression that may participate in the regulation of circadian biological processes. Rhythmic cycles of gene expression occur under constant darkness in both populations of coral larvae that lack zooxanthellae and in individual adult tissue containing zooxanthellae, indicating that transcription is under the control of a biological clock. In addition to genes potentially involved in regulating circadian processes, many other pathways were found to display diel cycles of transcription. PMID:21949855

  11. Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?

    NASA Technical Reports Server (NTRS)

    Fuller, Patrick M.; Jones, Timothy A.; Jones, Sherri M.; Fuller, Charles A.

    2002-01-01

    Chronic exposure to increased force environments (+G) has pronounced effects on the circadian and homeostatic regulation of body temperature (T(b)), ambulatory activity (Act), heart rate, feeding, and adiposity. By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses. The present study used the C57BL6JEi-het mouse strain (het), which lacks macular otoconia, to elucidate the contribution of specific vestibular receptors. In this study, eight het and eight WT mice were exposed to 2G for 8 weeks by means of chronic centrifugation. In addition, eight het and eight WT mice were maintained as 1G controls in similar conditions. Upon 2G exposure, the WT exhibited a decrease in T(b) and an attenuated T(b) circadian rhythm. Act means and rhythms also were attenuated. Body mass and food intake were significantly lower than the 1G controls. After 8 weeks, percent body fat was significantly lower in the WT mice (P < 0.0001). In contrast, the het mice did not exhibit a decrease in mean T(b) and only a slight decrease in T(b) circadian amplitude. het Act levels were attenuated similarly to the WT mice. Body mass and food intake were only slightly attenuated in the het mice, and percent body fat, after 8 weeks, was not different in the 2G het group. These results link the vestibular macular receptors with specific alterations in homeostatic and circadian regulation.

  12. Role of Circadian Rhythms in Potassium Homeostasis

    PubMed Central

    Gumz, Michelle L.; Rabinowitz, Lawrence

    2013-01-01

    It has been known for decades that urinary potassium excretion varies with a circadian pattern. In this review, we consider the historical evidence for this phenomenon and present an overview of recent developments in the field. Extensive evidence from the latter part of the last century clearly demonstrates that circadian potassium excretion does not depend on endogenous aldosterone. Of note is the recent discovery that the expression of several renal potassium transporters varies with a circadian pattern that appears to be consistent with substantial clinical data regarding daily fluctuations in urinary potassium levels. We propose the circadian clock mechanism as a key regulator of renal potassium transporters, and consequently renal potassium excretion. Further investigation into the mechanism of regulation of renal potassium transport by the circadian clock is warranted in order to increase our understanding of the clinical relevance of circadian rhythms to potassium homeostasis. PMID:23953800

  13. CIRCADIAN RHYTHM REPROGRAMMING DURING LUNG INFLAMMATION

    PubMed Central

    Haspel, Jeffrey A.; Chettimada, Sukrutha; Shaik, Rahamthulla S.; Chu, Jen-Hwa; Raby, Benjamin A.; Cernadas, Manuela; Carey, Vincent; Process, Vanessa; Hunninghake, G. Matthew; Ifedigbo, Emeka; Lederer, James A.; Englert, Joshua; Pelton, Ashley; Coronata, Anna; Fredenburgh, Laura E.; Choi, Augustine M. K.

    2014-01-01

    Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here, we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian program exhibits unique features, including a divergent group of rhythmic genes and metabolites compared to the basal state and a distinct periodicity and phase distribution. At the cellular level endotoxin treatment also alters circadian rhythms of leukocyte counts within the lung in a bmal1-dependent manner, such that granulocytes rather than lymphocytes become the dominant oscillating cell type. Our results show that inflammation produces a complex reorganization of cellular and molecular circadian rhythms that are relevant to early events in lung injury. PMID:25208554

  14. Mechanism of the circadian clock in physiology

    PubMed Central

    Richards, Jacob

    2013-01-01

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

  15. Metabolic and Nontranscriptional Circadian Clocks: Eukaryotes

    PubMed Central

    Reddy, Akhilesh B.; Rey, Guillaume

    2016-01-01

    Circadian clocks are cellular timekeeping mechanisms that coordinate behavior and physiology around the 24-h day in most living organisms. Misalignment of an organism’s clock with its environment is associated with long-term adverse fitness consequences, as exemplified by the link between circadian disruption and various age-related diseases in humans. Current eukaryotic models of the circadian oscillator rely on transcription/translation feedback loop mechanisms, supplemented with accessory cytosolic loops that connect them to cellular physiology. However, there is mounting evidence questioning the absolute necessity of transcription-based oscillators for circadian rhythmicity, supported by the recent discovery of oxidation-reduction cycles of peroxiredoxin proteins, which persist even in the absence of transcription. A more fundamental mechanism based on metabolic cycles could thus underlie circadian transcriptional and cytosolic rhythms, thereby promoting circadian oscillations to integral properties of cellular metabolism. PMID:24606143

  16. Molecular studies of the uncoupling protein

    SciTech Connect

    Ricquier, D.; Casteilla, L.; Bouillaud, F. )

    1991-06-01

    The uncoupling protein (UCP) is a proton/anion transporter found in the inner mitochondrial membrane of brown adipocyte. Although UCP has nor been detected in mitochondria from any other tissue, it shares structural and catalytic properties with several other mitochondrial carrier proteins. Although UCP was discovered only recently it is one of the most extensively studied mitochondrial carrier proteins.More recently, the mouse, rat, and human genes encoding for UCP have been isolated and sequenced. The availability of these various tools has led to several significant observations. UCP gene expression is strongly controlled at the level of transcription by signals that are activated after the stimulation of brown adipocytes by norepinephrine. The comparison of UCP gene with the genes encoding the adenine nucleotide translocator revealed the existence of structural and evolutionary homologies. Moreover, in humans the UCP gene and one form of adenine nucleotide translocator gene are located on the same chromosome. Recently, the expression of functional UCp in various heterologous systems was achieved (Xenopus oocytes, CHO cells, yeasts). These data will facilitate studies of the structure/function relationship in UCP (identification of residues involved in H{sup +} transport, Cl{sup {minus}} transport, nucleotide binding, mitochondrial targeting). Another aspect of the present research on UCP is the understanding of mechanisms that control UCP gene and the differentiated commitment of adipose precursor cells to thermogenic brown adipocytes.

  17. Properties of substituted 2-trifluoromethylbenzimidazoles as uncouplers of oxidative phosphorylation

    PubMed Central

    Jones, O. T. G.; Watson, W. A.

    1967-01-01

    1. The activity of 25 substituted 2-trifluoromethylbenzimidazoles in uncoupling oxidative phosphorylation by rat-liver mitochondria has been compared. 2. For halogen- or mixed-halogen- and alkyl-substituted analogues, uncoupling activity was proportional to the acidity of the imidazole −NH group. Tetrachloro-2-trifluoromethylbenzimidazole was the most active (50% uncoupling of oxidative phosphorylation at 7·9×10−8m, pK5·04). Nitro-substituted analogues were less active than predicted from pK considerations or from partition-coefficient measurements. 3. Introduction of an −NH2 or −CO2H substitutent caused a loss of uncoupling activity, as did alkylation at position 1 of the imidazole ring. 4. Benzimidazoles active as uncouplers stimulated mitochondrial adenosine triphosphatase but not all stimulated the oxidation of succinate in the absence of a phosphate acceptor. 5. 4,5-Dichloro-2-trifluoromethylbenzimidazole inhibited the succinate-oxidase system at about the same concentration required for uncoupling (0·52μm for 50% inhibition of both activities) and the site of this inhibition appears to lie between succinate dehydrogenase and cytochrome b. PMID:4291494

  18. Properties of substituted 2-trifluoromethylbenzimidazoles as uncouplers of oxidative phosphorylation.

    PubMed

    Jones, O T; Watson, W A

    1967-02-01

    1. The activity of 25 substituted 2-trifluoromethylbenzimidazoles in uncoupling oxidative phosphorylation by rat-liver mitochondria has been compared. 2. For halogen- or mixed-halogen- and alkyl-substituted analogues, uncoupling activity was proportional to the acidity of the imidazole -NH group. Tetrachloro-2-trifluoromethylbenzimidazole was the most active (50% uncoupling of oxidative phosphorylation at 7.9x10(-8)m, pK5.04). Nitro-substituted analogues were less active than predicted from pK considerations or from partition-coefficient measurements. 3. Introduction of an -NH(2) or -CO(2)H substitutent caused a loss of uncoupling activity, as did alkylation at position 1 of the imidazole ring. 4. Benzimidazoles active as uncouplers stimulated mitochondrial adenosine triphosphatase but not all stimulated the oxidation of succinate in the absence of a phosphate acceptor. 5. 4,5-Dichloro-2-trifluoromethylbenzimidazole inhibited the succinate-oxidase system at about the same concentration required for uncoupling (0.52mum for 50% inhibition of both activities) and the site of this inhibition appears to lie between succinate dehydrogenase and cytochrome b. PMID:4291494

  19. Effect of Circadian Rhythm on Clinical and Pathophysiological Conditions and Inflammation.

    PubMed

    Kizaki, Takako; Sato, Shogo; Shirato, Ken; Sakurai, Takuya; Ogasawara, Junetsu; Izawa, Tetsuya; Ohira, Yoshinobu; Suzuki, Kenji; Ohno, Hideki

    2015-01-01

    Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging-related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases. PMID:26757391

  20. Circadian clocks: lessons from fish.

    PubMed

    Idda, M Laura; Bertolucci, Cristiano; Vallone, Daniela; Gothilf, Yoav; Sánchez-Vázquez, Francisco Javier; Foulkes, Nicholas S

    2012-01-01

    Our understanding of the molecular and cellular organization of the circadian timing system in vertebrates has increased enormously over the past decade. In large part, progress has been based on genetic studies in the mouse as well as on fundamental similarities between vertebrate and Drosophila clocks. The zebrafish was initially considered as a potentially attractive genetic model for identifying vertebrate clock genes. However, instead, fish have ultimately proven to be valuable complementary models for studying various aspects of clock biology. For example, many fish can shift from diurnal to nocturnal activity implying specific flexibility in their clock function. We have learned much about the function of light input pathways, and the ontogeny and function of the pineal organ, the fish central pacemaker. Finally, blind cavefish have also provided new insight into the evolution of the circadian clock under extreme environmental conditions. PMID:22877658

  1. Circadian Rhythm Control: Neurophysiological Investigations

    NASA Technical Reports Server (NTRS)

    Glotzbach, S. F.

    1985-01-01

    The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.

  2. Circadian rhythmometry of mammalian radiosensitivity

    NASA Technical Reports Server (NTRS)

    Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

    1974-01-01

    In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

  3. Circadian rhythms: glucocorticoids and arthritis.

    PubMed

    Cutolo, Maurizio; Sulli, Alberto; Pizzorni, Carmen; Secchi, Maria Elena; Soldano, Stefano; Seriolo, Bruno; Straub, Rainer H; Otsa, Kati; Maestroni, Georges J

    2006-06-01

    Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms. PMID:16855156

  4. Circadian rhythms and cancer chemotherapy.

    PubMed

    Wood, P A; Hrushesky, W J

    1996-01-01

    Temporal coordination of biologic processes with an approximately 24-h cycle (circadian) is common throughout the animal and plant kingdom and even in some prokaryotic organisms. In all organisms studied, the capability to keep biologic time is an inherited characteristic located intracellularly. These biological clocks anticipate and get the organism ready for regular environmental changes. This indicates both the ubiquity and the weight of the selective environmental pressure to keep time accurately. Several molecular strategies for biologic time keeping have apparently arisen independently several times throughout evolution. The anatomic, biochemical, and molecular mechanisms of the clock are in the process of being defined. This temporal organization at the cellular, organ, and organismic levels results in predictable differences in the capacity of plants, animals, and human beings to respond to therapeutic interventions administered at different times throughout important biologic cycles (e.g., circadian timed therapy). In the treatment of the cancer bearing host, circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, enhanced tumor control, and improved host survival. The routine clinical application of such principles is facilitated by the availability of programmable drug delivery devices. Rhythm frequency ranges other than 24-h (e.g., low frequency: menstrual; high frequency: 10 to 120 min) may also be important to understanding health and disease and to designing successful therapy in diseases as diverse as cancer, infertility, and diabetes. PMID:8959371

  5. Uncoupled thermoelasticity solutions applied on beam dumps

    NASA Astrophysics Data System (ADS)

    Ouzia, A.; Antonakakis, T.

    2016-06-01

    In particle accelerators the process of beam absorption is vital. At CERN particle beams are accelerated at energies of the order of TeV. In the event of a system failure or following collisions, the beam needs to be safely absorbed by dedicated protecting blocks. The thermal shock caused by the rapid energy deposition within the absorbing block causes thermal stresses that may rise above critical levels. The present paper provides a convenient expression of such stresses under hypotheses described hereafter. The temperature field caused by the beam energy deposition is assumed to be Gaussian. Such a field models a non-diffusive heat deposition. These effects are described as thermoelastic as long as the stresses remain below the proportional limit and can be analytically modeled by the coupled equations of thermoelasticity. The analytical solution to the uncoupled thermoelastic problem in an infinite domain is presented herein and matched with a finite unit radius sphere. The assumption of zero diffusion as well as the validity of the match with a finite geometry is quantified such that the obtained solutions can be rigorously applied to real problems. Furthermore, truncated series solutions, which are not novel, are used for comparison purposes. All quantities are nondimensional and the problem reduces to a dependence of five dimensionless parameters. The equations of elasticity are presented in the potential formulation where the shear potential is assumed to be nil due to the source being a gradient and the absence of boundaries. Nevertheless equivalent three-dimensional stresses are computed using the compressive potential and optimized using standard analytical optimization methods. An alternative algorithm for finding the critical points of the three-dimensional stress function is presented. Finally, a case study concerning the proton synchrotron booster dump is presented where the aforementioned analytical solutions are used and the preceding assumptions

  6. Uncoupling of bone turnover following hip replacement.

    PubMed

    Whitson, H; DeMarco, D; Reilly, D; Murphy, S; Yett, H S; Mattingly, D; Greenspan, S L

    2002-07-01

    Studies using total hip replacement surgery as a model for acute hip injury have shown that bone mineral density of the proximal femur decreases 6-18% in the 6 months following surgery. To examine the acute biochemical mechanism associated with bone loss, we measured two indicators of bone formation [serum osteocalcin (OC), serum bone-specific alkaline phosphatase (BSAP)], as well as two markers for bone resorption [urine and serum N-telopeptide cross-linked collagen type 1 (NTx)], in 20 patients (10 men, 10 women, mean age 59.4 years) prior to hip replacement and 1-2 days postsurgery. The average OC value (ng/ml) decreased by 57.3% following surgery (7.5 +/- 4.3 to 3.2 +/- 1.1, P <0.001), and the average BSAP level (U/L) decreased by 27.6% (19.9 +/- 5.6 to 14.4 +/- 3.7, P <0.001). In contrast, levels of urine NTx (nmol BCE/mmol Cr) did not change significantly after the surgery (73.9 +/- 47.2 to 70.1 +/- 29.7). In addition, there was no change in serum NTx (nmol BCE) after surgery (11.8 +/- 2.3 to 11.8 +/- 3.0). Six months after surgery, bone mass had not changed significantly from baseline. These findings suggest that there is an uncoupling of bone turnover following hip replacement surgery which is characterized by significant reductions in bone formation without compensatory decreases in bone resorption, potentially leading to bone loss. Longer periods of follow-up are needed to assess long-term bone mass changes. PMID:12200656

  7. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    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

  8. Identifying Novel Transcriptional Regulators with Circadian Expression

    PubMed Central

    Schick, Sandra; Thakurela, Sudhir; Fournier, David; Hampel, Mareike Hildegard

    2015-01-01

    Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms. PMID:26644408

  9. INTRINSIC CIRCADIAN RHYTHMS IN THE CARDIOMYOCYTE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cardiomyocyte possesses a fully functional circadian clock. Circadian clocks are a set of proteins that generate self-sustained transcriptional positive and negative feedback loops with a free-running period of 24 hours. These intracellular molecular mechanisms confer the selective advantage of ...

  10. Circadian regulation of ATP release in astrocytes.

    PubMed

    Marpegan, Luciano; Swanstrom, Adrienne E; Chung, Kevin; Simon, Tatiana; Haydon, Philip G; Khan, Sanjoy K; Liu, Andrew C; Herzog, Erik D; Beaulé, Christian

    2011-06-01

    Circadian clocks sustain daily oscillations in gene expression, physiology, and behavior, relying on transcription-translation feedback loops of clock genes for rhythm generation. Cultured astrocytes display daily oscillations of extracellular ATP, suggesting that ATP release is a circadian output. We hypothesized that the circadian clock modulates ATP release via mechanisms that regulate acute ATP release from glia. To test the molecular basis for circadian ATP release, we developed methods to measure in real-time ATP release and Bmal1::dLuc circadian reporter expression in cortical astrocyte cultures from mice of different genotypes. Daily rhythms of gene expression required functional Clock and Bmal1, both Per1 and Per2, and both Cry1 and Cry2 genes. Similarly, high-level, circadian ATP release also required a functional clock mechanism. Whereas blocking IP(3) signaling significantly disrupted ATP rhythms with no effect on Bmal1::dLuc cycling, blocking vesicular release did not alter circadian ATP release or gene expression. We conclude that astrocytes depend on circadian clock genes and IP(3) signaling to express daily rhythms in ATP release. PMID:21653839

  11. Circadian regulation of ATP release in astrocytes

    PubMed Central

    Marpegan, Luciano; Swanstrom, Adrienne E.; Chung, Kevin; Simon, Tatiana; Haydon, Philip G.; Khan, Sanjoy K.; Liu, Andrew C.; Herzog, Erik D.; Beaulé, Christian

    2011-01-01

    Circadian clocks sustain daily oscillations in gene expression, physiology and behavior, relying on transcription-translation feedback loops of clock genes for rhythm generation. Cultured astrocytes display daily oscillations of extracellular ATP, suggesting that ATP release is a circadian output. We hypothesized that the circadian clock modulates ATP release via mechanisms that regulate acute ATP release from glia. To test the molecular basis for circadian ATP release, we developed methods to measure in real-time ATP release and Bmal1::dLuc circadian reporter expression in cortical astrocyte cultures from mice of different genotypes. Daily rhythms of gene expression required functional Clock and Bmal1, both Per1 and Per2, and both Cry1 and Cry2 genes. Similarly, high level, circadian ATP release also required a functional clock mechanism. Whereas blocking IP3 signaling significantly disrupted ATP rhythms with no effect on Bmal1::dLuc cycling, blocking vesicular release did not alter circadian ATP release or gene expression. We conclude that astrocytes depend on circadian clock genes and IP3 signaling to express daily rhythms in ATP release. PMID:21653839

  12. The Circadian Clock and Human Health.

    PubMed

    Roenneberg, Till; Merrow, Martha

    2016-05-23

    Epidemiological studies provided the first evidence suggesting a connection between the circadian clock and human health. Mutant mice convincingly demonstrate the principle that dysregulation of the circadian system leads to a multitude of pathologies. Chrono-medicine is one of the most important upcoming themes in the field of circadian biology. Although treatments counteracting circadian dysregulation are already being applied (e.g., prescribing strong and regular zeitgebers), we need to comprehend entrainment throughout the body's entire circadian network before understanding the mechanisms that tie circadian dysregulation to pathology. Here, we attempt to provide a systematic approach to understanding the connection between the circadian clock and health. This taxonomy of (mis)alignments on one hand exposes how little we know about entrainment within any organism and which 'eigen-zeitgeber' signals are used for entrainment by the different cells and tissues. On the other hand, it provides focus for experimental approaches and tools that will logically map out how circadian systems contribute to disease as well as how we can treat and prevent them. PMID:27218855

  13. Circadian dysregulation disrupts bile acid homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bile acids are potentially toxic compounds and their levels of hepatic production, uptake, and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. Both restricted feedi...

  14. Circadian dysfunction induces leptin resistance in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt over...

  15. [Circadian rhythm sleep disorders in psychiatric diseases].

    PubMed

    Bromundt, Vivien

    2014-11-01

    Circadian rhythm sleep disorders are prevalent among psychiatric patients. This is most probable due to a close relationship between functional disturbances of the internal clock, sleep regulation and mental health. Mechanisms on molecular level of the circadian clock and neurotransmitter signalling are involved in the development of both disorders. Moreover, circadian disorders and psychiatric diseases favour each other by accessory symptoms such as stress or social isolation. Actimetry to objectively quantify the rest-activity cycle and salivary melatonin profiles as marker for the circadian phase help to diagnose circadian rhythm sleep disorders in psychiatric patients. Chronotherapeutics such as bright light therapy, dark therapy, melatonin administration, and wake therapy are used to synchronise and consolidate circadian rhythms and help in the treatment of depression and other psychiatric disorders, but are still neglected in medicine. More molecular to behavioural research is needed for the understanding of the development of circadian disorders and their relationship to psychiatric illnesses. This will help to boost the awareness and treatment of circadian rhythm sleep disorders in psychiatry. PMID:25377290

  16. Circadian regulation of insect olfactory learning.

    PubMed

    Decker, Susan; McConnaughey, Shannon; Page, Terry L

    2007-10-01

    Olfactory learning in insects has been used extensively for studies on the neurobiology, genetics, and molecular biology of learning and memory. We show here that the ability of the cockroach Leucophaea maderae to acquire olfactory memories is regulated by the circadian system. We investigated the effect of training and testing at different circadian phases on performance in an odor-discrimination test administered 30 min after training (short-term memory) or 48 h after training (long-term memory). When odor preference was tested by allowing animals to choose between two odors (peppermint and vanilla), untrained cockroaches showed a clear preference for vanilla at all circadian phases, indicating that there was no circadian modulation of initial odor preference or ability to discriminate between odors. After differential conditioning, in which peppermint odor was associated with a positive unconditioned stimulus of sucrose solution and vanilla odor was associated with a negative unconditioned stimulus of saline solution, cockroaches conditioned in the early subjective night showed a strong preference for peppermint and retained the memory for at least 2 days. Animals trained and tested at other circadian phases showed significant deficits in performance for both short- and long-term memory. Performance depended on the circadian time (CT) of training, not the CT of testing, and results indicate that memory acquisition rather than retention or recall is modulated by the circadian system. The data suggest that the circadian system can have profound effects on olfactory learning in insects. PMID:17893338

  17. THE INTRINSIC CIRCADIAN CLOCK WITHIN THE CARDIOMYOCYTE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully...

  18. A colorful model of the circadian clock.

    PubMed

    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

  19. Circadian rhythms in myocardial metabolism and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral...

  20. eNOS-uncoupling in age-related erectile dysfunction

    PubMed Central

    Johnson, JM; Bivalacqua, TJ; Lagoda, GA; Burnett, AL; Musicki, B

    2011-01-01

    Aging is associated with ED. Although age-related ED is attributed largely to increased oxidative stress and endothelial dysfunction in the penis, the molecular mechanisms underlying this effect are not fully defined. We evaluated whether endothelial nitric oxide synthase (eNOS) uncoupling in the aged rat penis is a contributing mechanism. Correlatively, we evaluated the effect of replacement with eNOS cofactor tetrahydrobiopterin (BH4) on erectile function in the aged rats. Male Fischer 344 ‘young’ (4-month-old) and ‘aged’ (19-month-old) rats were treated with a BH4 precursor sepiapterin (10 mg/kg intraperitoneally) or vehicle for 4 days. After 1-day washout, erectile function was assessed in response to electrical stimulation of the cavernous nerve. Endothelial dysfunction (eNOS uncoupling) and oxidative stress (thiobarbituric acid reactive substances, TBARS) were measured by conducting western blot in penes samples. Erectile response was significantly reduced in aged rats, whereas eNOS uncoupling and TBARS production were significantly increased in the aged rat penis compared with young rats. Sepiapterin significantly improved erectile response in aged rats and prevented increase in TBARS production, but did not affect eNOS uncoupling in the penis of aged rats. These findings suggest that aging induces eNOS uncoupling in the penis, resulting in increased oxidative stress and ED. PMID:21289638

  1. Metabolic consequences of sleep and circadian disorders

    PubMed Central

    Depner, Christopher M.; Stothard, Ellen R.; Wright, Kenneth P.

    2014-01-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID:24816752

  2. Circadian regulation of human cortical excitability.

    PubMed

    Ly, Julien Q M; Gaggioni, Giulia; Chellappa, Sarah L; Papachilleos, Soterios; Brzozowski, Alexandre; Borsu, Chloé; Rosanova, Mario; Sarasso, Simone; Middleton, Benita; Luxen, André; Archer, Simon N; Phillips, Christophe; Dijk, Derk-Jan; Maquet, Pierre; Massimini, Marcello; Vandewalle, Gilles

    2016-01-01

    Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp electroencephalography (EEG) responses to transcranial magnetic stimulation in 22 participants during 29 h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that are strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlates with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homoeostasis alone. These findings have implications for clinical applications such as non-invasive brain stimulation in neurorehabilitation. PMID:27339884

  3. Genetic Basis of Human Circadian Rhythm Disorders

    PubMed Central

    Jones, Christopher R.; Huang, Angela L.; Ptáček, Louis J.; Fu, Ying-Hui

    2012-01-01

    Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health. PMID:22849821

  4. Circadian regulation of human cortical excitability

    PubMed Central

    Ly, Julien Q. M.; Gaggioni, Giulia; Chellappa, Sarah L.; Papachilleos, Soterios; Brzozowski, Alexandre; Borsu, Chloé; Rosanova, Mario; Sarasso, Simone; Middleton, Benita; Luxen, André; Archer, Simon N.; Phillips, Christophe; Dijk, Derk-Jan; Maquet, Pierre; Massimini, Marcello; Vandewalle, Gilles

    2016-01-01

    Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp electroencephalography (EEG) responses to transcranial magnetic stimulation in 22 participants during 29 h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that are strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlates with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homoeostasis alone. These findings have implications for clinical applications such as non-invasive brain stimulation in neurorehabilitation. PMID:27339884

  5. Circadian light-input pathways in Drosophila.

    PubMed

    Yoshii, Taishi; Hermann-Luibl, Christiane; Helfrich-Förster, Charlotte

    2016-01-01

    Light is the most important environmental cue to entrain the circadian clock in most animals. In the fruit fly Drosophila melanogaster, the light entrainment mechanisms of the clock have been well-studied. The Drosophila brain contains approximately 150 neurons that rhythmically express circadian clock genes. These neurons are called "clock neurons" and control behavioral activity rhythms. Many clock neurons express the Cryptochrome (CRY) protein, which is sensitive to UV and blue light, and thus enables clock neurons deep in the brain to directly perceive light. In addition to the CRY protein, external photoreceptors in the Drosophila eyes play an important role in circadian light-input pathways. Recent studies have provided new insights into the mechanisms that integrate these light inputs into the circadian network of the brain. In this review, we will summarize the current knowledge on the light entrainment pathways in the Drosophila circadian clock. PMID:27066180

  6. Sludge reduction by uncoupling metabolism: SBR tests with para-nitrophenol and a commercial uncoupler.

    PubMed

    Zuriaga-Agustí, E; Mendoza-Roca, J A; Bes-Piá, A; Alonso-Molina, J L; Amorós-Muñoz, I

    2016-11-01

    Nowadays cost reduction is a very important issue in wastewater treatment plants. One way, is to minimize the sludge production. Microorganisms break down the organic matter into inorganic compounds through catabolism. Uncoupling metabolism is a method which promote catabolism reactions instead of anabolism ones, where adenosine triphosphate synthesis is inhibited. In this work, the influence of the addition of para-nitrophenol and a commercial reagent to a sequencing batch reactor (SBR) on sludge production and process performance has been analyzed. Three laboratory SBRs were operated in parallel to compare the effect of the addition of both reagents with a control reactor. SBRs were fed with synthetic wastewater and were operated with the same conditions. Results showed that sludge production was slightly reduced for the tested para-nitrophenol concentrations (20 and 25 mg/L) and for a LODOred dose of 1 mL/day. Biological process performance was not influenced and high COD removals were achieved. PMID:27505165

  7. The circadian system: plasticity at many levels.

    PubMed

    Muraro, N I; Pírez, N; Ceriani, M F

    2013-09-01

    Over the years it has become crystal clear that a variety of processes encode time-of-day information, ranging from gene expression, protein stability, or subcellular localization of key proteins, to the fine tuning of network properties and modulation of input signals, ultimately ensuring that physiology and behavior are properly synchronized to a changing environment. The purpose of this review is to put forward examples (as opposed to generate a comprehensive revision of all the available literature) in which the circadian system displays a remarkable degree of plasticity, from cell autonomous to circuit-based levels. In the literature, the term circadian plasticity has been used to refer to different concepts. The obvious one, more literally, refers to any change that follows a circadian (circa=around, diem=day) pattern, i.e. a daily change of a given parameter. The discovery of daily remodeling of neuronal structures will be referred herein as structural circadian plasticity, and represents an additional and novel phenomenon modified daily. Finally, any plasticity that has to do with a circadian parameter would represent a type of circadian plasticity; as an example, adjustments that allow organisms to adapt their daily behavior to the annual changes in photoperiod is a form of circadian plasticity at a higher organizational level, which is an emergent property of the whole circadian system. Throughout this work we will revisit these types of changes by reviewing recent literature delving around circadian control of clock outputs, from the most immediate ones within pacemaker neurons to the circadian modulation of rest-activity cycles. PMID:23727010

  8. Molecular cloning of amphioxus uncoupling protein and assessment of its uncoupling activity using a yeast heterologous expression system

    SciTech Connect

    Chen, Kun; Sun, Guoxun; Lv, Zhiyuan; Wang, Chen; Jiang, Xueyuan; Li, Donghai; Zhang, Chenyu

    2010-10-01

    Research highlights: {yields} Invertebrates, for example amphioxus, do express uncoupling proteins. {yields} Both the sequence and the uncoupling activity of amphioxus UCP resemble UCP2. {yields} UCP1 is the only UCP that can form dimer on yeast mitochondria. -- Abstract: The present study describes the molecular cloning of a novel cDNA fragment from amphioxus (Branchiostoma belcheri) encoding a 343-amino acid protein that is highly homologous to human uncoupling proteins (UCP), this protein is therefore named amphioxus UCP. This amphioxus UCP shares more homology with and is phylogenetically more related to mammalian UCP2 as compared with UCP1. To further assess the functional similarity of amphioxus UCP to mammalian UCP1 and -2, the amphioxus UCP, rat UCP1, and human UCP2 were separately expressed in Saccharomyces cerevisiae, and the recombinant yeast mitochondria were isolated and assayed for the state 4 respiration rate and proton leak, using pYES2 empty vector as the control. UCP1 increased the state 4 respiration rate by 2.8-fold, and the uncoupling activity was strongly inhibited by GDP, while UCP2 and amphioxus UCP only increased the state 4 respiration rate by 1.5-fold and 1.7-fold in a GDP-insensitive manner, moreover, the proton leak kinetics of amphioxus UCP was very similar to UCP2, but much different from UCP1. In conclusion, the amphioxus UCP has a mild, unregulated uncoupling activity in the yeast system, which resembles mammalian UCP2, but not UCP1.

  9. An Energy-Optimal Approach for Entrainment of Uncertain Circadian Oscillators

    PubMed Central

    Wilson, Dan; Moehlis, Jeff

    2014-01-01

    We develop an approach to find an energy-optimal stimulus that entrains an ensemble of uncertain, uncoupled limit cycle oscillators. Furthermore, when entrainment occurs, the phase shift between oscillators is constrained to be less than a predetermined amount. This approach is illustrated for a model of Drosophila circadian activity, for which it performs better than a standard 24-h light-dark cycle. Because this method explicitly accounts for uncertainty in a given system and only requires information that is experimentally obtainable, it is well suited for experimental implementation and could ultimately represent what is believed to be a novel treatment for patients suffering from advanced/delayed sleep-phase syndrome. PMID:25296328

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

    PubMed

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

    2016-01-01

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

  11. The on/off switches of the mitochondrial uncoupling proteins

    PubMed Central

    Azzu, Vian; Brand, Martin D.

    2013-01-01

    Mitochondrial uncoupling proteins disengage substrate oxidation from ADP phosphorylation by dissipating the proton electrochemical gradient that is required for ATP synthesis. In doing this, the archetypal uncoupling protein, UCP1, mediates adaptive thermogenesis. By contrast, its paralogues UCP2 and UCP3 are not thought to mediate whole body thermogenesis in mammals. Instead, they have been implicated in a variety of physiological and pathological processes, including protection from oxidative stress, negative regulation of glucose sensing systems and the adaptation of fatty acid oxidation capacity to starving. Although much work has been devoted to how these proteins are activated, little is known of the mechanisms that reverse this activation. PMID:20006514

  12. Incorporating Uncoupled Stress Effects into FEHM Modeling of HDR Reservoirs

    SciTech Connect

    Birdsell, Stephen A.

    1988-07-01

    Thermal and pressure-induced stress effects are extremely important aspects of modeling HDR reservoirs because these effects will control the transient behavior of reservoir flow impedance, water loss and flow distribution. Uncoupled stress effects will be added to the existing three-dimensional Finite Element Heat and Mass Transfer (FEHM) model (Birdsell, 1988) in order to more realistically simulate HDR reservoirs. Stress effects will be uncoupled in the new model since a fully-coupled code will not be available for some time.

  13. Nonphotic entrainment of the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Rimmer, D. W.; Dijk, D. J.; Kronauer, R. E.; Rizzo, J. F. 3rd; Czeisler, C. A.

    1998-01-01

    In organisms as diverse as single-celled algae and humans, light is the primary stimulus mediating entrainment of the circadian biological clock. Reports that some totally blind individuals appear entrained to the 24-h day have suggested that nonphotic stimuli may also be effective circadian synchronizers in humans, although the nonphotic stimuli are probably comparatively weak synchronizers, because the circadian rhythms of many totally blind individuals "free run" even when they maintain a 24-h activity-rest schedule. To investigate entrainment by nonphotic synchronizers, we studied the endogenous circadian melatonin and core body temperature rhythms of 15 totally blind subjects who lacked conscious light perception and exhibited no suppression of plasma melatonin in response to ocular bright-light exposure. Nine of these fifteen blind individuals were able to maintain synchronization to the 24-h day, albeit often at an atypical phase angle of entrainment. Nonphotic stimuli also synchronized the endogenous circadian rhythms of a totally blind individual to a non-24-h schedule while living in constant near darkness. We conclude that nonphotic stimuli can entrain the human circadian pacemaker in some individuals lacking ocular circadian photoreception.

  14. Circadian Clock Regulates Bone Resorption in Mice.

    PubMed

    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. Circadian Rhythms, Sleep Deprivation, and Human Performance

    PubMed Central

    Goel, Namni; Basner, Mathias; Rao, Hengyi; Dinges, David F.

    2014-01-01

    Much of the current science on, and mathematical modeling of, dynamic changes in human performance within and between days is dominated by the two-process model of sleep–wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep), and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance. Endogenous circadian rhythms in neurobehavioral functions, including physiological alertness and cognitive performance, have been demonstrated using special laboratory protocols that reveal the interaction of the biological clock with the sleep homeostatic drive. Individual differences in circadian rhythms and genetic and other components underlying such differences also influence waking neurobehavioral functions. Both acute total sleep deprivation and chronic sleep restriction increase homeostatic sleep drive and degrade waking neurobehavioral functions as reflected in sleepiness, attention, cognitive speed, and memory. Recent evidence indicating a high degree of stability in neurobehavioral responses to sleep loss suggests that these trait-like individual differences are phenotypic and likely involve genetic components, including circadian genes. Recent experiments have revealed both sleep homeostatic and circadian effects on brain metabolism and neural activation. Investigation of the neural and genetic mechanisms underlying the dynamically complex interaction between sleep homeostasis and circadian systems is beginning. A key goal of this work is to identify biomarkers that accurately predict human performance in situations in which the circadian and sleep homeostatic systems are perturbed. PMID:23899598

  16. Design principles underlying circadian clocks.

    PubMed Central

    Rand, D. A.; Shulgin, B. V.; Salazar, D.; 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 the flexibility of clock networks and the relationships between various desirable properties such as robust entrainment, temperature compensation, and stability to environmental variations and parameter fluctuations. We use this to argue that the complexity provides the flexibility necessary to simultaneously attain multiple key properties of circadian clocks. As part of our analysis we show how to quantify the key evolutionary aims using infinitesimal response curves, a tool that we believe will be of general utility in the analysis of regulatory networks. Our results suggest that regulatory and signalling networks might be much less flexible and of lower dimension than their apparent complexity would suggest. PMID:16849158

  17. Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase

    NASA Technical Reports Server (NTRS)

    Duffy, J. F.; Rimmer, D. W.; Czeisler, C. A.

    2001-01-01

    The biological basis of preferences for morning or evening activity patterns ("early birds" and "night owls") has been hypothesized but has remained elusive. The authors reported that, compared with evening types, the circadian pacemaker of morning types was entrained to an earlier hour with respect to both clock time and wake time. The present study explores a chronobiological mechanism by which the biological clock of morning types may be set to an earlier hour. Intrinsic period, a fundamental property of the circadian system, was measured in a month-long inpatient study. A subset of participants also had their circadian phase assessed. Participants completed a morningness-eveningness questionnaire before study. Circadian period was correlated with morningness-eveningness, circadian phase, and wake time, demonstrating that a fundamental property of the circadian pacemaker is correlated with the behavioral trait of morningness-eveningness.

  18. Characterisation of circadian rhythms of various duckweeds.

    PubMed

    Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T

    2015-01-01

    The plant circadian clock controls various physiological phenomena that are important for adaptation to natural day-night cycles. Many components of the circadian clock have been identified in Arabidopsis thaliana, the model plant for molecular genetic studies. Recent studies revealed evolutionary conservation of clock components in green plants. Homologues of clock-related genes have been isolated from Lemna gibba and Lemna aequinoctialis, and it has been demonstrated that these homologues function in the clock system in a manner similar to their functioning in Arabidopsis. While clock components are widely conserved, circadian phenomena display diversity even within the Lemna genus. In order to survey the full extent of diversity in circadian rhythms among duckweed plants, we characterised the circadian rhythms of duckweed by employing a semi-transient bioluminescent reporter system. Using a particle bombardment method, circadian bioluminescent reporters were introduced into nine strains representing five duckweed species: Spirodela polyrhiza, Landoltia punctata, Lemna gibba, L. aequinoctialis and Wolffia columbiana. We then monitored luciferase (luc+) reporter activities driven by AtCCA1, ZmUBQ1 or CaMV35S promoters under entrainment and free-running conditions. Under entrainment, AtCCA1::luc+ showed similar diurnal rhythms in all strains. This suggests that the mechanism of biological timing under day-night cycles is conserved throughout the evolution of duckweeds. Under free-running conditions, we observed circadian rhythms of AtCCA1::luc+, ZmUBQ1::luc+ and CaMV35S::luc+. These circadian rhythms showed diversity in period length and sustainability, suggesting that circadian clock mechanisms are somewhat diversified among duckweeds. PMID:24942699

  19. The circadian timing system in clinical oncology.

    PubMed

    Innominato, Pasquale F; Roche, Véronique P; Palesh, Oxana G; Ulusakarya, Ayhan; Spiegel, David; Lévi, Francis A

    2014-06-01

    The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest- activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P=0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving

  20. Circadian rhythms of women with fibromyalgia

    NASA Technical Reports Server (NTRS)

    Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.

    2001-01-01

    Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.

  1. Circadian Redox and Metabolic Oscillations in Mammalian Systems

    PubMed Central

    Feeney, Kevin A.

    2014-01-01

    Abstract Significance: A substantial proportion of mammalian physiology is organized around the day/night cycle, being regulated by the co-ordinated action of numerous cell-autonomous circadian oscillators throughout the body. Disruption of internal timekeeping, by genetic or environmental perturbation, leads to metabolic dysregulation, whereas changes in metabolism affect timekeeping. Recent Advances: While gene expression cycles are essential for the temporal coordination of normal physiology, it has become clear that rhythms in metabolism and redox balance are cell-intrinsic phenomena, which may regulate gene expression cycles reciprocally, but persist in their absence. For example, a circadian rhythm in peroxiredoxin oxidation was recently observed in isolated human erythrocytes, fibroblast cell lines in vitro, and mouse liver in vivo. Critical Issues: Mammalian timekeeping is a cellular phenomenon. While we understand many of the cellular systems that contribute to this biological oscillation's fidelity and robustness, a comprehensive mechanistic understanding remains elusive. Moreover, the formerly clear distinction between “core clock components” and rhythmic cellular outputs is blurred since several outputs, for example, redox balance, can feed back to regulate timekeeping. As with any cyclical system, establishing causality becomes problematic. Future Directions: A detailed molecular understanding of the temporal crosstalk between cellular systems, and the coincidence detection mechanisms that allow a cell to discriminate clock-relevant from irrelevant stimuli, will be essential as we move toward an integrated model of how this daily biological oscillation works. Such knowledge will highlight new avenues by which the functional consequences of circadian timekeeping can be explored in the context of human health and disease. Antioxid. Redox Signal. 20, 2966–2981. PMID:24063592

  2. Genetic analysis of ectopic circadian clock induction in Drosophila.

    PubMed

    Kilman, Valerie L; Allada, Ravi

    2009-10-01

    Cell-autonomous feedback loops underlie the molecular oscillations that define circadian clocks. In Drosophila the transcription factor Clk activates multiple clock components of feedback loops many of which feed back and regulate Clk expression or activity. Previously the authors evoked similar molecular oscillations in putatively naïve neurons in Drosophila by ectopic expression of a single gene, Clk, suggesting a master regulator function. Using molecular oscillations of the core clock component PERIOD (PER), the authors observed dramatic and widespread molecular oscillations throughout the brain in flies expressing ectopic Clk. Consistent with the master regulator hypothesis, they found that Clk is uniquely capable of inducing ectopic clocks as ectopic induction of other clock components fails to induce circadian rhythms. Clk also induces oscillations even when expression is adult restricted, suggesting that ectopic clocks can even be induced in differentiated cells. However, if transgene expression is discontinued, PER expression disappears, indicating that Clk must be continually active to sustain ectopic clock function. In some cases Clk-mediated PER induction was observed without apparent synchronous cycling, perhaps due to desynchronization of rhythms between clocks or truly cell autonomous arrhythmic PER expression, indicating that additional factors may be necessary for coherent rhythms in cells ectopically expressing Clk. To determine minimal requirements for circadian clock induction by Clk, the authors determined the genetic requirements of ectopic clocks. No ectopic clocks are induced in mutants of Clk's heterodimeric partner cyc. In addition, noncycling PER is observed when ectopic Clk is induced in a cryb mutant background. While other factors may contribute, these results indicate that persistent Clock induction is uniquely capable of broadly inducing ectopic rhythms even in adults, consistent with a special role at the top of a clock gene

  3. Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms

    PubMed Central

    Patel, Sonal A.; Velingkaar, Nikkhil; Makwana, Kuldeep; Chaudhari, Amol; Kondratov, Roman

    2016-01-01

    Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources. PMID:27170536

  4. Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms.

    PubMed

    Patel, Sonal A; Velingkaar, Nikkhil; Makwana, Kuldeep; Chaudhari, Amol; Kondratov, Roman

    2016-01-01

    Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources. PMID:27170536

  5. Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers.

    PubMed

    Thomas, Rusha; Kim, Myoung H

    2007-02-01

    Hypoxia inducible factor-1 (HIF-1) is central to most adaptation responses of tumors to hypoxia, and consists of a hypoxia inducible HIF-1alpha or -2alpha subunit, and a constitutively expressed HIF-1beta subunit. Previously, mitochondrial uncouplers, rottlerin and FCCP, were shown to increase the rate of cellular O(2 )consumption. In this study, we determined that mitochondrial uncouplers, rottlerin and FCCP, significantly decreased hypoxic as well as normoxic HIF-1 transcriptional activity which was in part mediated by down-regulation of the oxygen labile HIF-1alpha and HIF-2alpha protein levels in PC-3 and DU-145 prostate cancer cells. Our results also revealed that mitochondrial uncouplers decreased the expression of HIF target genes, VEGF and VEGF receptor-2. Taken together, our results indicate that functional mitochondria are important in HIF-1alpha and HIF-2alpha protein stability and transcriptional activity during normoxia as well as in hypoxia, and that mitochondrial uncouplers may be useful in the inhibition of HIF pathway in tumors. PMID:16924414

  6. Do UCP2 and mild uncoupling improve longevity?

    PubMed

    Dikov, Daniel; Aulbach, Angelique; Muster, Britta; Dröse, Stefan; Jendrach, Marina; Bereiter-Hahn, Jürgen

    2010-08-01

    Mild uncoupling of mitochondrial respiration is considered to prolong life span of organisms by reducing the production of reactive oxygen species (ROS). Experimental evidence against this hypothesis has been brought forward by premature senescence in cell cultures treated with uncouplers. Exposing HUVEC to a mixture of nutritionally important fatty acids (oil extract of chicken yolk) mild uncoupling with "naturally acting substances" was performed. This treatment also resulted in premature senescence although ROS production did not increase. Fatty acids activate uncoupling proteins (UCP) in the inner mitochondrial membrane. UCP2 expression proved to be sensitive to the presence of fatty acids but remains unchanged during the ageing process. UCP3 expression in senescent HUVEC and avUCP expression in senescent CEF were considerably less than in young cultures. No indication for protonophoric reduction of mitochondrial membrane potential was found in UCP2 overexpressing HeLa cells and only little in HUVEC. ROS levels increased instead of being reduced in these cells. Stable transfection with UCP2-GFP was possible only in chick embryo fibroblasts and HeLa cells and resulted in decreased proliferation. Stable transfection of HUVEC with UCP2-GFP resulted in death of cultures within one or two weeks. The reason for this behaviour most probably is apoptosis preceded by mitochondrial fragmentation and loss of membrane potential. PMID:20332018

  7. A mitochondria-targeted protonophoric uncoupler derived from fluorescein.

    PubMed

    Denisov, Stepan S; Kotova, Elena A; Plotnikov, Egor Y; Tikhonov, Artur A; Zorov, Dmitry B; Korshunova, Galina A; Antonenko, Yuri N

    2014-12-18

    Linking decyl-triphenyl-phosphonium to fluorescein yields a fluorescent probe that accumulates in energized mitochondria, facilitates proton transfer across membranes and stimulates mitochondrial respiration. This features a mitochondria-targeted uncoupler, being of potential interest for therapeutic use against oxidative stress-related diseases. PMID:25349923

  8. Penetrating cations enhance uncoupling activity of anionic protonophores in mitochondria.

    PubMed

    Antonenko, Yuri N; Khailova, Ljudmila S; Knorre, Dmitry A; Markova, Olga V; Rokitskaya, Tatyana I; Ilyasova, Tatyana M; Severina, Inna I; Kotova, Elena A; Karavaeva, Yulia E; Prikhodko, Anastasia S; Severin, Fedor F; Skulachev, Vladimir P

    2013-01-01

    Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H(+) ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore-mediated uncoupling is assumed to be useful for medical applications of low (non-toxic) concentrations of protonophores. PMID:23626747

  9. Penetrating Cations Enhance Uncoupling Activity of Anionic Protonophores in Mitochondria

    PubMed Central

    Antonenko, Yuri N.; Khailova, Ljudmila S.; Knorre, Dmitry A.; Markova, Olga V.; Rokitskaya, Tatyana I.; Ilyasova, Tatyana M.; Severina, Inna I.; Kotova, Elena A.; Karavaeva, Yulia E.; Prikhodko, Anastasia S.; Severin, Fedor F.; Skulachev, Vladimir P.

    2013-01-01

    Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H+ ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore-mediated uncoupling is assumed to be useful for medical applications of low (non-toxic) concentrations of protonophores. PMID:23626747

  10. Uncoupling activity of the anthelmintic oxyclozanide in rodents

    PubMed Central

    Veenendaal, G.H.; De Waal, M.J.

    1974-01-01

    The uncoupling activity of oxyclozanide in warm blooded animals has been studied in whole animals, isolated tissue in vitro and on mitochondrial preparations. The onset of post mortem rigidity in mice and rats is accelerated and a contracture of striated muscle is produced. Oxyclozanide (1 μM) stimulated rat liver mitochondrial respiration and stimulated an ATP-ase activity. PMID:4277750

  11. Plasticity of circadian clocks and consequences for metabolism.

    PubMed

    Coomans, C P; Lucassen, E A; Kooijman, S; Fifel, K; Deboer, T; Rensen, P C N; Michel, S; Meijer, J H

    2015-09-01

    The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans. PMID:26332970

  12. The Nuclear Receptor Rev-erbα Controls Circadian Thermogenic Plasticity

    PubMed Central

    Gerhart-Hines, Zachary; Everett, Logan J.; Loro, Emanuele; Briggs, Erika R.; Bugge, Anne; Hou, Catherine; Ferrara, Christine; Seale, Patrick; Pryma, Daniel A.; Khurana, Tejvir S.; Lazar, Mitchell A.

    2013-01-01

    Circadian oscillation of body temperature is a basic, evolutionary-conserved feature of mammalian biology1. Additionally, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure2. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbα, a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare dramatically better at 5 AM (Zeitgeber time 22) when Rev-erbα is barely expressed than at 5 PM (ZT10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 5 PM, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (UCP1) by cold temperatures is preceded by rapid down-regulation of Rev-erbα in BAT. Rev-erbα represses UCP1 in a brown adipose cell-autonomous manner and BAT UCP1 levels are high in Rev-erbα-null mice even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands. PMID:24162845

  13. Circadian control of mRNA polyadenylation dynamics regulates rhythmic protein expression

    PubMed Central

    Kojima, Shihoko; Sher-Chen, Elaine L.; Green, Carla B.

    2012-01-01

    Poly(A) tails are 3′ modifications of eukaryotic mRNAs that are important in the control of translation and mRNA stability. We identified hundreds of mouse liver mRNAs that exhibit robust circadian rhythms in the length of their poly(A) tails. Approximately 80% of these are primarily the result of nuclear adenylation coupled with rhythmic transcription. However, unique decay kinetics distinguish these mRNAs from other mRNAs that are transcribed rhythmically but do not exhibit poly(A) tail rhythms. The remaining 20% are uncoupled from transcription and exhibit poly(A) tail rhythms even though the steady-state mRNA levels are not rhythmic. These are under the control of rhythmic cytoplasmic polyadenylation, regulated at least in some cases by cytoplasmic polyadenylation element-binding proteins (CPEBs). Importantly, we found that the rhythmicity in poly(A) tail length is closely correlated with rhythmic protein expression, with a several-hour delay between the time of longest tail and the time of highest protein level. Our study demonstrates that the circadian clock regulates the dynamic polyadenylation status of mRNAs, which can result in rhythmic protein expression independent of the steady-state levels of the message. PMID:23249735

  14. The nuclear receptor Rev-erbα controls circadian thermogenic plasticity.

    PubMed

    Gerhart-Hines, Zachary; Feng, Dan; Emmett, Matthew J; Everett, Logan J; Loro, Emanuele; Briggs, Erika R; Bugge, Anne; Hou, Catherine; Ferrara, Christine; Seale, Patrick; Pryma, Daniel A; Khurana, Tejvir S; Lazar, Mitchell A

    2013-11-21

    Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erbα (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erbα is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbα is abundant. Deletion of Rev-erbα markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erbα in BAT. Rev-erbα represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erbα-null mice, even at thermoneutrality. Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands. PMID:24162845

  15. Modulation of sphingosine receptors influences circadian pattern of cardiac autonomic regulation.

    PubMed

    Simula, Sakari; Laitinen, Tomi P; Laitinen, Tiina M; Hartikainen, Päivi; Hartikainen, Juha E K

    2016-09-01

    Fingolimod is an oral sphingosine-1-phospate (S1P) receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). In addition to therapeutic effects on lymphoid and neural tissue, fingolimod influences cardiovascular system by specific S1P-receptor modulation. The effects of S1P-receptor modulation on the endogenous circadian pattern of cardiac autonomic regulation (CAR), however, are not known. We examined the effects of fingolimod on the circadian pattern of CAR Ambulatory 24-h ECG recordings were undertaken in 27 RRMS patients before fingolimod (baseline), at the day of fingolimod initiation (1D) and after 3 months of fingolimod treatment (3M). The mean time between two consecutive R-peaks (RR-interval) and mean values for measures of heart rate variability (HRV) in time- and frequency domain were calculated from ECG recording at daytime and nighttime. The mean night:day-ratio of RR-interval was 1.23 ± 0.12 at baseline, decreased temporarily at 1D (1.16 ± 0.12; P < 0.01) and was higher at 3M (1.32 ± 0.11; P < 0.001) than at baseline. The night:day-ratio of HRV parameters reflecting parasympathetic cardiac regulation (pNN50, rMSSD, HFnu) decreased at 1D but recovered back to baseline at 3M (P < 0.05 for all). On the other hand, the night:day-ratio of TP, a parameter reflecting overall HRV gradually decreased and was lower at 3M than at baseline (P < 0.05). Our findings suggest that physiological relation between the circadian pattern of RR-interval and overall HRV as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment. In addition, fingolimod shifts the circadian equilibrium of CAR toward greater daytime dominance of overall HRV Accordingly, S1P-receptor modulation influences circadian pattern of CAR. PMID:27624686

  16. Reciprocal interactions between circadian clocks and aging.

    PubMed

    Banks, Gareth; Nolan, Patrick M; Peirson, Stuart N

    2016-08-01

    Virtually, all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. This circadian clock undergoes a number of age-related changes, at both the physiological and molecular levels. While these changes have been considered to be part of the normal aging process, there is increasing evidence that disruptions to the circadian system can substantially impact upon aging and these impacts will have clear health implications. Here we review the current data of how both the physiological and core molecular clocks change with age and how feedback from external cues may modulate the aging of the circadian system. PMID:27137838

  17. Photopic transduction implicated in human circadian entrainment

    NASA Technical Reports Server (NTRS)

    Zeitzer, J. M.; Kronauer, R. E.; Czeisler, C. A.

    1997-01-01

    Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.

  18. Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis.

    PubMed

    Masri, Selma; Papagiannakopoulos, Thales; Kinouchi, Kenichiro; Liu, Yu; Cervantes, Marlene; Baldi, Pierre; Jacks, Tyler; Sassone-Corsi, Paolo

    2016-05-01

    The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous "zeitgebers," such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver. PAPERCLIP. PMID:27153497

  19. Effects of circadian disruption on cardiometabolic system

    PubMed Central

    Rüger, Melanie; Scheer, Frank A.J.L.

    2011-01-01

    The presence of day-night variations in cardiovascular and metabolic functioning is well known. However, only recently it has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep/wake cycle but are partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac autonomic activity, glucose metabolism and leptin —involved in appetite control—all show circadian variation (i.e., under constant behavioral and environmental conditions). This knowledge of behavioral vs. circadian modulation of cardiometabolic function is of clinical relevance given the morning peak in adverse cardiovascular incidents observed in epidemiological studies and given the increased risk for the development of diabetes, obesity, and cardiovascular disease in shift workers. We will review the evidence for circadian control of cardiometabolic functioning, as well its sensitivity to light and melatonin, and discuss potential implication for therapy. PMID:19784781

  20. Circadian expression of clock and putative clock-controlled genes in skeletal muscle of the zebrafish.

    PubMed

    Amaral, Ian P G; Johnston, Ian A

    2012-01-01

    To identify circadian patterns of gene expression in skeletal muscle, adult male zebrafish were acclimated for 2 wk to a 12:12-h light-dark photoperiod and then exposed to continuous darkness for 86 h with ad libitum feeding. The increase in gut food content associated with the subjective light period was much diminished by the third cycle, enabling feeding and circadian rhythms to be distinguished. Expression of zebrafish paralogs of mammalian transcriptional activators of the circadian mechanism (bmal1, clock1, and rora) followed a rhythmic pattern with a ∼24-h periodicity. Peak expression of rora paralogs occurred at the beginning of the subjective light period [Zeitgeber time (ZT)07 and ZT02 for roraa and rorab], whereas the highest expression of bmal1 and clock paralogs occurred 12 h later (ZT13-15 and ZT16 for bmal and clock paralogs). Expression of the transcriptional repressors cry1a, per1a/1b, per2, per3, nr1d2a/2b, and nr1d1 also followed a circadian pattern with peak expression at ZT0-02. Expression of the two paralogs of cry2 occurred in phase with clock1a/1b. Duplicated genes had a high correlation of expression except for paralogs of clock1, nr1d2, and per1, with cry1b showing no circadian pattern. The highest expression difference was 9.2-fold for the activator bmal1b and 51.7-fold for the repressor per1a. Out of 32 candidate clock-controlled genes, only myf6, igfbp3, igfbp5b, and hsf2 showed circadian expression patterns. Igfbp3, igfbp5b, and myf6 were expressed in phase with clock1a/1b and had an average of twofold change in expression from peak to trough, whereas hsf2 transcripts were expressed in phase with cry1a and had a 7.2-fold-change in expression. The changes in expression of clock and clock-controlled genes observed during continuous darkness were also observed at similar ZTs in fish exposed to a normal photoperiod in a separate control experiment. The role of circadian clocks in regulating muscle maintenance and growth are discussed

  1. Pilot Fatigue and Circadian Desynchronosis

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Pilot fatigue and circadian desynchronosis, its significance to air transport safety, and research approaches, were examined. There is a need for better data on sleep, activity, and other pertinent factors from pilots flying a variety of demanding schedules. Simulation studies of flight crew performance should be utilized to determine the degree of fatigue induced by demanding schedules and to delineate more precisely the factors responsible for performance decrements in flight and to test solutions proposed to resolve problems induced by fatigue and desynchronosis. It was concluded that there is a safety problem of uncertain magnitude due to transmeridian flying and a potential problem due to fatigue associated with various factors found in air transport operations.

  2. Circadian periodicity of tryptophan metabolism

    PubMed Central

    Rapoport, Morton I.; Beisel, William R.

    1968-01-01

    Rhythmicity of tryptophan metabolism via the kynurenine pathway has been demonstrated in man. Normal subjects given 3 g of tryptophan at 0900 hours excreted almost three times the quantity of kynurenine, kynurenic acid, and xanthurenic acid than did subjects given the same dose at 2100 hours. Other metabolites of the kynurenine pathway varied in the same fashion but with lesser magnitude. In contrast, indican, a tryptophan metabolite not in the kynurenine pathway, varied inversely with the other metabolites measured. The data suggest that the liver enzyme tryptophan pyrrolase has a circadian rhythm in man similar to that already described in mice in a previous study. Tryptophan tolerance tests in the future should be controlled relative to time of amino acid administration. PMID:5641628

  3. Circadian rhythms of performance: new trends

    NASA Technical Reports Server (NTRS)

    Carrier, J.; Monk, T. H.

    2000-01-01

    This brief review is concerned with how human performance efficiency changes as a function of time of day. It presents an overview of some of the research paradigms and conceptual models that have been used to investigate circadian performance rhythms. The influence of homeostatic and circadian processes on performance regulation is discussed. The review also briefly presents recent mathematical models of alertness that have been used to predict cognitive performance. Related topics such as interindividual differences and the postlunch dip are presented.

  4. The early bee catches the flower - circadian rhythmicity influences learning performance in honey bees, Apis mellifera

    PubMed Central

    Lehmann, Marina; Gustav, David

    2010-01-01

    Circadian rhythmicity plays an important role for many aspects of honey bees’ lives. However, the question whether it also affects learning and memory remained unanswered. To address this question, we studied the effect of circadian timing on olfactory learning and memory in honey bees Apis mellifera using the olfactory conditioning of the proboscis extension reflex paradigm. Bees were differentially conditioned to odours and tested for their odour learning at four different “Zeitgeber” time points. We show that learning behaviour is influenced by circadian timing. Honey bees perform best in the morning compared to the other times of day. Additionally, we found influences of the light condition bees were trained at on the olfactory learning. This circadian-mediated learning is independent from feeding times bees were entrained to, indicating an inherited and not acquired mechanism. We hypothesise that a co-evolutionary mechanism between the honey bee as a pollinator and plants might be the driving force for the evolution of the time-dependent learning abilities of bees. Electronic supplementary material The online version of this article (doi:10.1007/s00265-010-1026-9) contains supplementary material, which is available to authorized users. PMID:21350590

  5. Circadian Metabolic Regulation through Crosstalk between Casein Kinase 1δ and Transcriptional Coactivator PGC-1α

    PubMed Central

    Li, Siming; Chen, Xiao-Wei; Yu, Lei; Saltiel, Alan R.

    2011-01-01

    Circadian clock coordinates behavior and physiology in mammals in response to light and feeding cycles. Disruption of normal clock function is associated with increased risk for cardiovascular and metabolic diseases, underscoring the emerging concept that temporal regulation of tissue metabolism is a fundamental aspect of energy homeostasis. We have previously demonstrated that transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), coordinates circadian metabolic rhythms through simultaneous regulation of metabolic and clock gene expression. In this study, we found that PGC-1α physically interacts with, and is phosphorylated by, casein kinase 1δ (CK1δ), a core component of the circadian pacemaker. CK1δ represses the transcriptional function of PGC-1α in cultured hepatocytes, resulting in decreased gluconeogenic gene expression and glucose secretion. At the molecular level, CK1δ phosphorylation of PGC-1α within its arginine/serine-rich domain enhances its degradation through the proteasome system. Together, these results elucidate a novel mechanism through which circadian pacemaker transduces timing signals to the metabolic regulatory network that controls hepatic energy metabolism. PMID:22052997

  6. Linking Core Promoter Classes to Circadian Transcription

    PubMed Central

    Westermark, Pål O.

    2016-01-01

    Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription. PMID:27504829

  7. Circadian Clock Control of Liver Metabolic Functions.

    PubMed

    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

  8. Neuroimaging, cognition, light and circadian rhythms.

    PubMed

    Gaggioni, Giulia; Maquet, Pierre; Schmidt, Christina; Dijk, Derk-Jan; Vandewalle, Gilles

    2014-01-01

    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. PMID:25071478

  9. Linking Core Promoter Classes to Circadian Transcription.

    PubMed

    Westermark, Pål O

    2016-08-01

    Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription. PMID:27504829

  10. Personalized medicine for pathological circadian dysfunctions

    PubMed Central

    Skelton, Rachel L.; Kornhauser, Jon M.; Tate, Barbara A.

    2015-01-01

    The recent approval of a therapeutic for a circadian disorder has increased interest in developing additional medicines for disorders characterized by circadian disruption. However, previous experience demonstrates that drug development for central nervous system (CNS) disorders has a high failure rate. Personalized medicine, or the approach to identifying the right treatment for the right patient, has recently become the standard for drug development in the oncology field. In addition to utilizing Companion Diagnostics (CDx) that identify specific genetic biomarkers to prescribe certain targeted therapies, patient profiling is regularly used to enrich for a responsive patient population during clinical trials, resulting in fewer patients required for statistical significance and a higher rate of success for demonstrating efficacy and hence receiving approval for the drug. This personalized medicine approach may be one mechanism that could reduce the high clinical trial failure rate in the development of CNS drugs. This review will discuss current circadian trials, the history of personalized medicine in oncology, lessons learned from a recently approved circadian therapeutic, and how personalized medicine can be tailored for use in future clinical trials for circadian disorders to ultimately lead to the approval of more therapeutics for patients suffering from circadian abnormalities. PMID:26150790

  11. Participation of the Olfactory Bulb in Circadian Organization during Early Postnatal Life in Rabbits

    PubMed Central

    Navarrete, Erika; Ortega-Bernal, Juan Roberto; Trejo-Muñoz, Lucero; Díaz, Georgina; Montúfar-Chaveznava, Rodrigo; Caldelas, Ivette

    2016-01-01

    Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB). We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1), pups were randomly assigned to one of the following conditions: intact pups (INT), intact pups fed by enteral gavage (INT+ENT), sham operated pups (SHAM), pups with unilateral lesions of the olfactory bulb (OBx-UNI), and pups with bilateral lesions of the olfactory bulb (OBx-BI). At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00), and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb. PMID:27305041

  12. Participation of the Olfactory Bulb in Circadian Organization during Early Postnatal Life in Rabbits.

    PubMed

    Navarrete, Erika; Ortega-Bernal, Juan Roberto; Trejo-Muñoz, Lucero; Díaz, Georgina; Montúfar-Chaveznava, Rodrigo; Caldelas, Ivette

    2016-01-01

    Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB). We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1), pups were randomly assigned to one of the following conditions: intact pups (INT), intact pups fed by enteral gavage (INT+ENT), sham operated pups (SHAM), pups with unilateral lesions of the olfactory bulb (OBx-UNI), and pups with bilateral lesions of the olfactory bulb (OBx-BI). At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00), and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb. PMID:27305041

  13. Circadian phenotyping of obese and diabetic db/db mice.

    PubMed

    Grosbellet, Edith; Dumont, Stephanie; Schuster-Klein, Carole; Guardiola-Lemaitre, Beatrice; Pevet, Paul; Criscuolo, François; Challet, Etienne

    2016-05-01

    Growing evidence links metabolic disorders to circadian alterations. Genetically obese db/db mice, lacking the long isoform of leptin receptor, are a recognized model of type 2 diabetes. In this study, we aimed at characterizing the potential circadian alterations of db/db mice in comparison to db/+ control mice. By using telemetry devices, we first reported arrhythmicity in general activity of most db/db mice under both light-dark cycle and constant darkness, while their rhythm of body temperature is less dramatically disrupted. Water access restricted to nighttime restores significant rhythmicity in behaviorally arrhythmic db/db mice, indicating a masking effect of polydipsia when water is available ad libitum. Endogenous period of temperature rhythm under constant dark conditions is significantly increased (+30 min) in db/db compared with db/+ mice. Next, we studied the oscillations of clock proteins (PER1, PER2 and BMAL1) in the suprachiasmatic nuclei (SCN), the site of the master clock, and detected no difference according to the genotype. Furthermore, c-FOS and P-ERK1/2 expression in response to a light pulse in late night was significantly increased (+80 and +55%, respectively) in the SCN of these diabetic mice. We previously showed that, in addition to altered activity rhythms, db/db mice exhibit altered feeding rhythm. Therefore, we investigated daily patterns of clock protein expression in medial hypothalamic oscillators involved in feeding behavior (arcuate nucleus, ventro- and dorso-medial hypothalamic nuclei). Compared with db/+ mice, very subtle or no difference in oscillations of PER1 and BMAL1 is found in the medial hypothalamus. Although we did not find a clear link between altered hypothalamic clockwork and behavioral rhythms in db/db mice, our results highlight a lengthened endogenous period and altered photic integration in these genetically obese and diabetic mice. PMID:26144489

  14. Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions.

    PubMed

    Brainard, Jason; Gobel, Merit; Bartels, Karsten; Scott, Benjamin; Koeppen, Michael; Eckle, Tobias

    2015-03-01

    The rotation of the earth and associated alternating cycles of light and dark--the basis of our circadian rhythms--are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts. PMID:25294583

  15. The frequency of hippocampal theta rhythm is modulated on a circadian period and is entrained by food availability

    PubMed Central

    Munn, Robert G. K.; Tyree, Susan M.; McNaughton, Neil; Bilkey, David K.

    2015-01-01

    The hippocampal formation plays a critical role in the generation of episodic memory. While the encoding of the spatial and contextual components of memory have been extensively studied, how the hippocampus encodes temporal information, especially at long time intervals, is less well understood. The activity of place cells in hippocampus has previously been shown to be modulated at a circadian time-scale, entrained by a behavioral stimulus, but not entrained by light. The experimental procedures used in the previous study of this phenomenon, however, necessarily conflated two alternative entraining stimuli, the exposure to the recording environment and the availability of food, making it impossible to distinguish between these possibilities. Here we demonstrate that the frequency of theta-band hippocampal EEG varies with a circadian period in freely moving animals and that this periodicity mirrors changes in the firing rate of hippocampal neurons. Theta activity serves, therefore, as a proxy of circadian-modulated hippocampal neuronal activity. We then demonstrate that the frequency of hippocampal theta driven by stimulation of the reticular formation also varies with a circadian period. Because this effect can be observed without having to feed the animal to encourage movement we were able to identify what stimulus entrains the circadian oscillation. We show that with reticular-activated recordings started at various times of the day the frequency of theta varies quasi-sinusoidally with a 25 h period and phase-aligned when referenced to the animal’s regular feeding time, but not the recording start time. Furthermore, we show that theta frequency consistently varied with a circadian period when the data obtained from repeated recordings started at various times of the day were referenced to the start of food availability in the recording chamber. This pattern did not occur when data were referenced to the start of the recording session or to the actual time of

  16. Barley Hv CIRCADIAN CLOCK ASSOCIATED 1 and Hv PHOTOPERIOD H1 Are Circadian Regulators That Can Affect Circadian Rhythms in Arabidopsis

    PubMed Central

    Martí, María C.; Laurie, David A.; Greenland, Andy J.; Hall, Anthony; Webb, Alex A. R.

    2015-01-01

    Circadian clocks regulate many aspects of plant physiology and development that contribute to essential agronomic traits. Circadian clocks contain transcriptional feedback loops that are thought to generate circadian timing. There is considerable similarity in the genes that comprise the transcriptional and translational feedback loops of the circadian clock in the plant Kingdom. Functional characterisation of circadian clock genes has been restricted to a few model species. Here we provide a functional characterisation of the Hordeum vulgare (barley) circadian clock genes Hv CIRCADIAN CLOCK ASSOCIATED 1 (HvCCA1) and Hv PHOTOPERIODH1, which are respectively most similar to Arabidopsis thaliana CIRCADIAN CLOCK ASSOCIATED 1 (AtCCA1) and PSEUDO RESPONSE REGULATOR 7 (AtPRR7). This provides insight into the circadian regulation of one of the major crop species of Northern Europe. Through a combination of physiological assays of circadian rhythms in barley and heterologous expression in wild type and mutant strains of A. thaliana we demonstrate that HvCCA1 has a conserved function to AtCCA1. We find that Hv PHOTOPERIOD H1 has AtPRR7-like functionality in A. thaliana and that the effects of the Hv photoperiod h1 mutation on photoperiodism and circadian rhythms are genetically separable. PMID:26076005

  17. The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy.

    PubMed

    Zhang, Jimmy; Nadtochiy, Sergiy M; Urciuoli, William R; Brookes, Paul S

    2016-01-01

    Mitochondrial quality control mechanisms have been implicated in protection against cardiac ischemia-reperfusion (IR) injury. Previously, cloxyquin (5-chloroquinolin-8-ol) was identified via phenotypic screening as a cardioprotective compound. Herein, cloxyquin was identified as a mitochondrial uncoupler in both isolated heart mitochondria and adult cardiomyocytes. Additionally, cardiomyocytes isolated from transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein light chain 3 showed increased autophagosome formation with cloxyquin treatment. The autophagy inhibitor chloroquine abolished cloxyquin-induced cardioprotection in both cellular and perfused heart (Langendorff) models of IR injury. Finally, in an in vivo murine left anterior descending coronary artery occlusion model of IR injury, cloxyquin significantly reduced infarct size from 31.4 ± 3.4% to 16.1 ± 2.2%. In conclusion, the cardioprotective compound cloxyquin simultaneously uncoupled mitochondria and induced autophagy. Importantly, autophagy appears to be required for cloxyquin-induced cardioprotection. PMID:26519034

  18. Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels

    PubMed Central

    Bartolome, Fernando; Wu, Hsiu-Chuan; Burchell, Victoria S.; Preza, Elisavet; Wray, Selina; Mahoney, Colin J.; Fox, Nick C.; Calvo, Andrea; Canosa, Antonio; Moglia, Cristina; Mandrioli, Jessica; Chiò, Adriano; Orrell, Richard W.; Houlden, Henry; Hardy, John; Abramov, Andrey Y.; Plun-Favreau, Helene

    2013-01-01

    Summary Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death. PMID:23498975

  19. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia.

    PubMed

    Fleury, C; Neverova, M; Collins, S; Raimbault, S; Champigny, O; Levi-Meyrueis, C; Bouillaud, F; Seldin, M F; Surwit, R S; Ricquier, D; Warden, C H

    1997-03-01

    A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli. PMID:9054939

  20. Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals.

    PubMed

    Schibler, Ueli; Gotic, Ivana; Saini, Camille; Gos, Pascal; Curie, Thomas; Emmenegger, Yann; Sinturel, Flore; Gosselin, Pauline; Gerber, Alan; Fleury-Olela, Fabienne; Rando, Gianpaolo; Demarque, Maud; Franken, Paul

    2015-01-01

    In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs. PMID:26683231

  1. Monitoring circadian time in rat plasma using a secreted Cypridina luciferase reporter.

    PubMed

    Yamada, Yoshiko; Nishide, Shin-Ya; Nakajima, Yoshihiro; Watanabe, Toshiyuki; Ohmiya, Yoshihiro; Honma, Ken-Ichi; Honma, Sato

    2013-08-15

    A firefly luciferase reporter enabled us to monitor promoter activity in vivo as well as ex vivo; however, this requires a sufficient supply of the substrate luciferin and specific monitoring devices. To overcome these disadvantages, we developed transgenic rats carrying a secreted enzyme Cypridina luciferase (CLuc) reporter under the promoter of clock gene Per2 (Per2-CLuc). Per2-CLuc activity in serially sampled blood from freely moving rats exhibited robust circadian rhythms with a peak at early morning. The Per2-CLuc bioluminescence could be quantified even with approximately 100pl of plasma. Plasma Per2-CLuc rhythms were phase reversed, and the level was reduced by restricting food access for 2h during the light phase, suggesting that the plasma Per2-CLuc rhythms reflect the phase of peripheral clocks entrained to feeding cues as well as fuel metabolism. Fasting for 2days did not alter the circadian Per2-CLuc rhythms in rats, suggesting that feeding per se did not affect the circadian Per2-CLuc rhythms. Tissue-specific Per2-CLuc rhythms were observed in culture medium of peripheral tissues. The Per2-CLuc reporter is a powerful tool to access gene expression in vivo as well as ex vivo with ordinary laboratory equipment. PMID:23624321

  2. Robots Would Couple And Uncouple Fluid And Electrical Lines

    NASA Technical Reports Server (NTRS)

    Del Castillo, Eduardo Lopez; Davis, Virgil; Ferguson, Bob; Reichle, Garland

    1992-01-01

    Robots make and break connections between umbilical plates and mating connectors on rockets about to be launched. Sensing and control systems include vision, force, and torque subsystems. Enhances safety by making it possible to couple and uncouple umbilical plates quickly, without exposing human technicians to hazards of leaking fuels and oxidizers. Significantly reduces time spent to manually connect umbilicals. Robots based on similar principles used in refueling of National AeroSpace Plane (NASP) and satellites and orbital transfer vehicles in space.

  3. Comparison of four chemical uncouplers for excess sludge reduction.

    PubMed

    Aragón, C; Quiroga, J M; Coello, M D

    2009-06-01

    A substantial part of the operating costs of wastewater treatment plants (WWTP) is associated with the management and treatment of the excess sludge generated during the treatment process. Different strategies have been applied for excess sludge reduction, such as the oxic-settling-anaerobic process, the high dissolved oxygen process, the uncoupler-containing activated sludge process, the ozonation-combined activated sludge process, control of sludge retention time and biodegradation of sludge in a membrane-assisted reactor. Chemical uncouplers have been shown to reduce excess sludge production, disassociating the energy coupling between catabolism and anabolism. These metabolic uncouplers may be organic compounds, such as 2,4-dinitrophenol (2,4-DNP) or 3,3',4',5-tetrachlorosalicylanilide (TCS), or heavy metals. In this paper, four different chemicals (2,4-DNP, TCS, copper (Cu) and zinc (Zn)) were chosen for short-term tests for studying their ability to reduce sludge yield (Y(x/s)) and, consequently, their potential for reducing excess sludge production. According to the results obtained, only TCS seems to be very effective in reducing sludge production from the activated sludge process. Compared with the control test, Y(x/s) can be reduced by over 30% at 0.8 mg/l TCS. It was also found that the substrate removal capability was not adversely affected by the presence of TCS. Furthermore, an increase in the microbial activity of the system was observed. PMID:19705608

  4. Uncoupling protein-2 knockdown mediates the cytotoxic effects of cisplatin.

    PubMed

    Santandreu, Francisca M; Roca, Pilar; Oliver, Jordi

    2010-08-15

    Cisplatin is among the most important chemotherapeutic agents ever developed. However, more than a generation after its clinical introduction, its exact mechanism of action on tumor cells is not fully defined. The aim of this study was to investigate the role of oxidative stress as a mediator of cisplatin action on colon cancer cells, studying the influence of mitochondrial physiology and composition on its effectiveness. The chemosensitivity shown by cancer cells to mechanistically dissimilar antitumor drugs is shown to be associated with their capacity to induce early alterations in mitochondrial and redox metabolism. Specifically, cisplatin exerted a marked pro-oxidative action on mitochondria by inhibiting resting respiration and stimulating the immediate generation of ROS in isolated mitochondria. Antioxidants and mitochondrial uncouplers counteracted cisplatin-induced cytotoxicity in tumor cells, reflecting that oxidative stress and the inhibition of mitochondrial uncoupling are relevant to its antiproliferative activity. Additionally, inhibition of uncoupling protein-2 (UCP2) caused cytotoxicity in colon cancer cells via ROS of mitochondrial origin. In conclusion, we show for the first time that UCP2 knockdown participates in the mechanism of action of cisplatin, thus providing evidence that targeting UCP2 may offer clinical benefit in the treatment of cancer. PMID:20595066

  5. Circadian Regulation of Kisspeptin in Female Reproductive Functioning

    PubMed Central

    2015-01-01

    Female reproductive functioning requires the precise temporal organization of numerous neuroendocrine events by a master circadian brain clock located in the suprachiasmatic nucleus. Across species, including humans, disruptions to circadian timing result in pronounced deficits in ovulation and fecundity. The present chapter provides an overview of the circadian control of female reproduction, underscoring the significance of kisspeptin as a key locus of integration for circadian and steroidal signaling necessary for the initiation of ovulation. PMID:23550016

  6. Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks.

    PubMed

    Saini, Camille; Liani, André; Curie, Thomas; Gos, Pascal; Kreppel, Florian; Emmenegger, Yann; Bonacina, Luigi; Wolf, Jean-Pierre; Poget, Yves-Alain; Franken, Paul; Schibler, Ueli

    2013-07-01

    The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase. PMID:23824542

  7. Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks

    PubMed Central

    Saini, Camille; Liani, André; Curie, Thomas; Gos, Pascal; Kreppel, Florian; Emmenegger, Yann; Bonacina, Luigi; Wolf, Jean-Pierre; Poget, Yves-Alain; Franken, Paul; Schibler, Ueli

    2013-01-01

    The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase. PMID:23824542

  8. Circadian Rhythms of Crawling and Swimming in the Nudibranch Mollusc Melibe leonina

    PubMed Central

    NEWCOMB, JAMES M.; KIROUAC, LAUREN E.; NAIMIE, AMANDA A.; BIXBY, KIMBERLY A.; LEE, COLIN; MALANGA, STEPHANIE; RAUBACH, MAUREEN; WATSON, WINSOR H.

    2015-01-01

    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 hypothesis that Melibe can use extraocular photoreceptors to synchronize its daily rhythms to natural light-dark cycles. To address these goals, we analyzed the behavior of 55 animals exposed to either artificial or natural light-dark cycles, followed by constant darkness. We also repeated this experiment using 10 animals that had their eyes removed. Individuals did not express daily rhythms of feeding, but they swam and crawled more at night. This pattern of locomotion persisted in constant darkness, indicating the presence of a circadian clock. Eyeless animals also expressed a daily rhythm of locomotion, with more locomotion at night. The fact that eyeless animals synchronized their locomotion to the light-dark cycle suggests that they can detect light using extraocular photoreceptors. However, in constant darkness, these rhythms deteriorated, suggesting that the clock neurons that influence locomotion may be located in, or near, the eyes. Thus, locomotion in Melibe appears to be influenced by both ocular and extraocular photoreceptors, although the former appear to have a greater influence on the expression of circadian rhythms. PMID:25572214

  9. Circadian rhythms of crawling and swimming in the nudibranch mollusc Melibe leonina.

    PubMed

    Newcomb, James M; Kirouac, Lauren E; Naimie, Amanda A; Bixby, Kimberly A; Lee, Colin; Malanga, Stephanie; Raubach, Maureen; Watson, Winsor H

    2014-12-01

    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 hypothesis that Melibe can use extraocular photoreceptors to synchronize its daily rhythms to natural light-dark cycles. To address these goals, we analyzed the behavior of 55 animals exposed to either artificial or natural light-dark cycles, followed by constant darkness. We also repeated this experiment using 10 animals that had their eyes removed. Individuals did not express daily rhythms of feeding, but they swam and crawled more at night. This pattern of locomotion persisted in constant darkness, indicating the presence of a circadian clock. Eyeless animals also expressed a daily rhythm of locomotion, with more locomotion at night. The fact that eyeless animals synchronized their locomotion to the light-dark cycle suggests that they can detect light using extraocular photoreceptors. However, in constant darkness, these rhythms deteriorated, suggesting that the clock neurons that influence locomotion may be located in, or near, the eyes. Thus, locomotion in Melibe appears to be influenced by both ocular and extraocular photoreceptors, although the former appear to have a greater influence on the expression of circadian rhythms. PMID:25572214

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

    PubMed

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

    2016-06-01

    Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways. PMID:27084392

  11. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    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

  12. Systems biology of circadian-immune interactions

    PubMed Central

    Mavroudis, P.D.; Scheff, J.D.; Calvano, S.E.; Androulakis, I.P.

    2013-01-01

    There is increasing evidence that immune system is regulated by circadian rhythms. A wide range of immune parameters, such as the number of red blood cells and peripheral blood mononuclear cells as well as the level of critical immune mediators such as cytokines, undergo daily fluctuations. Current experimental data indicates that circadian information reaches immune tissues mainly through diurnal patterns of autonomic and endocrine rhythms. In addition, immune factors such as cytokines can also influence the phase of the circadian clock, providing bidirectional flow of circadian information between the neuroendocrine and immune system. This network of neuroendocrine-immune interactions consists of complexly integrated molecular feedback and feedforward loops that function in synchrony in order to optimize immune response. Chronic stress can disrupt this intrinsic orchestration, as several endocrine signals of chronically stressed patients present blunted rhythmic characteristics. Reprogramming of biological rhythms has recently gained much attention as a potent method to leverage homeostatic circadian controls to ultimately improve clinical outcomes. Elucidation of the intrinsic properties of such complex systems and optimization of intervention strategies requires not only an accurate identification of the signaling pathways that mediate host’s response, but also a systems-level description and evaluation. PMID:23006670

  13. The circadian basis of winter depression

    PubMed Central

    Lewy, Alfred J.; Lefler, Bryan J.; Emens, Jonathan S.; Bauer, Vance K.

    2006-01-01

    The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phase revealed a therapeutic window for optimal alignment of circadian rhythms that also appears to be useful for phase-typing SAD patients for the purpose of administering treatment at the correct time. These analyses also provide estimates of the circadian component of SAD that may apply to the antidepressant mechanism of action of appropriately timed bright light exposure, the treatment of choice. SAD may be the first psychiatric disorder in which a physiological marker correlates with symptom severity before, and in the course of, treatment in the same patients. The findings support the phase-shift hypothesis for SAD, as well as suggest a way to assess the circadian component of other psychiatric, sleep, and chronobiologic disorders. PMID:16648247

  14. Circadian systems biology: When time matters

    PubMed Central

    Fuhr, Luise; Abreu, Mónica; Pett, Patrick; Relógio, Angela

    2015-01-01

    The circadian clock is a powerful endogenous timing system, which allows organisms to fine-tune their physiology and behaviour to the geophysical time. The interplay of a distinct set of core-clock genes and proteins generates oscillations in expression of output target genes which temporally regulate numerous molecular and cellular processes. The study of the circadian timing at the organismal as well as at the cellular level outlines the field of chronobiology, which has been highly interdisciplinary ever since its origins. The development of high-throughput approaches enables the study of the clock at a systems level. In addition to experimental approaches, computational clock models exist which allow the analysis of rhythmic properties of the clock network. Such mathematical models aid mechanistic understanding and can be used to predict outcomes of distinct perturbations in clock components, thereby generating new hypotheses regarding the putative function of particular clock genes. Perturbations in the circadian timing system are linked to numerous molecular dysfunctions and may result in severe pathologies including cancer. A comprehensive knowledge regarding the mechanistic of the circadian system is crucial to develop new procedures to investigate pathologies associated with a deregulated clock. 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. PMID:26288701

  15. Systems biology of circadian-immune interactions.

    PubMed

    Mavroudis, P D; Scheff, J D; Calvano, S E; Androulakis, I P

    2013-01-01

    There is increasing evidence that the immune system is regulated by circadian rhythms. A wide range of immune parameters, such as the number of red blood cells and peripheral blood mononuclear cells as well as the level of critical immune mediators, such as cytokines, undergo daily fluctuations. Current experimental data indicate that circadian information reaches immune tissues mainly through diurnal patterns of autonomic and endocrine rhythms. In addition, immune factors such as cytokines can also influence the phase of the circadian clock, providing bidirectional flow of circadian information between the neuroendocrine and immune systems. This network of neuroendocrine-immune interactions consists of complexly integrated molecular feedback and feedforward loops that function in synchrony in order to optimize immune response. Chronic stress can disrupt this intrinsic orchestration, as several endocrine signals of chronically stressed patients present blunted rhythmic characteristics. Reprogramming of biological rhythms has recently gained much attention as a potent method to leverage homeostatic circadian controls to ultimately improve clinical outcomes. Elucidation of the intrinsic properties of such complex systems and optimization of intervention strategies require not only an accurate identification of the signaling pathways that mediate host responses, but also a system-level description and evaluation. PMID:23006670

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

    PubMed

    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

  17. Circadian rhythms in Macaca mulatta monkeys during Bion 11 flight

    NASA Technical Reports Server (NTRS)

    Alpatov, A. M.; Hoban-Higgins, T. M.; Klimovitsky, V. Y.; Tumurova, E. G.; Fuller, C. A.

    2000-01-01

    Circadian rhythms of primate brain temperature, head and ankle skin temperature, motor activity, and heart rate were studied during spaceflight and on the ground. In space, the circadian rhythms of all the parameters were synchronized with diurnal Zeitgebers. However, in space the brain temperature rhythm showed a significantly more delayed phase angle, which may be ascribed to an increase of the endogenous circadian period.

  18. A novel animal model linking adiposity to altered circadian rhythms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metab...

  19. The circadian clock in cancer development and therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    PubMed Central

    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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 i...

  2. Circadian typology: a comprehensive review.

    PubMed

    Adan, Ana; Archer, Simon N; Hidalgo, Maria Paz; Di Milia, Lee; Natale, Vincenzo; Randler, Christoph

    2012-11-01

    The interest in the systematic study of the circadian typology (CT) is relatively recent and has developed rapidly in the two last decades. All the existing data suggest that this individual difference affects our biological and psychological functioning, not only in health, but also in disease. In the present study, we review the current literature concerning the psychometric properties and validity of CT measures as well as individual, environmental and genetic factors that influence the CT. We present a brief overview of the biological markers that are used to define differences between CT groups (sleep-wake cycle, body temperature, cortisol and melatonin), and we assess the implications for CT and adjustment to shiftwork and jet lag. We also review the differences between CT in terms of cognitive abilities, personality traits and the incidence of psychiatric disorders. When necessary, we have emphasized the methodological limitations that exist today and suggested some future avenues of work in order to overcome these. This is a new field of interest to professionals in many different areas (research, labor, academic and clinical), and this review provides a state of the art discussion to allow professionals to integrate chronobiological aspects of human behavior into their daily practice. PMID:23004349

  3. Quantification of Circadian Rhythms in Single Cells

    PubMed Central

    Westermark, Pål O.; Welsh, David K.; Okamura, Hitoshi; Herzel, Hanspeter

    2009-01-01

    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). PMID:19956762

  4. Developmental alcohol and circadian clock function.

    PubMed

    Earnest, D J; Chen, W J; West, J R

    2001-01-01

    Studies in rats found that alcohol exposure during the early postnatal period, particularly during the brain-growth-spurt period, can result in cell loss in various brain regions and persistent behavioral impairments. Some investigators have speculated that the body's internal clock, which is located in the suprachiasmatic nuclei (SCN) in the brain, may also be affected by developmental alcohol exposure. For example, alcohol-induced damage to the SCN cells and their function could result in disturbances of the circadian timekeeping function, and these disturbances might contribute to the behavioral impairments and affective disorders observed in people prenatally exposed to alcohol. Preliminary findings of studies conducted in rats suggest that developmental alcohol exposure may indeed interfere with circadian clock function as evidenced by a shortened circadian sleep-wake cycle and changes in the release of certain brain chemicals (i.e., neuropeptides) by SCN cells. PMID:11584552

  5. Optimal Implementations for Reliable Circadian Clocks

    NASA Astrophysics Data System (ADS)

    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.

  6. Effect of Light on Human Circadian Physiology

    PubMed Central

    Duffy, Jeanne F.; Czeisler, Charles A.

    2009-01-01

    Synopsis The circadian system in animals and humans, being near but not exactly 24-hours in cycle length, must be reset on a daily basis in order to remain in synchrony with external environmental time. This process of entrainment is achieved in most mammals through regular exposure to light and darkness. In this chapter, we review the results of studies conducted in our laboratory and others over the past 25 years in which the effects of light on the human circadian timing system were investigated. These studies have revealed, how the timing, intensity, duration, and wavelength of light affect the human biological clock. Our most recent studies also demonstrate that there is much yet to learn about the effects of light on the human circadian timing system. PMID:20161220

  7. Intact Interval Timing in Circadian CLOCK Mutants

    PubMed Central

    Cordes, Sara; Gallistel, C. R.

    2008-01-01

    While progress has been made in determining the molecular basis for the circadian clock, the mechanism by which mammalian brains time intervals measured in seconds to minutes remains a mystery. An obvious question is whether the interval timing mechanism shares molecular machinery with the circadian timing mechanism. In the current study, we trained circadian CLOCK +/− and −/− mutant male mice in a peak-interval procedure with 10 and 20-s criteria. The mutant mice were more active than their wild-type littermates, but there were no reliable deficits in the accuracy or precision of their timing as compared with wild-type littermates. This suggests that expression of the CLOCK protein is not necessary for normal interval timing. PMID:18602902

  8. [Molecular oscillatory machinery of circadian rhythms].

    PubMed

    Yamaguchi, Yoshiaki; Okamura, Hitoshi

    2012-07-01

    Many metabolic and physiological processes display daily rhythms oscillated by the internal circadian clock system. This rhythm is generated by interlocked transcription-(post) translation feedback loops of clock genes: the core oscillatory loop, being composed of CLOCK/BMAL1 heterodimer activating the expressions of PER and CRY that directly repress CLOCK/BMAL1, is accompanied by accessory loops consisted with REV-ERB nuclear receptor repressing Bmal1 or with DBP competing with E4BP4 on D-box site. These clock proteins are regulated by phosphorylation and ubiquitination (PER/CRY), and acetylation (CLOCK/BMAL1). Recently, a deacetylating protein SIRT1 mediated metabolic pathway is discovered to be interlocked with core oscillatory loop via Nampt expression, a late-limiting enzyme in NAD+ salvage pathway. Since many key-step enzymes of metabolisms are regulated by the circadian clock, circadian clock system may intimately link to cellular metabolism. PMID:22844791

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

    PubMed Central

    2010-01-01

    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. PMID:20576144

  10. Circadian oscillations of cytosolic and chloroplastic free calcium in plants

    NASA Technical Reports Server (NTRS)

    Johnson, C. H.; Knight, M. R.; Kondo, T.; Masson, P.; Sedbrook, J.; Haley, A.; Trewavas, A.

    1995-01-01

    Tobacco and Arabidopsis plants, expressing a transgene for the calcium-sensitive luminescent protein apoaequorin, revealed circadian oscillations in free cytosolic calcium that can be phase-shifted by light-dark signals. When apoaequorin was targeted to the chloroplast, circadian chloroplast calcium rhythms were likewise observed after transfer of the seedlings to constant darkness. Circadian oscillations in free calcium concentrations can be expected to control many calcium-dependent enzymes and processes accounting for circadian outputs. Regulation of calcium flux is therefore fundamental to the organization of circadian systems.

  11. Circadian and Circalunar Clock Interactions in a Marine Annelid

    PubMed Central

    Zantke, Juliane; Ishikawa-Fujiwara, Tomoko; Arboleda, Enrique; Lohs, Claudia; Schipany, Katharina; Hallay, Natalia; Straw, Andrew D.; Todo, Takeshi; Tessmar-Raible, Kristin

    2013-01-01

    Summary Life is controlled by multiple rhythms. Although the interaction of the daily (circadian) clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly) clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1δ/ε. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function. PMID:24075994

  12. p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α.

    PubMed

    Hallenborg, Philip; Fjære, Even; Liaset, Bjørn; Petersen, Rasmus Koefoed; Murano, Incoronata; Sonne, Si Brask; Falkerslev, Mathias; Winther, Sally; Jensen, Benjamin Anderschou Holbech; Ma, Tao; Hansen, Jacob B; Cinti, Saverio; Blagoev, Blagoy; Madsen, Lise; Kristiansen, Karsten

    2016-01-15

    The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity. PMID:26578713

  13. An antennal circadian clock and circadian rhythms in peripheral pheromone reception in the moth Spodoptera littoralis.

    PubMed

    Merlin, Christine; Lucas, Philippe; Rochat, Didier; François, Marie-Christine; Maïbèche-Coisne, Martine; Jacquin-Joly, Emmanuelle

    2007-12-01

    Circadian rhythms are observed in mating behaviors in moths: females emit sex pheromones and males are attracted by these pheromones in rhythmic fashions. In the moth Spodoptera littoralis, we demonstrated the occurrence of a circadian oscillator in the antenna, the peripheral olfactory organ. We identified different clock genes, period (per), cryptochrome1 (cry1) and cryptochrome2 (cry2), in this organ. Using quantitative real-time PCR (qPCR), we found that their corresponding transcripts cycled circadianly in the antenna as well as in the brain. Electroantennogram (EAG) recordings over 24 h demonstrated for the first time a circadian rhythm in antennal responses of a moth to sex pheromone. qPCR showed that out of one pheromone-binding protein (PBP), one olfactory receptor (OR), and one odorant-degrading enzyme (ODE), all putatively involved in the pheromone reception, only the ODE transcript presented a circadian rhythm that may be related to rhythms in olfactory signal resolution. Peripheral or central circadian clock control of olfaction is then discussed in light of recent data. PMID:18057325

  14. Time-restricted feeding and the realignment of biological rhythms: translational opportunities and challenges.

    PubMed

    Sunderram, Jag; Sofou, Stavroula; Kamisoglu, Kubra; Karantza, Vassiliki; Androulakis, Ioannis P

    2014-01-01

    It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects, exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted, and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the time of feeding in relation to individualized day-night cycles for patients receiving enteral nutrition, in an attempt to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability; and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding. Finally, we discuss the challenges and opportunities for translating these ideas to the bedside. PMID:24674294

  15. Circadian metabolism in the light of evolution.

    PubMed

    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

  16. Circadian rhythms in liver metabolism and disease

    PubMed Central

    Ferrell, Jessica M.; Chiang, John Y.L.

    2015-01-01

    Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436

  17. Temperature compensation and entrainment in circadian rhythms

    NASA Astrophysics Data System (ADS)

    Bodenstein, C.; Heiland, I.; Schuster, S.

    2012-06-01

    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.

  18. Circadian Typology and Style of Thinking Differences

    ERIC Educational Resources Information Center

    Fabbri, Marco; Antonietti, Alessandro; Giorgetti, Marisa; Tonetti, Lorenzo; Natale, Vincenzo

    2007-01-01

    The purpose of the present study aims to investigate the relationship between circadian typology and learning-thinking styles conceptualised as a preference toward information processing typical of the right vs. the left cerebral hemisphere. A sample of 1254 undergraduates (380 boys and 874 girls; mean age=21.86+/-2.37,) was administered the…

  19. Circadian rhythms in liver metabolism and disease.

    PubMed

    Ferrell, Jessica M; Chiang, John Y L

    2015-03-01

    Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436

  20. Procedures for numerical analysis of circadian rhythms

    PubMed Central

    REFINETTI, ROBERTO; LISSEN, GERMAINE CORNÉ; HALBERG, FRANZ

    2010-01-01

    This article reviews various procedures used in the analysis of circadian rhythms at the populational, organismal, cellular and molecular levels. The procedures range from visual inspection of time plots and actograms to several mathematical methods of time series analysis. Computational steps are described in some detail, and additional bibliographic resources and computer programs are listed. PMID:23710111

  1. Circadian Metabolism in the Light of Evolution

    PubMed Central

    2015-01-01

    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

  2. Neuroanatomy of the Extended Circadian Rhythm System

    PubMed Central

    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 serotonergic pathway and the geniculohypothalamic (GHT), NPY-containing pathway from the thalamic intergeniculate leaflet (IGL). Beyond this simple framework, the number of anatomical routes that could theoretically be involved in rhythm regulation is enormous, with the SCN projecting to 15 regions and being directly innervated by about 35. If multisynaptic afferents to the SCN are included, the number expands to approximately brain 85 areas providing input to the SCN. The IGL, a known contributor to circadian rhythm regulation, has a still greater level of complexity. This nucleus connects abundantly throughout the brain (to approximately 100 regions) by pathways that are largely bilateral and reciprocal. Few of these sites have been evaluated for their contributions to circadian rhythm regulation, although most have a theoretical possibility of doing so via the GHT. The anatomy of IGL connections suggests that one of its functions may be regulation of eye movements during sleep. Together, neural circuits of the SCN and IGL are complex and interconnected. As yet, few have been tested with respect to their involvement in rhythm regulation. PMID:22766204

  3. Circadian rhythm of gravitaxis in Euglena gracilis.

    PubMed

    Lebert, M; Porst, M; Hader, D P

    1999-09-01

    Euglena gracilis, a unicellular, photosynthetic flagellate is a model system for environmentally controlled behavioral reactions. One pronounced reaction is the orientation with respect to gravity. In synchronized cultures with no cell growth a distinct circadian rhythm of negative gravitactic orientation could be observed. The main maximum of sensitivity was detected 5 h after the beginning of the subjective day, the main minimum 5 h before the beginning of the subjective day. Transferring synchronized cultures to continuous light resulted in an almost instantaneous loss of rhythmicity. In contrast, after transfer to permanent darkness cells exhibited a circadian rhythm with a progressive shortening of the period for more than 5 days. These findings are in contrast to the circadian rhythm of phototaxis in Euglena, where a free-running period of 24 h was observed. Parallel measurements of negative gravitactic orientation, velocity, cell shape as well as cAMP concentration in synchronized cultures revealed a circadian rhythm of all reactions. The results are discussed with regard to the possible role of cell shape and cAMP in gravitactic orientation. PMID:11542916

  4. Peripheral circadian clocks--a conserved phenotype?

    PubMed

    Weigl, Yuval; Harbour, Valerie L; Robinson, Barry; Dufresne, Line; Amir, Shimon

    2013-05-01

    The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock

  5. Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters.

    PubMed

    Bradley, Sean P; Prendergast, Brian J

    2014-06-01

    This article is part of a Special Issue "Energy Balance". Both the light-dark cycle and the timing of food intake can entrain circadian rhythms. Entrainment to food is mediated by a food entrainable circadian oscillator (FEO) that is formally and mechanistically separable from the hypothalamic light-entrainable oscillator. This experiment examined whether seasonal changes in day length affect the function of the FEO in male Siberian hamsters (Phodopus sungorus). Hamsters housed in long (LD; 15 h light/day) or short (SD; 9h light/day) photoperiods were subjected to a timed-feeding schedule for 10 days, during which food was available only during a 5h interval of the light phase. Running wheel activity occurring within a 3h window immediately prior to actual or anticipated food delivery was operationally-defined as food anticipatory activity (FAA). After the timed-feeding interval, hamsters were fed ad libitum, and FAA was assessed 2 and 7 days later via probe trials of total food deprivation. During timed-feeding, all hamsters exhibited increases FAA, but FAA emerged more rapidly in SD; in probe trials, FAA was greater in magnitude and persistence in SD. Gonadectomy in LD did not induce the SD-like FAA phenotype, indicating that withdrawal of gonadal hormones is not sufficient to mediate the effects of photoperiod on FAA. Entrainment of the circadian system to light markedly affects the functional output of the FEO via gonadal hormone-independent mechanisms. Rapid emergence and persistent expression of FAA in SD may reflect a seasonal adaptation that directs behavior toward sources of nutrition with high temporal precision at times of year when food is scarce. PMID:24666779

  6. Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters

    PubMed Central

    Bradley, Sean P.; Prendergast, Brian J.

    2014-01-01

    Both the light-dark cycle and the timing of food intake can entrain circadian rhythms. Entrainment to food is mediated by a food entrainable circadian oscillator (FEO) that is formally and mechanistically separable from the hypothalamic light-entrainable oscillator. This experiment examined whether seasonal changes in day length affect the function of the FEO in male Siberian hamsters (Phodopus sungorus). Hamsters housed in long (LD; 15 h light/day) or short (SD; 9 h light/day) photoperiods were subjected to a timed-feeding schedule for 10 days, during which food was available only during a 5 h interval of the light phase. Running wheel activity occurring within a 3 h window immediately prior to actual or anticipated food delivery was operationally-defined as food anticipatory activity (FAA). After the timed-feeding interval, hamsters were fed ad libitum, and FAA was assessed 2 and 7 days later via probe trials of total food deprivation. During timed-feeding, all hamsters exhibited increases FAA, but FAA emerged more rapidly in SD; in probe trials, FAA was greater in magnitude and persistence in SD. Gonadectomy in LD did not induce the SD-like FAA phenotype, indicating that withdrawal of gonadal hormones is not sufficient to mediate the effects of photoperiod on FAA. Entrainment of the circadian system to light markedly affects the functional output of the FEO via gonadal hormone-independent mechanisms. Rapid emergence and persistent expression of FAA in SD may reflect a seasonal adaptation that directs behavior toward sources of nutrition with high temporal precision at times of year when food is scarce. PMID:24666779

  7. Skin, Reactive Oxygen Species, and Circadian Clocks

    PubMed Central

    Ndiaye, Mary A.; Nihal, Minakshi; Wood, Gary S.

    2014-01-01

    Abstract Significance: Skin, a complex organ and the body's first line of defense against environmental insults, plays a critical role in maintaining homeostasis in an organism. This balance is maintained through a complex network of cellular machinery and signaling events, including those regulating oxidative stress and circadian rhythms. These regulatory mechanisms have developed integral systems to protect skin cells and to signal to the rest of the body in the event of internal and environmental stresses. Recent Advances: Interestingly, several signaling pathways and many bioactive molecules have been found to be involved and even important in the regulation of oxidative stress and circadian rhythms, especially in the skin. It is becoming increasingly evident that these two regulatory systems may, in fact, be interconnected in the regulation of homeostasis. Important examples of molecules that connect the two systems include serotonin, melatonin, vitamin D, and vitamin A. Critical Issues: Excessive reactive oxygen species and/or dysregulation of antioxidant system and circadian rhythms can cause critical errors in maintaining proper barrier function and skin health, as well as overall homeostasis. Unfortunately, the modern lifestyle seems to contribute to increasing alterations in redox balance and circadian rhythms, thereby posing a critical problem for normal functioning of the living system. Future Directions: Since the oxidative stress and circadian rhythm systems seem to have areas of overlap, future research needs to be focused on defining the interactions between these two important systems. This may be especially important in the skin where both systems play critical roles in protecting the whole body. Antioxid. Redox Signal. 20, 2982–2996. PMID:24111846

  8. Metabolic circadian rhythms in embryonic turtles.

    PubMed

    Loudon, Fiona Kay; Spencer, Ricky-John; Strassmeyer, Alana; Harland, Karen

    2013-07-01

    Oviparous species are model organisms for investigating embryonic development of endogenous physiological circadian rhythms without the influence of maternal biorhythms. Recent studies have demonstrated that heart rates and metabolic rates of embryonic turtles are not constant or always maximal and can be altered in response to the presence of embryos at a more advanced stage of development within the nest. A first step in understanding the physiological mechanisms underpinning these responses in embryonic ectothermic organisms is to develop metabolic profiles (e.g., heart rate) at different temperatures throughout incubation. Heart beat and rhythmic patterns or changes in development may represent important signals or cues within a nest and may be vital to coordinate synchronous hatching well in advance of the final stages of incubation. We developed baseline embryonic heart-rate profiles of embryos of the short-necked Murray River turtle (Emydura macquarii) to determine the stage of embryogenesis that metabolic circadian rhythms become established, if at all. Eggs were incubated at constant temperatures (26°C and 30°C) and heart rates were monitored at 6-h intervals over 24 h every 7-11 days until hatching. Circadian heart rate rhythms were detected at the mid-gestation period and were maintained until hatching. Heart rates throughout the day varied by up to 20% over 24 h and were not related to time of day. This study demonstrated that endogenous metabolic circadian rhythms in developing embryos in turtle eggs establish earlier in embryogenesis than those documented in other vertebrate taxa during embryogenesis. Early establishment of circadian rhythms in heart rates may be critical for communication among embryos and synchrony in hatching and emergence from the nest. PMID:23652198

  9. Circadian rhythms, sleep, and performance in space

    NASA Technical Reports Server (NTRS)

    Mallis, M. M.; DeRoshia, C. W.

    2005-01-01

    Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and

  10. Circadian rhythms, sleep, and performance in space.

    PubMed

    Mallis, M M; DeRoshia, C W

    2005-06-01

    Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and

  11. Uncouplers of rat-liver mitochondrial oxidative phosphorylation

    PubMed Central

    Parker, V. H.

    1965-01-01

    1. The ability of a series of compounds to uncouple oxidative phosphorylation of rat-liver mitochondria has been investigated. 2. The compounds were: 2-amino-1,1,3-tricyanopropene; carbonyl cyanide phenylhydrazone and its m-chloro and p-trifluoromethoxy derivatives; 4,5,6,7-tetrachloro-, 5-chloro-4-nitro-, 5-nitro-and 4,5,6,7-tetrachloro-1-methyl-benzotriazole; 4-hydroxy-3,5-di-iodo-, 3,5-di-bromo-4-hydroxy- and 3,5-dichloro-4-hydroxy-benzonitrile; and pentafluorophenol. 3. In a medium the components and physical condition of which were, as far as possible, kept constant, each compound was tested for ability to stimulate adenosine triphosphatase, to stimulate respiration in the presence of pyruvate as substrate, to inhibit phosphate uptake and to prevent swelling by trimethyltin. 4. Each compound was also examined with respect to its ability to produce rapid rigor mortis in mice. 5. The biological properties were compared with the dissociation constant and the hexane–water partition coefficient for each compound. 6. With the exception of 4,5,6,7-tetrachloro-1-methylbenzotriazole, all the compounds behaved qualitatively as 2,4-dinitrophenol. 7. Within each class of compound there is a relation between biological activity and the physical attributes measured. 8. The most efficient uncouplers were the most acidic and the most hydrophobic. PMID:5881655

  12. Two types of ammonium uncoupling in pea chloroplasts.

    PubMed

    Opanasenko, V K; Vasyukhina, L A; Naydov, I A

    2010-06-01

    The effect of ammonium on ATP synthesis, electron transfer, and light-induced uptake of hydrogen ions in pea chloroplasts was studied. It is shown that the dependence of these reactions on ammonium concentration could be due to effects of two different uncoupling processes. The first process is induced by low ammonium concentrations (<0.2 mM); the second one is observed in the NH(4)Cl concentration interval of 0.5-5.0 mM. The first type of uncoupling is stimulated by palmitic acid or by N,N'-dicyclohexylcarbodiimide, while the second is stimulated by chloroplast thylakoid swelling caused by energy-dependent osmotic gradients. In the presence of the fluorescent dye sulforhodamine B, which does not penetrate through the cell membrane, this swelling causes the dye to enter the lumens. It is supposed that ammonium activates two different routes of cation leakage from the lumen. The first route involves channel proteins, while the second is a mechanosensitive pore that opens in response to osmotic gradients. PMID:20636271

  13. Cline coupling and uncoupling in a stickleback hybrid zone.

    PubMed

    Vines, Timothy H; Dalziel, Anne C; Albert, Arianne Y K; Veen, Thor; Schulte, Patricia M; Schluter, Dolph

    2016-05-01

    Strong ecological selection on a genetic locus can maintain allele frequency differences between populations in different environments, even in the face of hybridization. When alleles at divergent loci come into tight linkage disequilibrium, selection acts on them as a unit and can significantly reduce gene flow. For populations interbreeding across a hybrid zone, linkage disequilibria between loci can force clines to share the same slopes and centers. However, strong ecological selection on a locus can also pull its cline away from the others, reducing linkage disequilibrium and weakening the barrier to gene flow. We looked for this "cline uncoupling" effect in a hybrid zone between stream resident and anadromous sticklebacks at two genes known to be under divergent natural selection (Eda and ATP1a1) and five morphological traits that repeatedly evolve in freshwater stickleback. These clines were all steep and located together at the top of the estuary, such that we found no evidence for cline uncoupling. However, we did not observe the stepped shape normally associated with steep concordant clines. It thus remains possible that these clines cluster together because their individual selection regimes are identical, but this would be very surprising given their diverse roles in osmoregulation, body armor, and swimming performance. PMID:27061719

  14. Seasonal uncoupling of demographic processes in a marine clonal plant

    NASA Astrophysics Data System (ADS)

    Mascaró, O.; Romero, J.; Pérez, M.

    2014-04-01

    In temperate regions, climatic factors impose a general seasonal pattern on seagrass growth that can be observed in leaf growth rates and, in small species, also in shoot density. Large variations in shoot density suggest a strong temporal uncoupling between shoot recruitment and shoot mortality, and the dependence of each of these processes on different drivers. Here we examine seasonal patterns of recruitment and mortality in the seagrass Cymodocea nodosa, one of the species most sensitive to seasonal forcing in the Mediterranean. We sampled two local populations submitted to different nutrient availability in Alfacs Bay (NW Mediterranean) and determined recruitment and mortality rates, as well as other plant traits, on a monthly basis. Our results confirm the hypothesized uncoupling, with maximum mortality 2 months after maximum recruitment. Whereas timing of recruitment was associated with light availability, and was supported by carbohydrate remobilisation, mortality was related to high water temperatures and probably also to light limitation in late summer due to self-shading. In the high-nutrient population, algal overgrowth caused further light deprivation, with mortality rates higher than in the low-nutrient population. It is emphasised that the demographic balance of the studied populations was negative for most of the year, with the exception of August and September. Therefore, caution is necessary when overall population trends are inferred from single annual sampling events.

  15. Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

    PubMed Central

    Lago, CU; Nowinski, SM; Rundhaug, JE; Pfeiffer, ME; Kiguchi, K; Hirasaka, K; Yang, X; Abramson, EM; Bratton, SB; Rho, O; Colavitti, R; Kenaston, MA; Nikawa, T; Trempus, C; DiGiovanni, J; Fischer, SM; Mills, EM

    2013-01-01

    Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment. PMID:22266853

  16. Chromatin Assembly at Kinetochores Is Uncoupled from DNA Replication

    PubMed Central

    Shelby, Richard D.; Monier, Karine; Sullivan, Kevin F.

    2000-01-01

    The specification of metazoan centromeres does not depend strictly on centromeric DNA sequences, but also requires epigenetic factors. The mechanistic basis for establishing a centromeric “state” on the DNA remains unclear. In this work, we have directly examined replication timing of the prekinetochore domain of human chromosomes. Kinetochores were labeled by expression of epitope-tagged CENP-A, which stably marks prekinetochore domains in human cells. By immunoprecipitating CENP-A mononucleosomes from synchronized cells pulsed with [3H]thymidine we demonstrate that CENP-A–associated DNA is replicated in mid-to-late S phase. Cytological analysis of DNA replication further demonstrated that centromeres replicate asynchronously in parallel with numerous other genomic regions. In contrast, quantitative Western blot analysis demonstrates that CENP-A protein synthesis occurs later, in G2. Quantitative fluorescence microscopy and transient transfection in the presence of aphidicolin, an inhibitor of DNA replication, show that CENP-A can assemble into centromeres in the absence of DNA replication. Thus, unlike most genomic chromatin, histone synthesis and assembly are uncoupled from DNA replication at the kinetochore. Uncoupling DNA replication from CENP-A synthesis suggests that regulated chromatin assembly or remodeling could play a role in epigenetic centromere propagation. PMID:11086012

  17. An uncoupled viscoplastic constitutive model for metals at elevated temperature

    NASA Technical Reports Server (NTRS)

    Haisler, W. E.; Cronenworth, J.

    1983-01-01

    An uncoupled constitutive model for predicting the transient response of thermal and rate dependent, inelastic material behavior is presented. The uncoupled model assumes that there is a temperature below which the total strain consists essentially of elastic and rate insensitive inelastic strains only. Above this temperature, the rate dependent inelastic strain (creep) dominates. The rate insensitive inelastic strain component is modeled in an incremental form with a yield function, flow rule and hardening law. Revisions to the hardening rule permit the model to predict temperature-dependent kinematic-isotropic hardening behavior, cyclic saturation, asymmetric stress-strain response upon stress reversal, and variable Bauschinger effect. The rate dependent inelastic strain component is modeled using a rate equation in terms of back stress, drag stress and exponent n as functions of temperature and strain. A sequence of hysteresis loops and relaxation tests are utilized to define the rate dependent inelastic strain rate. Evaluation of the model is performed by comparison with experiments involving various thermal and mechanical load histories on 5086 aluminum alloy, 304 stainless steel and Hastelloy-X.

  18. Age-associated circadian period changes in Arabidopsis leaves

    PubMed Central

    Kim, Hyunmin; Kim, Yumi; Yeom, Miji; Lim, Junhyun; Nam, Hong Gil

    2016-01-01

    As most organisms age, their appearance, physiology, and behaviour alters as part of a life history strategy that maximizes their fitness over their lifetime. The passage of time is measured by organisms and is used to modulate these age-related changes. Organisms have an endogenous time measurement system called the circadian clock. This endogenous clock regulates many physiological responses throughout the life history of organisms to enhance their fitness. However, little is known about the relation between ageing and the circadian clock in plants. Here, we investigate the association of leaf ageing with circadian rhythm changes to better understand the regulation of life-history strategy in Arabidopsis. The circadian periods of clock output genes were approximately 1h shorter in older leaves than younger leaves. The periods of the core clock genes were also consistently shorter in older leaves, indicating an effect of ageing on regulation of the circadian period. Shortening of the circadian period with leaf age occurred faster in plants grown under a long photoperiod compared with a short photoperiod. We screened for a regulatory gene that links ageing and the circadian clock among multiple clock gene mutants. Only mutants for the clock oscillator TOC1 did not show a shortened circadian period during leaf ageing, suggesting that TOC1 may link age to changes in the circadian clock period. Our findings suggest that age-related information is incorporated into the regulation of the circadian period and that TOC1 is necessary for this integrative process. PMID:27012281

  19. Oscillating primary transcripts harbor miRNAs with circadian functions

    PubMed Central

    Wang, Haifang; Fan, Zenghua; Zhao, Meng; Li, Juan; Lu, Minghua; Liu, Wei; Ying, Hao; Liu, Mofang; Yan, Jun

    2016-01-01

    The roles of miRNAs as important post-transcriptional regulators in the circadian clock have been suggested in several studies. But the search for circadian miRNAs has led to disparate results. Here we demonstrated that at least 57 miRNA primary transcripts are rhythmically transcribed in mouse liver. Most of these transcripts are under the regulation of circadian transcription factors such as BMAL1/CLOCK and REV-ERBα/β. However, the mature miRNAs derived from these transcripts are either not oscillating or oscillating at low amplitudes, which could explain the inconsistency of different circadian miRNA studies. In order to show that these circadian primary transcripts can give rise to miRNAs with circadian functions, we over-expressed one of them, miR-378, in mouse by adenovirus injection. We found a significant over-representation of circadian oscillating genes under-expressed by miR-378 over-expression in liver. In particular, we observed that miR-378 modulates the oscillation amplitudes of Cdkn1a in the control of cell cycle and Por in the regulation of oxidation reduction by forming partnership with different circadian transcription factors. Our study suggests that circadian transcription of miRNA at primary transcript level can be a good indicator for circadian miRNA functions. PMID:26898952

  20. Circadian desynchrony and metabolic dysfunction; did light pollution make us fat?

    PubMed

    Wyse, C A; Selman, C; Page, M M; Coogan, A N; Hazlerigg, D G

    2011-12-01

    Circadian rhythms are daily oscillations in physiology and behaviour that recur with a period of 24h, and that are entrained by the daily photoperiod. The cycle of sunrise and sunset provided a reliable time cue for many thousands of years, until the advent of artificial lighting disrupted the entrainment of human circadian rhythms to the solar photoperiod. Circadian desynchrony (CD) occurs when endogenous rhythms become misaligned with daily photoperiodic cycles, and this condition is facilitated by artificial lighting. This review examines the hypothesis that chronic CD that has accompanied the availability of electric lighting in the developed world induces a metabolic and behavioural phenotype that is predisposed to the development of obesity. The evidence to support this hypothesis is based on epidemiological data showing coincidence between the appearance of obesity and the availability of artificial light, both geographically, and historically. This association links CD to obesity in humans, and is corroborated by experimental studies that demonstrate that CD can induce obesity and metabolic dysfunction in humans and in rodents. This association between CD and obesity has far reaching implications for human health, lifestyle and work practices. Attention to the rhythmicity of daily sleep, exercise, work and feeding schedules could be beneficial in targeting or reversing the modern human predisposition to obesity. PMID:21983352

  1. Energy intake and the circadian rhythm of core body temperature in sheep

    PubMed Central

    Maloney, Shane K; Meyer, Leith C R; Blache, D; Fuller, A

    2013-01-01

    We tested the hypothesis that different levels of energy intake would alter the circadian rhythm of core body temperature (Tc) in ovariectomized sheep. We measured arterial blood temperature every 5 min while ten sheep were offered a maintenance diet, 70% of maintenance requirements, or 150% of maintenance requirements, for 12 days, and later fasted for 2 days. The rhythmicity of Tc was analyzed for its dominant period and then a least-squares cosine wave was fitted to the data that generated a mesor, amplitude, and acrophase for the rhythm. When energy intake was less than maintenance requirements we observed a significant decrease in the mesor and minimum, and a significant increase in the amplitude and goodness of fit, of the body temperature rhythm. Fasting also resulted in a decrease in the maximum of the body temperature rhythm. Feeding the sheep to excess did not affect the mesor or maximum of the rhythm, but did result in a decrease in the goodness of fit of the rhythm in those sheep that consumed more energy than when they were on the maintenance diet, indicating that circadian rhythmicity was decreased when energy intake increased. Our data indicate that modulation of the circadian rhythm of body temperature, characterized by inactive-phase hypothermia, occurs when energy intake is reduced. The response may be an adaptation to energy imbalance in large mammals. PMID:24303185

  2. The plant circadian clock looks like a traditional Japanese clock rather than a modern Western clock

    PubMed Central

    Mizuno, Takeshi; Yamashino, Takafumi

    2015-01-01

    Life cycle adaptation to seasonal changes in photoperiod and ambient temperature is a major determinant of the ecological success behind the widespread domestication of flowering plants. The circadian clock plays a role in the underlying mechanism for adaptation through generating endogenous rhythms that allow plants to adapt and adjust to both the 24 h diurnal rotation and 365 d seasonal revolution. Nevertheless, the mechanism by which the circadian clock tracks seasonal changes in photoperiod and temperature is a longstanding subject in the field. Recently, we have begun to understand the question of how the light and ambient temperature signals feed into the circadian clock transcriptional circuitry in day-night cycles in order to track seasonal changes in photoperiod and ambient temperature.1-4 Our results collectively indicate that the evening complex (EC) nighttime repressor consisting of LUX-ELF3-ELF4 plays a crucial role in this respect. Here, we discuss about these recent studies to add further implications. PMID:26382718

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

    PubMed

    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

  4. Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic Nucleus Ex Vivo

    PubMed Central

    Koo, Jinmi; Choe, Han Kyoung; Kim, Hee-Dae; Chun, Sung Kook; Son, Gi Hoon

    2015-01-01

    Background In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. Methods We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. Results Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. Conclusion These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock. PMID:25491783

  5. 6-ketocholestanol abolishes the effect of the most potent uncouplers of oxidative phosphorylation in mitochondria.

    PubMed

    Starkov, A A; Dedukhova, V I; Skulachev, V P

    1994-12-01

    The effect of a keto-derivative of cholesterol, namely, 6-ketocholestanol (5 alpha-cholestan-3 beta-ol-6-one; kCh) on the uncoupling of oxidation and phosphorylation by various uncouplers was studied in rat heart mitochondria. kCh was found to completely abolish the uncoupling effect (the increase in the respiration rate under the respiratory control conditions and the decrease in the membrane potential) caused of FCCP, CCCP and SF6847 and partially by TTFB at low concentrations of uncouplers. It was without effect on the uncoupling by PCP, DNP and palmitate. Carboxyatractylate, a specific inhibitor of the ADP/ATP-antiporter, was shown to almost completely abolish the uncoupling induced by palmitate and partially by low concentration of TTFB, PCP and DNP. Effects of high concentrations of all these uncouplers as well as of any concentrations of gramicidin proved to be kCh- and carboxyatractilate-insensitive. The data are discussed in terms of the hypothesis on the protein-mediated mechanism of the protonophorous uncoupling. PMID:7988694

  6. Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice

    PubMed Central

    Keipert, Susanne; Voigt, Anja; Klaus, Susanne

    2011-01-01

    Little is known about how diet and energy metabolism interact in determination of lifespan under ad libitum feeding. From 12 weeks of age until death, male and female wild-type (WT) and transgenic (TG) mice with increased skeletal muscle mitochondrial uncoupling (HSA-mUCP1 mice) were fed one of three different semisynthetic diets differing in macronutrient ratio: control (high-carbohydrate/low-fat-HCLF) and two high-fat diets: high-carbohydrate/high-fat (HCHF), and low-carbohydrate/high-fat (LCHF). Compared to control and LCHF, HCHF feeding rapidly and significantly increased body fat content in WT. Median lifespan of WT was decreased by 33% (HCHF) and 7% (LCHF) compared to HCLF. HCHF significantly increased insulin resistance (HOMA) of WT from 24 weeks on compared to control. TG mice had lower lean body mass and increased energy expenditure, insulin sensitivity, and maximum lifespan (+10%) compared to WT. They showed a delayed development of obesity on HCHF but reached similar maximum adiposity as WT. TG median lifespan was only slightly reduced by HCHF (−7%) and unaffected by LCHF compared to control. Correlation analyses showed that decreased longevity was more strongly linked to a high rate of fat gain than to adiposity itself. Furthermore, insulin resistance was negatively and weight-specific energy expenditure was positively correlated with longevity. We conclude that (i) dietary macronutrient ratios strongly affected obesity development, glucose homeostasis, and longevity, (ii) that skeletal muscle mitochondrial uncoupling alleviated the detrimental effects of high-fat diets, and (iii) that early imbalances in energy homeostasis leading to increased insulin resistance are predictive for a decreased lifespan. PMID:21070590

  7. Preliminary characterization of persisting circadian rhythms during space flight: Neurospora as a model system

    NASA Technical Reports Server (NTRS)

    Sulzman, F. W.

    1981-01-01

    The effects of the Spacelab environment on the circadian rhythms in microorganisms are investigated. Neurospora is chosen because of its well characterized circadian rhythm of growth. Growth rate, banding patterns, and circadian period and phase information are studied.

  8. Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

    PubMed Central

    Nowinski, Sara M.; Solmonson, Ashley; Rundhaug, Joyce E.; Rho, Okkyung; Cho, Jiyoon; Lago, Cory U.; Riley, Christopher L.; Lee, Sunhee; Kohno, Shohei; Dao, Christine K.; Nikawa, Takeshi; Bratton, Shawn B.; Wright, Casey W.; Fischer, Susan M.; DiGiovanni, John; Mills, Edward M.

    2015-01-01

    To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling. PMID:26310111

  9. Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis.

    PubMed

    Nowinski, Sara M; Solmonson, Ashley; Rundhaug, Joyce E; Rho, Okkyung; Cho, Jiyoon; Lago, Cory U; Riley, Christopher L; Lee, Sunhee; Kohno, Shohei; Dao, Christine K; Nikawa, Takeshi; Bratton, Shawn B; Wright, Casey W; Fischer, Susan M; DiGiovanni, John; Mills, Edward M

    2015-01-01

    To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling. PMID:26310111

  10. Uncoupling effect of fatty acids in halo- and alkalotolerant bacterium Bacillus pseudofirmus FTU.

    PubMed

    Popova, I V; Bodrova, M E; Mokhova, E N; Muntyan, M S

    2004-10-01

    Natural uncouplers of oxidative phosphorylation, long-chain non-esterified fatty acids, cause uncoupling in the alkalo- and halotolerant bacterium Bacillus pseudofirmus FTU. The uncoupling effect in the bacterial cells was manifested as decrease of membrane potential and increase of respiratory activity. The membrane potential decrease was detected only in bacterial cells exhausted by their endogenous substrates. In proteoliposomes containing reconstituted bacterial cytochrome c oxidase, fatty acids caused a "mild" uncoupling effect by reducing membrane potential only at low rate of membrane potential generation. "Free respiration" induced by the "mild" uncouplers, the fatty acids, can be considered as possible mechanism responsible for adaptation of the bacteria to a constantly changed environment. PMID:15527418

  11. Changes in GDP binding to brown adipose tissue mitochondria and the uncoupling protein

    SciTech Connect

    Swick, A.G.; Swick, R.W. )

    1988-12-01

    Incubation in vitro of brown adipose tissue (BAT) mitochondria with divalent cations, spermine, or alkaline phosphatase led to a marked increase in the binding of ({sup 3}H)GDP. The effect of Mg{sup 2+} appeared to be the most specific and led to the largest increase in GDP binding. A simplified method was developed for measuring GDP binding to purified uncoupling protein from rat BAT mitochondria. Application of this method indicates that uncoupling protein from cold-acclimated rats binds twice as much GDP as uncoupling protein from cold-acclimated rats that were briefly returned to thermoneutrality, paralleling changes in GDP binding to the mitochondria. Incubation of BAT mitochondria with Mg{sup 2+} led to a smaller increase in GDP binding to the subsequently purified uncoupling protein, suggesting that divalent cations may somehow participate in the regulation of the activity of the uncoupling protein.

  12. Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.

    PubMed

    Arble, Deanna M; Bass, Joseph; Behn, Cecilia Diniz; Butler, Matthew P; Challet, Etienne; Czeisler, Charles; Depner, Christopher M; Elmquist, Joel; Franken, Paul; Grandner, Michael A; Hanlon, Erin C; Keene, Alex C; Joyner, Michael J; Karatsoreos, Ilia; Kern, Philip A; Klein, Samuel; Morris, Christopher J; Pack, Allan I; Panda, Satchidananda; Ptacek, Louis J; Punjabi, Naresh M; Sassone-Corsi, Paolo; Scheer, Frank A; Saxena, Richa; Seaquest, Elizabeth R; Thimgan, Matthew S; Van Cauter, Eve; Wright, Kenneth P

    2015-12-01

    A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice. PMID:26564131

  13. Impact of circadian misalignment on energy metabolism during simulated nightshift work

    PubMed Central

    McHill, Andrew W.; Melanson, Edward L.; Higgins, Janine; Connick, Elizabeth; Moehlman, Thomas M.; Stothard, Ellen R.; Wright, Kenneth P.

    2014-01-01

    Eating at a time when the internal circadian clock promotes sleep is a novel risk factor for weight gain and obesity, yet little is known about mechanisms by which circadian misalignment leads to metabolic dysregulation in humans. We studied 14 adults in a 6-d inpatient simulated shiftwork protocol and quantified changes in energy expenditure, macronutrient utilization, appetitive hormones, sleep, and circadian phase during day versus nightshift work. We found that total daily energy expenditure increased by ∼4% on the transition day to the first nightshift, which consisted of an afternoon nap and extended wakefulness, whereas total daily energy expenditure decreased by ∼3% on each of the second and third nightshift days, which consisted of daytime sleep followed by afternoon and nighttime wakefulness. Contrary to expectations, energy expenditure decreased by ∼12–16% during scheduled daytime sleep opportunities despite disturbed sleep. The thermic effect of feeding also decreased in response to a late dinner on the first nightshift. Total daily fat utilization increased on the first and second nightshift days, contrary to expectations, and carbohydrate and protein utilization were reduced on the second nightshift day. Ratings of hunger were decreased during nightshift days despite decreases in 24-h levels of the satiety hormones leptin and peptide-YY. Findings suggest that reduced total daily energy expenditure during nightshift schedules and reduced energy expenditure in response to dinner represent contributing mechanisms by which humans working and eating during the biological night, when the circadian clock is promoting sleep, may increase the risk of weight gain and obesity. PMID:25404342

  14. The circadian oscillator in Synechococcus elongatus controls metabolite partitioning during diurnal growth

    PubMed Central

    Diamond, Spencer; Jun, Darae; Rubin, Benjamin E.; Golden, Susan S.

    2015-01-01

    Synechococcus elongatus PCC 7942 is a genetically tractable model cyanobacterium that has been engineered to produce industrially relevant biomolecules and is the best-studied model for a prokaryotic circadian clock. However, the organism is commonly grown in continuous light in the laboratory, and data on metabolic processes under diurnal conditions are lacking. Moreover, the influence of the circadian clock on diurnal metabolism has been investigated only briefly. Here, we demonstrate that the circadian oscillator influences rhythms of metabolism during diurnal growth, even though light–dark cycles can drive metabolic rhythms independently. Moreover, the phenotype associated with loss of the core oscillator protein, KaiC, is distinct from that caused by absence of the circadian output transcriptional regulator, RpaA (regulator of phycobilisome-associated A). Although RpaA activity is important for carbon degradation at night, KaiC is dispensable for those processes. Untargeted metabolomics analysis and glycogen kinetics suggest that functional KaiC is important for metabolite partitioning in the morning. Additionally, output from the oscillator functions to inhibit RpaA activity in the morning, and kaiC-null strains expressing a mutant KaiC phosphomimetic, KaiC-pST, in which the oscillator is locked in the most active output state, phenocopies a ΔrpaA strain. Inhibition of RpaA by the oscillator in the morning suppresses metabolic processes that normally are active at night, and kaiC-null strains show indications of oxidative pentose phosphate pathway activation as well as increased abundance of primary metabolites. Inhibitory clock output may serve to allow secondary metabolite biosynthesis in the morning, and some metabolites resulting from these processes may feed back to reinforce clock timing. PMID:25825710

  15. The role of circadian rhythm in breast cancer

    PubMed Central

    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

  16. Circadian Organization of Behavior and Physiology in Drosophila

    PubMed Central

    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

  17. A tunable artificial circadian clock in clock-defective mice

    PubMed Central

    D'Alessandro, Matthew; Beesley, Stephen; Kim, Jae Kyoung; Chen, Rongmin; Abich, Estela; Cheng, Wayne; Yi, Paul; Takahashi, Joseph S.; Lee, Choogon

    2015-01-01

    Self-sustaining oscillations are essential for diverse physiological functions such as the cell cycle, insulin secretion and circadian rhythms. Synthetic oscillators using biochemical feedback circuits have been generated in cell culture. These synthetic systems provide important insight into design principles for biological oscillators, but have limited similarity to physiological pathways. Here we report the generation of an artificial, mammalian circadian clock in vivo, capable of generating robust, tunable circadian rhythms. In mice deficient in Per1 and Per2 genes (thus lacking circadian rhythms), we artificially generate PER2 rhythms and restore circadian sleep/wake cycles with an inducible Per2 transgene. Our artificial clock is tunable as the period and phase of the rhythms can be modulated predictably. This feature, and other design principles of our work, might enhance the study and treatment of circadian dysfunction and broader aspects of physiology involving biological oscillators. PMID:26617050

  18. The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities.

    PubMed

    Coogan, Andrew N; Schutová, Barbora; Husung, Susanne; Furczyk, Karolina; Baune, Bernhard T; Kropp, Peter; Häßler, Frank; Thome, Johannes

    2013-09-01

    Alzheimer's disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions. PMID:23273723

  19. Neuroendocrine underpinnings of sex differences in circadian timing systems.

    PubMed

    Yan, Lily; Silver, Rae

    2016-06-01

    There are compelling reasons to study the role of steroids and sex differences in the circadian timing system. A solid history of research demonstrates the ubiquity of circadian changes that impact virtually all behavioral and biological responses. Furthermore, steroid hormones can modulate every attribute of circadian responses including the period, amplitude and phase. Finally, desynchronization of circadian rhythmicity, and either enhancing or damping amplitude of various circadian responses can produce different effects in the sexes. Studies of the neuroendocrine underpinnings of circadian timing systems and underlying sex differences have paralleled the overall development of the field as a whole. Early experimental studies established the ubiquity of circadian rhythms by cataloging daily and seasonal changes in whole organism responses. The next generation of experiments demonstrated that daily changes are not a result of environmental synchronizing cues, and are internally orchestrated, and that these differ in the sexes. This work was followed by the revelation of molecular circadian rhythms within individual cells. At present, there is a proliferation of work on the consequences of these daily oscillations in health and in disease, and awareness that these may differ in the sexes. In the present discourse we describe the paradigms used to examine circadian oscillation, to characterize how these internal timing signals are synchronized to local environmental conditions, and how hormones of gonadal and/or adrenal origin modulate circadian responses. Evidence pointing to endocrinologically and genetically mediated sex differences in circadian timing systems can be seen at many levels of the neuroendocrine and endocrine systems, from the cell, the gland and organ, and to whole animal behavior, including sleep/wake or rest/activity cycles, responses to external stimuli, and responses to drugs. We review evidence indicating that the analysis of the circadian

  20. Methods to Record Circadian Rhythm Wheel Running Activity in Mice

    PubMed Central

    Siepka, Sandra M.; Takahashi, Joseph S.

    2013-01-01

    Forward genetic approaches (phenotype to gene) are powerful methods to identify mouse circadian clock components. The success of these approaches, however, is highly dependent on the quality of the phenotype— specifically, the ability to measure circadian rhythms in individual mice. This article outlines the factors necessary to measure mouse circadian rhythms, including choice of mouse strain, facilities and equipment design and construction, experimental design, high-throughput methods, and finally methods for data analysis. PMID:15817291

  1. Traumatic Brain Injury-Induced Dysregulation of the Circadian Clock

    PubMed Central

    Boone, Deborah R.; Sell, Stacy L.; Micci, Maria-Adelaide; Crookshanks, Jeanna M.; Parsley, Margaret; Uchida, Tatsuo; Prough, Donald S.; DeWitt, Douglas S.; Hellmich, Helen L.

    2012-01-01

    Circadian rhythm disturbances are frequently reported in patients recovering from traumatic brain injury (TBI). Since circadian clock output is mediated by some of the same molecular signaling cascades that regulate memory formation (cAMP/MAPK/CREB), cognitive problems reported by TBI survivors may be related to injury-induced dysregulation of the circadian clock. In laboratory animals, aberrant circadian rhythms in the hippocampus have been linked to cognitive and memory dysfunction. Here, we addressed the hypothesis that circadian rhythm disruption after TBI is mediated by changes in expression of clock genes in the suprachiasmatic nuclei (SCN) and hippocampus. After fluid-percussion TBI or sham surgery, male Sprague-Dawley rats were euthanized at 4 h intervals, over a 48 h period for tissue collection. Expression of circadian clock genes was measured using quantitative real-time PCR in the SCN and hippocampus obtained by laser capture and manual microdissection respectively. Immunofluorescence and Western blot analysis were used to correlate TBI-induced changes in circadian gene expression with changes in protein expression. In separate groups of rats, locomotor activity was monitored for 48 h. TBI altered circadian gene expression patterns in both the SCN and the hippocampus. Dysregulated expression of key circadian clock genes, such as Bmal1 and Cry1, was detected, suggesting perturbation of transcriptional-translational feedback loops that are central to circadian timing. In fact, disruption of circadian locomotor activity rhythms in injured animals occurred concurrently. These results provide an explanation for how TBI causes disruption of circadian rhythms as well as a rationale for the consideration of drugs with chronobiotic properties as part of a treatment strategy for TBI. PMID:23056261

  2. Feeding Tubes

    MedlinePlus

    ... administer the TPN. Tubes Used for Enteral Feeds NG (Nasogastric Tube) A flexible tube is placed via ... down through the esophagus into the stomach. The NG tube can be used to empty the stomach ...

  3. Circadian rhythms and addiction: Mechanistic insights and future directions

    PubMed Central

    Logan, Ryan W.; Williams, Wilbur P.; McClung, Colleen A.

    2014-01-01

    Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes, may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction, and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction. PMID:24731209

  4. Endotoxin Disrupts Circadian Rhythms in Macrophages via Reactive Oxygen Species

    PubMed Central

    Wang, Yusi; Pati, Paramita; Xu, Yiming; Chen, Feng; Stepp, David W.; Huo, Yuqing; Rudic, R. Daniel; Fulton, David J. R.

    2016-01-01

    The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1) was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS) whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration. These results

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

    PubMed

    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

  6. Circadian Control of Antibacterial Immunity: Findings from Animal Models

    PubMed Central

    Tsoumtsa, Landry L.; Torre, Cedric; Ghigo, Eric

    2016-01-01

    Most of the biological functions, including the immune system, are linked to circadian rhythms in living organisms. Changes occurring to biological parameters as the result of these circadian rhythms can therefore affect the outcome of a disease. For decades, model organisms have proven to be a great tool to understanding biological mechanisms such as circadian cycle and immunity. In this review, we created an inventory of the use of model organisms in order to decipher the relation between circadian rhythms and antibacterial immunity. PMID:27242972

  7. CGRP neurons mediate sleep-specific circadian output in Drosophila

    PubMed Central

    Kunst, Michael; Hughes, Michael E.; Raccuglia, Davide; Felix, Mario; Li, Michael; Barnett, Gregory; Duah, Janelle; Nitabach, Michael N.

    2014-01-01

    Summary Background Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep is regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study we describe a novel role for DIURETIC HORMONE 31 (DH31), the fly homologue of the vertebrate neuropeptide CALCITONIN GENE RELATED PEPTIDE (CGRP), as a circadian wake-promoting signal that awakens the fly in anticipation of dawn. Results Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide PIGMENT DISPERSING FACTOR (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDFR in DH31 positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep. Conclusions We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal/cellular channels. PMID:25455031

  8. NONO couples the circadian clock to the cell cycle

    PubMed Central

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

    2013-01-01

    Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization. PMID:23267082

  9. Sleep, Circadian Rhythms, and Anxious Traits.

    PubMed

    Coles, Meredith E; Schubert, Jessica R; Nota, Jacob A

    2015-09-01

    Anxiety is adaptive and plays an important role in keeping us safe. However, when anxiety becomes too extreme, it can cause significant disruptions and distress. Understanding the mechanisms underlying excessive anxiety and how to best treat it is a priority for researchers and clinicians. There is increasing recognition that disruptions in the amount and timing of sleep are associated with anxiety symptoms and characteristics. In the current paper, we explore the intersections between sleep, circadian rhythms, and anxiety. First, we review accumulating evidence that anxiety is associated with disruptions in sleep and circadian rhythms in both clinical and nonclinical samples and across ages. Next, we discuss the data linking sleep disruptions with anxiety-related traits (anxiety sensitivity, neuroticism, and perfectionism) and patterns of cognition and emotion. Finally, potential treatment implications are highlighted. Overall, these data suggest that delineating the role of disruptions in the amount and timing of sleep holds promise for improving the lives of individuals with heightened anxiety. PMID:26216591

  10. Circadian responses to endotoxin treatment in mice.

    PubMed

    Marpegán, Luciano; Bekinschtein, Tristán A; Costas, Monica A; Golombek, Diego A

    2005-03-01

    We tested the ability of Escherichia coli lipopolysaccharide (LPS) to phase-shift the activity circadian rhythm in C57Bl/6J mice. Intraperitoneal administration of 25 microg/kg LPS induced photic-like phase delays (-43+/-10 min) during the early subjective night. These delays were non-additive to those induced by light at CT 15, and were reduced by the previous administration of sulfasalazine, a NF-kappaB activation inhibitor. At CT 15, LPS induced c-Fos expression in the dorsal area of the suprachiasmatic nuclei (SCN). Our results suggest that the activation of the immune system should be considered an entraining signal for the murine circadian clock. PMID:15710463

  11. Avian circadian organization: a chorus of clocks.

    PubMed

    Cassone, Vincent M

    2014-01-01

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

  12. Uncoupling Promoter Opening from Start-Site Scanning.

    PubMed

    Murakami, Kenji; Mattei, Pierre-Jean; Davis, Ralph E; Jin, Huiyan; Kaplan, Craig D; Kornberg, Roger D

    2015-07-01

    Whereas RNA polymerase II (Pol II) transcription start sites (TSSs) occur about 30-35 bp downstream of the TATA box in metazoans, TSSs are located 40-120 bp downstream in S. cerevisiae. Promoter melting begins about 12 bp downstream in all eukaryotes, so Pol II is presumed to "scan" further downstream before starting transcription in yeast. Here we report that removal of the kinase complex TFIIK from TFIIH shifts the TSS in a yeast system upstream to the location observed in metazoans. Conversely, moving the normal TSS to an upstream location enables a high level of TFIIK-independent transcription in the yeast system. We distinguish two stages of the transcription initiation process: bubble formation by TFIIH, which fills the Pol II active center with single-stranded DNA, and subsequent scanning downstream, also driven by TFIIH, which requires displacement of the initial bubble. Omission of TFIIK uncouples the two stages of the process. PMID:26073544

  13. Uncoupling binding of substrate CO from turnover by vanadium nitrogenase

    PubMed Central

    Lee, Chi Chung; Fay, Aaron W.; Weng, Tsu-Chien; Krest, Courtney M.; Hedman, Britt; Hodgson, Keith O.; Hu, Yilin; Ribbe, Markus W.

    2015-01-01

    Biocatalysis by nitrogenase, particularly the reduction of N2 and CO by this enzyme, has tremendous significance in environment- and energy-related areas. Elucidation of the detailed mechanism of nitrogenase has been hampered by the inability to trap substrates or intermediates in a well-defined state. Here, we report the capture of substrate CO on the resting-state vanadium-nitrogenase in a catalytically competent conformation. The close resemblance of this active CO-bound conformation to the recently described structure of CO-inhibited molybdenum-nitrogenase points to the mechanistic relevance of sulfur displacement to the activation of iron sites in the cofactor for CO binding. Moreover, the ability of vanadium-nitrogenase to bind substrate in the resting-state uncouples substrate binding from subsequent turnover, providing a platform for generation of defined intermediate(s) of both CO and N2 reduction. PMID:26515097

  14. Uncoupling primer and releaser responses to pheromone in honey bees

    NASA Astrophysics Data System (ADS)

    Grozinger, Christina M.; Fischer, Patrick; Hampton, Jacob E.

    2007-05-01

    Pheromones produce dramatic behavioral and physiological responses in a wide variety of species. Releaser pheromones elicit rapid responses within seconds or minutes, while primer pheromones produce long-term changes which may take days to manifest. Honeybee queen mandibular pheromone (QMP) elicits multiple distinct behavioral and physiological responses in worker bees, as both a releaser and primer, and thus produces responses on vastly different time scales. In this study, we demonstrate that releaser and primer responses to QMP can be uncoupled. First, treatment with the juvenile hormone analog methoprene leaves a releaser response (attraction to QMP) intact, but modulates QMP’s primer effects on sucrose responsiveness. Secondly, two components of QMP (9-ODA and 9-HDA) do not elicit a releaser response (attraction) but are as effective as QMP at modulating a primer response, downregulation of foraging-related brain gene expression. These results suggest that different responses to a single pheromone may be produced via distinct pathways.

  15. Uncouplers of Oxidative Phosphorylation Can Enhance a Fas Death Signal

    PubMed Central

    Linsinger, Georg; Wilhelm, Sabine; Wagner, Hermann; Häcker, Georg

    1999-01-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential ΔΨm. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP) reduce ΔΨm by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  16. Uncouplers of oxidative phosphorylation can enhance a Fas death signal.

    PubMed

    Linsinger, G; Wilhelm, S; Wagner, H; Häcker, G

    1999-05-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential DeltaPsim. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2, 4-dinitrophenol (DNP) reduce DeltaPsim by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  17. Uncoupling of Secretion From Growth in Some Hormone Secretory Tissues

    PubMed Central

    2014-01-01

    Context: Most syndromes with benign primary excess of a hormone show positive coupling of hormone secretion to size or proliferation in the affected hormone secretory tissue. Syndromes that lack this coupling seem rare and have not been examined for unifying features among each other. Evidence Acquisition: Selected clinical and basic features were analyzed from original reports and reviews. We examined indices of excess secretion of a hormone and indices of size of secretory tissue within the following three syndromes, each suggestive of uncoupling between these two indices: familial hypocalciuric hypercalcemia, congenital diazoxide-resistant hyperinsulinism, and congenital primary hyperaldosteronism type III (with G151E mutation of the KCNJ5 gene). Evidence Synthesis: Some unifying features among the three syndromes were different from features present among common tumors secreting the same hormone. The unifying and distinguishing features included: 1) expression of hormone excess as early as the first days of life; 2) normal size of tissue that oversecretes a hormone; 3) diffuse histologic expression in the hormonal tissue; 4) resistance to treatment by subtotal ablation of the hormone-secreting tissue; 5) causation by a germline mutation; 6) low potential of the same mutation to cause a tumor by somatic mutation; and 7) expression of the mutated molecule in a pathway between sensing of a serum metabolite and secretion of hormone regulating that metabolite. Conclusion: Some shared clinical and basic features of uncoupling of secretion from size in a hormonal tissue characterize three uncommon states of hormone excess. These features differ importantly from features of common hormonal neoplasm of that tissue. PMID:25004249

  18. Glaucoma Alters the Circadian Timing System

    PubMed Central

    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

  19. Shift work and circadian dysregulation of reproduction.

    PubMed

    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

  20. Photoreception for circadian, neuroendocrine, and neurobehavioral regulation.

    PubMed

    Hanifin, John P; Brainard, George C

    2007-03-01

    In the art and science of lighting, four traditional objectives have been to provide light that: 1) is optimum for visual performance; 2) is visually comfortable; 3) permits aesthetic appreciation of the space; and 4) conserves energy. Over the past 25 years, it has been demonstrated that there are nonvisual, systemic effects of light in healthy humans. Furthermore, light has been used to successfully treat patients with selected affective and sleep disorders as well as healthy individuals who have circadian disruption due to shift work, transcontinental jet travel, or space flight. Recently, there has been an upheaval in the understanding of photoreceptive input to the circadian system of humans and other mammals. Analytical action spectra in rodents, primates, and humans have identified 446-484 nm (predominantly the blue part of the spectrum) as the most potent wavelength region for neuroendocrine, circadian, and neurobehavioral responses. Those studies suggested that a novel photosensory system, distinct from the visual rods and cones, is primarily responsible for this regulation. Studies have now shown that this new photosensory system is based on a small population of widely dispersed retinal ganglion cells that are intrinsically responsive to light, and project to the suprachiasmatic nuclei and other nonvisual centers in the brain. These light-sensitive retinal ganglion cells contain melanopsin, a vitamin A photopigment that mediates the cellular phototransduction cascade. Although light detection for circadian and neuroendocrine phototransduction seems to be mediated principally by a novel photosensory system in the eye, the classic rod and cone photoreceptors appear to play a role as well. These findings are important in understanding how humans adapt to lighting conditions in modern society and will provide the basis for major changes in future architectural lighting strategies. PMID:17435349

  1. The Circadian Clock, Reward, and Memory

    PubMed Central

    Albrecht, Urs

    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. PMID:22084628

  2. Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria.

    PubMed

    Chang, Yong-Gang; Cohen, Susan E; Phong, Connie; Myers, William K; Kim, Yong-Ick; Tseng, Roger; Lin, Jenny; Zhang, Li; Boyd, Joseph S; Lee, Yvonne; Kang, Shannon; Lee, David; Li, Sheng; Britt, R David; Rust, Michael J; Golden, Susan S; LiWang, Andy

    2015-07-17

    Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ~24-hour rhythms. The clock of cyanobacteria is driven by a three-protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator. PMID:26113641

  3. Epidemiology of the human circadian clock.

    PubMed

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

    2007-12-01

    Humans show large inter-individual differences in organising their behaviour within the 24-h day-this is most obvious in their preferred timing of sleep and wakefulness. Sleep and wake times show a near-Gaussian distribution in a given population, with extreme early types waking up when extreme late types fall asleep. This distribution is predominantly based on differences in an individuals' circadian clock. The relationship between the circadian system and different "chronotypes" is formally and genetically well established in experimental studies in organisms ranging from unicells to mammals. To investigate the epidemiology of the human circadian clock, we developed a simple questionnaire (Munich ChronoType Questionnaire, MCTQ) to assess chronotype. So far, more than 55,000 people have completed the MCTQ, which has been validated with respect to the Horne-Østberg morningness-eveningness questionnaire (MEQ), objective measures of activity and rest (sleep-logs and actimetry), and physiological parameters. As a result of this large survey, we established an algorithm which optimises chronotype assessment by incorporating the information on timing of sleep and wakefulness for both work and free days. The timing and duration of sleep are generally independent. However, when the two are analysed separately for work and free days, sleep duration strongly depends on chronotype. In addition, chronotype is both age- and sex-dependent. PMID:17936039

  4. Adaptive temperature compensation in circadian oscillations.

    PubMed

    François, Paul; Despierre, Nicolas; Siggia, Eric D

    2012-01-01

    A temperature independent period and temperature entrainment are two defining features of circadian oscillators. A default model of distributed temperature compensation satisfies these basic facts yet is not easily reconciled with other properties of circadian clocks, such as many mutants with altered but temperature compensated periods. The default model also suggests that the shape of the circadian limit cycle and the associated phase response curves (PRC) will vary since the average concentrations of clock proteins change with temperature. We propose an alternative class of models where the twin properties of a fixed period and entrainment are structural and arise from an underlying adaptive system that buffers temperature changes. These models are distinguished by a PRC whose shape is temperature independent and orbits whose extrema are temperature independent. They are readily evolved by local, hill climbing, optimization of gene networks for a common quality measure of biological clocks, phase anticipation. Interestingly a standard realization of the Goodwin model for temperature compensation displays properties of adaptive rather than distributed temperature compensation. PMID:22807663

  5. Links between Circadian Rhythms and Psychiatric Disease

    PubMed Central

    Karatsoreos, Ilia N.

    2014-01-01

    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. PMID:24834040

  6. Adaptive Temperature Compensation in Circadian Oscillations

    PubMed Central

    François, Paul; Despierre, Nicolas; Siggia, Eric D.

    2012-01-01

    A temperature independent period and temperature entrainment are two defining features of circadian oscillators. A default model of distributed temperature compensation satisfies these basic facts yet is not easily reconciled with other properties of circadian clocks, such as many mutants with altered but temperature compensated periods. The default model also suggests that the shape of the circadian limit cycle and the associated phase response curves (PRC) will vary since the average concentrations of clock proteins change with temperature. We propose an alternative class of models where the twin properties of a fixed period and entrainment are structural and arise from an underlying adaptive system that buffers temperature changes. These models are distinguished by a PRC whose shape is temperature independent and orbits whose extrema are temperature independent. They are readily evolved by local, hill climbing, optimization of gene networks for a common quality measure of biological clocks, phase anticipation. Interestingly a standard realization of the Goodwin model for temperature compensation displays properties of adaptive rather than distributed temperature compensation. PMID:22807663

  7. Circadian Behaviour in Neuroglobin Deficient Mice

    PubMed Central

    Hundahl, Christian A.; Fahrenkrug, Jan; Hay-Schmidt, Anders; Georg, Birgitte; Faltoft, Birgitte; Hannibal, Jens

    2012-01-01

    Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID:22496809

  8. Environmental synchronizers of squirrel monkey circadian rhythms

    NASA Technical Reports Server (NTRS)

    Sulzman, F. M.; Fuller, C. A.; Moore-Ede, M. C.

    1977-01-01

    Various temporal signals in the environment were tested to determine if they could synchronize the circadian timing system of the squirrel monkey (Saimiri sciureus). The influence of cycles of light and dark, eating and fasting, water availability and deprivation, warm and cool temperature, sound and quiet, and social interaction and isolation on the drinking and activity rhythms of unrestrained monkeys was examined. In the absence of other time cues, 24-hr cycles of each of these potential synchronizers were applied for up to 3 wk, and the periods of the monkey's circadian rhythms were examined. Only light-dark cycles and cycles of food availability were shown to be entraining agents, since they were effective in determining the period and phase of the rhythmic variables. In the presence of each of the other environmental cycles, the monkey's circadian rhythms exhibited free-running periods which were significantly different from 24 hr with all possible phase relationships between the rhythms and the environmental cycles being examined.

  9. Coupling governs entrainment range of circadian clocks

    PubMed Central

    Abraham, Ute; Granada, Adrián E; Westermark, Pål O; Heine, Markus; Kramer, Achim; Herzel, Hanspeter

    2010-01-01

    Circadian clocks are endogenous oscillators driving daily rhythms in physiology and behavior. Synchronization of these timers to environmental light–dark cycles (‘entrainment') is crucial for an organism's fitness. Little is known about which oscillator qualities determine entrainment, i.e., entrainment range, phase and amplitude. In a systematic theoretical and experimental study, we uncovered these qualities for circadian oscillators in the suprachiasmatic nucleus (SCN—the master clock in mammals) and the lung (a peripheral clock): (i) the ratio between stimulus (zeitgeber) strength and oscillator amplitude and (ii) the rigidity of the oscillatory system (relaxation rate upon perturbation) determine entrainment properties. Coupling among oscillators affects both qualities resulting in increased amplitude and rigidity. These principles explain our experimental findings that lung clocks entrain to extreme zeitgeber cycles, whereas SCN clocks do not. We confirmed our theoretical predictions by showing that pharmacological inhibition of coupling in the SCN leads to larger ranges of entrainment. These differences between master and the peripheral clocks suggest that coupling-induced rigidity in the SCN filters environmental noise to create a robust circadian system. PMID:21119632

  10. Tuning the phase of circadian entrainment

    PubMed Central

    Bordyugov, Grigory; Abraham, Ute; Granada, Adrian; Rose, Pia; Imkeller, Katharina; Kramer, Achim; Herzel, Hanspeter

    2015-01-01

    The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues (‘zeitgebers’), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference ψ between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment ψ depends on the mismatch between the intrinsic period τ and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches τ − T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies. PMID:26136227

  11. Tuning the phase of circadian entrainment.

    PubMed

    Bordyugov, Grigory; Abraham, Ute; Granada, Adrian; Rose, Pia; Imkeller, Katharina; Kramer, Achim; Herzel, Hanspeter

    2015-07-01

    The circadian clock coordinates daily physiological, metabolic and behavioural rhythms. These endogenous oscillations are synchronized with external cues ('zeitgebers'), such as daily light and temperature cycles. When the circadian clock is entrained by a zeitgeber, the phase difference ψ between the phase of a clock-controlled rhythm and the phase of the zeitgeber is of fundamental importance for the fitness of the organism. The phase of entrainment ψ depends on the mismatch between the intrinsic period τ and the zeitgeber period T and on the ratio of the zeitgeber strength to oscillator amplitude. Motivated by the intriguing complexity of empirical data and by our own experiments on temperature entrainment of mouse suprachiasmatic nucleus (SCN) slices, we present a theory on how clock and zeitgeber properties determine the phase of entrainment. The wide applicability of the theory is demonstrated using mathematical models of different complexity as well as by experimental data. Predictions of the theory are confirmed by published data on Neurospora crassa strains for different period mismatches τ - T and varying photoperiods. We apply a novel regression technique to analyse entrainment of SCN slices by temperature cycles. We find that mathematical models can explain not only the stable asymptotic phase of entrainment, but also transient phase dynamics. Our theory provides the potential to explore seasonal variations of circadian rhythms, jet lag and shift work in forthcoming studies. PMID:26136227

  12. Cardiovascular tissues contain independent circadian clocks

    NASA Technical Reports Server (NTRS)

    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.

  13. Circadian clock system in the pineal gland.

    PubMed

    Fukada, Yoshitaka; Okano, Toshiyuki

    2002-02-01

    The pineal gland is a neuroendocrine organ that functions as a central circadian oscillator in a variety of nonmammalian vertebrates. In many cases, the pineal gland retains photic input and endocrinal-output pathways both linked tightly to the oscillator. This contrasts well with the mammalian pineal gland equipped only with the output of melatonin production that is subject to neuronal regulation by central circadian oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Molecular studies on animal clock genes were performed first in Drosophila and later developed in rodents. More recently, clock genes such as Per, Cry, Clock, and Bmal have been found in a variety of vertebrate clock structures including the avian pineal gland. The profiles of the temporal change of the clock gene expression in the avian pineal gland are more similar to those in the mammalian SCN rather than to those in the mammalian pineal gland. Avian pineal gland and mammalian SCN seem to share a fundamental molecular framework of the clock oscillator composed of a transcription/translation-based autoregulatory feedback loop. The circadian time-keeping mechanism also requires several post-translational events, such as protein translocation and degradation processes, in which protein phosphorylation plays a very important role for the stable 24-h cycling of the oscillator and/or the photic-input pathway for entrainment of the clock. PMID:11890455

  14. Aligning work and circadian time in shift workers improves sleep and reduces circadian disruption.

    PubMed

    Vetter, Céline; Fischer, Dorothee; Matera, Joana L; Roenneberg, Till

    2015-03-30

    Sleep loss and circadian disruption-a state of misalignment between physiological functions and imposed sleep/wake behavior-supposedly play central roles in the etiology of shift work-related pathologies [1-4]. Circadian entrainment is, however, highly individual [5], resulting in different chronotypes [6, 7]. Chronotype in turn modulates the effects of working times: compared to late chronotypes, earlier ones sleep worse and shorter and show higher levels of circadian misalignment during night shifts, while late types experience more sleep and circadian disruption than early types when working morning shifts [8]. To promote sleep and reduce the mismatch between circadian and working time, we implemented a chronotype-adjusted (CTA) shift schedule in a factory. We abolished the most strenuous shifts for extreme chronotypes (i.e., mornings for late chronotypes, nights for early ones) and examined whether sleep duration and quality, social jetlag [9, 10], wellbeing, subjective stress perception, and satisfaction with leisure time improved in this schedule. Intermediate chronotypes (quartiles 2 and 3) served as a control group, still working morning (6:00-14:00), evening (14:00-22:00), and night (22:00-6:00) shifts, with two strenuous shifts (out of twelve per month) replaced by evening ones. We observed a significant increase of self-reported sleep duration and quality, along with increased wellbeing ratings on workdays among extreme chronotypes. The CTA schedule reduced overall social jetlag by 1 hr, did not alter stress levels, and increased satisfaction with leisure time (early types only). Chronotype-based schedules thus can reduce circadian disruption and improve sleep; potential long-term effects on health and economic indicators need to be elucidated in future studies. PMID:25772446

  15. Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans

    PubMed Central

    Eastman, Charmane I.; Suh, Christina; Tomaka, Victoria A.; Crowley, Stephanie J.

    2015-01-01

    Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period, and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals. PMID:25670162

  16. Circadian food anticipatory activity: Entrainment limits and scalar properties re-examined.

    PubMed

    Petersen, Christian C; Patton, Danica F; Parfyonov, Maksim; Mistlberger, Ralph E

    2014-12-01

    Rats can anticipate a daily feeding time. This has been interpreted as a rhythm controlled by food-entrainable circadian oscillators, because the rhythm persists during several cycles of total food deprivation and fails to track mealtimes if the feeding schedule deviates substantially from 24. These and other properties distinguish anticipation of daily meals from anticipation of food rewards provided at intervals in the seconds-to-minutes range, suggesting distinct mechanisms. It has been reported that rats can anticipate meals at long, but noncircadian, intervals if they are required to work for food, and that anticipation of daily meals, expressed in operant behavior, shows the scalar property, a hallmark of timing intervals in the seconds-to-minutes range. These observations raise the possibility of a universal timing system, rather than unique mechanisms for circadian and noncircadian intervals. To test whether circadian constraints on daily meal timing depend on the measure of behavior, we re-examined formal properties of food anticipation using lever pressing and motion sensors. We observed robust anticipation in both measures to meals at 24-hr intervals but no anticipation of meals at 18-hr intervals in light-dark or constant light and no evidence that the duration of anticipation scales with the interval between lighting transitions and mealtime. We are therefore unable to confirm reports that operant measures can reveal timing at long, but noncircadian, intervals. If timing processes exist that do permit anticipation of events at long, but noncircadian, intervals, the conditions under which these can be revealed are evidently highly constrained. PMID:25285457

  17. Circadian control of glucose metabolism

    PubMed Central

    Kalsbeek, Andries; la Fleur, Susanne; Fliers, Eric

    2014-01-01

    The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis. PMID:24944897

  18. Circadian rhythms in diving behavior and ventilatory response to asphyxia in canvasback ducks.

    PubMed

    Woodin, M; Stephenson, R

    1998-03-01

    Underwater feeding behavior was measured in 10 captive canvasback ducks (Aythya valisineria) for 12 days under a 12:12-h light-dark photoperiod. Feeding activity exhibited a daily rhythm, with 76% of dives occurring at night. In separate experiments on six of these ducks, a circadian rhythm was observed in the duration of voluntary dives. Dives at night (14.7 +/- 0.7 s) were significantly longer than those during the day (10.7 +/- 0.7 s). These day-night differences in diving behavior were accompanied by day-night differences in respiratory responses to progressive asphyxia. In the same six ducks, ventilation increased exponentially as a function of inspired CO2 concentration during rebreathing in a closed-circuit barometric plethysmograph. The exponential rate constant for inspired ventilation was significantly smaller at night (0.23 +/- 0.02) than during the day (0.26 +/- 0.01). We suggest that intermittent apneic exercise is facilitated by reduced respiratory chemosensitivity and that the respiratory and behavioral control systems are synchronized by the circadian timing system in diving ducks. PMID:9530234

  19. Circadian entrainment by light and host in the Chagas disease vector, Triatoma infestans.

    PubMed

    Valentinuzzi, Verónica Sandra; Amelotti, Ivana; Gorla, David Eladio; Catalá, Silvia Susana; Ralph, Martin Roland

    2014-03-01

    Triatoma infestans (Reduviidae: Triatominae, "kissing bug") is the main insect vector of Trypanosoma cruzi, the causative agent of Chagas disease, a chronic trypanosomiasis infecting 10 million people world-wide. This hematophagous bug feeds on diurnal and nocturnal species during each host's quiescent time. As the hosts are also its major predators, kissing bugs are subjected to dual selective pressures from a single source. Therefore, synchronization of feeding with the host's behavior is critical to the insects' survival. We show that nonphotic signals linked to the host eclipse the role of light and dark as the primary circadian zeitgeber for these bugs, although light still strongly inhibits locomotor behavior directly. In nature, this combination provides the insect with great flexibility in organizing physiology and behavior: anticipating a quiescent host or avoiding its potential predation while remaining directly responsive to immediate environmental conditions. Manipulation of nonphotic entrainment could be a useful chronobiotic tool in the control of Chagas disease. PMID:24156522

  20. Time-restricted feeding of a high-fat diet reduces diet-induced obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reducing obesity may alleviate many medical complications including diabetes, cardiovascular disease and cancer. It has been suggested that obesity is contributed by the disruption of the circadian rhythms in addition to increased caloric intake. Restricting feeding to particular times of the day ma...

  1. Time-restricted feeding reduces adiposity in mice fed a high-fat diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Disruption of the circadian rhythm contributes to obesity. The present study investigated the effects of time-restricted feeding (TRF) of a high-fat diet on adiposity in male C57BL/6 mice. Three-week-old mice were fed a low-fat or high-fat diet (16% or 45% of energy from corn oil) ad libitum (ad l...

  2. Caged mitochondrial uncouplers that are released in response to hydrogen peroxide.

    PubMed

    Quin, Caroline; Robertson, Linsey; McQuaker, Stephen J; Price, Nicholas C; Brand, Martin D; Hartley, Richard C

    2010-03-27

    Caged versions of the most common mitochondrial uncouplers (proton translocators) have been prepared that sense the reactive oxygen species (ROS) hydrogen peroxide to release the uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) from caged states with second order rate constants of 10 (+/-0.8) M(-1) s(-1) and 64.8 (+/-0.6) M(-1) s(-1), respectively. The trigger mechanism involves conversion of an arylboronate into a phenol followed by fragmentation. Hydrogen peroxide-activated uncouplers may be useful for studying the biological process of ageing. PMID:20418941

  3. Caged mitochondrial uncouplers that are released in response to hydrogen peroxide

    PubMed Central

    Quin, Caroline; Robertson, Linsey; McQuaker, Stephen J.; Price, Nicholas C.; Brand, Martin D.; Hartley, Richard C.

    2010-01-01

    Caged versions of the most common mitochondrial uncouplers (proton translocators) have been prepared that sense the reactive oxygen species (ROS) hydrogen peroxide to release the uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) from caged states with second order rate constants of 10 (±0.8) M−1 s−1 and 64.8 (±0.6) M−1 s−1, respectively. The trigger mechanism involves conversion of an arylboronate into a phenol followed by fragmentation. Hydrogen peroxide-activated uncouplers may be useful for studying the biological process of ageing. PMID:20418941

  4. Health Impact of Fasting in Saudi Arabia during Ramadan: Association with Disturbed Circadian Rhythm and Metabolic and Sleeping Patterns

    PubMed Central

    Ajabnoor, Ghada M.; Bahijri, Suhad; Borai, Anwar; Abdulkhaliq, Altaf A.; Al-Aama, Jumana Y.; Chrousos, George P.

    2014-01-01

    Background Muslims go through strict Ramadan fasting from dawn till sunset for one month yearly. These practices are associated with disturbed feeding and sleep patterns. We recently demonstrated that, during Ramadan, circadian cortisol rhythm of Saudis is abolished, exposing these subjects to continuously increased cortisol levels. Hypothesis Secretory patterns of other hormones and metabolic parameters associated with cortisol, and insulin resistance, might be affected during Ramadan. Protocol Ramadan practitioners (18 males, 5 females; mean age ±SEM = 23.16±1.2 years) were evaluated before and two weeks into Ramadan. Blood was collected for measurements of endocrine and metabolic parameters at 9 am (±1 hour) and again twelve hours later. Results In Ramadan, glucose concentration was kept within normal range, with a significant increase in the morning. Mean morning concentration of leptin was significantly higher than pre-Ramadan values (p = 0.001), in contrast to that of adiponectin, which was significantly lower (p<0.001). These changes were associated with increased insulin resistance in morning and evening. Concentrations of hsCRP were lower during Ramadan than those during regular living conditions, however, normal circadian fluctuation was abolished (p = 0.49). Even though means of liver enzymes, total bilirubin, total protein and albumin were all decreased during Ramadan, statistically lower means were only noted for GGT, total protein, and albumin (p = 0.018, 0.002 and 0.001 respectively). Discussion Saudi Ramadan practitioners have altered adipokine patterns, typical of insulin resistance. The noted decreases of hsCRP, liver enzymes, total protein, and albumin, are most likely a result of fasting, while loss of circadian rhythmicity of hsCRP is probably due to loss of circadian cortisol rhythm. Conclusions Modern Ramadan practices in Saudi Arabia, which are associated with evening hypercortisolism, are also characterized by altered

  5. Feeding guilt.

    PubMed

    Byrom, Anna

    2013-03-01

    Breastfeeding is increasingly equated to ideologies of the 'good mother' in our society in response to a growing body of evidence identifying its benefits. Women who choose not to or are unable to breastfeed can experience a sense of guilt in response to cultural expectations that 'breast is best'. These negative feelings can impact upon their adaptation to and enjoyment of motherhood. This discussion paper examines the experience of maternal guilt with specific reference to infant feeding. An exploration of the reasons mothers may feel guilty about their feeding experiences is offered. Finally some suggestions are made about how midwives and breastfeeding advocates might improve care for mothers' emotional wellbeing. PMID:23590082

  6. Physiological effects of light on the human circadian pacemaker

    NASA Technical Reports Server (NTRS)

    Shanahan, T. L.; Czeisler, C. A.

    2000-01-01

    The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.

  7. Mammalian retinal Müller cells have circadian clock function

    PubMed Central

    Xu, Lili; Ruan, Guoxiang; Dai, Heng; Liu, Andrew C.; Penn, John

    2016-01-01

    Purpose To test whether Müller glia of the mammalian retina have circadian rhythms. Methods We used Müller glia cultures isolated from mouse lines or from humans and bioluminescent reporters of circadian clock genes to monitor molecular circadian rhythms. The clock gene dependence of the Müller cell rhythms was tested using clock gene knockout mouse lines or with siRNA for specific clock genes. Results We demonstrated that retinal Müller glia express canonical circadian clock genes, are capable of sustained circadian oscillations in isolation from other cell types, and exhibit unique features of their molecular circadian clock compared to the retina as a whole. Mouse and human Müller cells demonstrated circadian clock function; however, they exhibited species-specific differences in the gene dependence of their clocks. Conclusions Müller cells are the first mammalian retinal cell type in which sustained circadian rhythms have been demonstrated in isolation from other retinal cells. PMID:27081298

  8. Circadian rhythms in liver physiology and liver diseases.

    PubMed

    Tong, Xin; Yin, Lei

    2013-04-01

    In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. As the driving force for circadian rhythmicity, the molecular clock is a self-sustained transcription-translational feedback loop system consisting of transcription factors, epigenetic modulators, kinases/phosphatases, and ubiquitin E3 ligases. The molecular clock exists not only in the suprachiasmatic nuclei of the hypothalamus but also in the peripheral tissues to regulate cellular and physiological function in a tissue-specific manner. The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Clock gene mutant animals display impaired glucose and lipid metabolism and are susceptible to diet-induced obesity and metabolic dysfunction, providing strong evidence for the connection between the circadian clock and metabolic homeostasis. Circadian-controlled hepatic metabolism is partially achieved by controlling the expression and/or activity of key metabolic enzymes, transcription factors, signaling molecules, and transporters. Reciprocally, intracellular metabolites modulate the molecular clock activity in response to the energy status. Although still at the early stage, circadian clock dysfunction has been implicated in common chronic liver diseases. Circadian dysregulation of lipid metabolism, detoxification, reactive oxygen species (ROS) production, and cell-cycle control might contribute to the onset and progression of liver steatosis, fibrosis, and even carcinogenesis. In summary, these findings call for a comprehensive study of the function and mechanisms of hepatic circadian clock to gain better understanding of liver physiology and diseases. PMID:23720334

  9. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons

    PubMed Central

    Webb, Alexis B.; Angelo, Nikhil; Huettner, James E.; Herzog, Erik D.

    2009-01-01

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm2 eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  10. Circadian Activity Rhythms, Time Urgency, and Achievement Concerns.

    ERIC Educational Resources Information Center

    Watts, Barbara L.

    Many physiological and psychological processes fluctuate throughout the day in fairly stable, rhythmic patterns. The relationship between individual differences in circadian activity rhythms and a sense of time urgency were explored as well as a number of achievement-related variables. Undergraduates (N=308), whose circadian activity rhythms were…

  11. Bidirectional Interactions between Circadian Entrainment and Cognitive Performance

    ERIC Educational Resources Information Center

    Gritton, Howard J.; Kantorowski, Ana; Sarter, Martin; Lee, Theresa M.

    2012-01-01

    Circadian rhythms influence a variety of physiological and behavioral processes; however, little is known about how circadian rhythms interact with the organisms' ability to acquire and retain information about their environment. These experiments tested whether rats trained outside their endogenous active period demonstrate the same rate of…

  12. Circadian clock genes universally control key agricultural traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  14. Circadian clocks and memory: time-place learning

    PubMed Central

    Mulder, C. K.; Gerkema, M. P.; Van der Zee, E. A.

    2013-01-01

    Time-Place learning (TPL) refers to the ability of animals to remember important events that vary in both time and place. This ability is thought to be functional to optimize resource localization and predator avoidance in a circadian changing environment. Various studies have indicated that animals use their circadian system for TPL. However, not much is known about this specific role of the circadian system in cognition. This review aims to put TPL in a broader context and to provide an overview of historical background, functional aspects, and future perspectives of TPL. Recent advances have increased our knowledge on establishing TPL in a laboratory setting, leading to the development of a behavioral paradigm demonstrating the circadian nature of TPL in mice. This has enabled the investigation of circadian clock components on a functional behavioral level. Circadian TPL (cTPL) was found to be Cry clock gene dependent, confirming the essential role of Cry genes in circadian rhythms. In contrast, preliminary results have shown that cTPL is independent of Per genes. Circadian system decline with aging predicts that cTPL is age sensitive, potentially qualifying TPL as a functional model for episodic memory and aging. The underlying neurobiological mechanism of TPL awaits further examination. Here we discuss some putative mechanisms. PMID:23596390

  15. Yes, circadian rhythms actually do affect almost everything.

    PubMed

    Dunlap, Jay C; Loros, Jennifer J

    2016-07-01

    Circadian rhythms in the level of intracellular Mg appear to be widely conserved phylogenetically, and have the potential to impact nearly all aspects of metabolism. Moreover, the clock regulates the ion channels that generate the rhythm, demonstrating that the whole cell operates as a circadian system. PMID:27241553

  16. Circadian rhythms and fractal fluctuations in forearm motion

    NASA Astrophysics Data System (ADS)

    Hu, Kun; Hilton, Michael F.

    2005-03-01

    Recent studies have shown that the circadian pacemaker --- an internal body clock located in the brain which is normally synchronized with the sleep/wake behavioral cycles --- influences key physiologic functions such as the body temperature, hormone secretion and heart rate. Surprisingly, no previous studies have investigated whether the circadian pacemaker impacts human motor activity --- a fundamental physiologic function. We investigate high-frequency actigraph recordings of forearm motion from a group of young and healthy subjects during a forced desynchrony protocol which allows to decouple the sleep/wake cycles from the endogenous circadian cycle while controlling scheduled behaviors. We investigate both static properties (mean value, standard deviation), dynamical characteristics (long-range correlations), and nonlinear features (magnitude and Fourier-phase correlations) in the fluctuations of forearm acceleration across different circadian phases. We demonstrate that while the static properties exhibit significant circadian rhythms with a broad peak in the afternoon, the dynamical and nonlinear characteristics remain invariant with circadian phase. This finding suggests an intrinsic multi-scale dynamic regulation of forearm motion the mechanism of which is not influenced by the circadian pacemaker, thus suggesting that increased cardiac risk in the early morning hours is not related to circadian-mediated influences on motor activity.

  17. Integration of human sleep-wake regulation and circadian rhythmicity

    NASA Technical Reports Server (NTRS)

    Dijk, Derk-Jan; Lockley, Steven W.

    2002-01-01

    The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.

  18. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons.

    PubMed

    Webb, Alexis B; Angelo, Nikhil; Huettner, James E; Herzog, Erik D

    2009-09-22

    Circadian rhythms are modeled as reliable and self-sustained oscillations generated by single cells. The mammalian suprachiasmatic nucleus (SCN) keeps near 24-h time in vivo and in vitro, but the identity of the individual cellular pacemakers is unknown. We tested the hypothesis that circadian cycling is intrinsic to a unique class of SCN neurons by measuring firing rate or Period2 gene expression in single neurons. We found that fully isolated SCN neurons can sustain circadian cycling for at least 1 week. Plating SCN neurons at <100 cells/mm(2) eliminated synaptic inputs and revealed circadian neurons that contained arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) or neither. Surprisingly, arrhythmic neurons (nearly 80% of recorded neurons) also expressed these neuropeptides. Furthermore, neurons were observed to lose or gain circadian rhythmicity in these dispersed cell cultures, both spontaneously and in response to forskolin stimulation. In SCN explants treated with tetrodotoxin to block spike-dependent signaling, neurons gained or lost circadian cycling over many days. The rate of PERIOD2 protein accumulation on the previous cycle reliably predicted the spontaneous onset of arrhythmicity. We conclude that individual SCN neurons can generate circadian oscillations; however, there is no evidence for a specialized or anatomically localized class of cell-autonomous pacemakers. Instead, these results indicate that AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling. PMID:19805326

  19. Regulation of circadian rhythms in mammals by behavioral arousal.

    PubMed

    Webb, Ian C; Antle, Michael C; Mistlberger, Ralph E

    2014-06-01

    Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light-entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans. PMID:24773430

  20. Circadian Modulation of Short-Term Memory in "Drosophila"

    ERIC Educational Resources Information Center

    Lyons, Lisa C.; Roman, Gregg

    2009-01-01

    Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term…

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

    PubMed Central

    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

  2. Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

    PubMed Central

    Arble, Deanna M.; Bass, Joseph; Behn, Cecilia Diniz; Butler, Matthew P.; Challet, Etienne; Czeisler, Charles; Depner, Christopher M.; Elmquist, Joel; Franken, Paul; Grandner, Michael A.; Hanlon, Erin C.; Keene, Alex C.; Joyner, Michael J.; Karatsoreos, Ilia; Kern, Philip A.; Klein, Samuel; Morris, Christopher J.; Pack, Allan I.; Panda, Satchidananda; Ptacek, Louis J.; Punjabi, Naresh M.; Sassone-Corsi, Paolo; Scheer, Frank A.; Saxena, Richa; Seaquest, Elizabeth R.; Thimgan, Matthew S.; Van Cauter, Eve; Wright, Kenneth P.

    2015-01-01

    A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice. Citation: Arble DM, Bass J, Behn CD, Butler MP, Challet E, Czeisler C, Depner CM, Elmquist J, Franken P, Grandner MA, Hanlon EC, Keene AC, Joyner MJ, Karatsoreos I, Kern PA, Klein S, Morris CJ, Pack AI, Panda S, Ptacek LJ, Punjabi NM, Sassone-Corsi P, Scheer FA, Saxena R, Seaquest ER, Thimgan MS, Van Cauter E, Wright KP. Impact of sleep and

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

    PubMed Central

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

    2015-01-01

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

  4. A circadian clock nanomachine that runs without transcription or translation

    PubMed Central

    Egli, Martin; Johnson, Carl Hirschie

    2013-01-01

    The biochemical basis of circadian timekeeping is best characterized in cyanobacteria. The structures of its key molecular players, KaiA, KaiB, and KaiC are known and these proteins can reconstitute a remarkable circadian oscillation in a test tube. KaiC is rhythmically phosphorylated and its phospho-status is a marker of circadian phase that regulates ATPase activity and the oscillating assembly of a nanomachine. Analyses of the nanomachines have revealed how their timing circuit is ratcheted to be unidirectional and how they stay in synch to ensure a robust oscillator. These insights are likely to elucidate circadian timekeeping in higher organisms, including how transcription and translation could appear to be a core circadian timer when the true pacemaker is an embedded biochemical oscillator. PMID:23571120

  5. A circadian clock nanomachine that runs without transcription or translation.

    PubMed

    Egli, Martin; Johnson, Carl Hirschie

    2013-10-01

    The biochemical basis of circadian timekeeping is best characterized in cyanobacteria. The structures of its key molecular players, KaiA, KaiB, and KaiC are known and these proteins can reconstitute a remarkable circadian oscillation in a test tube. KaiC is rhythmically phosphorylated and its phospho-status is a marker of circadian phase that regulates ATPase activity and the oscillating assembly of a nanomachine. Analyses of the nanomachines have revealed how their timing circuit is ratcheted to be unidirectional and how they stay in synch to ensure a robust oscillator. These insights are likely to elucidate circadian timekeeping in higher organisms, including how transcription and translation could appear to be a core circadian timer when the true pacemaker is an embedded biochemical oscillator. PMID:23571120

  6. Can small shifts in circadian phase affect performance?

    PubMed Central

    Burgess, Helen J.; Legasto, Carlo S.; Fogg, Louis F.; Smith, Mark R.

    2012-01-01

    Small shifts in circadian timing occur frequently as a result of daylight saving time or later weekend sleep. These subtle shifts in circadian phase have been shown to influence subjective sleepiness, but it remains unclear if they can significantly affect performance. In a retrospective analysis we examined performance on the Psychomotor Vigilance Test before bedtime and after wake time in 11 healthy adults on fixed sleep schedules based on their habitual sleep times. The dim light melatonin onset, a marker of circadian timing, was measured on two occasions. An average 1.1 hour shift away from a proposed optimal circadian phase angle (6 hours between melatonin onset and midpoint of sleep) significantly slowed mean, median and fastest 10% reaction times before bedtime and after wake time (p<0.05). These results add to previous reports that suggest that humans may be sensitive to commonly occurring small shifts in circadian timing. PMID:22695081

  7. Sex Differences in Circadian Timing Systems: Implications for Disease

    PubMed Central

    Bailey, Matthew; Silver, Rae

    2014-01-01

    Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamicadrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions. PMID:24287074

  8. A role for circadian clock in metabolic disease.

    PubMed

    Shimizu, Ippei; Yoshida, Yohko; Minamino, Tohru

    2016-07-01

    Many human behaviors and physiological activities show circadian rhythms. Circadian rhythms generated by central and peripheral clocks maintain homeostasis, including the regulation of metabolic processes. Biological rhythmicity is important for metabolic health, but circadian rhythms are affected and impaired by nocturnal activities and irregular food intake in modern society. Disruption of sleep is an established risk factor for diabetes and is known to promote systemic metabolic dysfunction in both humans and rodents. Metabolic stress promotes circadian clock disorders and modulation of clock gene expression has a causal role in the development of metabolic dysfunction. Maintenance of a physiological circadian rhythm is crucial for metabolic health and is an important strategy for combating obesity. PMID:26888117

  9. Circadian System and Glucose Metabolism: Implications for Physiology and Disease.

    PubMed

    Qian, Jingyi; Scheer, Frank A J L

    2016-05-01

    The circadian system serves one of the most fundamental properties present in nearly all organisms: it generates 24-h rhythms in behavioral and physiological processes and enables anticipating and adapting to daily environmental changes. Recent studies indicate that the circadian system is important in regulating the daily rhythm in glucose metabolism. Disturbance of this circadian control or of its coordination relative to the environmental/behavioral cycle, such as in shift work, eating late, or due to genetic changes, results in disturbed glucose control and increased type 2 diabetes risk. Therefore, an in-depth understanding of the mechanisms underlying glucose regulation by the circadian system and its disturbance may help in the development of therapeutic interventions against the deleterious health consequences of circadian disruption. PMID:27079518

  10. Circadian clock and pathology of the ageing brain

    PubMed Central

    Kondratova, A.A.; Kondratov, R.V.

    2013-01-01

    Ageing leads to functional deterioration of many brain systems, including the circadian clock - an internal time-keeping system that generates 24 hr rhythms in physiology and behaviour. Numerous clinical studies have established a direct correlation between the severity of neurodegenerative disorders, sleep disturbances and weakening of circadian clock functions. The latest data from model organisms, gene expression studies and clinical trials imply that the dysfunction of the circadian clock may contribute to the progression of ageing and age-associated pathologies, suggesting a functional link between the circadian clock, and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation. PMID:22395806

  11. Breast Feeding.

    ERIC Educational Resources Information Center

    International Children's Centre, Paris (France).

    This set of documents consists of English, French, and Spanish translations of four pamphlets on breast-feeding. The pamphlets provide information designed for lay persons, academics and professionals, health personnel and educators, and policy-makers. The contents cover health-related differences between breast and bottle milk; patterns of…

  12. Tube Feedings.

    ERIC Educational Resources Information Center

    Plummer, Nancy

    This module on tube feedings is intended for use in inservice or continuing education programs for persons who work in long-term care. Instructor information, including teaching suggestions and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then provided. A brief discussion follows…

  13. Effect of uncouplers on radiosensitivity and mutagenicity in x-irradiated mammalian cells.

    PubMed Central

    Laval, F

    1980-01-01

    The number of x-irradiated mammalian cells surviving is markedly increased when the cells are incubated with an uncoupler of oxidative phosphorylation prior to or immediately after irradiation. This increase is greater in plateau-phase cells than in exponentially growing cells. The increase in survival is related to the potency of the uncouplers, which do not modify the effective x-ray dose. The influence of uncouplers on survival is related to an increase of repair and semiconservative DNA synthesis. The mutation frequency (8-azaguanine-resistant mutants) is significantly higher in irradiated cells treated with uncouplers than in untreated cells. These results suggest the existence of an error-prone repair process in mammalian cells. PMID:6930660

  14. The influence of uncouplers on facilitated diffusion of sorbose in Saccharomyces cerevisiae.

    PubMed

    Van den Broek, P J; Haasnoot, C J; Van Leeuwen, C C; Van Steveninck, J

    1982-08-12

    Sorbose uptake in Saccharomyces cerevisiae, strain Delft 1, proceeds via mediated passive transport. In the cell sorbose is distributed in at least two compartments. Efflux studies showed that sorbose uptake in one of these compartments is not readily reversible. Uncouplers of oxidative phosphorylation inhibit both transport velocity and steady-state uptake level. It could be shown that these two effects are caused by different modes of action of the uncouplers. None of these two effects could be ascribed to changes of the electrochemical H+ gradient or of the intracellular pH. It is suggested that the inhibition of uptake velocity is caused by binding of the uncoupler to the sorbose translocator, thus lowering the transport activity. The uncoupler binding site is probably located at the intracellular fragment of the carrier. The second effect, reduction of the steady-state uptake level, is probably due to blocking of sorbose influx into the compartment that exhibits poor reversibility. PMID:6751390

  15. Effect of uncouplers on radiosensitivity and mutagenicity in x-irradiated mammalian cells

    SciTech Connect

    Laval, F.

    1980-05-01

    The number of x-irradiated mammalian cells surviving is markedly increased when the cells are incubated with an uncoupler of oxidative phosphorylation prior to or immediately after irradiation. This increase is greater in plateau-phase cells than in exponentially growing cells. The increase in survival is related to the potency of the uncouplers, which do not modify the effective x-ray dose. The influence of uncouplers on survival is related to an increase of repair and semiconservative DNA synthesis. The mutation frequency (8-azaguanine-resistant mutants) is significantly higher in irradiated cells treated with uncouplers than in untreated cells. These results suggest the existence of an error-prone repair process in mammalian cells.

  16. Effects of cold exposure in vivo and uncouplers and recouplers in vitro on potato tuber mitochondria.

    PubMed

    Popov, V N; Markova, O V; Mokhova, E N; Skulachev, V P

    2002-02-15

    Effects of cold exposure in vivo and treatment with laurate, carboxyatractylate, atractylate, nucleotides, and BSA in vitro on potato tuber mitochondria have been studied. Cold exposure of tubers for 48-96 h resulted in some uncoupling that could be reversed completely by BSA and partially by ADP, ATP, UDP, carboxyatractylate, and atractylate. UDP was less effective than ADP and ATP, and atractylate was less effective than carboxyatractylate. The recoupling effects of nucleotides were absent when the nucleotides were added after carboxyatractylate. GDP, UDP, and CDP did not recouple mitochondria from either the control or the cold-exposed tubers. This indicates that the cold-induced fatty acid-mediated uncoupling in potato tuber mitochondria is partially due to the operation of the ATP/ADP antiporter. As to the plant uncoupling protein, its contribution to the uncoupling in tuber is negligible or, under the conditions used, somehow desensitized to nucleotides. PMID:11997132

  17. The effect of uncouplers on catecholamine incorporation by vesicles of chromaffin granules.

    PubMed Central

    Bashford, C L; Casey, R P; Radda, G K; Ritchie, G A

    1975-01-01

    It is shown that uncouplers inhibit the incorporation of catecholamines by vesicles of chromaffin granules in parallel with their stimulatory effect on the membrane-bound adenosine triphosphatase. PMID:125589

  18. Stimulation of glycolysis in Ehrlich ascites carcinoma cells with phenylhydrazonopropanedinitrile and others uncouplers of oxidative phosphorylation.

    PubMed

    Sturdík, E; Cullý, J; Sturdíková, M; Durcová, E

    1986-01-01

    The metabolic consequences of the uncoupling effect of phenylhydrazonopropanedinitrile and others uncouplers of oxidative phosphorylation on Ehrlich ascites carcinoma (EAC) cells were investigated. Upon application of uncouplers in concentrations stimulating the respiration of EAC cells the accelerate glucose uptake and lactate production was observed. The maximal glycolysis stimulation was fourfold in relation to control at the given experimental conditions. Simultaneously the degree of conversion of glucose on lactate was increased. The acceleration of glycolysis was accompanied by stimulation of 14C-labeled adenine and valine incorporation indicating the increased rate of biosynthetic processes. The prolongation of uncoupler action time and application of their higher concentrations cause the inhibition of glycolysis and biosynthetic processes which is evoked with nonspecific effects of the compounds. PMID:3785464

  19. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

    PubMed Central

    Srivastava, Shireesh; Kashiwaya, Yoshihiro; King, M. Todd; Baxa, Ulrich; Tam, Joseph; Niu, Gang; Chen, Xiaoyuan; Clarke, Kieran; Veech, Richard L.

    2012-01-01

    We measured the effects of a diet in which d-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [18F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.—Srivastava, S., Kashiwaya, Y., King, M. T. Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R. L. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. PMID:22362892

  20. Circadian variation in witnessed out of hospital cardiac arrest

    PubMed Central

    Soo, L; Gray, D; Young, T; Hampton, J

    2000-01-01

    OBJECTIVES—To examine the effect on circadian variation of out of hospital cardiac arrest according to the underlying aetiology and presenting rhythm of arrest, and to explore strategies that might help to improve survival outcome using circadian variation.
DESIGN—Population based retrospective study.
SETTING—County of Nottinghamshire with a total population of 993 914 and an area of 2183 km2.
SUBJECTS—Between 1 January 1991 and 3 December 1994, all witnessed cardiac arrests attended by the Nottinghamshire Ambulance Service, of which 1196 patients had a cardiac cause for their arrest (ICD, 9th revision, codes 390-414 and 420-429) and 339 had a non-cardiac cause.
RESULTS—The circadian variation of the cardiac cases was not significantly different from that of non-cardiac cases (p = 0.587), even when adjusted for age, sex, or presenting rhythm of arrest. For cardiac cases, the circadian variation of those who presented with ventricular fibrillation was significantly different from those presenting with a rhythm other than ventricular fibrillation (p = 0.005), but was similar to the circadian variation of bystander cardiopulmonary resuscitation (p = 0.306) and survivors (p = 0.542). Ambulance response time was also found to have a circadian variation.
CONCLUSIONS—There is a common circadian variation of out of hospital cardiac arrest, irrespective of underlying aetiology, where the presenting rhythm is other than ventricular fibrillation. This is different from the circadian variation of cases of cardiac aetiology presenting with ventricular fibrillation. The circadian variation of ventricular fibrillation, and consequently survival, may be affected by the availability of bystander cardiopulmonary resuscitation and the speed of ambulance response.


Keywords: out of hospital; cardiac arrest; circadian variation PMID:10995402

  1. HIV Tat protein affects circadian rhythmicity by interfering with the circadian system

    PubMed Central

    Wang, T; Jiang, Z; Hou, W; Li, Z; Cheng, S; Green, LA; Wang, Y; Wen, X; Cai, L; Clauss, M; Wang, Z

    2014-01-01

    Objectives Sleep disorders are common in patients with HIV/AIDS, and can lead to poor quality of life. Although many studies have investigated the aetiology of these disorders, it is still unclear whether impaired sleep quality is associated with HIV itself, social problems, or side effects of antiretroviral therapy (ART). Moreover, despite its known neurological associations, little is known about the role of the trans-activator of transcription (Tat) protein in sleep disorders in patients with HIV/AIDS. The purpose of this study was to test the hypothesis that the sleep quality of patients with HIV/AIDS affected by an altered circadian rhythm correlates with cerebrospinal HIV Tat protein concentration. Methods Ninety-six patients with HIV/AIDS between 20 and 69 years old completed the Pittsburgh Sleep Quality Index. Their circadian rhythm parameters of blood pressure, Tat concentration in cerebrospinal fluid, melatonin concentration, CD4 cell count and HIV RNA viral load in serum were measured. Results The circadian amplitude of systolic blood pressure and the score for sleep quality (Pittsburgh Sleep Quality Index) were negatively correlated with HIV Tat protein concentration, while the melatonin value was positively correlated with Tat protein concentration. Conclusions The HIV Tat protein affects circadian rhythmicity by interfering with the circadian system in patients with HIV/AIDS and further increases the melatonin excretion value. A Tat protein-related high melatonin value may counteract HIV-related poor sleep quality during the progression of HIV infection. This study provides the first clinical evidence offering an explanation for why sleep quality did not show an association with progression of HIV infection in previous studies. PMID:24750691

  2. Effects of Gravity on Insect Circadian Rhythmicity

    NASA Technical Reports Server (NTRS)

    Hoban-Higgins, Tana M.

    2000-01-01

    Circadian rhythms - endogenous daily rhythmic fluctuations in virtually all characteristics of life - are generated and coordinated by the circadian timing system (CTS). The CTS is synchronized to the external 24-hour day by time cues such as the light/dark cycle. In an environment without time cues, the length of an animal's day is determined by the period of its internal pacemaker (tau) and the animal is said to be free-running. All life on earth evolved under the solar day; the CTS exists as an adaptation that allows organisms to anticipate and to prepare for rhythmic environmental fluctuations. All life on earth also evolved under the force of earth's gravitational environment. While it is therefore not surprising that changes in the lighting environment affect the CTS, it is surprising that changes in the gravitational environment would do so. However, recent data from one of our laboratories using the brn-3.1 knockout mouse revealed that this model, which lacks the sensory receptor hair cells within the neurovestibular system, does not respond to exposure to a hyperdynamic environment in the same fashion as normal mice. The brn-3.1 mice did not show the expected suppression of circadian rhythmicity shown by control mice exposed to 2G. Exposure to altered ambient force environments affects the amplitude, mean and timing of circadian rhythms in species from unicellular organisms to man. In addition, there is a circadian influence on the homeostatic response to acute 2G acceleration and pulses of 2G can act as a time cue, synchronizing the CTS. This is of significance because maintenance of internal and external temporal coordination is critical for normal physiological and psychological function. Typically, during adaptation to an increased gravitational environment (+G), an initial acute reaction is followed by adaptation and, eventually, a new steady state (14-16), which can take weeks to months to establish. Until the development of space stations, exposure

  3. Circadian molecular clock in lung pathophysiology.

    PubMed

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

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

  4. Circadian Rhythms in Floral Scent Emission.

    PubMed

    Fenske, Myles P; Imaizumi, Takato

    2016-01-01

    To successfully recruit pollinators, plants often release attractive floral scents at specific times of day to coincide with pollinator foraging. This timing of scent emission is thought to be evolutionarily beneficial to maximize resource efficiency while attracting only useful pollinators. Temporal regulation of scent emission is tied to the activity of the specific metabolic pathways responsible for scent production. Although floral volatile profiling in various plants indicated a contribution by the circadian clock, the mechanisms by which the circadian clock regulates timing of floral scent emission remained elusive. Recent studies using two species in the Solanaceae family provided initial insight into molecular clock regulation of scent emission timing. In Petunia hybrida, the floral volatile benzenoid/phenylpropanoid (FVBP) pathway is the major metabolic pathway that produces floral volatiles. Three MYB-type transcription factors, ODORANT 1 (ODO1), EMISSION OF BENZENOIDS I (EOBI), and EOBII, all of which show diurnal rhythms in mRNA expression, act as positive regulators for several enzyme genes in the FVBP pathway. Recently, in P. hybrida and Nicotiana attenuata, homologs of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL (LHY) have been shown to have a similar role in the circadian clock in these plants, and to also determine the timing of scent emission. In addition, in P. hybrida, PhLHY directly represses ODO1 and several enzyme genes in the FVBP pathway during the morning as an important negative regulator of scent emission. These findings facilitate our understanding of the relationship between a molecular timekeeper and the timing of scent emission, which may influence reproductive success. PMID:27148293

  5. Circadian photoentrainment: parameters of phase delaying.

    PubMed

    DeCoursey, P J

    1986-01-01

    Experiments were carried out using simulated den cages to delineate specific characteristics of phase delaying in circadian photoentrainment of a nocturnal rodent, the flying squirrel. The principal experiments entailed presentation of one to five consecutive 15-min white-light pulses per activity cycle at activity onset to animals free-running in darkness, in order to determine the immediate and final phase-shifting effect. Auxiliary experiments recorded entrainment patterns on light-dark (LD) schedules in the den cages. Phase response curves (PRCs) based on 15-min white-light pulses in standard wheel cages were also constructed for these animals as background information for interpreting the phase-delaying experiments. Exposure of a den animal to light by light sampling at the time of initial arousal from the rest state at circadian time (CT) 12, either by an LD schedule or by a 15-min light pulse, resulted in a return to the nest box for a short rest period. The phase delay occurring after a single light exposure at activity onset was equal to the induced rest, thus suggesting an immediate phase shift. The maximum delay was about 1 1/2 hr/cycle, with the amount of delay related to the number of light exposures. During the photoentrained state on an LD schedule, the activity rhythm of a den-housed animal was essentially free-running on the days following a phase delay. The data are used to expand current models for photoentrainment of circadian activity rhythms in nocturnal rodents. PMID:2979583

  6. Circadian Rhythms in Floral Scent Emission

    PubMed Central

    Fenske, Myles P.; Imaizumi, Takato

    2016-01-01

    To successfully recruit pollinators, plants often release attractive floral scents at specific times of day to coincide with pollinator foraging. This timing of scent emission is thought to be evolutionarily beneficial to maximize resource efficiency while attracting only useful pollinators. Temporal regulation of scent emission is tied to the activity of the specific metabolic pathways responsible for scent production. Although floral volatile profiling in various plants indicated a contribution by the circadian clock, the mechanisms by which the circadian clock regulates timing of floral scent emission remained elusive. Recent studies using two species in the Solanaceae family provided initial insight into molecular clock regulation of scent emission timing. In Petunia hybrida, the floral volatile benzenoid/phenylpropanoid (FVBP) pathway is the major metabolic pathway that produces floral volatiles. Three MYB-type transcription factors, ODORANT 1 (ODO1), EMISSION OF BENZENOIDS I (EOBI), and EOBII, all of which show diurnal rhythms in mRNA expression, act as positive regulators for several enzyme genes in the FVBP pathway. Recently, in P. hybrida and Nicotiana attenuata, homologs of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL (LHY) have been shown to have a similar role in the circadian clock in these plants, and to also determine the timing of scent emission. In addition, in P. hybrida, PhLHY directly represses ODO1 and several enzyme genes in the FVBP pathway during the morning as an important negative regulator of scent emission. These findings facilitate our understanding of the relationship between a molecular timekeeper and the timing of scent emission, which may influence reproductive success. PMID:27148293

  7. Ontogenetic development of the mammalian circadian system.

    PubMed

    Weinert, Dietmar

    2005-01-01

    This review summarizes the current knowledge about the ontogenetic development of the circadian system in mammals. The developmental changes of overt rhythms are discussed, although the main focus of the review is the underlying neuronal and molecular mechanisms. In addition, the review describes ontogenetic development, not only as a process of morpho-functional maturation. The need of repeated adaptations and readaptations due to changing developmental stage and environmental conditions is also considered. The review analyzes mainly rodent data, obtained from the literature and from the author's own studies. Results from other species, including humans, are presented to demonstrate common features and species-dependent differences. The review first describes the development of the suprachiasmatic nuclei as the central pacemaker system and shows that intrinsic circadian rhythms are already generated in the mammalian fetus. As in adult organisms, the period length is different from 24 h and needs continuous correction by environmental periodicities, or zeitgebers. The investigation of the ontogenetic development of the mechanisms of entrainment reveals that, at prenatal and early postnatal stages, non-photic cues deriving from the mother are effective. Light-dark entrainment develops later. At a certain age, both photic and non-photic zeitgebers may act in parallel, even though the respective time information is 12 h out of phase. That leads to a temporary internal desynchronization. Because rhythmic information needs to be transferred to effector organs, the corresponding neural and humoral signalling pathways are also briefly described. Finally, to be able to transform a rhythmic signal into an overt rhythm, the corresponding effector organs must be functionally mature. As many of these organs are able to generate their own intrinsic rhythms, another aspect of the review is dedicated to the development of peripheral oscillators and mechanisms of their entrainment

  8. Circadian rhythm asynchrony in man during hypokinesis.

    NASA Technical Reports Server (NTRS)

    Winget, C. M.; Vernikos-Danellis, J.; Cronin, S. E.; Leach, C. S.; Rambaut, P. C.; Mack, P. B.

    1972-01-01

    Posture and exercise were investigated as synchronizers of certain physiologic rhythms in eight healthy male subjects in a defined environment. Four subjects exercised during bed rest. Body temperature (BT), heart rate, plasma thyroid hormone, and plasma steroid data were obtained from the subjects for a 6-day ambulatory equilibration period before bed rest, 56 days of bed rest, and a 10-day recovery period after bed rest. The results indicate that the mechanism regulating the circadian rhythmicity of the cardiovascular system is rigorously controlled and independent of the endocrine system, while the BT rhythm is more closely aligned to the endocrine system.

  9. The insensitivity to uncouplers of testis mitochondrial ATPase.

    PubMed

    Vázquez-Memije, M E; Izquierdo-Reyes, V; Delhumeau-Ongay, G

    1988-01-01

    Albumin-free testis mitochondrial ATPase activity failed to be stimulated by either 2,4-dinitrophenol (DNP) or carbonyl cyanide rho-trifluoromethoxyphenylhydrazone (FCCP). DNP scarcely enhanced the state 4 respiration and mitochondria proved to be poorly coupled. When 1% bovine serum albumin was added to the isolation medium, DNP or FCCP stimulated ATPase nearly twofold and the dose-response curves for the uncouplers on the QO2 reached a plateau at five- to sixfold. The DNP coupling index (q) also showed a 30-40% improvement. A dose-response curve for oligomycin on the rate of [gamma-32P]ATP synthesis showed a stimulation of ATP synthase activity by 10-100 ng inhibitor/mg protein, suggesting a possible blockade of "open" F0 channels. In the albumin preparation oligomycin inhibited ATP synthesis in the range 10-100 ng/mg protein. Since testis ATPase is known to be loosely bound to the membrane, an effect of albumin, improving tightness in the interaction of the F1 and the F0 sectors of the ATPase, is suggested. PMID:2449129

  10. Reversible uncoupling of oxidative phosphorylation at low oxygen tension.

    PubMed Central

    Kramer, R S; Pearlstein, R D

    1983-01-01

    The stoichiometry of oxidative phosphorylation at low oxygen tension (less than 3 torr; O2 less than 5 microM) has been measured in rat liver mitochondria. In a steady-state model in which respiration rate was experimentally controlled by either oxygen or substrate (succinate) limitation, flux-dependent variation in the phosphorylation efficiency (P/O ratio) of stimulated mitochondrial respiration was evaluated. P/O ratio remained constant over a wide range of respiration rates in mitochondria limited only by substrate availability. In contrast, oxygen-limited mitochondria demonstrated a continuous decline in P/O ratio as respiration was increasingly restricted. Significant differences in the two test conditions were demonstrated throughout the range of analysis. The effect of oxygen limitation on phosphorylation efficiency was shown to be completely reversed by restoring zero-order kinetics associated with high oxygen tension. These findings are discussed in regard to a proposed uncoupling of mitochondrial coupling site II at low oxygen tension arising as a consequence of energy-dissipating electron flux through the ubiquinone-cytochrome b-c1 region of the respiratory chain (complex III). PMID:6577456

  11. Early neurovascular uncoupling in the brain during community acquired pneumonia

    PubMed Central

    2012-01-01

    Introduction Sepsis leads to microcirculatory dysfunction and therefore a disturbed neurovascular coupling in the brain. To investigate if the dysfunction is also present in less severe inflammatory diseases we studied the neurovascular coupling in patients suffering from community acquired pneumonia. Methods Patients were investigated in the acute phase of pneumonia and after recovery. The neurovascular coupling was investigated with a simultaneous electroencephalogram (EEG)-Doppler technique applying a visual stimulation paradigm. Resting EEG frequencies, visual evoked potentials as well as resting and stimulated hemodynamic responses were obtained. Disease severity was characterized by laboratory and cognitive parameters as well as related scoring systems. Data were compared to a control group. Results Whereas visually evoked potentials (VEP) remained stable a significant slowing and therefore uncoupling of the hemodynamic responses were found in the acute phase of pneumonia (Rate time: control group: 3.6 ± 2.5 vs. acute pneumonia: 1.6 ± 2.4 s; P < 0.0005). In the initial investigation, patients who deteriorated showed a decreased hemodynamic response as compared with those who recovered (gain: recovered: 15% ± 4% vs. deteriorated: 9% ± 3%, P < 0.05; control: 14% ± 5%). After recovery the coupling normalized. Conclusions Our study underlines the role of an early microcirculatory dysfunction in inflammatory syndromes that become evident in pre-septic conditions with a gradual decline according to disease severity. PMID:22520083

  12. The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

    PubMed Central

    Rabender, Christopher S.; Alam, Asim; Sundaresan, Gobalakrishnan; Cardnell, Robert J.; Yakovlev, Vasily A.; Mukhopadhyay, Nitai D.; Graves, Paul; Zweit, Jamal; Mikkelsen, Ross B.

    2015-01-01

    Here evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast to normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on HPLC analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid and head and neck tumors compared to normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by clonogenic assay, Ki67 staining and 18F-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and as a consequence nitric oxide synthase activity generates more peroxynitrite and superoxide anion than nitric oxide resulting in important tumor growth promoting and anti-apoptotic signaling properties. Implications The synthetic BH4, Kuvan®, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. PMID:25724429

  13. Rhythms of Life: The Plant Circadian Clock - (By Katherine Hubbard and Antony Dodd).

    PubMed

    2016-04-01

    Summaryplantcell;28/4/tpc.116.tt0416/FIG1F1fig1This teaching tool explores circadian rhythms in plants. The topic is presented as a series of concepts illustrated by examples, including the architecture of circadian clocks and the connections between the oscillator and circadian-regulated processes such as metabolism and flowering. The Teaching Tool introduces some of the techniques used to investigate circadian biology and explores how understanding circadian rhythms could lead to crop improvement. PMID:27169989

  14. p38 MAP kinase regulates circadian rhythms in Drosophila.

    PubMed

    Vrailas-Mortimer, Alysia D; Ryan, Sarah M; Avey, Matthew J; Mortimer, Nathan T; Dowse, Harold; Sanyal, Subhabrata

    2014-12-01

    The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways. PMID:25403440

  15. Redox rhythm reinforces the circadian clock to gate immune response

    PubMed Central

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

    2015-01-01

    Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism’s metabolic activities1–3. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated4–7. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant’s redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid (SA) does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism. PMID:26098366

  16. Establishment of human cell lines showing circadian rhythms of bioluminescence.

    PubMed

    Yoshikawa, Aki; Shimada, Hiroko; Numazawa, Kahori; Sasaki, Tsukasa; Ikeda, Masaaki; Kawashima, Minae; Kato, Nobumasa; Tokunaga, Katsushi; Ebisawa, Takashi

    2008-11-28

    We have established human retinal pigment epithelial cell lines stably expressing the luciferase gene, driven by the human Bmal1 promoter, to obtain human-derived cells that show circadian rhythms of bioluminescence after dexamethasone treatment. The average circadian period of bioluminescence for the obtained clones was 24.07+/-0.48 h. Lithium (10 mM) in the medium significantly lengthened the circadian period of bioluminescence, which is consistent with previous reports, while 2 mM or 5 mM lithium had no effect. This is the first report on the establishment of human-derived cell lines that proliferate infinitely and show circadian rhythms of bioluminescence, and also the first to investigate the effects of low-dose lithium on the circadian rhythms of human-derived cells in vitro. The established cells will be useful for various in vitro studies of human circadian rhythms and for the development of new therapies for human disorders related to circadian rhythm disturbances. PMID:18809466

  17. Implicit Associations Have a Circadian Rhythm

    PubMed Central

    Zadra, Jonathan R.; Proffitt, Dennis R.

    2014-01-01

    The current study shows that people's ability to inhibit implicit associations that run counter to their explicit views varies in a circadian pattern. The presence of this rhythmic variation suggests the involvement of a biological process in regulating automatic associations—specifically, with the current data, associations that form undesirable social biases. In 1998, Greenwald, McGhee, and Schwartz introduced the Implicit Association Test as a means of measuring individual differences in implicit cognition. The IAT is a powerful tool that has become widely used. Perhaps most visibly, studies employing the IAT demonstrate that people generally hold implicit biases against social groups, which often conflict with their explicitly held views. The IAT engages inhibitory processes similar to those inherent in self-control tasks. Because the latter processes are known to be resource-limited, we considered whether IAT scores might likewise be resource dependent. Analyzing IAT performance from over a million participants across all times of day, we found a clear circadian pattern in scores. This finding suggests that the IAT measures not only the strength of implicit associations, but also the effect of variations in the physiological resources available to inhibit their undesirable influences on explicit behavior. PMID:25365254

  18. Circadian Rhythms: Hijacking the Cyanobacterial Clock

    PubMed Central

    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

  19. Meal time shift disturbs circadian rhythmicity along with metabolic and behavioral alterations in mice.

    PubMed

    Yoon, Ji-Ae; Han, Dong-Hee; Noh, Jong-Yun; Kim, Mi-Hee; Son, Gi Hoon; Kim, Kyungjin; Kim, Chang-Ju; Pak, Youngmi Kim; Cho, Sehyung

    2012-01-01

    In modern society, growing numbers of people are engaged in various forms of shift works or trans-meridian travels. Such circadian misalignment is known to disturb endogenous diurnal rhythms, which may lead to harmful physiological consequences including metabolic syndrome, obesity, cancer, cardiovascular disorders, and gastric disorders as well as other physical and mental disorders. However, the precise mechanism(s) underlying these changes are yet unclear. The present work, therefore examined the effects of 6 h advance or delay of usual meal time on diurnal rhythmicities in home cage activity (HCA), body temperature (BT), blood metabolic markers, glucose homeostasis, and expression of genes that are involved in cholesterol homeostasis by feeding young adult male mice in a time-restrictive manner. Delay of meal time caused locomotive hyperactivity in a significant portion (42%) of subjects, while 6 h advance caused a torpor-like symptom during the late scotophase. Accordingly, daily rhythms of blood glucose and triglyceride were differentially affected by time-restrictive feeding regimen with concurrent metabolic alterations. Along with these physiological changes, time-restrictive feeding also influenced the circadian expression patterns of low density lipoprotein receptor (LDLR) as well as most LDLR regulatory factors. Strikingly, chronic advance of meal time induced insulin resistance, while chronic delay significantly elevated blood glucose levels. Taken together, our findings indicate that persistent shifts in usual meal time impact the diurnal rhythms of carbohydrate and lipid metabolisms in addition to HCA and BT, thereby posing critical implications for the health and diseases of shift workers. PMID:22952870

  20. Circadian Role in Daily Pattern of Cardiovascular Risk

    NASA Astrophysics Data System (ADS)

    Ivanov, Plamen Ch.; Hu, Kun; Chen, Zhi; Hilton, Michael F.; Stanley, H. Eugene; Shea, Steven A.

    2004-03-01

    Numerous epidemiological studies demonstrate that sudden cardiac death, pulmonary embolism, myocardial infarction, and stroke have a 24-hour daily pattern with a broad peak between 9-11am. Such a daily pattern in cardiovascular risk could be attributable to external factors, such as the daily behavior patterns, including sleep-wake cycles and activity levels, or internal factors, such as the endogenous circadian pacemaker. Findings of significant alternations in the temporal organization and nonlinear properties of heartbeat fluctuations with disease and with sleep-wake transitions raise the intriguing possibility that changes in the mechanism of control associated with behavioral sleep-wake transition may be responsible for the increased cardiac instability observed in particular circadian phases. Alternatively, we hypothesize that there is a circadian clock, independent of the sleep-wake cycle, which affects the cardiac dynamics leading to increased cardiovascular risk. We analyzed continuous recordings from healthy subjects during 7 cycles of forced desynchrony routine wherein subjects' sleep-wake cycles are adjusted to 28 hours so that their behaviors occur across all circadian phases. Heartbeat data were divided into one-hour segments. For each segment, we estimated the correlations and the nonlinear properties of the heartbeat fluctuations at the corresponding circadian phase. Since the sleep and wake contributions are equally weighted in our experiment, a change of the properties of the heartbeat dynamics with circadian phase suggest a circadian rhythm. We show significant circadian-mediated alterations in the correlation and nonlinear properties of the heartbeat resembling those observed in patients with heart failure. Remarkably, these dynamical alterations are centered at 60 degrees circadian phase, coinciding with the 9-11am window of cardiac risk.

  1. Ethanol consumption in mice: relationships with circadian period and entrainment

    PubMed Central

    Trujillo, Jennifer L.; Do, David T.; Grahame, Nicholas J.; Roberts, Amanda J.; Gorman, Michael R.

    2011-01-01

    A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep and body temperature, and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred High- (HAP) and Low- (LAP) Alcohol Preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 h or 22 h or remained in a standard 24 h cycle. Upon discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake. PMID:20880659

  2. Ethanol consumption in mice: relationships with circadian period and entrainment.

    PubMed

    Trujillo, Jennifer L; Do, David T; Grahame, Nicholas J; Roberts, Amanda J; Gorman, Michael R

    2011-03-01

    A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep, and body temperature; and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred high- (HAP) and low- (LAP) alcohol preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 or 22 h or remained in a standard 24 h cycle. On discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake. PMID:20880659

  3. Getting through to circadian oscillators: why use constant routines?

    NASA Technical Reports Server (NTRS)

    Duffy, Jeanne F.; Dijk, Derk-Jan

    2002-01-01

    Overt 24-h rhythmicity is composed of both exogenous and endogenous components, reflecting the product of multiple (periodic) feedback loops with a core pacemaker at their center. Researchers attempting to reveal the endogenous circadian (near 24-h) component of rhythms commonly conduct their experiments under constant environmental conditions. However, even under constant environmental conditions, rhythmic changes in behavior, such as food intake or the sleep-wake cycle, can contribute to observed rhythmicity in many physiological and endocrine variables. Assessment of characteristics of the core circadian pacemaker and its direct contribution to rhythmicity in different variables, including rhythmicity in gene expression, may be more reliable when such periodic behaviors are eliminated or kept constant across all circadian phases. This is relevant for the assessment of the status of the circadian pacemaker in situations in which the sleep-wake cycle or food intake regimes are altered because of external conditions, such as in shift work or jet lag. It is also relevant for situations in which differences in overt rhythmicity could be due to changes in either sleep oscillatory processes or circadian rhythmicity, such as advanced or delayed sleep phase syndromes, in aging, or in particular clinical conditions. Researchers studying human circadian rhythms have developed constant routine protocols to assess the status of the circadian pacemaker in constant behavioral and environmental conditions, whereas this technique is often thought to be unnecessary in the study of animal rhythms. In this short review, the authors summarize constant routine methodology and what has been learned from constant routines and argue that animal and human circadian rhythm researchers should (continue to) use constant routines as a step on the road to getting through to central and peripheral circadian oscillators in the intact organism.

  4. A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus

    PubMed Central

    Guilding, Clare; Hughes, Alun TL; Brown, Timothy M; Namvar, Sara; Piggins, Hugh D

    2009-01-01

    Background In mammals, the synchronized activity of cell autonomous clocks in the suprachiasmatic nuclei (SCN) enables this structure to function as the master circadian clock, coordinating daily rhythms in physiology and behavior. However, the dominance of this clock has been challenged by the observations that metabolic duress can over-ride SCN controlled rhythms, and that clock genes are expressed in many brain areas, including those implicated in the regulation of appetite and feeding. The recent development of mice in which clock gene/protein activity is reported by bioluminescent constructs (luciferase or luc) now enables us to track molecular oscillations in numerous tissues ex vivo. Consequently we determined both clock activities and responsiveness to metabolic perturbations of cells and tissues within the mediobasal hypothalamus (MBH), a site pivotal for optimal internal homeostatic regulation. Results Here we demonstrate endogenous circadian rhythms of PER2::LUC expression in discrete subdivisions of the arcuate (Arc) and dorsomedial nuclei (DMH). Rhythms resolved to single cells did not maintain long-term synchrony with one-another, leading to a damping of oscillations at both cell and tissue levels. Complementary electrophysiology recordings revealed rhythms in neuronal activity in the Arc and DMH. Further, PER2::LUC rhythms were detected in the ependymal layer of the third ventricle and in the median eminence/pars tuberalis (ME/PT). A high-fat diet had no effect on the molecular oscillations in the MBH, whereas food deprivation resulted in an altered phase in the ME/PT. Conclusion Our results provide the first single cell resolution of endogenous circadian rhythms in clock gene expression in any intact tissue outside the SCN, reveal the cellular basis for tissue level damping in extra-SCN oscillators and demonstrate that an oscillator in the ME/PT is responsive to changes in metabolism. PMID:19712475

  5. Circadian rhythms in fatty acid-induced depression of myocardial contractile function: Potential mediation by the circadian clock within the cardiomyocyte

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian rhythms in susceptibility to cardiovascular (CV) pathologic events (e.g., arrhythmias, myocardial infarction) are well established. These phenomena have been explained largely by diurnal variations in neurohumoral influences, such as sympathetic activity. Circadian clocks are intracellular...

  6. Sleep Deprivation and Circadian Disruption: Stress, Allostasis, and Allostatic Load.

    PubMed

    McEwen, Bruce S; Karatsoreos, Ilia N

    2015-03-01

    Sleep has important homeostatic functions, and circadian rhythms organize physiology and behavior on a daily basis to insure optimal function. Sleep deprivation and circadian disruption can be stressors, enhancers of other stressors that have consequences for the brain and many body systems. Whether the origins of circadian disruption and sleep disruption and deprivation are from anxiety, depression, shift work, long-distance air travel, or a hectic lifestyle, there are consequences that impair brain functions and contribute to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation. PMID:26055668

  7. The circadian cycle: daily rhythms from behaviour to genes

    PubMed Central

    Merrow, Martha; Spoelstra, Kamiel; Roenneberg, Till

    2005-01-01

    The daily recurrence of activity and rest are so common as to seem trivial. However, they reflect a ubiquitous temporal programme called the circadian clock. In the absence of either anatomical clock structures or clock genes, the timing of sleep and wakefulness is disrupted. The complex nature of circadian behaviour is evident in the fact that phasing of the cycle during the day varies widely for individuals, resulting in extremes colloquially called 'larks' and 'owls'. These behavioural oscillations are mirrored in the levels of physiology and gene expression. Deciphering the underlying mechanisms will provide important insights into how the circadian clock affects health and disease. PMID:16222241

  8. [Directional hearing in relation to individual circadian biorhythm].

    PubMed

    Karnicki, C

    1990-01-01

    Acuity angle of the directional hearing was investigated in connection with the individual circadian rhythm. Two groups of 15 persons represented the morning and evening form of the circadian rhythm. Body temperature fixed the rhythm character. The evaluations of the angle acuity of the directional hearing were performed in the highest and the lowest point of body temperature as well as in the neutral point, which was determined in the morning group in the middle between the two extremes. The possibility of the sound localization in individual and linked with the body temperature circadian rhythm. PMID:2234972

  9. Ca2+-induced uncoupling of Aplysia bag cell neurons.

    PubMed

    Dargaei, Zahra; Standage, Dominic; Groten, Christopher J; Blohm, Gunnar; Magoski, Neil S

    2015-02-01

    Electrical transmission is a dynamically regulated form of communication and key to synchronizing neuronal activity. The bag cell neurons of Aplysia are a group of electrically coupled neuroendocrine cells that initiate ovulation by secreting egg-laying hormone during a prolonged period of synchronous firing called the afterdischarge. Accompanying the afterdischarge is an increase in intracellular Ca2+ and the activation of protein kinase C (PKC). We used whole cell recording from paired cultured bag cell neurons to demonstrate that electrical coupling is regulated by both Ca2+ and PKC. Elevating Ca2+ with a train of voltage steps, mimicking the onset of the afterdischarge, decreased junctional current for up to 30 min. Inhibition was most effective when Ca2+ entry occurred in both neurons. Depletion of Ca2+ from the mitochondria, but not the endoplasmic reticulum, also attenuated the electrical synapse. Buffering Ca2+ with high intracellular EGTA or inhibiting calmodulin kinase prevented uncoupling. Furthermore, activating PKC produced a small but clear decrease in junctional current, while triggering both Ca2+ influx and PKC inhibited the electrical synapse to a greater extent than Ca2+ alone. Finally, the amplitude and time course of the postsynaptic electrotonic response were attenuated after Ca2+ influx. A mathematical model of electrically connected neurons showed that excessive coupling reduced recruitment of the cells to fire, whereas less coupling led to spiking of essentially all neurons. Thus a decrease in electrical synapses could promote the afterdischarge by ensuring prompt recovery of electrotonic potentials or making the neurons more responsive to current spreading through the network. PMID:25411460

  10. Uncoupling of mitochondrial oxidative phosphorylation by DNA gyrase inhibitors

    SciTech Connect

    Gallagher, M.; Weinberg, R.; Simpson, M.V.

    1986-05-01

    Supercoiled mtDNA and the swivel requirement for its replication suggest the existence of a mtDNA gyrase. The authors published studies on isolated mitochondria showing that novobiocin, coumermycin, nalidixic acid, and oxolinic acid promote relaxed DNA formation at the expense of supercoiled DNA are in accord with this view. However, their inability to directly detect the enzyme led them to ask whether these drugs act elsewhere. Their results with isolated rat liver mitochondria show that novo, nal, but not oxo, stimulate O/sub 2/ uptake as much as does 2.4-dinitrophenol (DNP). This possible uncoupling effect was confirmed by a standard (/sup 32/P) assay showing the following inhibitions of ATP synthesis: 0.2 mM novo, 95% (0.4 mM, 100%) 0.4 mM nal, 37%; oxo to at least 1.9 mM, 0%; (0.5 mM 2,4-DNP, 100%). Thus, oxo remains a useful tool for intact mitochondrial studies. Because these three drugs, especially novo, are being used to study the role of DNA superhelicity on pro- and eucaryotic (and mitochondrial) gene expression, the authors studied their effect on oxidative phosphorylation in such cells. In these cases the drugs did not affect DNP-sensitive (/sup 14/C)glutamine transport into E. coli cells (an established measure of ATP level), nor, in an S. cerevisiae mutant permeable to novo, did novo affect the steady state ATP level. Studies on cultured mammalian cells are in progress.

  11. Uncoupling protein 2 gene polymorphisms are associated with obesity

    PubMed Central

    2012-01-01

    Background Uncoupling protein 2 (UCP2) gene polymorphisms have been reported as genetic risk factors for obesity and type 2 diabetes mellitus (T2DM). We examined the association of commonly observed UCP2 G(−866)A (rs659366) and Ala55Val (C > T) (rs660339) single nucleotide polymorphisms (SNPs) with obesity, high fasting plasma glucose, and serum lipids in a Balinese population. Methods A total of 603 participants (278 urban and 325 rural subjects) were recruited from Bali Island, Indonesia. Fasting plasma glucose (FPG), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were measured. Obesity was determined based on WHO classifications for adult Asians. Participants were genotyped for G(−866)A and Ala55Val polymorphisms of the UCP2 gene. Results Obesity prevalence was higher in urban subjects (51%) as compared to rural subjects (23%). The genotype, minor allele (MAF), and heterozygosity frequencies were similar between urban and rural subjects for both SNPs. All genotype frequencies were in Hardy-Weinberg equilibrium. A combined analysis of genotypes and environment revealed that the urban subjects carrying the A/A genotype of the G(−866)A SNP have higher BMI than the rural subjects with the same genotype. Since the two SNPs showed strong linkage disequilibrium (D’ = 0.946, r2 = 0.657), a haplotype analysis was performed. We found that the AT haplotype was associated with high BMI only when the urban environment was taken into account. Conclusions We have demonstrated the importance of environmental settings in studying the influence of the common UCP2 gene polymorphisms in the development of obesity in a Balinese population. PMID:22533685

  12. Ryanodine receptors are uncoupled from contraction in rat vena cava.

    PubMed

    Tykocki, N R; Thompson, J M; Jackson, W F; Watts, S W

    2013-02-01

    Ryanodine receptors (RyR) are Ca(2+)-sensitive ion channels in the sarcoplasmic reticulum (SR) membrane, and are important effectors of SR Ca(2+) release and smooth muscle excitation-contraction coupling. While the relationship between RyR activation and contraction is well characterized in arteries, little is known about the role of RyR in excitation-contraction coupling in veins. We hypothesized that RyR are present and directly coupled to contraction in rat aorta (RA) and vena cava (RVC). RA and RVC expressed mRNA for all 3 RyR subtypes, and immunofluorescence showed RyR protein was present in RA and RVC smooth muscle cells. RA and RVC rings contracted when Ca(2+) was re-introduced after stores depletion with thapsigargin (1μM), indicating both tissues contained intracellular Ca(2+) stores. To assess RyR function, contraction was then measured in RA and RVC exposed to the RyR activator caffeine (20mM). In RA, caffeine caused contraction that was attenuated by the RyR antagonists ryanodine (10μM) and tetracaine (100μM). However, caffeine (20mM) did not contract RVC. We next measured contraction and intracellular Ca(2+) (Ca(2+)(i)) simultaneously in RA and RVC exposed to caffeine. While caffeine increased Ca(2+)(i) and contracted RA, it had no significant effect on Ca(2+)(i) or contraction in RVC. These data suggest that ryanodine receptors, while present in both RA and RVC, are inactive and uncoupled from Ca(2+) release and contraction in RVC. PMID:23177664

  13. Glaciers and rivers: Pleistocene uncoupling in a Mediterranean mountain karst

    NASA Astrophysics Data System (ADS)

    Adamson, K. R.; Woodward, J. C.; Hughes, P. D.

    2014-06-01

    Large-scale coupling between headwater catchments and downstream depocentres is a critical influence on long-term fluvial system behaviour and on the creation of the fluvial sedimentary record. However, it is often difficult to examine this control over multiple Quaternary glacial cycles and it has not been fully explored in karst basins. By investigating the Pleistocene glacial and fluvial records on and around Mount Orjen (1894 m) in Montenegro, we show how the changing connectivity between glaciated mountain headwater source zones and downstream alluvial basins is a key feature of long-term karst system behaviour - especially in relation to the creation and preservation of the surface sedimentary record. Middle and Late Pleistocene glacial deposits are well preserved on Mount Orjen. Uranium-series dating of 27 carbonate cements in fluvial sediments shows that many alluvial depocentres were completely filled with coarse glacial outwash before 350 ka during the largest recorded glaciation. This major glaciation is correlated with the Skamnellian Stage in Greece and Marine Isotope Stage 12 (MIS 12, c 480-420 ka). This was a period of profound landscape change in many glaciated catchments on the Balkan Peninsula. Later glaciations were much less extensive and sediment supply to fluvial systems was much diminished. The extreme base level falls of the Late Miocene produced the world's deepest karst networks around the Mediterranean. After MIS 12, the subterranean karst of Mount Orjen formed the dominant pathway for meltwater and sediment transfer so that the depositional basins below 1000 m became disconnected (uncoupled) from the glaciated headwaters. There is little evidence of post-MIS 12 aggradation or incision in these basins. This absence of later Pleistocene and Holocene fluvial activity means these basins contain some of the thickest and best-preserved outwash deposits in the Mediterranean.

  14. Circadian rhythms. Atomic-scale origins of slowness in the cyanobacterial circadian clock.

    PubMed

    Abe, Jun; Hiyama, Takuya B; Mukaiyama, Atsushi; Son, Seyoung; Mori, Toshifumi; Saito, Shinji; Osako, Masato; Wolanin, Julie; Yamashita, Eiki; Kondo, Takao; Akiyama, Shuji

    2015-07-17

    Circadian clocks generate slow and ordered cellular dynamics but consist of fast-moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear. We identified the adenosine triphosphate (ATP) catalytic region [adenosine triphosphatase (ATPase)] in the amino-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock. Crystal structures of the ATPase revealed that the slowness of this ATPase arises from sequestration of a lytic water molecule in an unfavorable position and coupling of ATP hydrolysis to a peptide isomerization with high activation energy. The slow ATPase is coupled with another ATPase catalyzing autodephosphorylation in the carboxyl-terminal half of KaiC, yielding the circadian response frequency of intermolecular interactions with other clock-related proteins that influences the transcription and translation cycle. PMID:26113637

  15. Effect of Phosphate and Uncouplers on Substrate Transport and Oxidation by Isolated Corn Mitochondria 1

    PubMed Central

    Day, David A.; Hanson, John B.

    1977-01-01

    A study was made to determine conditions under which malate oxidation rates in corn (Zea mays L.) mitochondria are limited by transport processes. In the absence of added ADP, inorganic phosphate increased malate oxidation rates by processes inhibited by mersalyl and oligomycin, but phosphate did not stimulate uncoupled respiration. However, the uncoupled oxidation rates were inhibited by butylmalonate and mersalyl. When uncoupler was added prior to substrate, subsequent O2 uptake rates were reduced when malate and succinate, but not exogenous NADH, were used. Uncoupler and butylmalonate also inhibited swelling in malate solutions and malate accumulation by these mitochondria, which were found to have a high endogenous phosphate content. Addition of uncoupler after malate or succinate produced an initial rapid oxidation which declined as the mitochondria lost solute and contracted. This decline was not affected by addition of ADP or AMP, and was not observed when exogenous NADH was substrate. Increasing K+ permeability with valinomycin increased the P-trifluoromethoxy (carboxylcyanide)phenyl hydrazone inhibition. Kinetic studies showed the slow rate of malate oxidation in the presence of uncoupler to be characterized by a high Km and a low Vmax, probably reflecting a diffusion-limited process. The results indicate that rapid malate and succinate oxidation require the operation of both the phosphate and dicarboxylate transporters, which in turn depend on maintenance of a proton motive force across the inner membrane. In addition, phosphate can stimulate acceptorless malate oxidation by reaction with the coupling mechanism, and in uncoupled mitochondria which are depleted of substrate there is a slow rate of oxidation which appears to be limited by diffusive entry. PMID:16659803

  16. Characterization of a Chinese hamster ovary cell line resistant to uncouplers.

    PubMed

    Freeman, K B; Yatscoff, R W; Mason, J R; Patel, H V; Buckle, M

    1983-08-01

    The chemiosmotic theory of oxidative phosphorylation and the action of uncouplers was examined by characterizing a clone, UH5, of Chinese hamster ovary (CHO TK-) cells resistant to 5-chloro-3-tert-butyl-2'-chloro-4'-nitrosalicylanilide (S-13), a potent uncoupler of oxidative phosphorylation. About 9-times and 4-times more S-13 was required to effect growth and respiration respectively of UH5 cells compared to the parental CHO TK- cells. UH5 cells were cross-resistant to the uncouplers SF-6847 (3,5-di-tert-butyl-4-hydroxy-benzylidenemalononitrile), carbonylcyanide p-trifluoromethoxyphenylhydrazone and 2,4-dinitrophenol but not to oligomycin, venturicidin or Tevenel. Size, chromosome number and DNA content indicated that the UH5 cell line was probably pseudotetraploid compared to the parental pseudodiploid CHO TK- cells. Hybrid and cybrid cells formed from crosses of UH5 cells and cytoplasts, respectively, with an uncoupler-sensitive cell line were sensitive to S-13 indicating that resistance is probably nuclear-determined. UH5 cell mitochondria had increased cytochrome oxidase and decreased H+-ATPase activities. A fivefold resistance of oxidative phosphorylation to uncouplers was found at the mitochondrial level with respiration driven by either succinate or ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine. In contrast, no difference in sensitivity was found to valinomycin between mitochondria from UH5 and CHO TK- cells. The oligomycin-sensitive H+-ATPase activity of UH5 and CHO TK- cell mitochondria was equally stimulated by the uncoupler S-13. Uncoupler-resistant mitochondria would not be expected on the basis of the chemiosmotic theory, and the relation of the results to other modes of coupling is considered. PMID:6223814

  17. The Effects of Gravity on the Circadian Timing System

    NASA Technical Reports Server (NTRS)

    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. Feed Formulation and Manufacture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This chapter provides information on feed formulation and manufacture. To formulate and manufacture high quality fish feeds, including tilapia feeds, one should have knowledge of nutrient requirements, nutrient composition, digestibility, and availability of feed ingredients; impacts of manufacturin...

  19. Daily Fasting Blood Glucose Rhythm in Male Mice: A Role of the Circadian Clock in the Liver.

    PubMed

    Ando, Hitoshi; Ushijima, Kentaro; Shimba, Shigeki; Fujimura, Akio

    2016-02-01

    Fasting blood glucose (FBG) and hepatic glucose production are regulated according to a circadian rhythm. An early morning increase in FBG levels, which is pronounced among diabetic patients, is known as the dawn phenomenon. Although the intracellular circadian clock generates various molecular rhythms, whether the hepatic clock is involved in FBG rhythm remains unclear. To address this issue, we investigated the effects of phase shift and disruption of the hepatic clock on the FBG rhythm. In both C57BL/6J and diabetic ob/ob mice, FBG exhibited significant daily rhythms with a peak at the beginning of the dark phase. Light-phase restricted feeding altered the phase of FBG rhythm mildly in C57BL/6J mice and greatly in ob/ob mice, in concert with the phase shifts of mRNA expression rhythms of the clock and glucose production-related genes in the liver. Moreover, the rhythmicity of FBG and Glut2 expression was not detected in liver-specific Bmal1-deficient mice. Furthermore, treatment with octreotide suppressed the plasma growth hormone concentration but did not affect the hepatic mRNA expression of the clock genes or the rise in FBG during the latter half of the resting phase in C57BL/6J mice. These results suggest that the hepatic circadian clock plays a critical role in regulating the daily FBG rhythm, including the dawn phenomenon. PMID:26653333

  20. Circadian regulation gene polymorphisms are associated with sleep disruption and duration, and circadian phase and rhythm in adults with HIV.

    PubMed

    Lee, Kathryn A; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E

    2015-01-01

    Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep-wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72 h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST

  1. [Circadian variations in rat serum and urinary calcium and phosphorus. Reflections on the Ca/PO4 ratio].

    PubMed

    Gaggi, R; Bartolomei, N; David, M; Ghelfi, C; Ceresi, E

    1978-01-01

    Daily variations of serum and urine calcium and phosphate were determined in young and adult rats of both sexes. The animals were maintained in natural conditions of illumination and feeding ad libitum. The twenty-four hour rhythm of the serum levels and urinary excretion of these electrolytes in male rats is confirmed. This rhythm is markedly modified in young females and less in adult females. Evidence for a circadian rhythm of the Ca/PO4 ratio appears in all groups of rats. The rhythms of serum and urine Ca/PO4 rations are similar in all experimental groups. PMID:555322

  2. Meal-feeding rodents and toxicology research.

    PubMed

    Carey, Gale B; Merrill, Lisa C

    2012-08-20

    Most laboratory rodents used for toxicology studies are fed ad libitum, with unlimited access to food. As a result, ad libitum-fed rodents tend to overeat. Research demonstrates that ad libitum-fed rodents are physiologically and metabolically different from rodents fed controlled amounts of food at scheduled times (meal-fed). Ad libitum-fed rodents can develop hypertriglyceridemia, hypercholesterolemia, diet-induced obesity, nephropathy, cardiomyopathy, and pituitary, pancreatic, adrenal, and thyroid tumors, conditions likely to affect the results of toxicology research studies. In contrast, meal-feeding synchronizes biological rhythms and leads to a longer life span, lower body weight, lower body temperature, hypertrophy of the small intestine, and synchronization of hepatic and digestive enzymes. The circadian rhythms present in nearly all living organisms are entrained by light intensity and food intake, and peripheral clocks in all organs of the body, especially the GI tract and liver, are particularly sensitive to food intake. Feeding schedule has been demonstrated to alter the toxicity and metabolism of drugs including sodium valproate, chloral hydrate, acetaminophen, gentamicin, and methotrexate. Feeding schedule alters the expression of genes that code for Phase I, II, and III proteins, thereby altering the rate and amplitude of drug disposition. Rhythms of plasma insulin and glucagon that fluctuate with food ingestion are also altered by feeding schedule; ad libitum feeding promotes hyperinsulinemia which is a precursor for developing diabetes. The emerging field of chronopharmacology, the interaction of biological rhythms and drugs, will lead to optimizing the design and delivery of drugs in a manner that matches biological rhythms, but it is wise for toxicology researchers to consider feeding schedule when designing these experiments. It has been 10 years since the Society for Toxicologic Pathology voiced its position that feeding schedule is an

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

    PubMed

    Gilardi, Federica; Migliavacca, Eugenia; Naldi, Aurélien; Baruchet, Michaël; Canella, Donatella; Le Martelot, Gwendal; Guex, Nicolas; Desvergne, Béatrice

    2014-03-01

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

  4. Pinealectomy shortens resynchronisation times of house sparrow (Passer domesticus) circadian rhythms.

    PubMed

    Kumar, Vinod; Gwinner, Eberhard

    2005-09-01

    In many birds periodic melatonin secretion by the pineal organ is essential for the high-amplitude self-sustained output of the circadian pacemaker, and thus for the persistence of rhythmicity in 24 h oscillations controlled by it. The elimination of the pineal melatonin rhythm, or a reduction of its amplitude, renders the circadian pacemaker a less self-sustained, often highly damped, oscillatory system. A reduction in the degree of self-sustainment of a rhythm should not only increase its range of entrainment but also shorten the resynchronization times following phase-shifts of the zeitgeber. This hypothesis has not yet been directly tested. We therefore carried out the present study in which house sparrows (Passer domesticus) were subjected to both 6-h advance and 6-h delay phase-shifts of the light-dark cycle before and after the pinealectomy, and the rhythms in locomotion and feeding were recorded. The results indicate that following the delay, but not the advance, phase shift, resynchronization times were significantly shorter after pinealectomy. The dependence of resynchronization times on the presence or absence of the pineal organ is not only of theoretical interest but might also be of functional significance in the natural life of birds. A reduction or elimination of the amplitude of the melatonin secretion rhythm by the pineal organ might be responsible for faster adjustment to changes in zeitgeber conditions in nature. PMID:16151793

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

    PubMed Central

    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

  6. Light masking of circadian rhythms of heat production, heat loss, and body temperature in squirrel monkeys

    NASA Technical Reports Server (NTRS)

    Robinson, E. L.; Fuller, C. A.

    1999-01-01

    Whole body heat production (HP) and heat loss (HL) were examined to determine their relative contributions to light masking of the circadian rhythm in body temperature (Tb). Squirrel monkey metabolism (n = 6) was monitored by both indirect and direct calorimetry, with telemetered measurement of body temperature and activity. Feeding was also measured. Responses to an entraining light-dark (LD) cycle (LD 12:12) and a masking LD cycle (LD 2:2) were compared. HP and HL contributed to both the daily rhythm and the masking changes in Tb. All variables showed phase-dependent masking responses. Masking transients at L or D transitions were generally greater during subjective day; however, L masking resulted in sustained elevation of Tb, HP, and HL during subjective night. Parallel, apparently compensatory, changes of HL and HP suggest action by both the circadian timing system and light masking on Tb set point. Furthermore, transient HL increases during subjective night suggest that gain change may supplement set point regulation of Tb.

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

    PubMed

    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

  8. Circadian Rhythmicity of Active GSK3 Isoforms Modulates Molecular Clock Gene Rhythms in the Suprachiasmatic Nucleus

    PubMed Central

    Besing, R.C.; Paul, J.R.; Hablitz, L.M.; Rogers, C.O.; Johnson, R.L.; Young, M.E.; Gamble, K.L.

    2015-01-01

    The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprised of clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least five core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3β isoform. Whether phosphorylation of the other primary isoform (GSK3α) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (α and β) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN from wild-type mice housed in constant darkness for two weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 μM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. PMID:25724980

  9. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane.

    PubMed

    Kenwood, Brandon M; Weaver, Janelle L; Bajwa, Amandeep; Poon, Ivan K; Byrne, Frances L; Murrow, Beverley A; Calderone, Joseph A; Huang, Liping; Divakaruni, Ajit S; Tomsig, Jose L; Okabe, Kohki; Lo, Ryan H; Cameron Coleman, G; Columbus, Linda; Yan, Zhen; Saucerman, Jeffrey J; Smith, Jeffrey S; Holmes, Jeffrey W; Lynch, Kevin R; Ravichandran, Kodi S; Uchiyama, Seiichi; Santos, Webster L; Rogers, George W; Okusa, Mark D; Bayliss, Douglas A; Hoehn, Kyle L

    2014-04-01

    Dysregulation of oxidative phosphorylation is associated with increased mitochondrial reactive oxygen species production and some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Chemical 'mitochondrial uncouplers' are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. Mitochondrial uncouplers also lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing production of reactive oxygen species. Thus, mitochondrial uncouplers are valuable chemical tools that enable the measurement of maximal mitochondrial respiration and they have been used therapeutically to decrease mitochondrial reactive oxygen species production. However, the most widely used protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol have off-target activity at other membranes that lead to a range of undesired effects including plasma membrane depolarization, mitochondrial inhibition, and cytotoxicity. These unwanted properties interfere with the measurement of mitochondrial function and result in a narrow therapeutic index that limits their usefulness in the clinic. To identify new mitochondrial uncouplers that lack off-target activity at the plasma membrane we screened a small molecule chemical library. Herein we report the identification and validation of a novel mitochondrial protonophore uncoupler (2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine, named BAM15, that does not depolarize the plasma membrane. Compared to FCCP, an uncoupler of equal potency, BAM15 treatment of cultured cells stimulates a higher maximum rate of mitochondrial respiration and is less cytotoxic. Furthermore, BAM15 is bioactive in vivo and dose

  10. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane☆

    PubMed Central

    Kenwood, Brandon M.; Weaver, Janelle L.; Bajwa, Amandeep; Poon, Ivan K.; Byrne, Frances L.; Murrow, Beverley A.; Calderone, Joseph A.; Huang, Liping; Divakaruni, Ajit S.; Tomsig, Jose L.; Okabe, Kohki; Lo, Ryan H.; Cameron Coleman, G.; Columbus, Linda; Yan, Zhen; Saucerman, Jeffrey J.; Smith, Jeffrey S.; Holmes, Jeffrey W.; Lynch, Kevin R.; Ravichandran, Kodi S.; Uchiyama, Seiichi; Santos, Webster L.; Rogers, George W.; Okusa, Mark D.; Bayliss, Douglas A.; Hoehn, Kyle L.

    2013-01-01

    Dysregulation of oxidative phosphorylation is associated with increased mitochondrial reactive oxygen species production and some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Chemical 'mitochondrial uncouplers' are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. Mitochondrial uncouplers also lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing production of reactive oxygen species. Thus, mitochondrial uncouplers are valuable chemical tools that enable the measurement of maximal mitochondrial respiration and they have been used therapeutically to decrease mitochondrial reactive oxygen species production. However, the most widely used protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol have off-target activity at other membranes that lead to a range of undesired effects including plasma membrane depolarization, mitochondrial inhibition, and cytotoxicity. These unwanted properties interfere with the measurement of mitochondrial function and result in a narrow therapeutic index that limits their usefulness in the clinic. To identify new mitochondrial uncouplers that lack off-target activity at the plasma membrane we screened a small molecule chemical library. Herein we report the identification and validation of a novel mitochondrial protonophore uncoupler (2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine, named BAM15, that does not depolarize the plasma membrane. Compared to FCCP, an uncoupler of equal potency, BAM15 treatment of cultured cells stimulates a higher maximum rate of mitochondrial respiration and is less cytotoxic. Furthermore, BAM15 is bioactive in vivo and dose

  11. Potent social synchronization can override photic entrainment of circadian rhythms

    PubMed Central

    Fuchikawa, Taro; Eban-Rothschild, Ada; Nagari, Moshe; Shemesh, Yair; Bloch, Guy

    2016-01-01

    Circadian rhythms in behaviour and physiology are important for animal health and survival. Studies with individually isolated animals in the laboratory have consistently emphasized the dominant role of light for the entrainment of circadian rhythms to relevant environmental cycles. Although in nature interactions with conspecifics are functionally significant, social signals are typically not considered important time-givers for the animal circadian clock. Our results challenge this view. By studying honeybees in an ecologically relevant context and using a massive data set, we demonstrate that social entrainment can be potent, may act without direct contact with other individuals and does not rely on gating the exposure to light. We show for the first time that social time cues stably entrain the clock, even in animals experiencing conflicting photic and social environmental cycles. These findings add to the growing appreciation for the importance of studying circadian rhythms in ecologically relevant contexts. PMID:27210069

  12. Similarities in the circadian clock and photoperiodism in plants

    PubMed Central

    Song, Young Hun; Ito, Shogo; Imaizumi, Takato

    2010-01-01

    Summary of recent advances Plants utilize circadian clocks to synchronize their physiological and developmental events with daily and yearly changes in the environment. Recent advances in Arabidopsis research have provided a better understanding of the molecular mechanisms of the circadian clock and photoperiodism. One of the most important questions is whether the mechanisms studied in Arabidopsis are conserved in other plants. Homologs of many Arabidopsis clock genes have been identified in various plants and some gene functions have been characterized. It seems that the circadian clocks in plants are similar. Recent success in molecular genetics has also revealed the mechanisms of photoperiodic flowering in cereals. The day-length sensing mechanisms appear to have diverged more between long-day plants and short-day plants than the circadian clock. PMID:20620097

  13. Circadian biology: a 2.5 billion year old clock.

    PubMed

    Loudon, Andrew S I

    2012-07-24

    A recent study suggests that circadian clocks may have evolved at the time of the Great Oxidation Event 2.5 billion years ago in order to drive detoxification of reactive oxygen species. PMID:22835791

  14. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy.

    PubMed

    Dallmann, Robert; Okyar, Alper; Lévi, Francis

    2016-05-01

    Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic understanding of the cell-autonomous molecular circadian oscillator and the circadian timing system as a whole has opened new conceptual and methodological lines of investigation to understand first, the clock's impact on a specific drug's daily variations or the effects/side effects of environmental substances, and second, how clock-controlled pathways are coordinated within a given tissue or organism. Today, there is an increased understanding of the circadian modulation of drug effects. Moreover, several molecular strategies are being developed to treat disease-dependent and drug-induced clock disruptions in humans. PMID:27066876

  15. Potent social synchronization can override photic entrainment of circadian rhythms.

    PubMed

    Fuchikawa, Taro; Eban-Rothschild, Ada; Nagari, Moshe; Shemesh, Yair; Bloch, Guy

    2016-01-01

    Circadian rhythms in behaviour and physiology are important for animal health and survival. Studies with individually isolated animals in the laboratory have consistently emphasized the dominant role of light for the entrainment of circadian rhythms to relevant environmental cycles. Although in nature interactions with conspecifics are functionally significant, social signals are typically not considered important time-givers for the animal circadian clock. Our results challenge this view. By studying honeybees in an ecologically relevant context and using a massive data set, we demonstrate that social entrainment can be potent, may act without direct contact with other individuals and does not rely on gating the exposure to light. We show for the first time that social time cues stably entrain the clock, even in animals experiencing conflicting photic and social environmental cycles. These findings add to the growing appreciation for the importance of studying circadian rhythms in ecologically relevant contexts. PMID:27210069

  16. Metabolic Compensation and Circadian Resilience in Prokaryotic Cyanobacteria

    PubMed Central

    Johnson, Carl Hirschie; Egli, Martin

    2014-01-01

    For a biological oscillator to function as a circadian pacemaker that confers a fitness advantage, its timing functions must be stable in response to environmental and metabolic fluctuations. One such stability enhancer, temperature compensation, has long been a defining characteristic of these timekeepers. However, an accurate biological timekeeper must also resist changes in metabolism, and this review suggests that temperature compensation is actually a subset of a larger phenomenon, namely metabolic compensation, which maintains the frequency of circadian oscillators in response to a host of factors that impinge on metabolism and would otherwise destabilize these clocks. The circadian system of prokaryotic cyanobacteria is an illustrative model because it is composed of transcriptional and nontranscriptional oscillators that are coupled to promote resilience. Moreover, the cyanobacterial circadian program regulates gene activity and metabolic pathways, and it can be manipulated to improve the expression of bioproducts that have practical value. PMID:24905782

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

    PubMed Central

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

    2014-01-01

    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 circadian clock at various checkpoints of the cell cycle and also how the cell cycle can influence biological rhythms. The reciprocal influence that the circadian clock and cell cycle exert on each other suggests that these intertwined biological circuits are essential and multiple regulatory/control steps have been instated to ensure proper timekeeping. PMID:23969329

  18. Preliminary characterization of persisting circadian rhythms during space flight

    NASA Technical Reports Server (NTRS)

    Sultzman, F. M.

    1984-01-01

    In order to evaluate the function of the circadian timing system in space, the circadian rhythm of conidiation of the fungus Neurospora crassa was monitored in constant darkness on the STS 9 flight of the Space Shuttle Columbia. During the first 7 days of spaceflight many tubes showed a marked reduction in the apparent amplitude of the conidiation rhythm, and some cultures appeared arrhythmic. There was more variability in the growth rate and circadian rhythms of individual cultures in space than is usually seen on earth. The results of this experiment indicate that while the circadian rhythm of Neurospora conidiation can persist outside of the earth's environment, either the timekeeping process or its expression is altered in space.

  19. Circadian rhythmicity as a predictor of weight-loss effectiveness

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Some of the major challenges associated with successful dietary weight management include the identification of individuals not responsive to specific interventions. The aim was to investigate the potential relationship between weight loss and circadian rhythmicity, using wrist temperature and actim...

  20. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators.

    PubMed

    Mohawk, Jennifer A; Takahashi, Joseph S

    2011-07-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this review we will highlight recent advances in our knowledge of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

  1. Modeling and Validating Chronic Pharmacological Manipulation of Circadian Rhythms

    PubMed Central

    Kim, J K; Forger, D B; Marconi, M; Wood, D; Doran, A; Wager, T; Chang, C; Walton, K M

    2013-01-01

    Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1δ/ε inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from the molecular to the behavioral level. By developing a systems pharmacology model, we predict and experimentally validate that chronic CK1δ/ε inhibition during the earlier hours of a LD cycle can produce a constant stable delay of rhythm. However, chronic dosing later during the day, or in the presence of longer light intervals, is not predicted to yield an entrained rhythm. We also propose a simple method based on phase response curves (PRCs) that predicts the effects of a LD cycle and chronic dosing of a circadian drug. This work indicates that dosing timing and environmental signals must be carefully considered for accurate pharmacological manipulation of circadian phase. PMID:23863866

  2. Circadian Phase Resetting via Single and Multiple Control Targets

    PubMed Central

    Bagheri, Neda; Stelling, Jörg; Doyle, Francis J.

    2008-01-01

    Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm) out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness. PMID:18795146

  3. Cell Autonomy and Synchrony of Suprachiasmatic Nucleus Circadian Oscillators

    PubMed Central

    Mohawk, Jennifer A.; Takahashi, Joseph S.

    2013-01-01

    The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this Review, we will highlight recent advances in our understanding of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

  4. Circadian Influence on Metabolism and Inflammation in Atherosclerosis.

    PubMed

    McAlpine, Cameron S; Swirski, Filip K

    2016-06-24

    Many aspects of human health and disease display daily rhythmicity. The brain's suprachiasmic nucleus, which interprets recurring external stimuli, and autonomous molecular networks in peripheral cells together, set our biological circadian clock. Disrupted or misaligned circadian rhythms promote multiple pathologies including chronic inflammatory and metabolic diseases such as atherosclerosis. Here, we discuss studies suggesting that circadian fluctuations in the vessel wall and in the circulation contribute to atherogenesis. Data from humans and mice indicate that an impaired molecular clock, disturbed sleep, and shifting light-dark patterns influence leukocyte and lipid supply in the circulation and alter cellular behavior in atherosclerotic lesions. We propose that a better understanding of both local and systemic circadian rhythms in atherosclerosis will enhance clinical management, treatment, and public health policy. PMID:27340272

  5. Thermoregulation is impaired in an environment without circadian time cues

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.; Sulzman, F. M.; Moore-Ede, M. C.

    1978-01-01

    Thirteen adult male squirrel monkeys were restrained to a metabolism chair for periods of two or more weeks within an isolation chamber having controlled environmental lighting and ambient temperature. The monkeys were subjected to mild 6-hour cold exposures at all circadian phases of the day. It was found that a prominent circadian rhythm in body temperature, regulated against mild cold exposure, was present in those monkeys synchronized in a 24-hour light-dark cycle. Cold exposures were found to produce decreased core body temperatures when the circadian rhythms were free running or when environmental time indicators were not present. It is concluded that the thermoregulating system depends on the internal synchronization of the circadian time-keeping system.

  6. Circadian Disruption and Metabolic Disease: Findings from Animal Models

    PubMed Central

    Arble, Deanna Marie; Ramsey, Kathryn Moynihan; Bass, Joseph

    2010-01-01

    Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease. PMID:21112026

  7. Effects of metabolic uncouplers on excess sludge reduction and microbial products of activated sludge.

    PubMed

    Fang, Fang; Hu, Hai-Lan; Qin, Min-Min; Xue, Zhao-Xia; Cao, Jia-Shun; Hu, Zhi-Rong

    2015-06-01

    The present study investigated the influences of three metabolic uncouplers (pCP, oCP and oNP) on excess activated sludge reduction and microbial products of extracellular polymeric substances (EPS) and intracellular storage product (polyhydroxybutyrate, PHB) in short-term tests. Results showed sludge was reduced 58.2%, 59.8% and 80.8%, respectively, at pCP, oCP and oNP concentrations of 20mg/L. The dosage of three uncouplers had no obviously influences on COD removal and sludge settleability, but had significant inhibition effect on ammonia removal, especially for oNP. Low concentration of pCP and oNP (5mg/L) dosing resulted in protein and polysaccharide content increased in EPS, however, they were decreased at high pCP and oNP concentrations (>5mg/L). To oCP, the protein content in EPS was increased linearly with oCP concentration. Furthermore, metabolic uncouplers addition stimulated the production of PHB. Among three uncouplers, oCP could be an alternative uncoupler for sludge reduction in activated sludge process. PMID:25746471

  8. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

    PubMed Central

    Echtay, Karim S.; Esteves, Telma C.; Pakay, Julian L.; Jekabsons, Mika B.; Lambert, Adrian J.; Portero-Otín, Manuel; Pamplona, Reinald; Vidal-Puig, Antonio J.; Wang, Steven; Roebuck, Stephen J.; Brand, Martin D.

    2003-01-01

    Oxidative stress and mitochondrial dysfunction are associated with disease and aging. Oxidative stress results from overproduction of reactive oxygen species (ROS), often leading to peroxidation of membrane phospholipids and production of reactive aldehydes, particularly 4-hydroxy-2-nonenal. Mild uncoupling of oxidative phosphorylation protects by decreasing mitochondrial ROS production. We find that hydroxynonenal and structurally related compounds (such as trans-retinoic acid, trans-retinal and other 2-alkenals) specifically induce uncoupling of mitochondria through the uncoupling proteins UCP1, UCP2 and UCP3 and the adenine nucleotide translocase (ANT). Hydroxynonenal-induced uncoupling was inhibited by potent inhibitors of ANT (carboxyatractylate and bongkrekate) and UCP (GDP). The GDP-sensitive proton conductance induced by hydroxynonenal correlated with tissue expression of UCPs, appeared in yeast mitochondria expressing UCP1 and was absent in skeletal muscle mitochondria from UCP3 knockout mice. The carboxyatractylate-sensitive hydroxynonenal stimulation correlated with ANT content in mitochondria from Drosophila melanogaster expressing different amounts of ANT. Our findings indicate that hydroxynonenal is not merely toxic, but may be a biological signal to induce uncoupling through UCPs and ANT and thus decrease mitochondrial ROS production. PMID:12912909

  9. Circadian clocks, obesity and cardiometabolic function.

    PubMed

    Scott, E M

    2015-09-01

    Life on earth is governed by the continuous 24-h cycle of light and dark. Organisms have adapted to this environment with clear diurnal rhythms in their physiology and metabolism, enabling them to anticipate predictable environmental fluctuations over the day and to optimize the timing of relevant biological processes to this cycle. These rhythms are regulated by molecular circadian clocks, and current evidence suggests that interactions between the central and peripheral molecular clocks are important in metabolic and vascular functions. Disrupting this process through mutations in the core clock genes or by interfering with the environmental zeitgebers that entrain the clock appear to modulate the function of cells and tissues, leading to an increased risk for cardiometabolic disease. PMID:26332972

  10. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity

    PubMed Central

    Parekh, Puja K.; McClung, Colleen A.

    2016-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  11. Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity.

    PubMed

    Parekh, Puja K; McClung, Colleen A

    2015-01-01

    Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward

  12. System identification of the Arabidopsis plant circadian system

    NASA Astrophysics Data System (ADS)

    Foo, Mathias; Somers, David E.; Kim, Pan-Jun

    2015-02-01

    The circadian system generates an endogenous oscillatory rhythm that governs the daily activities of organisms in nature. It offers adaptive advantages to organisms through a coordination of their biological functions with the optimal time of day. In this paper, a model of the circadian system in the plant Arabidopsis (species thaliana) is built by using system identification techniques. Prior knowledge about the physical interactions of the genes and the proteins in the plant circadian system is incorporated in the model building exercise. The model is built by using primarily experimentally-verified direct interactions between the genes and the proteins with the available data on mRNA and protein abundances from the circadian system. Our analysis reveals a great performance of the model in predicting the dynamics of the plant circadian system through the effect of diverse internal and external perturbations (gene knockouts and day-length changes). Furthermore, we found that the circadian oscillatory rhythm is robust and does not vary much with the biochemical parameters except those of a light-sensitive protein P and a transcription factor TOC1. In other words, the circadian rhythmic profile is largely a consequence of the network's architecture rather than its particular parameters. Our work suggests that the current experimental knowledge of the gene-to-protein interactions in the plant Arabidopsis, without considering any additional hypothetical interactions, seems to suffice for system-level modeling of the circadian system of this plant and to present an exemplary platform for the control of network dynamics in complex living organisms.

  13. Circadian regulation of slow waves in human sleep: Topographical aspects

    PubMed Central

    Lazar, Alpar S.; Lazar, Zsolt I.; Dijk, Derk-Jan

    2015-01-01

    Slow waves (SWs, 0.5–4 Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  14. Circadian regulation of slow waves in human sleep: Topographical aspects.

    PubMed

    Lazar, Alpar S; Lazar, Zsolt I; Dijk, Derk-Jan

    2015-08-01

    Slow waves (SWs, 0.5-4Hz) in field potentials during sleep reflect synchronized alternations between bursts of action potentials and periods of membrane hyperpolarization of cortical neurons. SWs decline during sleep and this is thought to be related to a reduction of synaptic strength in cortical networks and to be central to sleep's role in maintaining brain function. A central assumption in current concepts of sleep function is that SWs during sleep, and associated recovery processes, are independent of circadian rhythmicity. We tested this hypothesis by quantifying all SWs from 12 EEG derivations in 34 participants in whom 231 sleep periods were scheduled across the circadian cycle in a 10-day forced-desynchrony protocol which allowed estimation of the separate circadian and sleep-dependent modulation of SWs. Circadian rhythmicity significantly modulated the incidence, amplitude, frequency and the slope of the SWs such that the peaks of the circadian rhythms in these slow-wave parameters were located during the biological day. Topographical analyses demonstrated that the sleep-dependent modulation of SW characteristics was most prominent in frontal brain areas whereas the circadian effect was similar to or greater than the sleep-dependent modulation over the central and posterior brain regions. The data demonstrate that circadian rhythmicity directly modulates characteristics of SWs thought to be related to synaptic plasticity and that this modulation depends on topography. These findings have implications for the understanding of local sleep regulation and conditions such as ageing, depression, and neurodegeneration which are associated with changes in SWs, neural plasticity and circadian rhythmicity. PMID:25979664

  15. Circadian Control Sheds Light on Fungal Bioluminescence

    PubMed Central

    Oliveira, Anderson G.; Stevani, Cassius V.; Waldenmaier, Hans E.; Viviani, Vadim; Emerson, Jillian M.; Loros, Jennifer J.; Dunlap, Jay C.

    2015-01-01

    Summary Bioluminescence, the creation and emission of light by organisms, affords insight into the lives of organisms doing it. Luminous living things are widespread and access diverse mechanisms to generate and control luminescence [1-5]. Among the least studied bioluminescent organisms are phylogenetically rare fungi – only 71 species, all within the ~9000 fungi of the temperate and tropical Agaricales Order - are reported from among ~100,000 described fungal species [6,7]. All require oxygen [8] and energy (NADH or NADPH) for bioluminescence, and are reported to emit green light (λmax 530 nm) continuously, implying a metabolic function for bioluminescence, perhaps as a by-product of oxidative metabolism in lignin degradation. Here, however, we report that bioluminescence from the mycelium of Neonothopanus gardneri is controlled by a temperature compensated circadian clock, the result of cycles in content/activity of the luciferase, reductase, and the luciferin that comprise the luminescent system. Because regulation implies an adaptive function for bioluminescence, a controversial question for more than two millenia [8-15], we examined interactions between luminescent fungi and insects [16]. Prosthetic acrylic resin “mushrooms”, internally illuminated by a green LED emitting light similar to the bioluminescence, attract staphilinid rove beetles (coleopterans) as well as hemipterans (true bugs), dipterans (flies), and hymenopterans (wasps and ants) at numbers far greater than dark control traps. Thus, circadian control may optimize energy use for when bioluminescence is most visible, attracting insects that can in turn help in spore dispersal, thereby benefitting fungi growing under the forest canopy where wind flow is greatly reduced. PMID:25802150

  16. Spectral sensitivity of the circadian system

    NASA Astrophysics Data System (ADS)

    Figueiro, Mariana G.; Bullough, John D.; Rea, Mark S.

    2004-01-01

    Light exposure regulates several circadian functions in normal humans including the sleep-wake cycle. Individuals with Alzheimer"s Disease (AD) often do not have regular patterns of activity and rest, but, rather, experience random periods of sleep and agitation during both day and night. Bright light during the day and darkness at night has been shown to consolidate activity periods during the day and rest periods at night in AD patients. The important characteristics of bright light exposure (quantity, spectrum, distribution, timing and duration) for achieving these results in AD patients is not yet understood. Recent research has shown that moderate (~18 lx at the cornea) blue (~470 nm) light is effective at suppressing melatonin in normal humans. It was hypothesized that blue light applied just before AD patients retire to their beds for the night would have a measurable impact on their behavior. A pilot study was conducted for 30 days in a senior health care facility using four individuals diagnosed with mild to moderate levels of dementia. Four AD patients were exposed to arrays of blue light from light emitting diodes (max wavelength = 470 nm) in two-hour sessions (18:00 to 20:00 hours) for 10 days. As a control, they were exposed to red light (max wavelength = 640 nm) in two-hour sessions for 10 days prior to the blue light exposure. Despite the modest sample size, exposure to blue LEDs has shown to affect sleep quality and median body temperature peak of these AD patients. Median body temperature peak was delayed by approximately 2 hours after exposure to blue LEDs compared to exposure to red LEDs and sleep quality was improved. This pilot study demonstrated that light, especially LEDs, can be an important contribution to helping AD patients regulate their circadian functions.

  17. Circadian control sheds light on fungal bioluminescence.

    PubMed

    Oliveira, Anderson G; Stevani, Cassius V; Waldenmaier, Hans E; Viviani, Vadim; Emerson, Jillian M; Loros, Jennifer J; Dunlap, Jay C

    2015-03-30

    Bioluminescence, the creation and emission of light by organisms, affords insight into the lives of organisms doing it. Luminous living things are widespread and access diverse mechanisms to generate and control luminescence [1-5]. Among the least studied bioluminescent organisms are phylogenetically rare fungi-only 71 species, all within the ∼ 9,000 fungi of the temperate and tropical Agaricales order-are reported from among ∼ 100,000 described fungal species [6, 7]. All require oxygen [8] and energy (NADH or NADPH) for bioluminescence and are reported to emit green light (λmax 530 nm) continuously, implying a metabolic function for bioluminescence, perhaps as a byproduct of oxidative metabolism in lignin degradation. Here, however, we report that bioluminescence from the mycelium of Neonothopanus gardneri is controlled by a temperature-compensated circadian clock, the result of cycles in content/activity of the luciferase, reductase, and luciferin that comprise the luminescent system. Because regulation implies an adaptive function for bioluminescence, a controversial question for more than two millennia [8-15], we examined interactions between luminescent fungi and insects [16]. Prosthetic acrylic resin "mushrooms," internally illuminated by a green LED emitting light similar to the bioluminescence, attract staphilinid rove beetles (coleopterans), as well as hemipterans (true bugs), dipterans (flies), and hymenopterans (wasps and ants), at numbers far greater than dark control traps. Thus, circadian control may optimize energy use for when bioluminescence is most visible, attracting insects that can in turn help in spore dispersal, thereby benefitting fungi growing under the forest canopy, where wind flow is greatly reduced. PMID:25802150

  18. Development of a circadian light source

    NASA Astrophysics Data System (ADS)

    Nicol, David B.; Ferguson, Ian T.

    2002-11-01

    Solid state lighting presents a new paradigm for lighting - controllability. Certain characteristics of the lighting environment can be manipulated, because of the possibility of using multiple LEDs of different emission wavelengths as the illumination source. This will provide a new, versatile, general illumination source due to the ability to vary the spectral power distribution. New effects beyond the visual may be achieved that are not possible with conventional light sources. Illumination has long been the primary function of lighting but as the lighting industry has matured the psychological aspects of lighting have been considered by designers; for example, choosing a particular lighting distribution or color variation in retail applications. The next step in the evolution of light is to consider the physiological effects of lighting that cause biological changes in a person within the environment. This work presents the development of a source that may have important bearing on this area of lighting. A circadian light source has been developed to provide an illumination source that works by modulating its correlated color temperature to mimic the changes in natural daylight through the day. In addition, this source can cause or control physiological effects for a person illuminated by it. The importance of this is seen in the human circadian rhythm's peak response corresponding to blue light at ~460 nm which corresponds to the primary spectral difference in increasing color temperature. The device works by adding blue light to a broadband source or mixing polychromatic light to mimic the variation of color temperature observed for the Planckian Locus on the CIE diagram. This device can have several applications including: a tool for researchers in this area, a general illumination lighting technology, and a light therapy device.

  19. Circadian variation in gastric vagal afferent mechanosensitivity.

    PubMed

    Kentish, Stephen J; Frisby, Claudine L; Kennaway, David J; Wittert, Gary A; Page, Amanda J

    2013-12-01

    Food intake is coordinated to cellular metabolism by clock gene expression with a master clock in the suprachiasmatic nucleus synchronized by light exposure. Gastric vagal afferents play a role in regulating food intake, but it is unknown whether they exhibit circadian variation in their mechanosensitivity. We aimed to determine whether gastric vagal afferents express clock genes and whether their response to mechanical stimuli oscillates throughout the light/dark cycle. Nodose ganglia were collected from 8-week-old female C57BL/6 mice every 3 h starting at lights off (1800 h) to quantify Bmal1, Per1, Per2, and Nr1d1 mRNA by qRT-PCR. Additionally in vitro single-fiber recordings of gastric vagal mechanoreceptors were taken at all time points. Per1, Per2, Bmal1, and Nr1d1 mRNA is expressed in the nodose ganglia and levels oscillated over a 24 h period. In mice fed ad libitum, gastric content was 3 times higher at 0000 h and 0300 h than 1200 h. The response of tension receptors to 3 g stretch was reduced by up to 70% at 2100 h, 0000 h, and 0300 h compared with 1200 h. Gastric mucosal receptor response to stroking with a 50 mg von Frey hair was 3 times greater at 1200 h and 1500 h than the response at 0000 h. Similar findings were obtained in mice fasted for 6 h or maintained in darkness for 3 d before study. Therefore, these changes do not result from food intake or the light/dark cycle. Thus, gastric vagal mechanoreceptors display circadian rhythm, which may act to control food intake differentially at different times of the day. PMID:24305819

  20. Changes in Gene Expression Patterns of Circadian-Clock, Transient Receptor Potential Vanilloid-1 and Nerve Growth Factor in Inflamed Human Esophagus

    PubMed Central

    Yang, Shu-Chuan; Chen, Chien-Lin; Yi, Chih-Hsun; Liu, Tso-Tsai; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythm is driven by the molecular circadian-clock system and regulates many physiological functions. Diurnal rhythms in the gastrointestinal tract are known to be related to feeding pattern, but whether these rhythms are also related to the gastrointestinal damage or injuries; for example, gastroesophageal reflux disease (GERD), is unclear. This study was conducted to determine whether expression of circadian-clock genes or factors involved in vagal stimulation or sensitization were altered in the esophagus of GERD patients. Diurnal patterns of PER1, PER2, BMAL1, CRY2, TRPV1, and NGF mRNA expression were found in patient controls, and these patterns were altered and significantly correlated to the GERD severity in GERD patients. Although levels of CRY1, TIM, CB1, NHE3, GDNF, and TAC1 mRNA expression did not show diurnal patterns, they were elevated and also correlated with GERD severity in GERD patients. Finally, strong correlations among PER1, TRPV1, NGF and CRY2 mRNA expression, and among PER2, TRPV1 and CRY2 expression were found. Expression levels of CRY1 mRNA highly correlated with levels of TIM, CB1, NHE3, GDNF and TAC1. This study suggests that the circadian rhythm in the esophagus may be important for the mediation of and/or the response to erosive damage in GERD patients. PMID:26337663