Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short-acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia.
Frank A J L Scheer
Full Text Available Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol, which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2 for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.
Micó, Víctor; Díez-Ricote, Laura; Daimiel, Lidia
Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future.
Bonmati-Carrion, Maria Angeles; Hild, Konstanze; Isherwood, Cheryl; Sweeney, Stephen J.; Revell, Victoria L.; Skene, Debra J.; Rol, Maria Angeles; Madrid, Juan Antonio
Intrinsically photosensitive retinal ganglion cells (ipRGCs), whose photopigment melanopsin has a peak of sensitivity in the short wavelength range of the spectrum, constitute a common light input pathway to the olivary pretectal nucleus (OPN), the pupillary light reflex (PLR) regulatory centre, and to the suprachiasmatic nuclei (SCN), the major pacemaker of the circadian system. Thus, evaluating PLR under short wavelength light (λmax ≤ 500 nm) and creating an integrated PLR parameter, as a possible tool to indirectly assess the status of the circadian system, becomes of interest. Nine monochromatic, photon-matched light stimuli (300 s), in 10 nm increments from λmax 420 to 500 nm were administered to 15 healthy young participants (8 females), analyzing: i) the PLR; ii) wrist temperature (WT) and motor activity rhythms (WA), iii) light exposure (L) pattern and iv) diurnal preference (Horne-Östberg), sleep quality (Pittsburgh) and daytime sleepiness (Epworth). Linear correlations between the different PLR parameters and circadian status index obtained from WT, WA and L recordings and scores from questionnaires were calculated. In summary, we found markers of robust circadian rhythms, namely high stability, reduced fragmentation, high amplitude, phase advance and low internal desynchronization, were correlated with a reduced PLR to 460–490 nm wavelengths. Integrated circadian (CSI) and PLR (cp-PLR) parameters are proposed, that also showed an inverse correlation. These results demonstrate, for the first time, the existence of a close relationship between the circadian system robustness and the pupillary reflex response, two non-visual functions primarily under melanopsin-ipRGC input. PMID:27636197
Frank A J L Scheer
Full Text Available BACKGROUND: Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (~9 AM, potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1 platelet function and (2 platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise. METHODOLOGY/PRINCIPAL FINDINGS: We studied 12 healthy adults (6 female who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p ≤ 0.01. These circadian peaks occurred at a circadian phase corresponding to 8-9 AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8 PM. The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors. CONCLUSIONS/SIGNIFICANCE: These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans--independent of the sleep/wake cycle, other behavioral influences and the environment. The 9 AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the
Roenneberg, Till; Merrow, Martha
Circadian systems direct many metabolic parameters and, at the same time, they appear to be exquisitely shielded from metabolic variations. Although the recent decade of circadian research has brought insights into how circadian periodicity may be generated at the molecular level, little is known ab
Lin, Li-Ling; Huang, Hsuan-Cheng; Juan, Hsueh-Fen
Systems biology, which can be defined as integrative biology, comprises multistage processes that can be used to understand components of complex biological systems of living organisms and provides hierarchical information to decoding life. Using systems biology approaches such as genomics, transcriptomics and proteomics, it is now possible to delineate more complicated interactions between circadian control systems and diseases. The circadian rhythm is a multiscale phenomenon existing within the body that influences numerous physiological activities such as changes in gene expression, protein turnover, metabolism and human behavior. In this review, we describe the relationships between the circadian control system and its related genes or proteins, and circadian rhythm disorders in systems biology studies. To maintain and modulate circadian oscillation, cells possess elaborative feedback loops composed of circadian core proteins that regulate the expression of other genes through their transcriptional activities. The disruption of these rhythms has been reported to be associated with diseases such as arrhythmia, obesity, insulin resistance, carcinogenesis and disruptions in natural oscillations in the control of cell growth. This review demonstrates that lifestyle is considered as a fundamental factor that modifies circadian rhythm, and the development of dysfunctions and diseases could be regulated by an underlying expression network with multiple circadian-associated signals.
Potter, Gregory D M; Cade, Janet E; Grant, Peter J; Hardie, Laura J
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.
Scheer, Frank A J L; Hu, Kun; Evoniuk, Heather; Kelly, Erin E; Malhotra, Atul; Hilton, Michael F; Shea, Steven A
The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.
Kenneth P Wright
Full Text Available Cognitive and affective processes vary over the course of the 24 hour day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24-hour period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei, to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety.
Goel, Namni; Basner, Mathias; Rao, Hengyi; Dinges, David F.
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
Labrecque, Nathalie; Cermakian, Nicolas
The immune system is a complex set of physiological mechanisms whose general aim is to defend the organism against non-self-bodies, such as pathogens (bacteria, viruses, parasites), as well as cancer cells. Circadian rhythms are endogenous 24-h variations found in virtually all physiological processes. These circadian rhythms are generated by circadian clocks, located in most cell types, including cells of the immune system. This review presents an overview of the clocks in the immune system and of the circadian regulation of the function of immune cells. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens. Consequently, alterations of circadian rhythms (e.g., clock gene mutation in mice or environmental disruption similar to shift work) lead to disturbed immune responses. We discuss the implications of these data for human health and the areas that future research should aim to address.
Full Text Available Mariana G Figueiro, Andrew Bierman, Mark S ReaLighting Research Center, Rensselaer Polytechnic Institute, Troy, NY, USAAbstract: A model of circadian phototransduction was published in 2005 to predict the spectral sensitivity of the human circadian system to narrow-band and polychromatic light sources by combining responses to light from the spectral-opponent “blue” versus “yellow” cone bipolar pathway with direct responses to light by the intrinsically photosensitive retinal ganglion cells. In the model, depolarizing “blue” responses, but not hyperpolarizing “yellow” responses, from the “blue” versus “yellow” pathway are combined with the intrinsically photosensitive retinal ganglion cell responses. Intrinsically photosensitive retinal ganglion cell neurons are known to be much slower to respond to light than the cone pathway, so an implication of the model is that periodic flashes of “blue” light, but not “yellow” light, would be effective for stimulating the circadian system. A within-subjects study was designed to test the implications of the model regarding retinal exposures to brief flashes of light. The study was also aimed at broadening the foundation for clinical treatment of circadian sleep disorders by delivering flashing light through closed eyelids while people were asleep. In addition to a dark control night, the eyelids of 16 subjects were exposed to three light-stimulus conditions in the phase delay portion of the phase response curve while they were asleep: (1 2-second flashes of 111 W/m2 of blue (λmax ≈ 480 nm light once every minute for 1 hour, (2 131 W/m2 of green (λmax ≈ 527 nm light, continuously on for 1 hour, and (3 2-second flashes of the same green light once every minute for 1 hour. Inferential statistics showed that the blue flash light-stimulus condition significantly delayed circadian phase and significantly suppressed nocturnal melatonin. The results of this study further our
Roenneberg, Till; Merrow, Martha
After approximately 50 years of circadian research, especially in selected circadian model systems (Drosophila, Neurospora, Gonyaulax and, more recently, cyanobacteria and mammals), we appreciate the enormous complexity of the circadian programme in organisms and cells, as well as in physiological a
Al-Nuaimi, Yusur; Hardman, Jonathan A; Bíró, Tamás; Haslam, Iain S; Philpott, Michael P; Tóth, Balázs I; Farjo, Nilofer; Farjo, Bessam; Baier, Gerold; Watson, Rachel E B; Grimaldi, Benedetto; Kloepper, Jennifer E; Paus, Ralf
The hair follicle (HF) is a continuously remodeled mini organ that cycles between growth (anagen), regression (catagen), and relative quiescence (telogen). As the anagen-to-catagen transformation of microdissected human scalp HFs can be observed in organ culture, it permits the study of the unknown controls of autonomous, rhythmic tissue remodeling of the HF, which intersects developmental, chronobiological, and growth-regulatory mechanisms. The hypothesis that the peripheral clock system is involved in hair cycle control, i.e., the anagen-to-catagen transformation, was tested. Here we show that in the absence of central clock influences, isolated, organ-cultured human HFs show circadian changes in the gene and protein expression of core clock genes (CLOCK, BMAL1, and Period1) and clock-controlled genes (c-Myc, NR1D1, and CDKN1A), with Period1 expression being hair cycle dependent. Knockdown of either BMAL1 or Period1 in human anagen HFs significantly prolonged anagen. This provides evidence that peripheral core clock genes modulate human HF cycling and are an integral component of the human hair cycle clock. Specifically, our study identifies BMAL1 and Period1 as potential therapeutic targets for modulating human hair growth.
sleep, including daily use of antihistamines or antidepressants. Subjects were of intermediate chronotype as determined by the Horne-Östberg...study of sleep and circadian rhythms. Sleep 26: 342–392. 12. Murphy PJ, Myers BL, Badia P (1996) Nonsteroidal anti-inflammatory drugs alter body
Full Text Available The basic principles of physiology postulated the necessity of the constancy of the internal environment to maintain a physiological equilibrium and do not front serious consequences in health. Now we know that physiology is rhythmic and that a break of this rhythmicity can generate serious consequences in health which even could be lethal. Circadian clocks, headed by the suprachiasmatic nucleus in the central nervous system, are the responsible for the generation of circadian rhythms. These clocks are affected by external signals as light (day-night cycles and feeding. This review examines the basic principles of the circadian system and the current knowledge in the neurobiology of biological clocks, making emphasis in the relationship between the circadian system, feeding behaviour, nutrition and metabolism, and the consequences that occur when these systems are not coordinated each other, as the development of metabolic and circadian pathologies.
National Aeronautics and Space Administration — The value of measuring sleep-wake cycles is significantly enhanced by measuring other physiological signals that depend on circadian rhythms (such as heart rate and...
Scheer, Frank A J L; Shea, Steven A
Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. Plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a key circulating prothrombotic factor that rises in the morning in humans. We tested whether this morning peak in PAI-1 is caused by the internal circadian system or by behaviors that typically occur in the morning, such as altered posture and physical activity. Twelve healthy adults underwent a 2-week protocol that enabled the distinction of endogenous circadian effects from behavioral and environmental effects. The results demonstrated a robust circadian rhythm in circulating PAI-1 with a peak corresponding to ∼6:30 am. This rhythm in PAI-1 was 8-times larger than changes in PAI-1 induced by standardized behavioral stressors, including head-up tilt and 15-minute cycle exercise. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events.
Carrasco-Benso, Maria P; Rivero-Gutierrez, Belen; Lopez-Minguez, Jesus; Anzola, Andrea; Diez-Noguera, Antoni; Madrid, Juan A; Lujan, Juan A; Martínez-Augustin, Olga; Scheer, Frank A J L; Garaulet, Marta
In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. © FASEB.
de Pedro, M A; Morán, J; Díaz, I; Murias, L; Fernández-Plaza, C; González, C; Díaz, E
Kisspeptin is an essential gatekeeper of reproductive function. During pregnancy high circulating levels of kisspeptin have been described, however the clear role of this neuropeptide in pregnancy remains unknown. We tested the existence of rhythmic kisspeptin expression in human full-term placenta from healthy pregnant women at six different time points during the day. The data obtained by Western blotting were fitted to a mathematical model (Fourier series), demonstrating, for the first time, the existence of a circadian rhythm in placental kisspeptin expression.
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.
Jiffin K Paulose
Full Text Available Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host's circadian clock. However, it is not clear how the host's clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks.
Full Text Available Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN. In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (approximately 50-70% of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system.
Hsu, Polly Yingshan; Harmer, Stacey L.
Circadian clocks integrate environmental signals with internal cues to coordinate diverse physiological outputs so that they occur at the most appropriate season or time of day. Recent studies using systems approaches, primarily in Arabidopsis, have expanded our understanding of the molecular regulation of the central circadian oscillator and its connections to input and output pathways. Similar approaches have also begun to reveal the importance of the clock for key agricultural traits in crop species. In this review, we discuss recent developments in the field, including: a new understanding of the molecular architecture underlying the plant clock; mechanistic links between clock components and input and output pathways; and our growing understanding of the importance of clock genes for agronomically important traits. PMID:24373845
Hsu, Polly Yingshan; Harmer, Stacey L
Circadian clocks integrate environmental signals with internal cues to coordinate diverse physiological outputs so that they occur at the most appropriate season or time of day. Recent studies using systems approaches, primarily in Arabidopsis, have expanded our understanding of the molecular regulation of the central circadian oscillator and its connections to input and output pathways. Similar approaches have also begun to reveal the importance of the clock for key agricultural traits in crop species. In this review, we discuss recent developments in the field, including a new understanding of the molecular architecture underlying the plant clock; mechanistic links between clock components and input and output pathways; and our growing understanding of the importance of clock genes for agronomically important traits.
Foo, Mathias; Somers, David E.; Kim, Pan-Jun
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.
Zeitzer, Jamie M.; Fisicaro, Ryan A.; Ruby, Norman F.; Heller, H. Craig
The human circadian timing system is most sensitive to the phase shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a two-week circadian stabilization protocol followed by a two-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n=7) or a sequence of 2-msec light flashes given every 30 seconds (n=6) from hours 2–3 after habitual bed time. Changes in circadian timing (phase), micro- and macroarchitecture of sleep were all assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm as compared to the control dark condition (P0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 seconds of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether there is an effect of these light flashes on sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans. PMID:25227334
Møller, Morten; Lund-Andersen, Casper; Rovsing, Louise
The photoneuroendocrine circadian system of the brain consists of (a) specialized photoreceptors in the retina, (b) a circadian generator located in the forebrain that contains "clock genes," (c) specialized nuclei in the forebrain involved in neuroendocrine secretion, and (d) the pineal gland....... The circadian generator is a nucleus, called the suprachiasmatic nucleus (SCN). The neurons of this nucleus contain "clock genes," the transcription of which exhibits a circadian rhythm. Most circadian rhythms are generated by the neurons of this nucleus and, via neuronal and humoral connections, the SCN...... controls circadian activity of the brain and peripheral tissues. The endogenous oscillator of the SCN is each day entrained to the length of the daily photoperiod by light that reach the retina, and specialized photoreceptors transmit impulses to the SCN via the optic nerves. Mass screening for day...
Hut, R. A.; Van der Zee, E. A.
This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor
Pasqualetti, P; Colantonio, D; Casale, R; Colangeli, S; Natali, G
Circadian rhythm of lymphocyte subsets was investigated in four healthy subjects, males, aged 35-58 years old. After a period of ambiental synchronization, venous blood samples were taken during a span of a day at 0.00 a.m., 4.00 a.m., 8.00 a.m., noon, 4.00 p.m. and 8.00 p.m. Lymphocyte subsets (OKT3, OKT4, OKT8, OKB7, OKJa1) were determined by monoclonal antibodies method, and serum level of cortisol by radioimmunoassay method. The OKT4/OKT8 ratio was also calculated. Data were analyzed by chronograms (mean +/- 1SD) and by cosinor method. Results show a significant circadian rhythm for each lymphocyte subset and for serum cortisol levels. The lowest levels of all circulating subsets were seen between noon and 4.00 p.m. and the highest levels around midnight, inversely related with the circadian rhythm of serum cortisol. The OKT4/OKT8 ratio, on the contrary, was relatively constant during the day, without a significant circadian rhythm. These observations have laboratoristic, clinical, and therapeutic implications and should be considered in the course of immunological studies.
Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V
The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the
Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V
The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the f
Johnston, Jonathan D; Scheer, Frank A; Turek, Fred W
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. PMID:26980824
Figueiro, Mariana G.; Bullough, John D.; Rea, Mark S.
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.
Isorna, Esther; de Pedro, Nuria; Valenciano, Ana I; Alonso-Gómez, Ángel L; Delgado, María J
The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs.
Sunil, S A; Srikanth, M V; Rao, N Sreenivasa; Uhumwangho, M U; Latha, K; Murthy, K V Ramana
The purpose of writing this review on chronotherapeutic drug delivery systems (ChrDDs) is to review the literatures with special focus on ChrDDs and the various dosage forms, techniques that are used to target the circadian rhythms (CR) of various diseases. Many functions of the human body vary considerably in a day. ChrDDs refers to a treatment method in which in vivo drug availability is timed to match circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. Several techniques have been developed but not many dosage forms for all the diseases are available in the market. ChrDDs are gaining importance in the field of pharmaceutical technology as these systems reduce dosing frequency, toxicity and deliver the drug that matches the CR of that particular disease when the symptoms are maximum to worse. Finally, the ultimate benefit goes to the patient due the compliance and convenience of the dosage form. Some diseases that follow circadian rhythms include cardiovascular diseases, asthma, arthritis, ulcers, diabetes etc. ChrDDs in the market were also discussed and the current technologies used to formulate were also stated. These technologies include Contin® , Chronotopic®, Pulsincaps®, Ceform®, Timerx®, Oros®, Codas®, Diffucaps®, Egalet®, Tablet in capsule device, Core-in-cup tablet technology. A coated drug-core tablet matrix, A bi-layered tablet, Multiparticulate-based chronotherapeutic drug delivery systems, Chronoset and Controlled release microchips.
Olcese, James; Lozier, Stephen; Paradise, Courtney
Although the onset of spontaneous human parturition has long been known to occur preferentially during the nighttime and early morning hours, no convincing physiological explanation for this pattern has yet been proposed. This review focuses on the circadian timing of mammalian parturition, particularly in the human. It is proposed that differences in the phasing of parturition among different species are likely a function of opposite uterine responses to humoral cues, in particular those coding for time of day. The brain hormone melatonin fulfills many of the prerequisites to serve as a circadian signal for initiating uterine contractions that lead to human parturition. These encompass direct actions of melatonin on myometrial smooth muscle cells that are synergistic with oxytocin in facilitating greater uterine contractions at night. This may not only help to explain the nocturnal phasing of human parturition but also open new avenues for the management of term and preterm labor.
Circadian variability of circulating leptin levels has been well established over the last decade. However, the circadian behavior of leptin in human adipose tissue remains unknown. This also applies to the soluble leptin receptor. We investigated the ex vivo circadian behavior of leptin and its rec...
Jo, Hang-Hyun; Kertész, János; Kaski, Kimmo
The temporal pattern of human communication is inhomogeneous and bursty, as reflected by the heavy tail distribution of the inter-event times. For the origin of this behavior two main mechanisms have been suggested: a) Externally driven inhomogeneities due to the circadian and weekly activity patterns and b) intrinsic correlation based inhomogeneity rooted deeply in the task handling strategies of humans. Here we address this question by providing systematic de-seasoning methods to remove the circadian and weekly patterns from the time series of communication events. We find that the heavy tails of the inter-event time distributions are robust with respect to this procedure indicating that burstiness is mostly caused by the latter mechanism b). Moreover, we find that our de-seasoning procedure improves the scaling behavior of the distribution.
Ruby, Norman F; Hwang, Calvin E; Wessells, Colin; Fernandez, Fabian; Zhang, Pei; Sapolsky, Robert; Heller, H Craig
Decades of studies have shown that eliminating circadian rhythms of mammals does not compromise their health or longevity in the laboratory in any obvious way. These observations have raised questions about the functional significance of the mammalian circadian system, but have been difficult to address for lack of an appropriate animal model. Surgical ablation of the suprachiasmatic nucleus (SCN) and clock gene knockouts eliminate rhythms, but also damage adjacent brain regions or cause developmental effects that may impair cognitive or other physiological functions. We developed a method that avoids these problems and eliminates rhythms by noninvasive means in Siberian hamsters (Phodopus sungorus). The present study evaluated cognitive function in arrhythmic animals by using a hippocampal-dependent learning task. Control hamsters exhibited normal circadian modulation of performance in a delayed novel-object recognition task. By contrast, arrhythmic animals could not discriminate a novel object from a familiar one only 20 or 60 min after training. Memory performance was not related to prior sleep history as sleep manipulations had no effect on performance. The GABA antagonist pentylenetetrazol restored learning without restoring circadian rhythms. We conclude that the circadian system is involved in memory function in a manner that is independent of sleep. Circadian influence on learning may be exerted via cyclic GABA output from the SCN to target sites involved in learning. Arrhythmic hamsters may have failed to perform this task because of chronic inhibitory signaling from the SCN that interfered with the plastic mechanisms that encode learning in the hippocampus.
Zhao, Yue; Liu, Min; Chan, Xue Ying; Tan, Sue Yee; Subramaniam, Sharrada; Fan, Yong; Loh, Eva; Chang, Kenneth Tou En; Tan, Thiam Chye; Chen, Qingfeng
Many immune parameters show circadian rhythms over the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells which display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, while for humans they remain unclear due to the lack of a proper model. In this study, we found that consistent with their natural host species, mouse and human circulating leukocytes exhibited opposite circadian oscillations in humanized mice. This cyclic pattern of trafficking correlated well with the diurnal expression levels of CXCR4 which were controlled by the intracellular HIF-lα/ARNTLl heterodimer. Furthermore, we also discovered that p38MAPK/MK2 had opposite effects between mice and humans in generating intracellular reactive oxygen species which subsequently regulated HIF-1α expression. In conclusion, we propose humanized mice as a robust model for human circadian studies and reveal insights on a novel molecular clock network in the human circadian rhythm. Copyright © 2017 American Society of Hematology.
Wang, T; Jiang, Z; Hou, W; Li, Z; Cheng, S; Green, L A; Wang, Y; Wen, X; Cai, L; Clauss, M; Wang, Z
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. 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. 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. 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. © 2014 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.
Roenneberg, Till; Kuehnle, Tim; Juda, Myriam; Kantermann, Thomas; Allebrandt, Karla; Gordijn, Marijke; Merrow, Martha
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
Steven A Brown
Full Text Available Mammalian circadian behavior is governed by a central clock in the suprachiasmatic nucleus of the brain hypothalamus, and its intrinsic period length is believed to affect the phase of daily activities. Measurement of this period length, normally accomplished by prolonged subject observation, is difficult and costly in humans. Because a circadian clock similar to that of the suprachiasmatic nucleus is present in most cell types, we were able to engineer a lentiviral circadian reporter that permits characterization of circadian rhythms in single skin biopsies. Using it, we have determined the period lengths of 19 human individuals. The average value from all subjects, 24.5 h, closely matches average values for human circadian physiology obtained in studies in which circadian period was assessed in the absence of the confounding effects of light input and sleep-wake cycle feedback. Nevertheless, the distribution of period lengths measured from biopsies from different individuals was wider than those reported for circadian physiology. A similar trend was observed when comparing wheel-running behavior with fibroblast period length in mouse strains containing circadian gene disruptions. In mice, inter-individual differences in fibroblast period length correlated with the period of running-wheel activity; in humans, fibroblasts from different individuals showed widely variant circadian periods. Given its robustness, the presented procedure should permit quantitative trait mapping of human period length.
Full Text Available Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduction of a light-dark cycle. In adulthood, previously-occluded eyes were challenged with visual stimuli. Whereas image-formation and motion-detection were markedly impaired by monocular occlusion, neither entrainment to a light-dark cycle, nor phase-resetting responses to shifts in the light-dark cycle were affected by prior monocular deprivation. Cholera toxin-b subunit fluorescent tract-tracing revealed that in monocularly-deprived hamsters the density of fibers projecting from the retina to the suprachiasmatic nucleus (SCN was comparable regardless of whether such fibers originated from occluded or exposed eyes. In addition, long-term monocular deprivation did not attenuate light-induced c-Fos expression in the SCN. Thus, in contrast to the thalamocortical projections of the primary visual system, retinohypothalamic projections terminating in the SCN develop into normal adult patterns and mediate circadian responses to light largely independent of light experience during development. The data identify a categorical difference in the requirement for light input during postnatal development between circadian and non-circadian visual systems.
Pittman-Polletta, Benjamin R; Scheer, Frank A J L; Butler, Matthew P; Shea, Steven A; Hu, Kun
Many neurophysiological variables such as heart rate, motor activity, and neural activity are known to exhibit intrinsic fractal fluctuations - similar temporal fluctuation patterns at different time scales. These fractal patterns contain information about health, as many pathological conditions are accompanied by their alteration or absence. In physical systems, such fluctuations are characteristic of critical states on the border between randomness and order, frequently arising from nonlinear feedback interactions between mechanisms operating on multiple scales. Thus, the existence of fractal fluctuations in physiology challenges traditional conceptions of health and disease, suggesting that high levels of integrity and adaptability are marked by complex variability, not constancy, and are properties of a neurophysiological network, not individual components. Despite the subject's theoretical and clinical interest, the neurophysiological mechanisms underlying fractal regulation remain largely unknown. The recent discovery that the circadian pacemaker (suprachiasmatic nucleus) plays a crucial role in generating fractal patterns in motor activity and heart rate sheds an entirely new light on both fractal control networks and the function of this master circadian clock, and builds a bridge between the fields of circadian biology and fractal physiology. In this review, we sketch the emerging picture of the developing interdisciplinary field of fractal neurophysiology by examining the circadian system's role in fractal regulation.
Harmer, Stacey L
The circadian clock regulates diverse aspects of plant growth and development and promotes plant fitness. Molecular identification of clock components, primarily in Arabidopsis, has led to recent rapid progress in our understanding of the clock mechanism in higher plants. Using mathematical modeling and experimental approaches, workers in the field have developed a model of the clock that incorporates both transcriptional and posttranscriptional regulation of clock genes. This cell-autonomous clock, or oscillator, generates rhythmic outputs that can be monitored at the cellular and whole-organism level. The clock not only confers daily rhythms in growth and metabolism, but also interacts with signaling pathways involved in plant responses to the environment. Future work will lead to a better understanding of how the clock and other signaling networks are integrated to provide plants with an adaptive advantage.
Makoto Akashi; Haruhiko Soma; Takuro Yamamoto; Asuka Tsugitomi; Shiko Yamashita; Takuya Yamamoto; Eisuke Nishida; Akio Yasuda; James K. Liao; Koichi Node; Joseph S. Takahashi
.... This limitation has greatly hampered our understanding of human circadian rhythm. Here we report a convenient, reliable, and less invasive method for detecting human clock gene expression using biopsy samples of hair follicle cells from the head or chin...
E. A twin study of the circadian and pulsatile variations of plasma cortisol: evidence for genetic control of the human circadian clock. Am J Physiol...Conference on Chronobiology , Irsee, Germany, September 29-October 4, 1991. Van Cauter, E. Effects of sleep on glucose regulation. Invited Speaker. Founding
Tung T Nguyen
Full Text Available As cellular variability and circadian rhythmicity play critical roles in immune and inflammatory responses, we present in this study an agent-based model of human endotoxemia to examine the interplay between circadian controls, cellular variability and stochastic dynamics of inflammatory cytokines. The model is qualitatively validated by its ability to reproduce circadian dynamics of inflammatory mediators and critical inflammatory responses after endotoxin administration in vivo. Novel computational concepts are proposed to characterize the cellular variability and synchronization of inflammatory cytokines in a population of heterogeneous leukocytes. Our results suggest that there is a decrease in cell-to-cell variability of inflammatory cytokines while their synchronization is increased after endotoxin challenge. Model parameters that are responsible for IκB production stimulated by NFκB activation and for the production of anti-inflammatory cytokines have large impacts on system behaviors. Additionally, examining time-dependent systemic responses revealed that the system is least vulnerable to endotoxin in the early morning and most vulnerable around midnight. Although much remains to be explored, proposed computational concepts and the model we have pioneered will provide important insights for future investigations and extensions, especially for single-cell studies to discover how cellular variability contributes to clinical implications.
Elena V Tsimakouridze
Full Text Available The cardiovascular system exhibits dramatic time-of-day dependent rhythms, for example the diurnal variation of heart rate, blood pressure, and timing of onset of adverse cardiovascular events such as heart attack and sudden cardiac death. Over the past decade, the circadian clock mechanism has emerged as a crucial factor regulating these daily fluctuations. Most recently, these studies have led to a growing clinical appreciation that targeting circadian biology offers a novel therapeutic approach towards cardiovascular (and other diseases. Here we describe leading-edge therapeutic applications of circadian biology including 1 timing of therapy to maximize efficacy in treating heart disease (chronotherapy; 2 novel biomarkers discovered by testing for genomic, proteomic, metabolomic or other factors at different times of day and night (chronobiomarkers; and 3 novel pharmacologic compounds that target the circadian mechanism with potential clinical applications (new chronobiology drugs. Cardiovascular disease remains a leading cause of death worldwide and new approaches in the management and treatment of heart disease are clearly warranted and can benefit patients clinically.
Full Text Available Since lactation is one of the most metabolically demanding states in adult female mammals, beautifully complex regulatory mechanisms are in place to time lactation to begin after birth and cease when the neonate is weaned. Lactation is regulated by numerous different homeorhetic factors, all of them tightly coordinated with the demands of milk production. Emerging evidence support that among these factors are the serotonergic and circadian clock systems. Here we review the serotoninergic and circadian clock systems and their roles in the regulation of mammary gland development and lactation physiology. We conclude by presenting our hypothesis that these two systems interact to accommodate the metabolic demands of lactation and thus adaptive changes in these systems occur to maintain mammary and systemic homeostasis through the reproductive cycles of female mammals.
Borisenkov, M F; Perminova, E V; Kosova, A L
The literature and results of own researches concerning the influence of climatic conditions of the North on human organism are analyzed in the paper. Experimental and clinical data are in accordance with a hypothesis of "circadian destruction" covering the mechanism of negative influence of factors of the North on human health. The model to describe the possible mechanism of action of electromagnetic radiations on circadian system of an organism is offered.
Dani M Long
Full Text Available Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD, are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01. No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism.
Skeldon, Anne C; Phillips, Andrew J K; Dijk, Derk-Jan
Why do we go to sleep late and struggle to wake up on time? Historically, light-dark cycles were dictated by the solar day, but now humans can extend light exposure by switching on artificial lights. We use a mathematical model incorporating effects of light, circadian rhythmicity and sleep homeostasis to provide a quantitative theoretical framework to understand effects of modern patterns of light consumption on the human circadian system. The model shows that without artificial light humans wakeup at dawn. Artificial light delays circadian rhythmicity and preferred sleep timing and compromises synchronisation to the solar day when wake-times are not enforced. When wake-times are enforced by social constraints, such as work or school, artificial light induces a mismatch between sleep timing and circadian rhythmicity ('social jet-lag'). The model implies that developmental changes in sleep homeostasis and circadian amplitude make adolescents particularly sensitive to effects of light consumption. The model predicts that ameliorating social jet-lag is more effectively achieved by reducing evening light consumption than by delaying social constraints, particularly in individuals with slow circadian clocks or when imposed wake-times occur after sunrise. These theory-informed predictions may aid design of interventions to prevent and treat circadian rhythm-sleep disorders and social jet-lag.
Hansen, J.; Timmers, S.; Moonen-Kornips, E.; Duez, H.; Staels, B.; Hesselink, M.K.; Schrauwen, P.
Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial respon...
Garaulet, Marta; Ordovás, José M; Gómez-Abellán, Purificación; Martínez, Jose A; Madrid, Juan A
Although it is well established that human adipose tissue (AT) shows circadian rhythmicity, published studies have been discussed as if tissues or systems showed only one or few circadian rhythms at a time. To provide an overall view of the internal temporal order of circadian rhythms in human AT including genes implicated in metabolic processes such as energy intake and expenditure, insulin resistance, adipocyte differentiation, dyslipidemia, and body fat distribution. Visceral and subcutaneous abdominal AT biopsies (n=6) were obtained from morbid obese women (BMI≥40 kg/m(2) ). To investigate rhythmic expression pattern, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h using quantitative real-time PCR. Clock genes, glucocorticoid metabolism-related genes, leptin, adiponectin and their receptors were studied. Significant differences were found both in achrophases and relative-amplitude among genes (P30%). When interpreting the phase map of gene expression in both depots, data indicated that circadian rhythmicity of the genes studied followed a predictable physiological pattern, particularly for subcutaneous AT. Interesting are the relationships between adiponectin, leptin, and glucocorticoid metabolism-related genes circadian profiles. Their metabolic significance is discussed. Visceral AT behaved in a different way than subcutaneous for most of the genes studied. For every gene, protein mRNA levels fluctuated during the day in synchrony with its receptors. We have provided an overall view of the internal temporal order of circadian rhythms in human adipose tissue.
McClung, C. Robertson; Gutiérrez, Rodrigo A.
Summary Whole-transcriptome analyses have established that the plant circadian clock regulates virtually every plant biological process and most prominently hormonal and stress response pathways. Systems biology efforts have successfully modeled the plant central clock machinery and an iterative process of model refinement and experimental validation has contributed significantly to the current view of the central clock machinery. The challenge now is to connect this central clock to the output pathways for understanding how the plant circadian clock contributes to plant growth and fitness in a changing environment. Undoubtedly, systems approaches will be needed to integrate and model the vastly increased volume of experimental data in order to extract meaningful biological information. Thus, we have entered an era of systems modeling, experimental testing, and refinement. This approach, coupled with advances from the genetic and biochemical analyses of clock function, is accelerating our progress towards a comprehensive understanding of the plant circadian clock network. PMID:20889330
Buxton, Orfeu M; Cain, Sean W; O'Connor, Shawn P; Porter, James H; Duffy, Jeanne F; Wang, Wei; Czeisler, Charles A; Shea, Steven A
Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.
Laermans, J; Depoortere, I
Although obesity is considered to result from an imbalance between energy uptake and energy expenditure, the strategy of dietary changes and physical exercise has failed to tackle the global obesity epidemic. In search of alternative and more adequate treatment options, research has aimed at further unravelling the mechanisms underlying this excessive weight gain. While numerous studies are focusing on the neuroendocrine alterations that occur after bariatric Roux-en-Y gastric bypass surgery, an increasing amount of chronobiological studies have started to raise awareness concerning the pivotal role of the circadian system in the development and exacerbation of obesity. This internal timekeeping mechanism rhythmically regulates metabolic and physiological processes in order to meet the fluctuating demands in energy use and supply throughout the 24-h day. This review elaborates on the extensive bidirectional interaction between the circadian system and metabolism and explains how disruption of body clocks by means of shift work, frequent time zone travelling or non-stop consumption of calorie-dense foods can evoke detrimental metabolic alterations that contribute to obesity. Altering the body's circadian rhythms by means of time-related dietary approaches (chrononutrition) or pharmacological substances (chronobiotics) may therefore represent a novel and interesting way to prevent or treat obesity and associated comorbidities.
Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.
It has been shown in animal studies that exposure to brief pulses of bright light can phase shift the circadian pacemaker, and that the resetting action of light is most efficient during the first minutes of light exposure. In humans, multiple consecutive days of exposure to brief bright light pulses have been shown to phase shift the circadian pacemaker. The aim of the present study was to determine if a single sequence of brief bright light pulses administered during the early biological ni...
Pablo Martinez-Lozano Sinues
Full Text Available Circadian clocks play a significant role in the correct timing of physiological metabolism, and clock disruption might lead to pathological changes of metabolism. One interesting method to assess the current state of metabolism is metabolomics. Metabolomics tries to capture the entirety of small molecules, i.e. the building blocks of metabolism, in a given matrix, such as blood, saliva or urine. Using mass spectrometric approaches we and others have shown that a significant portion of the human metabolome in saliva and blood exhibits circadian modulation; independent of food intake or sleep/wake rhythms. Recent advances in mass spectrometry techniques have introduced completely non-invasive breathprinting; a method to instantaneously assess small metabolites in human breath. In this proof-of-principle study, we extend these findings about the impact of circadian clocks on metabolomics to exhaled breath. As previously established, our method allows for real-time analysis of a rich matrix during frequent non-invasive sampling. We sampled the breath of three healthy, non-smoking human volunteers in hourly intervals for 24 hours during total sleep deprivation, and found 111 features in the breath of all individuals, 36-49% of which showed significant circadian variation in at least one individual. Our data suggest that real-time mass spectrometric "breathprinting" has high potential to become a useful tool to understand circadian metabolism, and develop new biomarkers to easily and in real-time assess circadian clock phase and function in experimental and clinical settings.
Keller, Jutta; Layer, Peter
It is unknown whether nonparallel pancreatic enzyme output occurs under basal conditions in humans. We aimed to determine whether the circadian or wake-sleep cycle influences the relationship among pancreatic enzymes or between pancreatic secretory and jejunal motor activity. Using orojejunal multilumen intubation, we measured enzyme outputs and proximal jejunal motility index during consecutive daytime and nighttime periods in each of seven fasting, healthy volunteers. Enzyme outputs were correlated tightly during daytime phases of wakefulness and nighttime phases of sleep (r > 0.72, P activity was directly correlated with jejunal motility index (r > 0.50, P enzymes dominates throughout the circadian cycle. Nonparallel secretion during nocturnal phases of wakefulness may be due to merely circadian effects or to the coupling of the wake-sleep and the circadian cycle. The association between fluctuations of secretory and motor activity appears to be particularly tight during the night.
Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan
Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples. DOI: http://dx.doi.org/10.7554/eLife.20214.001 PMID:28218891
Akman, Ozgur E; Watterson, Steven; Parton, Andrew; Binns, Nigel; Millar, Andrew J; Ghazal, Peter
The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day-night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of more complex clocks, as well as other circuits with different qualitative dynamics. In particular, we anticipate
Lucassen, Eliane Alinda
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the
Yamanaka, Yujiro; Hashimoto, Satoko; Masubuchi, Satoru; Natsubori, Akiyo; Nishide, Shin-Ya; Honma, Sato; Honma, Ken-Ichi
Our previous study demonstrated that physical exercise under dim lights (cycle but not the circadian melatonin rhythm to an 8-h phase-advanced sleep schedule, indicating differential effects of physical exercise on the human circadian system. The present study examined the effects of bright light (>5,000 lux) on exercise-induced acceleration of reentrainment because timed bright lights are known to reset the circadian pacemaker. Fifteen male subjects spent 12 days in temporal isolation. The sleep schedule was advanced from habitual sleep times by 8 h for 4 days, which was followed by a free-run session. In the shift session, bright lights were given during the waking time. Subjects in the exercise group performed 2-h bicycle running twice a day. Subjects in the control kept quiet. As a result, the sleep-wake cycle was fully entrained by the shift schedule in both groups. Bright light may strengthen the resetting potency of the shift schedule. By contrast, the circadian melatonin rhythm was phase-advanced by 6.9 h on average in the exercise group but only by 2.0 h in the control. Thus physical exercise prevented otherwise unavoidable internal desynchronization. Polysomnographical analyses revealed that deterioration of sleep quality by shift schedule was protected by physical exercise under bright lights. These findings indicate differential regulation of sleep-wake cycle and circadian melatonin rhythm by physical exercise in humans. The melatonin rhythm is regulated primarily by bright lights, whereas the sleep-wake cycle is by nonphotic time cues, such as physical exercise and shift schedule.
Gundel, A; Polyakov, V V; Zulley, J
Numerous anecdotes in the past suggest the concept that sleep disturbances in astronauts occur more frequently during spaceflight than on ground. Such disturbances may be caused in part by exogenous factors, but also an altered physiological state under microgravity may add to reducing sleep quality in a spacecraft. The present investigation aims at a better understanding of possible sleep disturbances under microgravity. For the first time, experiments were conducted in which sleep and circadian regulation could be simultaneously assessed in space. Four astronauts took part in this study aboard the Russian MIR station. Sleep was recorded polygraphically on tape together with body temperature. For a comparison, the same parameters were measured during baseline periods preceding the flights. The circadian phase of body temperature was found to be delayed by about 2 h in space compared with baseline data. A free-run was not observed during the first 30 d in space. Sleep was shorter and more disturbed than on earth. In addition, the structure of sleep was significantly altered. In space, the latency to the first REM episode was shorter, and slow-wave sleep was redistributed from the first to the second sleep cycle. Several mechanisms may be responsible for these alterations in sleep regulation and circadian phase. Most likely, altered circadian zeitgebers on MIR and a deficiency in the process S of Borbély's sleep model cause the observed findings. The change in process S may be related to changes in physical activity as a result of weightlessness.
K. Lech (Karolina); K. Ackermann (Katrin); V.L. Revell (Victoria); O.S.C.A.R. Lao; D.J. Skene (Debra); M.H. Kayser (Manfred)
textabstractThe identification and investigation of novel clock-controlled genes (CCGs) has been conducted thus far mainly in model organisms such as nocturnal rodents, with limited information in humans. Here, we aimed to characterize daily and circadian expression rhythms of CCGs in human
Malcolm Von Schantz
Circadian rhythms and sleep are two separate but intimately related processes. Circadian rhythms are generated through the precisely controlled, cyclic expression of a number of genes designated clock genes. Genetic variability in these genes has been associated with a number of phenotypic differences in circadian as well as sleep parameters, both in mouse models and in humans. Diurnal preferences as determined by the selfreported Horne–Östberg (HÖ) questionnaire, has been associated with polymorphisms in the human genes CLOCK, PER1, PER2 and PER3. Circadian rhythm-related sleep disorders have also been associated with mutations and polymorphisms in clock genes, with the advanced type cosegrating in an autosomal dominant inheritance pattern with mutations in the genes PER2 and CSNK1D, and the delayed type associating without discernible Mendelian inheritance with polymorphisms in CLOCK and PER3. Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep loss, confirming the close association between the processes of circadian rhythms and sleep at the genetic level.
Wright, Kenneth P; McHill, Andrew W; Birks, Brian R; Griffin, Brandon R; Rusterholz, Thomas; Chinoy, Evan D
The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle , and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.
Eva Herrero; Seth J. Davis
Circadian clocks mediate adaptation to the 24-h world.In Arabidopsis,most circadian-clock components act in the nucleus as transcriptional regulators and generate rhythmic oscillations of transcript accumulation.In this review,we focus on post-transcriptional events that modulate the activity of circadian-clock components,such as phosphorylation,ubiquitination and proteasome-mediated degradation,changes in cellular localization,and protein-protein interactions.These processes have been found to be essential for circadian function,not only in plants,but also in other circadian systems.Moreover,light and clock signaling networks are highly interconnected.In the nucleus,light and clock components work together to generate transcriptional rhythms,leading to a general control of the timing of plant physiological processes.
Full Text Available BACKGROUND: Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls", clock properties measured in human fibroblasts correlated with extreme diurnal behavior. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. CONCLUSIONS/SIGNIFICANCE: We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness.
Pichon, Gaston; Treuil, Jean-Pierre
The larval parasites of the pantropical lymphatic filariasis exhibit two types of circadian behaviour. Typically, they only appear in the human bloodstream at nighttime, synchronised with their mosquito vectors. In Polynesia and parts of Southeast Asia, free of nocturnal vectors, they are found at all hours, and each population biorhythm differs. Through a geometrical approach, we explain this circadian diversity by a single, dominant mutation: the clocks of individual parasites are set at midnight (ubiquitous) or at 2 p.m. Compared to other circadian genes, this mutation must be very old, as it is shared by four biologically remote genera of parasites. This seniority sheds new light on several theoretical and practical aspects of vector-parasite temporal relations.
Ruger, M; Gordijn, MCM; Beersma, DGM; de Vries, B; Daan, S
Light can influence physiology and performance of humans in two distinct ways. It can acutely change the level of physiological and behavioral parameters, and it can induce a phase shift in the circadian oscillators underlying variations in these levels. Until recently, both effects were thought to
Petrova, Elena S; Afanasova, Anastasia I
This paper is presenting a software development for simulating and processing thermometry data. The motivation of this research is the miniaturization of actuators attached to human body which allow frequent temperature measurements and improve the medical diagnosis procedures related to circadian dynamics.
Full Text Available A wide range of organisms features molecular machines, circadian clocks, which generate endogenous oscillations with ~24 h periodicity and thereby synchronize biological processes to diurnal environmental fluctuations. Recently, it has become clear that plants harbor more complex gene regulatory circuits within the core circadian clocks than other organisms, inspiring a fundamental question: are all these regulatory interactions between clock genes equally crucial for the establishment and maintenance of circadian rhythms? Our mechanistic simulation for Arabidopsis thaliana demonstrates that at least half of the total regulatory interactions must be present to express the circadian molecular profiles observed in wild-type plants. A set of those essential interactions is called herein a kernel of the circadian system. The kernel structure unbiasedly reveals four interlocked negative feedback loops contributing to circadian rhythms, and three feedback loops among them drive the autonomous oscillation itself. Strikingly, the kernel structure, as well as the whole clock circuitry, is overwhelmingly composed of inhibitory, rather than activating, interactions between genes. We found that this tendency underlies plant circadian molecular profiles which often exhibit sharply-shaped, cuspidate waveforms. Through the generation of these cuspidate profiles, inhibitory interactions may facilitate the global coordination of temporally-distant clock events that are markedly peaked at very specific times of day. Our systematic approach resulting in experimentally-testable predictions provides insights into a design principle of biological clockwork, with implications for synthetic biology.
Ciarleglio, C M; Resuehr, H E S; McMahon, D G
The serotonin and circadian systems are principal regulatory networks of the brain. Each consists of a unique set of neurons that make widespread neural connections and a defined gene network of transcriptional regulators and signaling genes that subserve serotonergic and circadian function at the genetic level. These master regulatory networks of the brain are extensively intertwined, with reciprocal circuit connections, expression of key genetic elements for serotonin signaling in clock neurons and expression of key clock genes in serotonergic neurons. The reciprocal connections of the serotonin and circadian systems likely have importance for neurobehavioral disorders, as suggested by their convergent contribution to a similar range of mood disorders including seasonal affective disorder (SAD), bipolar disorder, and major depression, and as suggested by their overlapping relationship with the developmental disorder, autism spectrum disorder. Here we review the neuroanatomical and genetic basis for serotonin-circadian interactions in the brain, their potential relationship with neurobehavioral disorders, and recent work examining the effects on the circadian system of genetic perturbation of the serotonergic system as well as the molecular and behavioral effects of developmental imprinting of the circadian system with perinatal seasonal light cycles. Copyright Â© 2011. Published by Elsevier Ltd.
Taylor, Stephanie R; Gunawan, Rudiyanto; Petzold, Linda R; Doyle, Francis J
Vital physiological behaviors exhibited daily by bacteria, plants, and animals are governed by endogenous oscillators called circadian clocks. The most salient feature of the circadian clock is its ability to change its internal time (phase) to match that of the external environment. The circadian clock, like many oscillators in nature, is regulated at the cellular level by a complex network of interacting components. As a complementary approach to traditional biological investigation, we utilize mathematical models and systems theoretic tools to elucidate these mechanisms. The models are systems of ordinary differential equations exhibiting stable limit cycle behavior. To study the robustness of circadian phase behavior, we use sensitivity analysis. As the standard set of sensitivity tools are not suitable for the study of phase behavior, we introduce a novel tool, the parametric impulse phase response curve (pIPRC).
Full Text Available One of the side effects of each electrical device work is the electromagnetic field generated near its workplace. All organisms, including humans, are exposed daily to the influence of different types of this field, characterized by various physical parameters. Therefore, it is important to accurately determine the effects of an electromagnetic field on the physiological and pathological processes occurring in cells, tissues, and organs. Numerous epidemiological and experimental data suggest that the extremely low frequency magnetic field generated by electrical transmission lines and electrically powered devices and the high frequencies electromagnetic radiation emitted by electronic devices have a potentially negative impact on the circadian system. On the other hand, several studies have found no influence of these fields on chronobiological parameters. According to the current state of knowledge, some previously proposed hypotheses, including one concerning the key role of melatonin secretion disruption in pathogenesis of electromagnetic field induced diseases, need to be revised. This paper reviews the data on the effect of electric, magnetic, and electromagnetic fields on melatonin and cortisol rhythms—two major markers of the circadian system as well as on sleep. It also provides the basic information about the nature, classification, parameters, and sources of these fields.
Rahman, Shadab A; Castanon-Cervantes, Oscar; Scheer, Frank A J L; Shea, Steven A; Czeisler, Charles A; Davidson, Alec J; Lockley, Steven W
Various aspects of immune response exhibit 24-h variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-h variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48h of baseline conditions with standard sleep-wake schedules and 40-50h of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-h rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-h rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function. Copyright © 2014 Elsevier Inc. All rights reserved.
Ritchie, Hannah K; Stothard, Ellen R; Wright, Kenneth P
A robust circadian timekeeping system is important for human health and well-being. Inappropriately timed light exposure can cause circadian and sleep disruption, which has been shown to have negative health consequences. Lighting in medical care facilities, such as the NICU, ICU, and nursing homes, is not typically controlled and may be associated with circadian disruption observed in such settings. Cycled lighting and increased exposure to sunlight in medical care facilities have been shown to have positive effects on patient recovery and well-being, and expedite hospital discharge. Additional clinical research is needed to determine the optimal light exposure timing, duration, intensity, and spectrum to best promote recovery, health and well-being in the context of medical care.
Johnston, Jonathan D
Emerging links between circadian rhythms and metabolism promise much for the understanding of metabolic physiology and pathophysiology, in which white adipose tissue (WAT) plays a prominent role. Many WAT endocrine molecules, termed adipokines, display rhythmic plasma concentration. Moreover, similar to most other tissues, WAT exhibits widespread 24-h variation in gene expression, with approximately 20% of the murine adipose transcriptome estimated to undergo daily variation. A major limitation to human chronobiology research is the availability of physiologically defined peripheral tissues. To date most analyses of in vivo human peripheral clocks has been limited to blood leucocytes. However, subcutaneous adipose tissue represents a novel opportunity to study peripheral molecular rhythms that are of clearly defined metabolic relevance. This review summarises basic concepts of circadian and metabolic physiology before then comparing alternative protocols used to analyse the rhythmic properties of human adipose tissue.
Pardini, L; Kaeffer, B; Trubuil, A; Bourreille, A; Galmiche, J-P
Biological clock components have been detected in many epithelial tissues of the digestive tract of mammals (oral mucosa, pancreas, and liver), suggesting the existence of peripheral circadian clocks that may be entrainable by food. Our aim was to investigate the expression of main peripheral clock genes in colonocytes of healthy humans and in human colon carcinoma cell lines. The presence of clock components was investigated in single intact colonic crypts isolated by chelation from the biopsies of 25 patients (free of any sign of colonic lesions) undergoing routine colonoscopy and in cell lines of human colon carcinoma (Caco2 and HT29 clone 19A). Per-1, per-2, and clock mRNA were detected by real-time RT-PCR. The three-dimensional distributions of PER-1, PER-2, CLOCK, and BMAL1 proteins were recorded along colonic crypts by immunofluorescent confocal imaging. We demonstrate the presence of per-1, per-2, and clock mRNA in samples prepared from colonic crypts of 5 patients and in all cell lines. We also demonstrate the presence of two circadian clock proteins, PER-1 and CLOCK, in human colonocytes on crypts isolated from 20 patients (15 patients for PER-1 and 6 for CLOCK) and in colon carcinoma cells. Establishing the presence of clock proteins in human colonic crypts is the first step toward the study of the regulation of the intestinal circadian clock by nutrients and feeding rhythms.
Prendergast, Brian J; Cable, Erin J; Patel, Priyesh N; Pyter, Leah M; Onishi, Kenneth G; Stevenson, Tyler J; Ruby, Norman F; Bradley, Sean P
The immune system is under strong circadian control, and circadian desynchrony is a risk factor for metabolic disorders, inflammatory responses and cancer. Signaling pathways that maintain circadian rhythms (CRs) in immune function in vivo, and the mechanisms by which circadian desynchrony impairs immune function, remain to be fully identified. These experiments tested the hypothesis that the hypothalamic circadian pacemaker in the suprachiasmatic nucleus (SCN) drives CRs in the immune system, using a non-invasive model of SCN circadian arrhythmia. Robust CRs in blood leukocyte trafficking, with a peak during the early light phase (ZT4) and nadir in the early dark phase (ZT18), were absent in arrhythmic hamsters, as were CRs in spleen clock gene (per1, bmal1) expression, indicating that a functional pacemaker in the SCN is required for the generation of CRs in leukocyte trafficking and for driving peripheral clocks in secondary lymphoid organs. Pinealectomy was without effect on CRs in leukocyte trafficking, but abolished CRs in spleen clock gene expression, indicating that nocturnal melatonin secretion is necessary for communicating circadian time information to the spleen. CRs in trafficking of antigen presenting cells (CD11c(+) dendritic cells) in the skin were abolished, and antigen-specific delayed-type hypersensitivity skin inflammatory responses were markedly impaired in arrhythmic hamsters. The SCN drives robust CRs in leukocyte trafficking and lymphoid clock gene expression; the latter of which is not expressed in the absence of melatonin. Robust entrainment of the circadian pacemaker provides a signal critical to diurnal rhythms in immunosurveilliance and optimal memory T-cell dependent immune responses. Copyright © 2013 Elsevier Inc. All rights reserved.
Sakata-Haga, Hiromi; Fukui, Yoshihiro
Ethanol exposure during gestation can have devastating consequences on the developing organism. Children who have a history of prenatally exposure to ethanol may show morphological and functional alterations, referred to as fetal alcohol spectrum disorders (FASD). Fetal alcohol syndrome (FAS), which is characterized by pre- and postnatal growth deficiency, specific cranial/facial features, and dysfunction of central nervous system, is the most severe end of FASD. FAS or FASD children are known to suffer from disturbance of sleep and/or food intake behaviors. These neuropsychiatric symptoms may be due to impairment of the system regulating circadian rhythms. Recently, animal studies revealed that ethanol exposure during brain development can cause alterations in the circadian rhythm and its regulating system. We examined the effects of pre- or postnatal exposure to ethanol on the circadian rhythm in adulthood by measuring deep body temperature and wheel running activity in rats. After a phase delay in the light/dark cycle, ethanol-exposed rats took longer than control rats to resynchronize to the new light/dark cycle. These results suggest that both pre- and postnatal ethanol exposure impair the development of the circadian clock response to light cue. Because abnormal development of the circadian clock system might contribute to the neuropsychiatric symptoms seen in FASD, it is believed that normalizing the disturbed rhythm improves the symptoms. However, the mechanisms of dysfunction and potential interventions for disturbance of circadian clock system still remain to be elucidated. Further investigations are required to fully understand long-term effects of ethanol on the development of circadian rhythms.
Rey, Guillaume; Valekunja, Utham K; Feeney, Kevin A; Wulund, Lisa; Milev, Nikolay B; Stangherlin, Alessandra; Ansel-Bollepalli, Laura; Velagapudi, Vidya; O'Neill, John S; Reddy, Akhilesh B
The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.
Roenneberg, Till; Merrow, Martha
The circadian clock provides a temporal structure that modulates biological functions from the level of gene expression to performance and behaviour. Pioneering work on the fruitfly Drosophila has provided a basis for understanding how the temporal sequence of daily events is controlled in mammals.
Dijk, D. J.
In humans, EEG power spectra in REM and NREM sleep, as well as characteristics of sleep spindles such as their duration, amplitude, frequency and incidence, vary with circadian phase. Recently it has been hypothesized that circadian variations in EEG spectra in humans are caused by variations in brain or body temperature and may not represent phenomena relevant to sleep regulatory processes. To test this directly, a further analysis of EEG power spectra - collected in a forced desynchrony protocol in which sleep episodes were scheduled to a 28-h period while the rhythms of body temperature and plasma melatonin were oscillating at their near 24-h period - was carried out. EEG power spectra were computed for NREM and REM sleep occurring between 90-120 and 270-300 degrees of the circadian melatonin rhythm, i.e. just after the clearance of melatonin from plasma in the 'morning' and just after the 'evening' increase in melatonin secretion. Average body temperatures during scheduled sleep at these two circadian phases were identical (36.72 degrees C). Despite identical body temperatures, the power spectra in NREM sleep were very different at these two circadian phases. EEG activity in the low frequency spindle range was significantly and markedly enhanced after the evening increase in plasma melatonin as compared to the morning phase. For REM sleep, significant differences in power spectra during these two circadian phases, in particular in the alpha range, were also observed. The results confirm that EEG power spectra in NREM and REM sleep vary with circadian phase, suggesting that the direct contribution of temperature to the circadian variation in EEG power spectra is absent or only minor, and are at variance with the hypothesis that circadian variations in EEG power spectra are caused by variations in temperature.
Boucher, Helene; Vanneaux, Valerie; Domet, Thomas; Parouchev, Alexandre; Larghero, Jerome
Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties.
Major conclusions: Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors. Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.
McClung, C Robertson; Gutiérrez, Rodrigo A
Whole-transcriptome analyses have established that the plant circadian clock regulates virtually every plant biological process and most prominently hormonal and stress response pathways. Systems biology efforts have successfully modeled the plant central clock machinery and an iterative process of model refinement and experimental validation has contributed significantly to the current view of the central clock machinery. The challenge now is to connect this central clock to the output pathways for understanding how the plant circadian clock contributes to plant growth and fitness in a changing environment. Undoubtedly, systems approaches will be needed to integrate and model the vastly increased volume of experimental data in order to extract meaningful biological information. Thus, we have entered an era of systems modeling, experimental testing, and refinement. This approach, coupled with advances from the genetic and biochemical analyses of clock function, is accelerating our progress towards a comprehensive understanding of the plant circadian clock network. Copyright © 2010 Elsevier Ltd. All rights reserved.
Niwa, Fumitoshi; Kuriyama, Nagato; Nakagawa, Masanori; Imanishi, Jiro
Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, including sleep and autonomic dysfunctions, controlled by circadian regulation. To evaluate the alteration of circadian rhythm in PD patients, we investigated both rest activities and autonomic functions. Twenty-seven patients with idiopathic PD and 30 age-matched control subjects were recruited. Group comparisons of controls (mean age: 68.93 years), early-PD patients classified as Hoehn-Yahr (HY) stage 1&2 (mean age: 70.78 years), and advanced-PD as HY 3&4 (mean age: 68.61 years) were conducted. Measurement of rest activities was performed using Actigraph for 7 continuous days, and included measuring rhythm patterns (activity patterns recorded in or out of bed) and circadian rhythm amplitudes (power of the cycle being closest to 24h). A power spectral analysis of heart rate variability (HRV) using 24-hour ambulatory ECG was also performed. The actigraphic measurements indicated that statistically PD patients have lower activity levels when out of bed and higher activity levels when in bed, and that, the circadian rest-activity rhythm in PD decreases with disease severity. The HRV analysis showed that the total frequency component and low frequency/high frequency ratio were low in PD patients, suggesting that autonomic activities and the circadian rhythm of the sympathetic nervous system are attenuated in PD. This study elucidated the disorganization in the rest activities and HRV of PD patients as well as the gradual alterations in the circadian rhythm. The circadian rhythm disturbances are important to consider the mechanism of non-motor symptoms that occur from early stage of PD.
Yoshida, Yusuke; Iigusa, Hideo; Wang, Niyan; Hasunuma, Kohji
The circadian system is composed of a number of feedback loops, and multiple feedback loops in the form of oscillators help to maintain stable rhythms. The filamentous fungus Neurospora crassa exhibits a circadian rhythm during asexual spore formation (conidiation banding) and has a major feedback loop that includes the FREQUENCY (FRQ)/WHITE COLLAR (WC) -1 and -2 oscillator (FWO). A mutation in superoxide dismutase (sod)-1, an antioxidant gene, causes a robust and stable circadian rhythm compared with that of wild-type (Wt). However, the mechanisms underlying the functions of reactive oxygen species (ROS) remain unknown. Here, we show that cellular ROS concentrations change in a circadian manner (ROS oscillation), and the amplitudes of ROS oscillation increase with each cycle and then become steady (ROS homeostasis). The ROS oscillation and homeostasis are produced by the ROS-destroying catalases (CATs) and ROS-generating NADPH oxidase (NOX). cat-1 is also induced by illumination, and it reduces ROS levels. Although ROS oscillation persists in the absence of frq, wc-1 or wc-2, its homeostasis is altered. Furthermore, genetic and biochemical evidence reveals that ROS concentration regulates the transcriptional function of WCC and a higher ROS concentration enhances conidiation banding. These findings suggest that the circadian system engages in cross-talk with the cellular redox state via ROS-regulatory factors.
Borisenkov, M F
In the inhabitants of the North during increase of geomagnetic activity and during magnetic calm the decrease of amplitude of circadian rhythm of total antioxidant capacity of saliva is observed. The most favorable conditions to display the circadian rhythm are observed at Kp from 0,5 up to 2. The long residing in the North is connected to influence of irregularly varying geomagnetic activity causing disturbance of function of circadian and antioxidant systems that, probably, is one of the reasons of acceleration of process of aging at northerner and of higher risk of occurrence in them the age associated diseases.
Ma, Lan; Ranganathan, Rama
Circadian clock is an essential molecular regulatory mechanism that coordinates daily biological processes. Toward understanding the design principles of the circadian mechanism in cyanobacteria, the only prokaryotes reported to possess circadian rhythmicity, mathematical models have been used as important tools to help elucidate the complicated biochemical processes. In this study, we focus on elucidating the underlying systems properties that drive the oscillation of the cyanobacterial clockwork. We apply combined methods of time scale separation, phase space analysis, bifurcation analysis and sensitivity analysis to a model of the in vitro cyanobacterial circadian clock proposed by us recently. The original model is reduced to a three-dimensional slow subsystem by time scale separation. Phase space analysis of the reduced subsystem shows that the null-surface of the Serine-phosphorylated state (S-state) of KaiC is a bistable surface, and that the characteristic of the phase portrait indicates that the kernel mechanism of the clockwork behaves as a relaxation oscillator induced by interlinked positive and negative feedback loops. Phase space analysis together with perturbation analysis supports our previous viewpoint that the S-state of KaiC is plausibly a key component for the protein regulatory network of the cyanobacterial circadian clock.
Tilden, Andrea R.; McCoole, Matthew D.; Harmon, Sarah M.; Baer, Kevin N.; Christie, Andrew E.
Essentially nothing is known about the molecular underpinnings of crustacean circadian clocks. The genome of Daphnia pulex, the only crustacean genome available for public use, provides a unique resource for identifying putative circadian proteins in this species. Here, the Daphnia genome was mined for putative circadian protein genes using Drosophila melanogaster queries. The sequences of core clock (e.g. CLOCK, CYCLE, PERIOD, TIMELESS and CRYPTOCHROME 2), clock input (CRYPTOCHROME 1) and clock output (PIGMENT DISPERSING HORMONE RECEPTOR) proteins were deduced. Structural analyses and alignment of the Daphnia proteins with their Drosophila counterparts revealed extensive sequence conservation, particularly in functional domains. Comparisons of the Daphnia proteins with other sequences showed that they are, in most cases, more similar to homologs from other species, including vertebrates, than they are to those of Drosophila. The presence of both CRYPTOCHROME 1 and 2 in Daphnia suggests the organization of its clock may be more similar to that of the butterfly Danaus plexippus than to that of Drosophila (which possesses CRYPTOCHROME 1 but not CRYPTOCHROME 2). These data represent the first description of a putative circadian system from any crustacean, and provide a foundation for future molecular, anatomical and physiological investigations of circadian signaling in Daphnia. PMID:21798832
Winget, C. M.; Lyman, J.; Beljan, J. R.
The light-intensity threshold for humans is not known. In past space flights owing to power restrictions, light intensities have been minimal and reported to be as low as 15 ft. c. This study was conducted to determine whether the light (L)/dark (D) environment of 16L : 8D at the relatively low light intensity of 15 ft. c. was adequate for the maintenance of circadian synchrony in human subjects. Six healthy male subjects aged 20-23 years were exposed for 21 days to a 16L : 8D photoperiod. During the first 7 days the light intensity was 100 ft. c.; it was reduced to 15 ft. c. during the next 7 days and increased again to 100 ft. c. during the last 7 days of the study. Rectal temperature (RT) and heart rate (HR) were recorded continuously throughout the 21 days of the study. In the 100 ft. c. 16L : 8D the RT and HR rhythms remained stable and circadian throughout. When the light intensity was decreased to 15 ft. c. the periodicity of the HR rhythm was significantly decreased and this rhythm showed marked instability. In contrast the period of the RT rhythm did not change but a consistent phase delay occurred due to a delay in the lights-on associated rise in RT. These divergent effects on these two rhythms in internal desynchronization and performance decrement during the 15 ft. c. exposure. The data emphasize the need for establishing accurately the minimal lighting requirements for the maintenance of circadian rhythms of humans in confined environments.
Oda, Gisele A; Friesen, W Otto
Several experimental studies have altered the phase relationship between photic and non-photic environmental, 24 h cycles (zeitgebers) in order to assess their role in the synchronization of circadian rhythms. To assist in the interpretation of the complex activity patterns that emerge from these "conflicting zeitgeber" protocols, we present computer simulations of coupled circadian oscillators forced by two independent zeitgebers. This circadian system configuration was first employed by Pittendrigh and Bruce (1959), to model their studies of the light and temperature entrainment of the eclosion oscillator in Drosophila. Whereas most of the recent experiments have restricted conflicting zeitgeber experiments to two experimental conditions, by comparing circadian oscillator phases under two distinct phase relationships between zeitgebers (usually 0 and 12 h), Pittendrigh and Bruce compared eclosion phase under 12 distinct phase relationships, spanning the 24 h interval. Our simulations using non-linear differential equations replicated complex non-linear phenomena, such as "phase jumps" and sudden switches in zeitgeber preferences, which had previously been difficult to interpret. Our simulations reveal that these phenomena generally arise when inter-oscillator coupling is high in relation to the zeitgeber strength. Manipulations in the structural symmetry of the model indicated that these results can be expected to apply to a wide range of system configurations. Finally, our studies recommend the use of the complete protocol employed by Pittendrigh and Bruce, because different system configurations can generate similar results when a "conflicting zeitgeber experiment" incorporates only two phase relationships between zeitgebers.
Gerben van Ooijen
Full Text Available The Earth's rotation has driven the evolution of cellular circadian clocks to facilitate anticipation of the solar cycle. Some evidence for timekeeping mechanism conserved from early unicellular life through to modern organisms was recently identified, but the components of this oscillator are currently unknown. Although very few clock components appear to be shared across higher species, Casein Kinase 1 (CK1 is known to affect timekeeping across metazoans and fungi, but has not previously been implicated in the circadian clock in the plant kingdom. We now show that modulation of CK1 function lengthens circadian rhythms in Ostreococcustauri, a unicellular marine algal species at the base of the green lineage, separated from humans by ~1.5 billion years of evolution. CK1 contributes to timekeeping in a phase-dependent manner, indicating clock-mediated gating of CK1 activity. Label-free proteomic analyses upon overexpression as well as inhibition revealed CK1-responsive phosphorylation events on a set of target proteins, including highly conserved potentially clock-relevant cellular regulator proteins. These results have major implications for our understanding of cellular timekeeping and can inform future studies in any circadian organism.
Hansen, Jan; Timmers, Silvie; Moonen-Kornips, Esther; Duez, Helene; Staels, Bart; Hesselink, Matthijs K. C.; Schrauwen, Patrick
Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status. PMID:27756900
... microbes. The study of circadian rhythms is called chronobiology. Are circadian rhythms the same thing as biological ... the eyes cross. Do circadian rhythms have a genetic component? Yes. Researchers have already identified genes that ...
Fanjul-Moles, María Luisa; Prieto-Sagredo, Julio; López, Dario Santiago; Bartolo-Orozco, Ramón; Cruz-Rosas, Hugo
Based on previous work in which we proposed midgut as a putative peripheral oscillator responsible for circadian reduced glutathione (GSH) crayfish status, herein we investigated the retina and optic lobe-brain (OL-B) circadian GSH system and its ability to deal with reactive oxygen species (ROS) produced as a consequence of metabolic rhythms and light variations. We characterized daily and antioxidant circadian variations of the different parameters of the glutathione system, including GSH, oxidized glutathione (GSSG), glutathione reductase (GR) and glutathione peroxidase (GPx), as well as metabolic and lipoperoxidative circadian oscillations in retina and OL-B, determining internal and external GSH-system synchrony. The results demonstrate statistically significant bi- and unimodal daily and circadian rhythms in all GSH-cycle parameters, substrates and enzymes in OL-B and retina, as well as an apparent direct effect of light on these rhythms, especially in the retina. The luminous condition appears to stimulate the GSH system to antagonize ROS and lipid peroxidation (LPO) daily and circadian rhythms occurring in both structures, oscillating with higher LPO under dark conditions. We suggest that the difference in the effect of light on GSH rhythmic mechanisms of both structures for antagonizing ROS could be due to differences in glutathione-system coupling strength with the circadian clock.
Full Text Available Abstract Metabolic, physiological and behavioral processes exhibit 24-hour rhythms in most organisms, including humans. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues. The transcription and translation feedback loops of multiple clock genes are involved in the molecular mechanism of the circadian system. Disturbed circadian rhythms are known to be closely related to many diseases, including sleep disorders. Advanced sleep phase type, delayed sleep phase type and nonentrained type of circadian rhythm sleep disorders (CRSDs are thought to result from disorganization of the circadian system. Evaluation of circadian phenotypes is indispensable to understanding the pathophysiology of CRSD. It is laborious and costly to assess an individual's circadian properties precisely, however, because the subject is usually required to stay in a laboratory environment free from external cues and masking effects for a minimum of several weeks. More convenient measurements of circadian rhythms are therefore needed to reduce patients' burden. In this review, we discuss the pathophysiology and pathogenesis of CRSD as well as surrogate measurements for assessing an individual's circadian phenotype.
Jewett, M. E.; Duffy, J. F.; Czeisler, C. A.
A double-stimulus experiment was conducted to evaluate the phase of the underlying circadian clock following light-induced phase shifts of the human circadian system. Circadian phase was assayed by constant routine from the rhythm in core body temperature before and after a three-cycle bright-light stimulus applied near the estimated minimum of the core body temperature rhythm. An identical, consecutive three-cycle light stimulus was then applied, and phase was reassessed. Phase shifts to these consecutive stimuli were no different from those obtained in a previous study following light stimuli applied under steady-state conditions over a range of circadian phases similar to those at which the consecutive stimuli were applied. These data suggest that circadian phase shifts of the core body temperature rhythm in response to a three-cycle stimulus occur within 24 h following the end of the 3-day light stimulus and that this poststimulus temperature rhythm accurately reflects the timing of the underlying circadian clock.
Perrin, Fabien; Peigneux, Philippe; Fuchs, Sonia; Verhaeghe, Stéphane; Laureys, Steven; Middleton, Benita; Degueldre, Christian; Del Fiore, Guy; Vandewalle, Gilles; Balteau, Evelyne; Poirrier, Robert; Moreau, Vincent; Luxen, André; Maquet, Pierre; Dijk, Derk-Jan
The brain processes light information to visually represent the environment but also to detect changes in ambient light level. The latter information induces non-image-forming responses and exerts powerful effects on physiology such as synchronization of the circadian clock and suppression of melatonin. In rodents, irradiance information is transduced from a discrete subset of photosensitive retinal ganglion cells via the retinohypothalamic tract to various hypothalamic and brainstem regulatory structures including the hypothalamic suprachiasmatic nuclei, the master circadian pacemaker. In humans, light also acutely modulates alertness, but the cerebral correlates of this effect are unknown. We assessed regional cerebral blood flow in 13 subjects attending to auditory and visual stimuli in near darkness following light exposures (>8000 lux) of different durations (0.5, 17, 16.5, and 0 min) during the biological night. The bright broadband polychromatic light suppressed melatonin and enhanced alertness. Functional imaging revealed that a large-scale occipito-parietal attention network, including the right intraparietal sulcus, was more active in proportion to the duration of light exposures preceding the scans. Activity in the hypothalamus decreased in proportion to previous illumination. These findings have important implications for understanding the effects of light on human behavior.
Dissertação de Mestrado apresentada à Faculdade de Medicina da Universidade de Coimbra com vista à obtenção do grau de Mestre no âmbito do ciclo de estudos de Mestrado Integrado em Medicina Objective: The goal of this paper is to discuss biological rhythms, focusing on chronotherapy in cancer. The objectives are to: (1) briefly describe the circadian timing system, its physiology and networks; (2) address causal issues that have prompt progress toward an understanding of mechanisms underly...
Trabalho final do 6º ano médico com vista à atribuição do grau de mestre (área científica de oncologia) no âmbito do ciclo de estudos de Mestrado Integrado em Medicina. Objective: The goal of this paper is to discuss biological rhythms, focusing on chronotherapy in cancer. The objectives are to: (1) briefly describe the circadian timing system, its physiology and networks; (2) address causal issues that have prompt progress toward an understanding of mechanisms underlying diseases as circa...
Weigl, Yuval; Ashkenazi, Israel E; Peleg, Leah
The circadian system shapes the rhythms of most biological functions. The regulation of the cell cycle by a circadian clock was suggested to operate via stages S, G2 and G2/M. This study investigated a possible time link at stages G1 and G1/S as well. The daily expression profiles of cell cycle markers (Ccnd1, Ccne1 and Pcna) and circadian clock genes (Per2 and Clock) were monitored in liver and esophagus (low and high proliferation index, respectively) of BALB/c mice. Locomotor activity displayed a 24 h rhythm, establishing the circadian organization of the suprachiasmatic nucleus. In the liver, the mRNA level of Per2 and Clock fitted the circadian rhythm with a 7.5 h shift. This temporal pattern suggests that the liver harbors a functional circadian clock. The rhythm of the analyzed cell cycle genes, however, was of low significance fitness and showed an opposite peak time between Pcna and Clock. These results indicate a weak regulatory role of the circadian clock. In the esophagus, the rhythms of Clock and Per2 mRNA had a similar peak time and non-circadian periods. These results suggest either that the esophagus does not harbor a functional circadian apparatus or that the phenotypes stem from differences in phase and amplitude of the rhythms of its various cell types. The similarity in the rhythm parameters of Clock, Ccne1 and Pcna transcripts questions the control of the circadian clock on the cell cycle along the G1 and G1/S stages. Yet the G1/S transition may play a role in modulating the local clock of proliferating tissues.
Nakahata, Yasukazu; Grimaldi, Benedetto; Sahar, Saurabh; Hirayama, Jun; Sassone-Corsi, Paolo
Circadian rhythms govern several fundamental physiological functions in almost all organisms, from prokaryotes to humans. The circadian clocks are intrinsic time-tracking systems with which organisms can anticipate environmental changes and adapt to the appropriate time of day. In mammals, circadian rhythms are generated in pacemaker neurons within the suprachiasmatic nuclei (SCN), a small area of the hypothalamus, and are entrained by environmental cues, principally light. Disruption of these rhythms can profoundly influence human health, being linked to depression, insomnia, jet lag, coronary heart disease and a variety of neurodegenerative disorders. It is now well established that circadian clocks operate via transcriptional feedback autoregulatory loops that involve the products of circadian clock genes. Furthermore, peripheral tissues also contain independent clocks, whose oscillatory function is orchestrated by the SCN. The complex program of gene expression that characterizes circadian physiology involves dynamic changes in chromatin transitions. These remodeling events are therefore of great importance to ensure the proper timing and extent of circadian regulation. How signaling influences chromatin remodeling through histone modifications is therefore highly relevant in the context of circadian oscillation. Recent advances in the field have revealed unexpected links between circadian regulators, chromatin remodeling and cellular metabolism.
Crowley, Stephanie J; Van Reen, Eliza; LeBourgeois, Monique K; Acebo, Christine; Tarokh, Leila; Seifer, Ronald; Barker, David H; Carskadon, Mary A
The aim of this descriptive analysis was to examine sleep timing, circadian phase, and phase angle of entrainment across adolescence in a longitudinal study design. Ninety-four adolescents participated; 38 (21 boys) were 9-10 years ("younger cohort") and 56 (30 boys) were 15-16 years ("older cohort") at the baseline assessment. Participants completed a baseline and then follow-up assessments approximately every six months for 2.5 years. At each assessment, participants wore a wrist actigraph for at least one week at home to measure self-selected sleep timing before salivary dim light melatonin onset (DLMO) phase - a marker of the circadian timing system - was measured in the laboratory. Weekday and weekend sleep onset and offset and weekend-weekday differences were derived from actigraphy. Phase angles were the time durations from DLMO to weekday sleep onset and offset times. Each cohort showed later sleep onset (weekend and weekday), later weekend sleep offset, and later DLMO with age. Weekday sleep offset shifted earlier with age in the younger cohort and later in the older cohort after age 17. Weekend-weekday sleep offset differences increased with age in the younger cohort and decreased in the older cohort after age 17. DLMO to sleep offset phase angle narrowed with age in the younger cohort and became broader in the older cohort. The older cohort had a wider sleep onset phase angle compared to the younger cohort; however, an age-related phase angle increase was seen in the younger cohort only. Individual differences were seen in these developmental trajectories. This descriptive study indicated that circadian phase and self-selected sleep delayed across adolescence, though school-day sleep offset advanced until no longer in high school, whereupon offset was later. Phase angle changes are described as an interaction of developmental changes in sleep regulation interacting with psychosocial factors (e.g., bedtime autonomy).
Stephanie J Crowley
Full Text Available The aim of this descriptive analysis was to examine sleep timing, circadian phase, and phase angle of entrainment across adolescence in a longitudinal study design. Ninety-four adolescents participated; 38 (21 boys were 9-10 years ("younger cohort" and 56 (30 boys were 15-16 years ("older cohort" at the baseline assessment. Participants completed a baseline and then follow-up assessments approximately every six months for 2.5 years. At each assessment, participants wore a wrist actigraph for at least one week at home to measure self-selected sleep timing before salivary dim light melatonin onset (DLMO phase - a marker of the circadian timing system - was measured in the laboratory. Weekday and weekend sleep onset and offset and weekend-weekday differences were derived from actigraphy. Phase angles were the time durations from DLMO to weekday sleep onset and offset times. Each cohort showed later sleep onset (weekend and weekday, later weekend sleep offset, and later DLMO with age. Weekday sleep offset shifted earlier with age in the younger cohort and later in the older cohort after age 17. Weekend-weekday sleep offset differences increased with age in the younger cohort and decreased in the older cohort after age 17. DLMO to sleep offset phase angle narrowed with age in the younger cohort and became broader in the older cohort. The older cohort had a wider sleep onset phase angle compared to the younger cohort; however, an age-related phase angle increase was seen in the younger cohort only. Individual differences were seen in these developmental trajectories. This descriptive study indicated that circadian phase and self-selected sleep delayed across adolescence, though school-day sleep offset advanced until no longer in high school, whereupon offset was later. Phase angle changes are described as an interaction of developmental changes in sleep regulation interacting with psychosocial factors (e.g., bedtime autonomy.
Brøndsted, Adam Elias; Lundeman, Jesper Holm; Kessel, Line
Photoentrainment of circadian rhythm begins with the stimulation of melanopsin containing retinal ganglion cells that respond directly to blue light. With age, the human lens becomes a strong colour filter attenuating transmission of short wavelengths. The purpose of the study was to examine...
Full Text Available Clock genes regulate circadian rhythm and are involved in various physiological processes, including digestion. We therefore investigated the association between the CLOCK 3111T/C single nucleotide polymorphism and the Period3 (PER3 variable-number tandem-repeat polymorphism (either 4 or 5 repeats 54 nt in length with morning gastric motility.Lifestyle questionnaires and anthropometric measurements were performed with 173 female volunteers (mean age, 19.4 years. Gastric motility, evaluated by electrogastrography (EGG, blood pressure, and heart rate levels were measured at 8:30 a.m. after an overnight fast. For gastric motility, the spectral powers (% normal power and dominant frequency (DF, peak of the power spectrum of the EGG were evaluated. The CLOCK and PER3 polymorphisms were determined by polymerase chain reaction (PCR restriction fragment length polymorphism analysis.Subjects with the CLOCK C allele (T/C or C/C genotypes: n = 59 showed a significantly lower DF (mean, 2.56 cpm than those with the T/T genotype (n = 114, 2.81 cpm, P < 0.05. Subjects with the longer PER3 allele (PER34/5 or PER35/5 genotypes: n = 65 also showed a significantly lower DF (2.55 cpm than those with the shorter PER34/4 genotype (n = 108, 2.83 cpm, P < 0.05. Furthermore, subjects with both the T/C or C/C and PER34/5 or PER35/5 genotypes showed a significantly lower DF (2.43 cpm, P < 0.05 than subjects with other combinations of the alleles (T/T and PER34/4 genotype, T/C or C/C and PER34/4 genotypes, and T/T and PER34/5 or PER35/5 genotypes.These results suggest that minor polymorphisms of the circadian rhythm genes CLOCK and PER3 may be associated with poor morning gastric motility, and may have a combinatorial effect. The present findings may offer a new viewpoint on the role of circadian rhythm genes on the peripheral circadian systems, including the time-keeping function of the gut.
Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali
Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.
Full Text Available Abstract Background Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure. Results We developed the in vitro real-time oscillation monitoring system (IV-ROMS by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, a natural ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ, triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Rorα mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-γ – and MAPKs (ERK, JNK, p38MAPK-independent. Conclusion Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight
Full Text Available Sleep and circadian activity rhythms become irregular with age which are characterized by fragmented sleep during the night and increased daytime sleepiness. These changes lead to a reduction in the quality of life due to cognitive impairments and emotional stress. More importantly, severely disrupted sleep and circadian rhythms have been associated with an increase in disease susceptibility. Many of the same brain areas affected by neurodegenerative diseases include the sleep and wake promoting systems. Any advances in our knowledge of these sleep/wake networks are necessary to target neural areas or connections for therapy. This review will discuss research that uses molecular, behavioral, genetic and anatomical methods to further our understanding of the interaction of these systems.
Vafopoulou, Xanthe; Terry, Katherine L; Steel, Colin G H
The brain of larval Rhodnius prolixus releases neurohormones with a circadian rhythm, indicating that a clock system exists in the larval brain. Larvae also possess a circadian locomotor rhythm. The present paper is a detailed analysis of the distribution and axonal projections of circadian clock cells in the brain of the fifth larval instar. Clock cells are identified as neurons that exhibit circadian cycling of both PER and TIM proteins. A group of eight lateral clock neurons (LNs) in the proximal optic lobe also contain pigment-dispersing factor (PDF) throughout their axons, enabling their detailed projections to be traced. LNs project to the accessory medulla and thence laterally toward the compound eye and medially into a massive area of arborizations in the anterior protocerebrum. Fine branches radiate from this area to most of the protocerebrum. A second group of clock cells (dorsal neurons [DNs]), situated in the posterior dorsal protocerebrum, are devoid of PDF. The DNs receive two fine axons from the LNs, indicating that clock cells throughout the brain are integrated into a timing network. Two axons of the LNs cross the midline, presumably coordinating the clock networks of left and right sides. The neuroarchitecture of this timing system is much more elaborate than any previously described for a larval insect and is very similar to those described in adult insects. This is the first report that an insect timing system regulates rhythmicity in both the endocrine system and behavior, implying extensive functional parallels with the mammalian suprachiasmatic nucleus. (c) 2009 Wiley-Liss, Inc.
Full Text Available BACKGROUND: In the first optic neuropil (lamina of the fly's visual system, monopolar cells L1 and L2 and glia show circadian rhythms in morphological plasticity. They change their size and shape during the day and night. The most pronounced changes have been detected in circadian size of the L2 axons. Looking for a functional significance of the circadian plasticity observed in axons, we examined the morphological plasticity of the L2 dendrites. They extend from axons and harbor postsynaptic sites of tetrad synaptic contacts from the photoreceptor terminals. METHODOLOGY/PRINCIPAL FINDINGS: The plasticity of L2 dendrites was evaluated by measuring an outline of the L2 dendritic trees. These were from confocal images of cross sections of L2 cells labeled with GFP. They were in wild-type and clock mutant flies held under different light conditions and sacrified at different time points. We found that the L2 dendrites are longest at the beginning of the day in both males and females. This rhythm observed under a day/night regime (LD was maintained in constant darkness (DD but not in continuous light (LL. This rhythm was not present in the arrhythmic per(01 mutant in LD or in DD. In the clock photoreceptor cry(b mutant the rhythm was maintained but its pattern was different than that observed in wild-type flies. CONCLUSIONS/SIGNIFICANCE: The results obtained showed that the L2 dendrites exhibit circadian structural plasticity. Their morphology is controlled by the per gene-dependent circadian clock. The L2 dendrites are longest at the beginning of the day when the daytime tetrad presynaptic sites are most numerous and L2 axons are swollen. The presence of the rhythm, but with a different pattern in cry(b mutants in LD and DD indicates a new role of cry in the visual system. The new role is in maintaining the circadian pattern of changes of the L2 dendrite length and shape.
Müller, L; Weinert, D
In a natural environment, social abilities of an animal are important for its survival. Particularly, it must recognize its own social rank and the social rank of a conspecific and have a good social memory. While the role of the circadian system for object and spatial recognition and memory is well known, the impact of the social rank and circadian disruptions on social recognition and memory were not investigated so far. In the present study, individual recognition of social rank and social memory performance of Djungarian hamsters revealing different circadian phenotypes were investigated. Wild type (WT) animals show a clear and well-synchronized daily activity rhythm, whereas in arrhythmic (AR) hamsters, the suprachiasmatic nuclei (SCN) do not generate a circadian signal. The aim of the study was to investigate putative consequences of these deteriorations in the circadian system for animalś cognitive abilities. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14l/10 D lighting regimen. Experimental animals were assigned to different groups (WT and AR) according to their activity pattern obtained by means of infrared motion sensors. Before the experiments, the animals were given to develop a dominant-subordinate relationship in a dyadic encounter. Experiment 1 dealt with individual recognition of social rank. Subordinate and dominant hamsters were tested in an open arena for their behavioral responses towards a familiar (known from the agonistic encounters) or an unfamiliar hamster (from another agonistic encounter) which had the same or an opposite social rank. The investigation time depended on the social rank of the WT subject hamster and its familiarity with the stimulus animal. Both subordinate and dominant WT hamsters preferred an unfamiliar subordinate stimulus animal. In contrast, neither subordinate nor dominant AR hamsters preferred any of the stimulus animals. Thus, disruptions in circadian
Full Text Available Alzheimer's disease (AD is a neurodegenerative disease often accompanied with disruption of sleep-wake cycle. The sleep-wake cycle is controlled by mechanisms involving internal timekeeping (circadian regulation. The aim of our present pilot study was to assess the circadian system in patients with mild form of AD in their home environment. In the study, 13 elderly AD patients and 13 age-matched healthy control subjects (the patient's spouses were enrolled. Sleep was recorded for 21 days by sleep diaries in all participants and checked by actigraphy in 4 of the AD patient/control couples. The samples of saliva and buccal mucosa were collected every 4 hours during the same 24 h-interval to detect melatonin and clock gene (PER1 and BMAL1 mRNA levels, respectively. The AD patients exhibited significantly longer inactivity interval during the 24 h and significantly higher number of daytime naps than controls. Daily profiles of melatonin levels exhibited circadian rhythms in both groups. Compared with controls, decline in amplitude of the melatonin rhythm in AD patients was not significant, however, in AD patients more melatonin profiles were dampened or had atypical waveforms. The clock genes PER1 and BMAL1 were expressed rhythmically with high amplitudes in both groups and no significant differences in phases between both groups were detected. Our results suggest moderate differences in functional state of the circadian system in patients with mild form of AD compared with healthy controls which are present in conditions of their home dwelling.
Full Text Available Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9-12 h period in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9-12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle.
Teschke, Mathias; Wendt, Sabrina; Kawaguchi, So; Kramer, Achim; Meyer, Bettina
Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9-12 h period) in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9-12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle.
Blasiak, Anna; Gundlach, Andrew L.; Hess, Grzegorz; Lewandowski, Marian H.
Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the “control” of the “master biological clock” reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements. PMID:28373831
Duffield, Giles E; Watson, Nathan P; Mantani, Akio; Peirson, Stuart N; Robles-Murguia, Maricela; Loros, Jennifer J; Israel, Mark A; Dunlap, Jay C
Inhibitor of DNA binding genes (Id1-Id4) encode helix-loop-helix (HLH) transcriptional repressors associated with development and tumorigenesis [1, 2], but little is known concerning the function(s) of these genes in normal adult animals. Id2 was identified in DNA microarray screens for rhythmically expressed genes [3-5], and further analysis revealed a circadian pattern of expression of all four Id genes in multiple tissues including the suprachiasmatic nucleus. To explore an in vivo function, we generated and characterized deletion mutations of Id2 and of Id4. Id2(-/-) mice exhibit abnormally rapid entrainment and an increase in the magnitude of the phase shift of the pacemaker. A significant proportion of mice also exhibit disrupted rhythms when maintained under constant darkness. Conversely, Id4(-/-) mice did not exhibit a noticeable circadian phenotype. In vitro studies using an mPer1 and an AVP promoter reporter revealed the potential for ID1, ID2, and ID3 proteins to interact with the canonical basic HLH clock proteins BMAL1 and CLOCK. These data suggest that the Id genes may be important for entrainment and operation of the mammalian circadian system, potentially acting through BMAL1 and CLOCK targets.
Akashi, Makoto; Hayasaka, Naoto; Yamazaki, Shin; Node, Koichi
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker driving behavioral and physiological rhythms in mammals. Circadian activation of mitogen-activated protein kinase [MAPK; also known as ERK (extracellular signal-regulated kinase)] is observed in vivo in the SCN under constant darkness, although the biological significance of this remains unclear. To elucidate this question, we first examined whether MAPK was autonomously activated in ex vivo SCN slices. Moreover, we investigated the effect of MAPK inhibition on circadian clock gene expression and neuronal firing rhythms using SCN-slice culture systems. We show herein that MAPK is autonomously activated in the SCN, and our data demonstrate that inhibition of the MAPK activity results in dampened rhythms and reduced basal levels in circadian clock gene expression at the SCN single-neuron level. Furthermore, MAPK inhibition attenuates autonomous circadian neuronal firing rhythms in the SCN. Thus, our data suggest that light-independent MAPK activity contributes to the robustness of the SCN autonomous circadian system.
Jewett, M. E.; Kronauer, R. E.; Brown, E. N. (Principal Investigator)
In 1990, Kronauer proposed a mathematical model of the effects of light on the human circadian pacemaker. Although this model predicted many general features of the response of the human circadian pacemaker to light exposure, additional data now available enable us to refine the original model. We first refined the original model by incorporating the results of a dose response curve to light into the model's predicted relationship between light intensity and the strength of the drive onto the pacemaker. Data from three bright light phase resetting experiments were then used to refine the amplitude recovery characteristics of the model. Finally, the model was tested and further refined using data from an extensive phase resetting experiment in which a 3-cycle bright light stimulus was presented against a background of dim light. In order to describe the results of the four resetting experiments, the following major refinements to the original model were necessary: (i) the relationship between light intensity (I) and drive onto the pacemaker was reduced from I1/3 to I0.23 for light levels between 150 and 10,000 lux; (ii) the van der Pol oscillator from the original model was replaced with a higher-order limit cycle oscillator so that amplitude recovery is slower near the singularity and faster near the limit cycle; (iii) a direct effect of light on circadian period (tau x) was incorporated into the model such that as I increases, tau x decreases, which is in accordance with "Aschoff's rule". This refined model generates the following testable predictions: it should be difficult to enhance normal circadian amplitude via bright light; near the critical point of a type 0 phase response curve (PRC) the slope should be steeper than it is in a type 1 PRC; and circadian period measured during forced desynchrony should be directly affected by ambient light intensity.
Full Text Available Cyanobacteria are the only model circadian clock system in which a circadian oscillator can be reconstituted in vitro. The underlying circadian mechanism appears to comprise two subcomponents: a post-translational oscillator (PTO and a transcriptional/translational feedback loop (TTFL. The PTO and TTFL have been hypothesized to operate as dual oscillator systems in cyanobacteria. However, we find that they have a definite hierarchical interdependency-the PTO is the core pacemaker while the TTFL is a slave oscillator that quickly damps when the PTO stops. By analysis of overexpression experiments and mutant clock proteins, we find that the circadian system is dependent upon the PTO and that suppression of the PTO leads to damped TTFL-based oscillations whose temperature compensation is not stable under different metabolic conditions. Mathematical modeling indicates that the experimental data are compatible with a core PTO driving the TTFL; the combined PTO/TTFL system is resilient to noise. Moreover, the modeling indicates a mechanism by which the TTFL can feed into the PTO such that new synthesis of clock proteins can phase-shift or entrain the core PTO pacemaker. This prediction was experimentally tested and confirmed by entraining the in vivo circadian system with cycles of new clock protein synthesis that modulate the phosphorylation status of the clock proteins in the PTO. In cyanobacteria, the PTO is the self-sustained core pacemaker that can operate independently of the TTFL, but the TTFL damps when the phosphorylation status of the PTO is clamped. However, the TTFL can provide entraining input into the PTO. This study is the first to our knowledge to experimentally and theoretically investigate the dynamics of a circadian clock in which a PTO is coupled to a TTFL. These results have important implications for eukaryotic clock systems in that they can explain how a TTFL could appear to be a core circadian clockwork when in fact the true
Jin-Hu Guo; Wei-Min Qu; Shan-Guang Chen; Xiao-Ping Chen; Ke Lv; Zhi-Li Huang; Yi-Lan Wu
The circadian clock and sleep are essential for human physiology and behavior; deregulation of circadian rhythms impairs health and performance. Circadian clocks and sleep evolved to adapt to Earth’s environment, which is characterized by a 24-hour light–dark cycle. Changes in gravity load, lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, in turn jeopardizing the mood, cognition and performance of orbiting astronauts. In this review, we summarize our understanding of both the influence of the space environment on the circadian timing system and sleep and the impact of these changes on astronaut physiology and performance.
Santhi, Nayantara; Lazar, Alpar S; McCabe, Patrick J; Lo, June C; Groeger, John A; Dijk, Derk-Jan
The sleep-wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep-wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.
Full Text Available In humans, sleep and wakefulness and the associated cognitive processes are regulated through interactions between sleep homeostasis and the circadian system. Chronic disruption of sleep and circadian rhythmicity is common in our society and there is a need for a better understanding of the brain mechanisms regulating sleep, wakefulness and associated cognitive processes. This review summarizes recent investigations which provide first neural correlates of the combined influence of sleep homeostasis and circadian rhythmicity on cognitive brain activity. Markers of interindividual variations in sleep-wake regulation, such as chronotype and polymorphisms in sleep and clock genes, are associated with changes in cognitive brain responses in subcortical and cortical areas in response to manipulations of the sleep-wake cycle. This review also includes recent data showing that cognitive brain activity is regulated by light, which is a powerful modulator of cognition and alertness and also directly impacts sleep and circadian rhythmicity. The effect of light varied with age, psychiatric status, PERIOD3 genotype and changes in sleep homeostasis and circadian phase. These data provide new insights into the contribution of demographic characteristics, the sleep-wake cycle, circadian rhythmicity and light to brain functioning.
Agostino, Patricia V; do Nascimento, Micaela; Bussi, Ivana L; Eguía, Manuel C; Golombek, Diego A
Temporal perception is fundamental to environmental adaptation in humans and other animals. To deal with timing and time perception, organisms have developed multiple systems that are active over a broad range of order of magnitude, the most important being circadian timing, interval timing and millisecond timing. The circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is driven by a self-sustaining oscillator with a period close to 24h. Time estimation in the second-to-minutes range--known as interval timing--involves the interaction of the basal ganglia and the prefrontal cortex. In this work we tested the hypothesis that interval timing in mice is sensitive to circadian modulations. Animals were trained following the peak-interval (PI) procedure. Results show significant differences in the estimation of 24-second intervals at different times of day, with a higher accuracy in the group trained at night, which were maintained under constant dark (DD) conditions. Interval timing was also studied in animals under constant light (LL) conditions, which abolish circadian rhythmicity. Mice under LL conditions were unable to acquire temporal control in the peak interval procedure. Moreover, short time estimation in animals subjected to circadian desynchronizations (modeling jet lag-like situations) was also affected. Taken together, our results indicate that short-time estimation is modulated by the circadian clock. Copyright © 2010 Elsevier B.V. All rights reserved.
Full Text Available Circadian clock genes are vital features of eukaryotes that have evolved such that organisms can adapt to our planet’s rotation in order to anticipate the coming day or night as well as unfavorable seasons. This circadian clock uses oscillation as a timekeeping element. However, circadian clock mechanisms exist also in prokaryotes. The circadian clock of Cyanobacteria is well studied. It is regulated by a cluster of three genes: kaiA, kaiB and kaiC. In this review, we will discuss the circadian system in cyanobacteria, and provide an overview and up-dated phylogenetic analysis of prokaryotic organisms that contain the main circadian genes. It is evident that the evolution of the kai genes has been influenced by lateral transfers but further and deeper studies are needed to get an in depth understanding of the exact evolutionary history of these genes. Interestingly, Legionella pneumophila an environmental bacterium and opportunistic human pathogen that parasitizes protozoa in fresh water environments also contains kaiB and kaiC, but their functions are not known. All of the residues described for the biochemical functions of the main pacemaker KaiC in Synechoccous elongates are also conserved in the L. pneumophila KaiC protein.
Udoh, Uduak S; Valcin, Jennifer A; Gamble, Karen L; Bailey, Shannon M
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.
Uduak S. Udoh
Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.
Rana, Sobia; Mahmood, Saqib
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 circ...
Vivanco, Pablo; Otalora, Beatriz Baño; Rol, Maria Angeles; Madrid, Juan Antonio
Octodon degus is a primarily diurnal rodent that presents great variation in its circadian chronotypes due to the interaction between two phase angles of entrainment, diurnal and nocturnal, and the graded masking effects of environmental light and temperature. The aim of this study was to test whether the circadian system of this diurnal rodent can be internally dissociated by imposing cycles shorter and longer than 24 h, and to determine the influence of degus chronotypes and wheel-running availability on such dissociation. To this end, wheel-running activity and body temperature rhythms were studied in degus subjected to symmetrical light-dark (LD) cycles of T28h and T21h. The results show that both T-cycles dissociate the degus circadian system in two different components: one light-dependent component (LDC) that is influenced by the presence of light, and a second non-light-dependent component (NLDC) that free-runs with a period different from the external lighting cycle. The LDC was more evident in the nocturnal than diurnal chronotype, and also when wheel running was available. Our results show that, in addition to rats and mice, degus must be added to the list of species that show an internal dissociation in their circadian rhythms when exposed to forced desynchronization protocols. The existence of a multioscillatory circadian system having two groups of oscillators with low coupling strength may explain the flexibility of degus chronotypes.
Logan, Ryan W; Arjona, Alvaro; Sarkar, Dipak K
Previous research in our laboratory has demonstrated robust circadian variations of cytokines and cytolytic factors in enriched NK cells from rat spleen, strongly suggesting these functions may be subject to circadian regulation. The SCN mediates timing information to peripheral tissues by both humoral and neural inputs. In particular, noradrenergic (NE) sympathetic nervous system (SNS) terminals innervate the spleen tissue communicating information between central and peripheral systems. However, whether these immune factors are subject to timing information conveyed through neural NE innervation to the spleen remained unknown. Indeed, we were able to characterize a circadian rhythm of NE content in the spleen, supporting the role of the SNS as a conveyor of timing information to splenocytes. By chemically producing a local splenic sympathectomy through guanethidine treatment, the splenic NE rhythm was abolished or shifted as indicated by a blunting of the expected peak at ZT7. Consequently, the daily variations of cytokine, TNF-α, and cytolytic factors, granzyme-B and perforin, in NK cells and splenocytes were altered. Only time-dependent mRNA expression of IFN-γ was altered in splenocytes, but not protein levels in NK cells, suggesting non-neural entrainment cues may be necessary to regulate specific immune factors. In addition, the rhythms of clock genes and proteins, Bmal1 and Per2, in these tissues also displayed significantly altered daily variations. Collectively, these results demonstrate rhythmic NE input to the spleen acts as an entrainment cue to modulate the molecular clock in NK cells and other spleen cells possibly playing a role in regulating the cytokine and cytolytic function of these cells. Copyright © 2010 Elsevier Inc. All rights reserved.
Valenzuela, F. J.; Vera, J.; Venegas, C.; Muñoz, S.; Oyarce, S.; Muñoz, K.; Lagunas, C.
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
F. J. Valenzuela
Full Text Available The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genes Clock, Bmal1, Per1–3, and Cry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined.
Skene, Debra J.; Arendt, Josephine; Cade, Janet E.; Grant, Peter J.; Hardie, Laura J.
Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important. PMID:27763782
Lopez-Minguez, Jesus; Ordoñana, Juan R; Sánchez-Romera, Juan F; Madrid, Juan A; Garaulet, Marta
Previous research shows that wrist temperature (WT) is a good marker to assess the circadian system health in different circumstances. However, no studies have been performed in order to know the genetic component of this circadian marker. For this purpose, the aim was to determine, using classical twin models, the relative genetic and environmental influences on WT. The study was performed in 53 pairs of female twins (28 monozygotic (MZ) and 25 dizygotic (DZ)), with a body mass index 25.9 ± 3.78 and mean age 52 ± 6 years. The sample was selected from the Murcia Twin Register. Circadian patterns were studied by analyzing WT during one week every 10 min "Circadianware®". Genetic influences to WT variability were estimated by comparing correlations of MZ and DZ twin pairs and fitting genetic structural equation models to measured variables. MZ twins showed higher intra-pair correlations than DZ twins for most of the parameters. Genetic factors were responsible for between 46% and 70% of variance (broad sense heritability) in parameters such as mean temperature, mesor, acrophase, Rayleigh test, percentage of rhythmicity and five hours of maximum temperature. The pattern of correlations and the genetic models point to moderate to high heritability for most of the WT parameters, suggesting a relevant genetic influence. The presence of these genetic factors points to endogenicity as the main cause of the coincidence of the WT rhythms. However, some WT parameters are still dependent on environment to a relevant extent and, hence, more amenable to change through external interventions.
International audience; It has been shown in animal studies that exposure to brief pulses of bright light can phase shift the circadian pacemaker and that the resetting action of light is most efficient during the first minutes of light exposure. In humans, multiple consecutive days of exposure to brief bright light pulses have been shown to phase shift the circadian pacemaker. The aim of the present study was to determine whether a single sequence of brief bright light pulses administered du...
... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION Circadian, Inc., Clean Energy Combustion, Inc. (n/k/a Clean Energy Combustion Systems, Inc... concerning the securities of Clean Energy Combustion, Inc. (n/k/a Clean Energy Combustion Systems, Inc...
Comas, M.; Beersma, D. G. M.; Spoelstra, K.; Daan, S.
To understand entrainment of circadian systems to different photoperiods in nature, it is important to know the effects of single light pulses of different durations on the free-running system. The authors studied the phase and period responses of laboratory mice (C57BL6J//OlaHsd) to single light
Oporto, G H; Bornhardt, T; Iturriaga, V; Salazar, L A
Bruxism (BRX) is a condition of great interest for researchers and clinicians in dental and medical areas. BRX has two circadian manifestations; it can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, WB). However, it can be suffered together. Recent investigations suggest that central nervous system neurotransmitters and their genes could be involved in the genesis of BRX. Serotonin is responsible for the circadian rhythm, maintaining arousal, regulating stress response, muscle tone and breathing. Thus, serotonin could be associated with BRX pathogenesis. The aim of this work was to evaluate the frequency of genetic polymorphisms in the genes HTR1A (rs6295), HTR2A (rs1923884, rs4941573, rs6313, rs2770304), HTR2C (rs17260565) and SLC6A4 (rs63749047) in subjects undergoing BRX treatment. Patients included were classified according to their diagnosis in awake bruxism (61 patients), sleep bruxism (26 patients) and both (43 patients). The control group included 59 healthy patients with no signs of BRX. Data showed significant differences in allelic frequencies for the HTR2A rs2770304 polymorphism, where the C allele was associated with increased risk of SB (odds ratio = 2·13, 95% confidence interval: 1·08-4·21, P = 0·03). Our results suggest that polymorphisms in serotonergic pathways are involved in sleep bruxism. Further research is needed to clarify and increase the current understanding of BRX physiopathology.
Pauley, Stephen M
The hypothesis that the suppression of melatonin (MLT) by exposure to light at night (LAN) may be one reason for the higher rates of breast and colorectal cancers in the developed world deserves more attention. The literature supports raising this subject for awareness as a growing public health issue. Evidence now exists that indirectly links exposures to LAN to human breast and colorectal cancers in shift workers. The hypothesis begs an even larger question: has medical science overlooked the suppression of MLT by LAN as a contributor to the overall incidence of cancer? The indirect linkage of breast cancer to LAN is further supported by laboratory rat experiments by David E. Blask and colleagues. Experiments involved the implanting of human MCF-7 breast cancer cell xenografts into the groins of rats and measurements were made of cancer cell growth rates, the uptake of linoleic acid (LA), and MLT levels. One group of implanted rats were placed in light-dark (12L:12D) and a second group in light-light (12L:12L) environments. Constant light suppressed MLT, increased cancer cell growth rates, and increased LA uptake into cancer cells. The opposite was seen in the light-dark group. The proposed mechanism is the suppression of nocturnal MLT by exposure to LAN and subsequent lack of protection by MLT on cancer cell receptor sites which allows the uptake of LA which in turn enhances the growth of cancer cells. MLT is a protective, oncostatic hormone and strong antioxidant having evolved in all plants and animals over the millennia. In vertebrates, MLT is normally produced by the pineal gland during the early morning hours of darkness, even in nocturnal animals, and is suppressed by exposure to LAN. Daily entrainment of the human circadian clock is important for good human health. These studies suggest that the proper use and color of indoor and outdoor lighting is important to the health of both humans and ecosystems. Lighting fixtures should be designed to minimize
In normal conditions, the temporal organization of blood pressure (BP) is mainly controlled by neuroendocrine mechanisms. Above all, the monoaminergic systems (including variations in activity of the autonomous nervous system, and in secretion of biogenic amines) appear to integrate the major driving factors of temporal variability, but evidence is available also for a role of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, and endothelial systems, as well as other vasoactive peptides. Many hormones with established actions on the cardiovascular system (arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, CRF, ACTH, TRH, endogenous opioids, and prostaglandin E2) are also involved in sleep induction or arousal, which in turn affects BP regulation. Hence, physical, mental, and pathological stimuli which may drive activation or inhibition of these neuroendocrine effectors of biological rhythmicity, may also interfere with the temporal BP structure. On the other hand, the immediate adaptation of the exogenous components of BP rhythms to the demands of the environment are modulated by the circadian-time-dependent responsiveness of the biological oscillators and their neuroendocrine effectors. These notions may contribute to a better understanding of the pathophysiology and therapeutics of hypertension, myocardial ischemia and infarction, cardiac arrhythmias and all kind of acute cardiovascular accidents. For instance, the normal temporal balance between external stimuli and neurohumoral influences with endogenous rhythmicity is preserved in uncomplicated, essential hypertension, whereas it is frequently lost in complicated and secondary forms of hypertension where gross alterations are found in the circadian profile of BP. When all the gates of the critical physiologic functions are aligned at the same time, the susceptibility, and thus risk, of adverse
Arushanyan, E B
The importance of circadian rhythms for the function of the cardiovascular system and its pharmacotherapy is discussed The central mechanisms regulating these rhythms at the level of suprachiasmatic hypothalamic nucleus and pineal gland are considered in conjunction with the approaches to modulating their activity for optimization of chronopharmnacotherapy of cardiovascular diseases.
in patients with lower than median pain levels for a three days period after laparoscopic cholecystectomy. In the series of studies included in this thesis we have systematically shown that circadian disturbances are found in the secretion of hormones, the sleep-wake cycle, core body temperature rhythm......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...
Duffield, G E; Ebling, F J
The aim of these studies was to investigate maternal entrainment of developing circadian locomotor activity rhythms in the Siberian hamster. In Experiment 1, mothers were transferred from a 16:8 LD cycle into constant dim red light (DD) from the day of parturition, and wheel-running activity of the mother and pups was individually monitored from the time of weaning. The phases of the individual pups' rhythms were found to be synchronized both to the phase of the mother and to the phase of lights off (ZT 12) of the photo cycle that the mother was exposed to until the day of parturition. To investigate whether this synchrony might reflect direct effects of light acting upon the fetal circadian system in late gestation, the experiment was repeated but with mothers placed into DD early in pregnancy (circadian system. The third experiment investigated whether this entrainment occurred during the postnatal period. Breeding pairs were maintained on alternative light-dark cycles, LD and DL, that were 12 h out of phase. Litters born to mothers on one light-dark cycle were exchanged on the day of birth with foster mothers from the reversed light-dark cycle, then raised in DD. Control litters exchanged between mothers from the same light-dark cycle had similar litter synchrony as shown by nonfostered litters of Experiment 1. However, pups cross-fostered with mothers on reversed LD cycles showed a very different distribution of pup phases. Pups were not synchronized to their natural mother but to their foster mother. Moreover, pups were more scattered over the 24-h period and were found to be significantly synchronized to the phase of the reversed LD cycle. These results demonstrate the occurrence of postnatal entrainment in the Siberian hamster. The increased scatter produced by the cross-fostering paradigm results from some litters being completely entrained to the phase of the foster mother, some with an intermediate distribution between the phase of the natural and foster
Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems. Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations. Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes.
Kantermann, Thomas; Juda, Myriam; Merrow, Martha; Roenneberg, Till
A quarter of the world's population is subjected to a 1 hr time change twice a year (daylight saving time, DST). This reflects a change in social clocks, not environmental ones (e.g., dawn). The impact of DST is poorly understood. Circadian clocks use daylight to synchronize (entrain) to the organis
Full Text Available The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBalpha represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.
Flyvholm, Anton; Sen, Sumit; Xylakis, Emmanouil
detection, actigraphy, etc.) and c) anthropological (mood and behaviour). This way, the effect of circadian lighting on well-being, can be also documented, before this new technology can be recommended for implementation in elderly housing. A test installation is planned at “Sundhedshuset” in Albertslund......With the rapid population ageing in Europe and in Denmark, there is an increasing interest in technologies and designs that can support the elderly citizens in sustaining well-being and health along with preventing functional decline . To date, the designs of lighting systems in elderly housing......, Denmark: 15 flats with frail elderly and 9 flats with people with dementia are used.  Lynch, J., & Draper, H. (2014). Ageing well with technology. University of Birmingham  Schlangen L, Lang D, Novotny P, Plischke H, Smolders K, Beersma D, et al. (2014). Lightning for well-being in education, work...
Pilleri, Manuela; Levedianos, Giorgio; Weis, Luca; Gasparoli, Elisabetta; Facchini, Silvia; Biundo, Roberta; Formento-Dojot, Patrizia; Antonini, Angelo
Clinical diagnostic criteria indicate presence of autonomic features as the primary hallmark of Multiple System Atrophy (MSA). However involvement of the autonomic system is also a recognized feature of Parkinson's Disease (PD), yielding a broad clinical overlap between the two diseases. Laboratory assessments may help in the differential diagnosis between PD and MSA. Ambulatory Monitoring of Blood Pressure (AMBP) is a suitable tool to study the circadian rhythm of blood pressure (BP) and heart rate (HR). Different studies reported a reduction of physiological BP nocturnal dipping in PD and MSA patients, but failed to identify a distinctive pattern discriminating the two diseases. On the other hand, HR nocturnal behavior has not been exhaustively analyzed. In the present study we compared the profiles of HR circadian rhythm in 61 PD and 19 MSA patients who underwent 24 h AMBP. We found higher nocturnal HR (nHR) (71.5 beats/min ± 7.4) in MSA compared with PD (63.8 beats/min ± 9.6) as well as significantly lower nocturnal decline of HR (ndHR) in MSA (7.3% ± 8.2) vs. PD (14% ± 7.5). At a Receiver Operating Curve analysis nHR and ndHR significantly discriminated MSA from PD. nHR showed a sensitivity of 84.2% and a specificity of 62.3% (AUC 0.76; 95% IC 0.65-0.85); ndHR showed a sensitivity of 68% of and a specificity of 77% (AUC 0.72; 95% IC 0.61-0.82). According to our findings, nHR is increased and ndHR is reduced in MSA compared to PD. Moreover, these two indices discriminate between the two diseases with acceptable accuracy.
Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T
Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system.
Popa-Wagner, Aurel; Catalin, Bogdan; Buga, Ana-Maria
The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms.
Pellman, Blake A; Kim, Earnest; Reilly, Melissa; Kashima, James; Motch, Oleksiy; de la Iglesia, Horacio O; Kim, Jeansok J
Virtually all animals have endogenous clock mechanisms that "entrain" to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms "entrained" to the LD cycle can be overridden by entrainment to daily recurring threats. We show that unsignaled nocturnal footshock caused rats living in an "ethological" apparatus to switch their natural foraging behavior from the dark to the light phase and that this switch was maintained as a free-running circadian rhythm upon removal of light cues and footshocks. Furthermore, this fear-entrained circadian behavior was dependent on an intact amygdala and suprachiasmatic nucleus. Thus, time-specific fear can act as a non-photic entraining stimulus for the circadian system, and limbic centers encoding aversive information are likely part of the circadian oscillator network that temporally organizes behavior.
There is a grooving evidence that dysfunction in circadian rhythm regulation andmelatonergic system function is involved in depression pathogenesis. It is known thatclinically used antidepressants have influence on melatonergic system, probably throughchanged ratio between melatonergic type 1 and 2 receptors. With the clinical use of newcompounds like agomelatine that directly regulates melatonergic system new opportunities in depression treatment emerged
Jason P. Debruyne
A functional mouse CLOCK protein has long been thought to be essential for mammalian circadian clockwork function, based mainly on studies of mice bearing a dominant negative, antimorphic mutation in the Clock gene. However, new discoveries using recently developed Clock-null mutant mice have shaken up this view. In this review, I discuss how this recent work impacts and alters the previous view of the role of CLOCK in the mouse circadian clockwork.
Dijk, D. J.; Duffy, J. F.
The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.
Primary pathophysiology of circadian rhythm sleep disorders(CRSDs) is a misalignment between the endogenous circadian rhythm phase and the desired or socially required sleep-wake schedule, or dysfunction of the circadian pacemaker and its afferent/efferent pathways. CRSDs consist of delayed sleep phase type, advanced sleep phase type, free-running type, irregular sleep-wake type, shift work type and jet lag type. Chronotherapy using strong zeitgebers (time cues), such as bright light and melatonin/ melatonin type 2 receptor agonist, is effective when administered with proper timing. Bright light is the strongest entraining agent of circadian rhythms. Bright light therapy (appropriately-timed exposure to bright light) for CRSDs is an effective treatment option, and can shift the sleep-wake cycle to earlier or later times, in order to correct for misalignment between the circadian system and the desired sleep-wake schedule. Timed administration of melatonin, either alone or in combination with light therapy has also been shown to be useful in the treatment of CRSDs.
Duffield, G E; Hastings, M H; Ebling, F J
Dopamine and melatonin have both been implicated in mediating maternal influences on the developing circadian system of altricial rodents. The aim of these studies was to investigate their role in the entrainment of the circadian system of the adult Siberian hamster (Phodopus sungorus). In-situ hybridization revealed that D1-dopamine receptor (D1-R) mRNA was expressed in the adult suprachiasmatic nucleus (SCN) at levels comparable to neonates. As dopamine has been postulated to mimic photic stimulation during early development, experiment 1 compared the effects of a D1-R agonist and a light pulse on free-running wheel running rhythms in hamsters maintained in constant dim red light. A phase response curve to light was generated, revealing clear phase delays early in the subjective night, and large phase advances in the late subjective night. However, the D1-R agonist (SKF 81297, 2 mg/kg, s.c.) did not produce consistent phase shifts at any circadian phase. Experiment 2 tested the ability of this dopaminergic agonist to modulate photic responses of the circadian system. Free-running animals were pre-treated with SKF 81297 (2 mg/kg, s.c.) 30 min before a 15 min light pulse given early or late in the subjective night. This agonist had no effect on the magnitude of phase shifts at either circadian time. In experiment 3, light pulses at CT13-15 induced expression of the immediate early gene c-fos in the SCN, as assessed by immunocytochemistry for the protein product. In contrast, SKF 81297 (2 mg/kg, s.c.) at the same phase did not induce c-fos in the SCN, despite marked c-fos induction in the caudate-putamen, nor did it affect photic induction of c-fos in the SCN. To investigate whether dopamine might be involved in nonphotic regulation of the circadian system in adult hamsters, experiment 4 compared the response of free-running hamsters to a series of injections of SKF 81297 (2 mg/kg, s.c.) or melatonin (1 mg/kg, s.c.), since melatonin receptor expression in the SCN
Borodin, Iu I; Letiagin, A Y
C57B1/6 inbred mice were placed in hypomagnetic condition during 14 days constantly. Degree of relaxation of geomagnetic field was 10(4). The increase of the number of eosinophil granulocytes was discovered in peripheral blood of mice. Measures of circadian rhythms of blood's absolute lymphocytosis, absolute number of cells in bone marrow, thymus, spleen and inguinal lymph nodes were safe. Adaptation of lymphoid system to hypomagnetic condition was manifested by desynchronization of circadian rhythmicity on the basis of different sensitivity of lymphoid organs, that realized in strengthening of ultradian rhythms with periods of 15 hours. There are indirect data, that show the increase of speed and/or volume of recirculation of lymphoid cells.
Yasenkov, Roman; Deboer, Tom
Sleep is regulated by circadian and homeostatic processes. The sleep homeostat keeps track of the duration of prior sleep and waking and determines the intensity of sleep. In mammals, the homeostatic process is reflected by the slow waves in the non-rapid eye movement (NREM) sleep electroencephalogram (EEG). The circadian process is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus and provides the sleep homeostat with a circadian framework. This review summarizes the changes in sleep obtained after different chronobiological interventions (changes in photoperiod, light availability, and running wheel availability), the influence of mutations or lesions in clock genes on sleep, and research on the interaction between sleep homeostasis and the circadian clock. Research in humans shows that the period of consolidated waking during the day is a consequence of the interaction between an increasing homeostatic sleep drive and a circadian signal, which promotes waking during the day and sleep during the night. In the rat, it was shown that, under constant homeostatic sleep pressure, with similar levels of slow waves in the NREM sleep EEG at all time points of the circadian cycle, still a small circadian modulation of the duration of waking and NREM sleep episodes was observed. Under similar conditions, humans show a clear circadian modulation in REM sleep, whereas in the rat, a circadian modulation in REM sleep was not present. Therefore, in the rat, the sleep homeostatic modulation in phase with the circadian clock seems to amplify the relatively weak circadian changes in sleep induced by the circadian clock. Knowledge about the interaction between sleep and the circadian clock and the circadian modulation of sleep in other species than humans is important to better understand the underlying regulatory mechanisms.
Adams, Kandis L; Castanon-Cervantes, Oscar; Evans, Jennifer A; Davidson, Alec J
The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these rhythms. LPS-induced IL-6 release in whole blood was regulated in a circadian manner, peaking during subjective day under both entrained and free-running conditions. This LPS-induced IL-6 release rhythm was associated with daily variation in both white blood cell counts and immune cell responsiveness. ECD increased the overall level of LPS-induced IL-6 release by increasing immune cell responsiveness and not by affecting immune cell number or the circadian regulation of this rhythm. This indicates that ECD produces pathological immune responses by increasing the proinflammatory responses of immune cells. Also, this newly developed whole blood assay can provide a noninvasive longitudinal method to quantify potential health consequences of circadian disruption in humans.
Monk, T. H.; Kupfer, D. J.
Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).
Castro, C; Briggs, W; Paschos, G K; FitzGerald, G A; Griffin, J L
Adipose tissue functions in terms of energy homeostasis as a rheostat for blood triglyceride, regulating its concentration, in response to external stimuli. In addition it acts as a barometer to inform the central nervous system of energy levels which can vary dramatically between meals and according to energy demand. Here a metabolomic approach, combining both Mass Spectrometry and Nuclear Magnetic Resonance spectroscopy, was used to analyse both white and brown adipose tissue in mice with adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component. The results are consistent with a peripheral circadian clock playing a central role in metabolic regulation of both brown and white adipose tissue in rodents and show that Arntl induced global changes in both tissues which were distinct for the two types. In particular, anterior subcutaneous white adipose tissue (ASWAT) tissue was effected by a reduction in the degree of unsaturation of fatty acids, while brown adipose tissue (BAT) changes were associated with a reduction in chain length. In addition the aqueous fraction of metabolites in BAT were profoundly affected by Arntl disruption, consistent with the dynamic role of this tissue in maintaining body temperature across the day-night cycle and an upregulation in fatty acid oxidation and citric acid cycle activity to generate heat during the day when rats are inactive (increases in 3-hydroxybutyrate and glutamate), and increased synthesis and storage of lipids during the night when rats feed more (increased concentrations of glycerol, choline and glycerophosphocholine).
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...... 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...
Summa, Keith C; Turek, Fred W
Recent advances in the understanding of the molecular, genetic, neural, and physiologic basis for the generation and organization of circadian clocks in mammals have revealed profound bidirectional interactions between the circadian clock system and pathways critical for the regulation of metabolism and energy balance. The discovery that mice harboring a mutation in the core circadian gene circadian locomotor output cycles kaput (Clock) develop obesity and evidence of the metabolic syndrome represented a seminal moment for the field, clearly establishing a link between circadian rhythms, energy balance, and metabolism at the genetic level. Subsequent studies have characterized in great detail the depth and magnitude of the circadian clock's crucial role in regulating body weight and other metabolic processes. Dietary nutrients have been shown to influence circadian rhythms at both molecular and behavioral levels; and many nuclear hormone receptors, which bind nutrients as well as other circulating ligands, have been observed to exhibit robust circadian rhythms of expression in peripheral metabolic tissues. Furthermore, the daily timing of food intake has itself been shown to affect body weight regulation in mammals, likely through, at least in part, regulation of the temporal expression patterns of metabolic genes. Taken together, these and other related findings have transformed our understanding of the important role of time, on a 24-h scale, in the complex physiologic processes of energy balance and coordinated regulation of metabolism. This research has implications for human metabolic disease and may provide unique and novel insights into the development of new therapeutic strategies to control and combat the epidemic of obesity.
Gögenur, Ismail; Rosenberg-Adamsen, Susan; Lie, Claus;
patients who had had major abdominal operations. INTERVENTIONS: Patients were monitored with 24-hour Holter ECG on the second postoperative day-evening-night. We calculated heart rate variability from the standard deviation of all normal R-R intervals (excluding ectopics-NN intervals) around the mean NN......OBJECTIVE: Most sudden postoperative deaths occur during the night and we conjectured that this was associated with circadian variations in the autonomic nervous tone, reflected in heart rate variability. DESIGN: Prospective clinical study. SETTINGS: University hospital, Denmark. SUBJECTS: 44...... OUTCOME MEASURES: Heart rate and heart rate variability. RESULTS: Circadian variation calculated from the SDNN (p = 0.43) the pNN50 (p = 0.11), the RMSSD (p = 0.47), and mean NN:SDNN ratio (p = 0.13) was absent postoperatively. Circadian variation in the heart rate was present but was set on a higher...
Gerhart-Hines, Zachary; Lazar, Mitchell A
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.
Mohamed, Ahmed A M; Wang, Qiushi; Bembenek, Jadwiga; Ichihara, Naoyuki; Hiragaki, Susumu; Suzuki, Takeshi; Takeda, Makio
Since its discovery in 1923, the biology of photoperiodism remains a mystery in many ways. We sought the link connecting the circadian system to an endocrine switch, using Antheraea pernyi. PER-, CLK- and CYC-ir were co-expressed in two pairs of dorsolateral neurons of the protocerebrum, suggesting that these are the circadian neurons that also express melatonin-, NAT- and HIOMT-ir. The results suggest that a melatonin pathway is present in the circadian neurons. Melatonin receptor (MT2 or MEL-1B-R)-ir in PTTH-ir neurons juxtaposing clock neurons suggests that melatonin gates PTTH release. RIA showed a melatonin rhythm with a peak four hours after lights off in adult brain both under LD16:8 (LD) and LD12:12 (SD), and both the peak and the baseline levels were higher under LD than SD, suggesting a photoperiodic influence. When pupae in diapause were exposed to 10 cycles of LD, or stored at 4 °C for 4 months under constant darkness, an increase of NAT activity was observed when PTTH released ecdysone. DNA sequence upstream of nat contained E-boxes to which CYC/CLK could bind, and nat transcription was turned off by clk or cyc dsRNA. dsRNA(NAT) caused dysfunction of photoperiodism. dsRNA(PER) upregulated nat transcription as anticipated, based on findings in the Drosophila melanogaster circadian system. Transcription of nat, cyc and clk peaked at ZT12. RIA showed that dsRNA(NAT) decreased melatonin while dsRNA(PER) increased melatonin. Thus nat, a clock controlled gene, is the critical link between the circadian clock and endocrine switch. MT-binding may release PTTH, resulting in termination of diapause. This study thus examined all of the basic functional units from the clock: a photoperiodic counter as an accumulator of mRNA(NAT), to endocrine switch for photoperiodism in A. pernyi showing this system is self-complete without additional device especially for photoperiodism.
Ahmed A M Mohamed
Full Text Available Since its discovery in 1923, the biology of photoperiodism remains a mystery in many ways. We sought the link connecting the circadian system to an endocrine switch, using Antheraea pernyi. PER-, CLK- and CYC-ir were co-expressed in two pairs of dorsolateral neurons of the protocerebrum, suggesting that these are the circadian neurons that also express melatonin-, NAT- and HIOMT-ir. The results suggest that a melatonin pathway is present in the circadian neurons. Melatonin receptor (MT2 or MEL-1B-R-ir in PTTH-ir neurons juxtaposing clock neurons suggests that melatonin gates PTTH release. RIA showed a melatonin rhythm with a peak four hours after lights off in adult brain both under LD16:8 (LD and LD12:12 (SD, and both the peak and the baseline levels were higher under LD than SD, suggesting a photoperiodic influence. When pupae in diapause were exposed to 10 cycles of LD, or stored at 4 °C for 4 months under constant darkness, an increase of NAT activity was observed when PTTH released ecdysone. DNA sequence upstream of nat contained E-boxes to which CYC/CLK could bind, and nat transcription was turned off by clk or cyc dsRNA. dsRNA(NAT caused dysfunction of photoperiodism. dsRNA(PER upregulated nat transcription as anticipated, based on findings in the Drosophila melanogaster circadian system. Transcription of nat, cyc and clk peaked at ZT12. RIA showed that dsRNA(NAT decreased melatonin while dsRNA(PER increased melatonin. Thus nat, a clock controlled gene, is the critical link between the circadian clock and endocrine switch. MT-binding may release PTTH, resulting in termination of diapause. This study thus examined all of the basic functional units from the clock: a photoperiodic counter as an accumulator of mRNA(NAT, to endocrine switch for photoperiodism in A. pernyi showing this system is self-complete without additional device especially for photoperiodism.
Van Leenen, Dik; Bijvoet, Agnes G. A.; Visser, Pim; Heuvelsland, Gerard F. M.; Verkerk, Anton; Van Der Horst, Gijsbertus T. J.; Reuser, Arnold J. J.
This paper describes the design and functioning of a low-cost computerized system for monitoring the voluntary activity of mice in running wheels. The required software is written in Turbo Pascal(r) and provided via the Internet (http://www.eur.nl/fgg/ch1/rodent.html). The system accommodates the simultaneous monitoring of 20 animals over a virtually unlimited period. Two applications of the system are presented; one monitors the circadian rhythm of mice, and the other tests muscle strength and endurance.
Hampel, Daniela; Shahab-Ferdows, Setareh; Islam, M Munirul; Peerson, Janet M; Allen, Lindsay H
Background: Human milk is the subject of many studies, but procedures for representative sample collection have not been established. Our improved methods for milk micronutrient analysis now enable systematic study of factors that affect its concentrations.Objective: We evaluated the effects of sample collection protocols, variations in circadian rhythms, subject variability, and acute maternal micronutrient supplementation on milk vitamin concentrations.Methods: In the BMQ (Breast-Milk-Quality) study, we recruited 18 healthy women (aged 18-26 y) in Dhaka, Bangladesh, at 2-4 mo of lactation for a 3-d supplementation study. On day 1, no supplements were given; on days 2 and 3, participants consumed ∼1 time and 2 times, respectively, the US-Canadian Recommended Dietary Allowances for vitamins at breakfast (0800-0859). Milk was collected during every feeding from the same breast over 24 h. Milk expressed in the first 2 min (aliquot I) was collected separately from the remainder (aliquot II); a third aliquot (aliquot III) was saved by combining aliquots I and II. Thiamin, riboflavin, niacin, and vitamins B-6, B-12, A, and E and fat were measured in each sample.Results: Significant but small differences (14-18%) between aliquots were found for all vitamins except for vitamins B-6 and B-12. Circadian variance was significant except for fat-adjusted vitamins A and E, with a higher contribution to total variance with supplementation. Between-subject variability accounted for most of the total variance. Afternoon and evening samples best reflected daily vitamin concentrations for all study days. Acute supplementation effects were found for thiamin, riboflavin, and vitamins B-6 and A at 2-4 h postdosing, with 0.1-6.17% passing into milk. Supplementation was reflected in fasting, 24-h postdose samples for riboflavin and vitamin B-6. Maximum amounts of dose-responding vitamins in 1 feeding ranged from 4.7% to 21.8% (day 2) and 8.2% to 35.0% (day 3) of Adequate Intake
Full Text Available Plant development is the result of an endogenous morphogenetic program that integrates environmental signals. The so-called circadian clock is a set of genes that integrates environmental inputs into an internal pacing system that gates growth and other outputs. Study of circadian growth responses requires high sampling rates to detect changes in growth and avoid aliasing. We have developed a flexible configurable growth chamber comprising a computer vision system that allows sampling rates ranging between one image per 30 s to hours/days. The vision system has a controlled illumination system, which allows the user to set up different configurations. The illumination system used emits a combination of wavelengths ensuring the optimal growth of species under analysis. In order to obtain high contrast of captured images, the capture system is composed of two CCD cameras, for day and night periods. Depending on the sample type, a flexible image processing software calculates different parameters based on geometric calculations. As a proof of concept we tested the system in three different plant tissues, growth of petunia- and snapdragon (Antirrhinum majus flowers and of cladodes from the cactus Opuntia ficus-indica. We found that petunia flowers grow at a steady pace and display a strong growth increase in the early morning, whereas Opuntia cladode growth turned out not to follow a circadian growth pattern under the growth conditions imposed. Furthermore we were able to identify a decoupling of increase in area and length indicating that two independent growth processes are responsible for the final size and shape of the cladode.
Navarro, Pedro J; Fernández, Carlos; Weiss, Julia; Egea-Cortines, Marcos
Plant development is the result of an endogenous morphogenetic program that integrates environmental signals. The so-called circadian clock is a set of genes that integrates environmental inputs into an internal pacing system that gates growth and other outputs. Study of circadian growth responses requires high sampling rates to detect changes in growth and avoid aliasing. We have developed a flexible configurable growth chamber comprising a computer vision system that allows sampling rates ranging between one image per 30 s to hours/days. The vision system has a controlled illumination system, which allows the user to set up different configurations. The illumination system used emits a combination of wavelengths ensuring the optimal growth of species under analysis. In order to obtain high contrast of captured images, the capture system is composed of two CCD cameras, for day and night periods. Depending on the sample type, a flexible image processing software calculates different parameters based on geometric calculations. As a proof of concept we tested the system in three different plant tissues, growth of petunia- and snapdragon (Antirrhinum majus) flowers and of cladodes from the cactus Opuntia ficus-indica. We found that petunia flowers grow at a steady pace and display a strong growth increase in the early morning, whereas Opuntia cladode growth turned out not to follow a circadian growth pattern under the growth conditions imposed. Furthermore we were able to identify a decoupling of increase in area and length indicating that two independent growth processes are responsible for the final size and shape of the cladode.
Graeber, R. Curtis
Recent statistical and experimental studies on the role of circadian rhythms in aircrew fatigue and aviation accidents are reviewed from a human-factors perspective, and typical data are presented in extensive graphs. Consideration is given to the biological clock and the limits of endurance, circadian desynchronization, sleep and sleepiness, short-haul and long-haul operational studies, and the potential advantages of cockpit automation.
Wenxue Wang, Christian Cajochen, Scott T. Grafton, Francis J. Doyle III. Modeling Circadian -Dependent Learning Performance of Sequence Structures...in zebrafish embryos to verify our theoretical predictions. The segmentation clock controls the somitogenesis in vertebrate development. It is...signaling synchronizes the cellular network (c.f. Figure 11). Treating wild-type zebrafish embryos with DAPT, a !-secretase inhibitor that suppresses
Wu, Y.-H.; Swaab, D.F.
Circadian rhythm disturbances, such as sleep disorders, are frequently seen in aging and are even more pronounced in Alzheimer's disease (AD). Alterations in the biological clock, the suprachiasmatic nucleus (SCN), and the pineal gland during aging and AD are considered to be the biological basis fo
Staiger, Dorothee; Shin, Jieun; Johansson, Mikael; Davis, Seth J
Large-scale biology among plant species, as well as comparative genomics of circadian clock architecture and clock-regulated output processes, have greatly advanced our understanding of the endogenous timing system in plants.
Rosenwasser, Alan M; Turek, Fred W
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.
The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.
Feillet, Céline; Horst, Gijsbertus Theodorus Johannes van der; Lévi, Francis A.; Rand, D. A.; Delaunay, Franck
Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two process...
David M. Virshup
Full Text Available An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep–wake cycle, feeding–fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.
Adaptation in the temporal environment is key to survival. This is achieved by the manifestation of periodicity in occurrence of vital behavioural and physiological processes at regular intervals--the biological rhythms. Biological rhythms (= biological clocks) are ubiquitous, can be demonstrated persisting at any level of organization in the living world, and are generated and controlled by some central pacemaker(s), mostly located in the brain. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the principal site of the endogenous circadian pacemaker, regulating many daily physiological and behavioural functions, although other neural structures could also be contributing to the circadian timekeeping system. In other vertebrates, the neural site(s) of the circadian pacemaker is(are) still unclear. An organism without brain can have the biological clock, as well, for fully functional 24-hour temporal organization has been identified in several invertebrates, including unicellular Paramecium and Gonyaulax as well as filamentous fungus, Neurospora. This article attempts to provide an update of the informations which have accumulated over the past decade about understanding of the neurophysiological and molecular bases of circadian rhythms in animals.
Full Text Available BACKGROUND: Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per or Cryptochrome1 and 2 (Cry are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Mice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. CONCLUSIONS/SIGNIFICANCE: Tumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.
A 24 hour variation of core body temperature in humans is primarily regulated by the endogenous circadian pacemaker located in the suprachiasmatic nucleus. And the expression of circadian rhythm is modified by the thermoregulatory mechanism controlling heat production and heat loss, which also show circadian rhythms. On the other hand, circadian rhythms in sleep-wakefulness are expressed by two independent but mutually coupled oscillators, the circadian pacemaker and the oscillator specific to sleep-wakefulness. However, neither the mechanism nor the site of oscillation of the latter is known. The time cues for these two oscillators are different. They are usually but frequently uncoupled under free-running conditions. Body temperature and sleep-wakefulness influence the counterpart in various extents, exerting masking effects on either circadian rhythm.
Khapre, Rohini V; Samsa, William E; Kondratov, Roman V
The circadian clock generates oscillations in physiology and behavior, known as circadian rhythms. Links between the circadian clock genes Periods, Bmal1, and Cryptochromes and aging and cancer are emerging. Circadian clock gene expression is changed in human pathologies, and transgenic mice with mutations in clock genes develop cancer and premature aging. Control of genome integrity and cell proliferation play key roles in the development of age-associated pathologies and carcinogenesis. Here, we review recent data on the connection between the circadian clock and control of the cell cycle. The circadian clock regulates the activity and expression of several critical cell cycle and cell cycle check-point-related proteins, and in turn cell cycle-associated proteins regulate circadian clock proteins. DNA damage can reset the circadian clock, which provides a molecular mechanism for reciprocal regulation between the circadian clock and the cell cycle. This circadian clock-dependent control of cell proliferation, together with other known physiological functions of the circadian clock such as the control of metabolism, oxidative and genotoxic stress response, and DNA repair, opens new horizons for understanding the mechanisms behind aging and carcinogenesis.
Karen L. Gamble
Full Text Available Health impairments, including reproductive issues, are associated with working nights or rotating shifts. For example, shift work has been associated with an increased risk of irregular menstrual cycles, endometriosis, infertility, miscarriage, low birth weight or pre-term delivery, and reduced incidence of breastfeeding. Based on what is known about circadian regulation of endocrine rhythms in rodents (and much less in humans, the circadian clock is an integral regulatory part of the reproductive system. When this 24-h program is disordered by environmental perturbation (such as shift work or genetic alterations, the endocrine system can be impaired. The purpose of this review is to explore the hypothesis that misalignment of reproductive hormones with the environmental light-dark cycle and/or sleep wake rhythms can disrupt menstrual cycles, pregnancy, and parturition. We highlight the role of the circadian clock in regulating human reproductive physiology and shift work-induced pathology within each step of the reproductive axis while exploring potential mechanisms from the animal model literature. In addition to documenting the reproductive hazards of shift work, we also point out important gaps in our knowledge as critical areas for future investigation. For example, future studies should examine whether forced desynchronization disrupts gonadotropin secretion rhythms and whether there are sleep/wake schedules that are better or worse for the adaptation of the reproductive system to shift work. These studies are necessary in order to define not only whether or not shift-work induced circadian misalignment impairs reproductive capacity, but also to identify strategies for the future that can minimize this desynchronization.
James K. Wyatt; Angela Ritz-De Cecco; Charles A. Czeisler; Derk-Jan Dijk
.... The circadian components of cognitive throughput, short-term memory, alertness, psychomotor vigilance, and sleep disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset...
Touitou, Yvan; Selmaoui, Brahim; Lambrozo, Jacques; Auzeby, André
The consequences of electromagnetic exposure on human health are receiving increasing scientific attention and have become the subject of a vigorous public debate. In the present study we evaluated the effects of magnetic field on pineal function in man and rat. Two groups of Wistar male rats were exposed to 50-Hz magnetic fields of either 1, 10 or 100 microT. The first group was exposed for 12 hours and the second for 30 days (18 hours per day). Short-term exposure depressed both pineal NAT activity and nocturnal serum melatonin concentration but only with the highest intensity used (100 microT). Long-term exposure to a magnetic field significantly depressed the nighttime peak of serum melatonin concentration and pineal NAT activity with 10 and 100 microT. Our results show that sinusoidal magnetic fields altered the production of melatonin through an inhibition of pineal NAT activity. Both duration and intensity of exposure played an important role in this effect. In the second step of this study, thirty-two young men (20-30 years old) were divided into two groups (control group, i.e., sham-exposed: 16 subjects; exposed group: 16 subjects). The subjects were exposed to the magnetic field from 23 h to 08 h (i.e. for 9 h) while lying down. In one experiment the exposure was continuous, in the second one, the magnetic field was intermittent. No significant differences were observed between sham-exposed (control) and exposed men for serum melatonin and 6-sulfatoxymelatonin. In our last and more recent study, we looked for the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 years, in the workplace and at home, to a 50 Hz (exposure 0.1 to > 0.3 microT) magnetic field. The results are compared to those for 15 unexposed men who served as controls. Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 years) and on a
Wendeu-Foyet, Méyomo G; Menegaux, Florence
Since the publication of the IARC Monograph in 2007 classifying night shift work leading to a disruption of circadian rhythm as probably carcinogenic to humans, there is an increasingly growing interest in understanding how circadian disruption may play a role in cancer development. This systematic review provides a comprehensive update on epidemiological evidences on circadian disruption and prostate cancer since the last review published in 2012. We identified 12 new studies evaluating the effects of several circadian disruptors such as night shift work, sleep patterns, and circadian genes in prostate cancer risk. In contrast, no new studies have focused on exposure to light at night. Several convincing and biologically plausible hypotheses have been proposed to understand how circadian disruption may be related to cancer. However, the current difficulty of concluding on the role of circadian disruption on prostate cancer risk requires further studies including a better characterization of the different night shift systems, data on sleep patterns and chronotype, measurement of biomarkers and investigations of polymorphisms in the genes regulating the biological clock.
Wang, Xiaoxue; Ma, Ligeng
The circadian clock is an endogenous timing system responsible for coordinating an organism's biological processes with its environment. Interlocked transcriptional feedback loops constitute the fundamental architecture of the circadian clock. In Arabidopsis, three feedback loops, the core loop, morning loop and evening loop, comprise a network that is the basis of the circadian clock. The components of these three loops are regulated in distinct ways, including transcriptional, post-transcriptional and posttranslational mechanisms. The discovery of the DNA-binding and repressive activities of TOC1 has overturned our initial concept of its function in the circadian clock. The alternative splicing of circadian clock-related genes plays an essential role in normal functioning of the clock and enables organisms to sense environmental changes. In this review, we describe the regulatory mechanisms of the circadian clock that have been identified in Arabidopsis.
XU Feng; WANG Min; ZANG Ling-he
Objective To further authenticate the role of melatonin on endogenous biologic clock system. Methods Pinealectomized mice were used in the experiments, a series of circadian rhythm of physiology index, such as glucocorticoid, amino acid neurotransmitter, immune function, sensitivity of algesia and body temperature were measured. Results Effects of melatonin on endogenous circadian rhythm roughly appeared four forms: 1) The model of inherent rhythm was invariant, but midvalue was removed. 2) Pacing function: pinealectomy and melatonin administration changed amplitude of the circadian vibration of aspartate, peripheral blood WBC and serum hemolysin. 3) Phase of rhythm changed, such as the effects on percentage of lymphocyte and sensitivity of algesia. 4) No effect, the circadian rhythm of body temperature belong to this form Conclusions Melatonin has effects some circadian rhythm, and it can adjust endogenous inherent rhythm and make the rhythm keep step with environmental cycle. Melatonin may be a kind of Zeitgeber, Pineal gland might being a rhythm bearing organ to some circadian rhythm.
Tortonese, D J; Preedy, D F; Hesketh, S A; Webb, H N; Wilkinson, E S; Allen, W R; Fuller, C J; Townsend, J; Short, R V
Abrupt alterations in the 24-h light : dark cycle, such as those resulting from transmeridian air travel, disrupt circadian biological rhythms in humans with detrimental consequences on cognitive and physical performance. In the present study, a jetlag-simulated phase shift in photoperiod temporally impaired circadian peaks of peripheral clock gene expression in racehorses but acutely enhanced athletic performance without causing stress. Indices of aerobic and anaerobic capacities were significantly increased by a phase-advance, enabling prolonged physical activity before fatigue occurred. This was accompanied by rapid re-entrainment of the molecular clockwork and the circadian pattern of melatonin, with no disturbance of the adrenal cortical axis, but a timely rise in prolactin, which is a hormone known to target organs critical for physical performance. Subsequent studies showed that, unlike the circadian pattern of melatonin, and in contrast to other species, the daily rhythm of locomotor activity was completely eliminated under constant darkness, but it was restored immediately upon the reintroduction of a light : dark cycle. Resetting of the rhythm of locomotion was remarkably fast, revealing a rapid mechanism of adaptation and a species dependency on light exposure for the expression of daily diurnal activity. These results show that horses are exquisitely sensitive to sudden changes in photoperiod and that, unlike humans, can benefit from them; this appears to arise from powerful effects of light underlying a fast and advantageous process of adjustment to the phase shift.
Johnson, Carl Hirschie
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...
As an experimental model system, the fruit fly Drosophila melanogaster has been seminal in shaping our understanding of the circadian clockwork. The wealth of genetic tools at our disposal over the past four decades has enabled discovery of the genetic and molecular bases of circadian rhythmicity. More recently, detailed investigation leading to the anatomical, neurochemical and electrophysiological characterization of the various neuronal subgroups that comprise the circadian machinery has revealed pathways through which these neurons come together to act as a neuronal circuit. Thus the D. melanogaster circadian pacemaker circuit presents a relatively simple and attractive model for the study of neuronal circuits and their functions.
Full Text Available Ilia N Karatsoreos Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Abstract: Circadian (daily rhythms are pervasive in nature, and expressed in nearly every behavioral and physiological process. In mammals, circadian rhythms are regulated by the master brain clock in the suprachiasmatic nucleus of the hypothalamus that coordinates the activity of “peripheral” oscillators throughout the brain and body. While much progress has been made in understanding the basic functioning of the circadian clock at the level of genes, molecules, and cells, our understanding of how these clocks interact with complex systems is still in its infancy. Much recent work has focused on the role of circadian clocks in the etiology of disorders as diverse as cancer, diabetes, and obesity. Given the rapid rise in obesity, and the economic costs involved in treating its associated cardiometabolic disorders such as heart disease and diabetes mellitus, understanding the development of obesity and metabolic dysregulation is crucial. Significant epidemiological data indicate a role for circadian rhythms in metabolic disorders. Shift workers have a higher incidence of obesity and diabetes, and laboratory studies in humans show misaligning sleep and the circadian clock leads to hyperinsulinemia. In animal models, body-wide “clock gene” knockout mice are prone to obesity. Further, disrupting the circadian clock by manipulating the light–dark cycle can result in metabolic dysregulation and development of obesity. At the molecular level, elegant studies have shown that targeted disruption of the genetic circadian clock in the pancreas leads to diabetes, highlighting the fact that the circadian clock is directly coupled to metabolism at the cellular level. Keywords: glucose, metabolism, sleep, rhythms, obesity
Cerullo, Michael J.
Main objectives of human resource accounting systems are to satisfy the informational demands made by investors and by operating managers. The paper's main concern is with the internal uses of a human asset system. (Author)
Navaz, A. S. Syed; Fiaz, A. S. Syed; Prabhadevi, C.; V.Sangeetha; Gopalakrishnan,S.
The paper titled HUMAN RESOURCE MANAGEMENT SYSTEM is basically concerned with managing the Administrator of HUMAN RESOURCE Department in a company. A Human Resource Management System, refers to the systems and processes at the intersection between human resource management and information technology. It merges HRM as a discipline and in particular its basic HR activities and processes with the information technology field, whereas the programming of data processing systems evolved into standa...
Ilia N Karatsoreos
Full Text Available Determining the cause of psychiatric disorders is a goal of modern neuroscience, and will hopefully lead to the discovery of treatments to either prevent or alleviate the suffering caused by these diseases. One roadblock to attaining this goal is the realization that neuropsychiatric diseases are rarely due to a single gene polymorphism, environmental exposure, or developmental insult. Rather, it is a complex interaction between these various influences that likely leads to the development of clinically relevant syndromes. Our lab is exploring the links between environmental exposures and neurobehavioral function by investigating how disruption of the circadian (daily clock alters the structure and function of neural circuits, with the hypothesis that disrupting this crucial homeostatic system can directly contribute to altered vulnerability of the organism to other factors that interact to produce psychiatric illness. This review explores some historical and more recent findings that link disrupted circadian clocks to neuropsychiatric disorders, particularly depression, mania, and schizophrenia. We take a comparative approach by exploring the effects observed in human populations, as well as some experimental models used in the laboratory to unravel mechanistic and causal relationships between disruption of the circadian clock and behavioral abnormalities. This is a rich area of research that we predict will contribute greatly to our understanding of how genes, environment, and development interact to modulate an individual’s vulnerability to psychiatric disorders.
Negoro, Hiromitsu; Kanematsu, Akihiro; Yoshimura, Koji; Ogawa, Osamu
Mammals urinate less frequently during the sleep period than the awake period. This is modulated by a triad of factors, including decreased arousal in the brain, a decreased urine production rate in the kidneys and increased functional bladder capacity during sleep. The circadian clock is genetic transcription-translation feedback machinery. It exists in most organs and cells, termed the peripheral clock, which is orchestrated by the central clock in the suprachiasmatic nucleus of the brain. We discuss the linkage between the day and night change in micturition frequency and the genetic rhythm maintained by the circadian clock system, focusing on the brain, kidney and bladder. We performed an inclusive review of the literature on the diurnal change in micturition frequency, urine volume, functional bladder capacity and urodynamics in humans and rodents, relating this to recent basic biological findings about the circadian clock. In humans various behavioral studies demonstrated a diurnal functional change in the kidney and bladder. Conversely, patients with nocturnal enuresis and nocturia showed impairment in this triad of factors. Rats and mice, which are nocturnal animals, also have a micturition frequency rhythm that is decreased during the day, which is the sleep phase for them. Mice with a genetically defective circadian clock system show impaired physiological rhythms in the triad of factors. The existence of the circadian clock has been proven in the brain, kidney and bladder, in which thousands of circadian oscillating genes exist. In the kidney they include genes involved in the regulation of water and major electrolytes. In the bladder they include connexin 43, a gene associated with the regulation of bladder capacity. Recent progress in molecular biology about the circadian clock provides an opportunity to investigate the genetic basis of the micturition rhythm or impairment of the rhythm in nocturnal enuresis and nocturia. If this approach is to be
Gunawan, Rudiyanto; Doyle, Francis J.
Circadian rhythms possess the ability to robustly entrain to the environmental cycles. This ability relies on the phase synchronization of circadian rhythm gene regulation to different environmental cues, of which light is the most obvious and important. The elucidation of the mechanism of circadian entrainment requires an understanding of circadian phase behavior. This article presents two phase analyses of oscillatory systems for infinitesimal and finite perturbations based on isochrons as ...
Roenneberg, T; Merrow, M
The circadian clock in all organisms is so intimately linked to light reception that it appears as if evolution has simply wired a timer into the mechanism that processes photic information. Several recent studies have provided new insights into the role of light input pathways in the circadian system of Arabidopsis.
Full Text Available Abstract Background Prediabetes (PreDM in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV. Hypothesis Systemic inflammation and glycemia influence circadian blood pressure variability. Methods Dahl salt-sensitive (S rats (n = 19 after weaning were fed either an American (AD or a standard (SD diet. The AD (high-glycemic-index, high-fat simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG, adipokines (leptin and adiponectin, and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1 and tumor necrosis factor-α (TNF-α] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP and heart rate (HR were recorded by telemetry every 5 minutes during both sleep (day and active (night periods. Pulse pressure (PP was calculated (PP = SBP-DBP. Results [mean(SEM]: The AD fed group displayed significant increase in body weight (after 90 days; p Conclusion These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system which generate abnormal CBPV.
Jacobs, Bart A W; Deenen, Maarten J; Pluim, Dick; van Hasselt, J G Coen; Krähenbühl, Martin D; van Geel, Robin M J M; de Vries, Niels; Rosing, Hilde; Meulendijks, Didier; Burylo, Artur M; Cats, Annemieke; Beijnen, Jos H; Huitema, Alwin D R; Schellens, Jan H M
AIMS: The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, we explored between-subject variability (BSV) and circadian rhythmicity in DPD and TS activity in h
Ramanathan, Chidambaram; Khan, Sanjoy K; Kathale, Nimish D; Xu, Haiyan; Liu, Andrew C
genome of both dividing and non-dividing cells. Once a reporter cell line is established, the dynamics of clock function can be examined through bioluminescence recording. We first describe the generation of P(Per2)-dLuc reporter lines, and then present data from this and other circadian reporters. In these assays, 3T3 mouse fibroblasts and U2OS human osteosarcoma cells are used as cellular models. We also discuss various ways of using these clock models in circadian studies. Methods described here can be applied to a great variety of cell types to study the cellular and molecular basis of circadian clocks, and may prove useful in tackling problems in other biological systems.
Harmon Frank G
Full Text Available Abstract Background The plant circadian clock orchestrates 24-hour rhythms in internal physiological processes to coordinate these activities with daily and seasonal changes in the environment. The circadian clock has a profound impact on many aspects of plant growth and development, including biomass accumulation and flowering time. Despite recent advances in understanding the circadian system of the model plant Arabidopsis thaliana, the contribution of the circadian oscillator to important agronomic traits in Zea mays and other cereals remains poorly defined. To address this deficit, this study investigated the transcriptional landscape of the maize circadian system. Results Since transcriptional regulation is a fundamental aspect of circadian systems, genes exhibiting circadian expression were identified in the sequenced maize inbred B73. Of the over 13,000 transcripts examined, approximately 10 percent displayed circadian expression patterns. The majority of cycling genes had peak expression at subjective dawn and dusk, similar to other plant circadian systems. The maize circadian clock organized co-regulation of genes participating in fundamental physiological processes, including photosynthesis, carbohydrate metabolism, cell wall biogenesis, and phytohormone biosynthesis pathways. Conclusions Circadian regulation of the maize genome was widespread and key genes in several major metabolic pathways had circadian expression waveforms. The maize circadian clock coordinated transcription to be coincident with oncoming day or night, which was consistent with the circadian oscillator acting to prepare the plant for these major recurring environmental changes. These findings highlighted the multiple processes in maize plants under circadian regulation and, as a result, provided insight into the important contribution this regulatory system makes to agronomic traits in maize and potentially other C4 plant species.
Full Text Available The mammalian timekeeping system generates circadian oscillations that rhythmically drive various functions in the body, including metabolic processes. In the liver, circadian clocks may respond both to actual feeding conditions and to the metabolic state. The temporal restriction of food availability to improper times of day (restricted feeding, RF leads to the development of food anticipatory activity (FAA and resets the hepatic clock accordingly. The aim of this study was to assess this response in a rat strain exhibiting complex pathophysiological symptoms involving spontaneous hypertension, an abnormal metabolic state and changes in the circadian system, i.e., in spontaneously hypertensive rats (SHR. The results revealed that SHR were more sensitive to RF compared with control rats, developing earlier and more pronounced FAA. Whereas in control rats, the RF only redistributed the activity profiles into two bouts (one corresponding to FAA and the other corresponding to the dark phase, in SHR the RF completely phase-advanced the locomotor activity according to the time of food presentation. The higher behavioral sensitivity to RF was correlated with larger phase advances of the hepatic clock in response to RF in SHR. Moreover, in contrast to the controls, RF did not suppress the amplitude of the hepatic clock oscillation in SHR. In the colon, no significant differences in response to RF between the two rat strains were detected. The results suggested the possible involvement of the Bmal2 gene in the higher sensitivity of the hepatic clock to RF in SHR because, in contrast to the Wistar rats, the rhythm of Bmal2 expression was advanced similarly to that of Bmal1 under RF. Altogether, the data demonstrate a higher behavioral and circadian responsiveness to RF in the rat strain with a cardiovascular and metabolic pathology and suggest a likely functional role for the Bmal2 gene within the circadian clock.
Antle, Michael C; Silver, Rae
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.
Zanello, S. B.; Boyle, R.
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
Arjona, Alvaro; Silver, Adam C; Walker, Wendy E; Fikrig, Erol
The circadian system ensures the generation and maintenance of self-sustained ~24-h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related disease. Here, we discuss the molecular links between the circadian and immune systems and examine their outputs and disease implications. Understanding the mechanisms that underlie circadian-immune crosstalk may prove valuable for devising novel prophylactic and therapeutic interventions.
Trufakin, Valery A; Shurlygina, Anna V
In recent times, a number of diseases involving immune system dysfunction have appeared. This increases the importance of research aimed at finding and developing optimized methods for immune system correction. Numerous studies have found a positive effect in using cytokines to treat a variety of diseases, yet the clinical use of cytokines is limited by their toxicity. Research in the field of chronotherapy, aimed at designing schedules of medicine intake using circadian biorhythms of endogenous production of factors, and receptors' expression to the factors on the target cells, as well as chronopharmacodynamics and chronopharmacokinetics of medicines may contribute to the solution of this problem. Advantages of chronotherapy include a greater effectiveness of treatment, reduced dose of required drugs, and minimized adverse effects. This review presents data on the presence of circadian rhythms of spontaneous and induced cytokine production, as well as the expression of cytokine receptors in the healthy body and in a number of diseases. The article reviews various effects of cytokines, used at different times of the day in humans and experimental animals, as well as possible mechanisms underlying the chronodependent effects of cytokines. The article presents the results of chronotherapeutic modes of administering IL-2, interferons, G-CSF, and GM-CSF in treatment of various types of cancer as well as in experimental models of immune suppression and inflammation, which lead to a greater effectiveness of therapy, the possibility of reducing or increasing the dosage, and reduced drug toxicity. Further research in this field will contribute to the effectiveness and safety of cytokine therapy.
黄文雅; 陆付耳; 董慧
The human gut harbours a certain quantity and variety of microbes called intestinal flora, which is in a state of balance under normal circumstances, and dysbacteriosis occurs when the balance of the intestinal flora is dis-turbed by the host and the changes of the external environment.Circadian clock is the biological regulation system to adapt to natural circadian rhythm, including central clock and peripheral clock.Circadian clock disturbance, particularly rotating shift-workers with irregular light-night schedules, is associated with an increased risk of immune-related diseases.The de-velopment of these diseases is closely related to intestinal dysbacteriosis.Therefore, the correlation between intestinal dys-bacteriosis and circadian clock disturbance has attracted much attention.This review aims to explore the pathophysiological basis of the development in some immune-related diseases based on the latest scientific findings about the relationship be-tween intestinal microbial flora and circadian clock.
Full Text Available New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL in comparison with control participants.Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min and a higher variability of the acrophase (from 2:24 PM to 9:25 PM with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day.We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.
Martin, Tristan; Moussay, Sébastien; Bulla, Ingo; Bulla, Jan; Toupet, Michel; Etard, Olivier; Denise, Pierre; Davenne, Damien; Coquerel, Antoine; Quarck, Gaëlle
New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants. Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day. We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.
Sato, Miho; Murakami, Mariko; Node, Koichi; Matsumura, Ritsuko; Akashi, Makoto
The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type-dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding-mediated tissue-specific entrainment.
Full Text Available The circadian clock is entrained to environmental cycles by external cue-mediated phase adjustment. Although the light input pathway has been well defined, the mechanism of feeding-induced phase resetting remains unclear. The tissue-specific sensitivity of peripheral entrainment to feeding suggests the involvement of multiple pathways, including humoral and neuronal signals. Previous in vitro studies with cultured cells indicate that endocrine factors may function as entrainment cues for peripheral clocks. However, blood-borne factors that are well characterized in actual feeding-induced resetting have yet to be identified. Here, we report that insulin may be involved in feeding-induced tissue-type-dependent entrainment in vivo. In ex vivo culture experiments, insulin-induced phase shift in peripheral clocks was dependent on tissue type, which was consistent with tissue-specific insulin sensitivity, and peripheral entrainment in insulin-sensitive tissues involved PI3K- and MAPK-mediated signaling pathways. These results suggest that insulin may be an immediate early factor in feeding-mediated tissue-specific entrainment.
Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M.; Giebultowicz, Jadwiga M.
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 exerci...
Gomes, Andre M.G.F.; Barber, Ruth C.; Dubrova, Yuri E., E-mail: email@example.com
Highlights: • We have analysed gene expression in the offspring of irradiated male mice. • CBA/Ca and BALB/c male mice were used in our study. • The pattern of gene expression was established in four tissues. • Expression of genes in involved in rhythmic process/circadian rhythm is compromised. • Our data may explain the phenomenon of transgenerational genomic instability. - Abstract: The circadian system represents a complex network which influences the timing of many biological processes. Recent studies have established that circadian alterations play an important role in the susceptibility to many human diseases, including cancer. Here we report that paternal irradiation in mice significantly affects the expression of genes involved in rhythmic processes in their first-generation offspring. Using microarrays, the patterns of gene expression were established for brain, kidney, liver and spleen samples from the non-exposed offspring of irradiated CBA/Ca and BALB/c male mice. The most over-represented categories among the genes differentially expressed in the offspring of control and irradiated males were those involved in rhythmic process, circadian rhythm and DNA-dependent regulation of transcription. The results of our study therefore provide a plausible explanation for the transgenerational effects of paternal irradiation, including increased transgenerational carcinogenesis described in other studies.
Full Text Available Aída Suárez-Barrientos,1 Borja Ibáñez1,21Cardiovascular Institute, Hospital Clínico San Carlos, 2Centro Nacional de Investigaciones Cardiovasculares, Madrid, SpainAbstract: The circadian rhythm influences cardiovascular system physiology, inducing diurnal variations in blood pressure, heart rate, cardiac output, endothelial functions, platelet aggregation, and coronary arterial flow, among other physiological parameters. Indeed, an internal circadian network modulates cardiovascular physiology by regulating heart rate, metabolism, and even myocyte growth and repair ability. Consequently, cardiovascular pathology is also controlled by circadian oscillations, with increased morning incidence of cardiovascular events. The potential circadian influence on the human tolerance to ischemia/reperfusion has not been systematically scrutinized until recently. It has since been proven, in both animals and humans, that infarct size varies during the day depending on the symptom onset time, while circadian fluctuations in spontaneous cardioprotection in humans with ST-segment elevation myocardial infarction (STEMI have also been demonstrated. Furthermore, several studies have proposed that the time of day at which revascularization occurs in patients with STEMI may also influence infarct size and reperfusion outcomes. The potential association of the circadian clock with infarct size advocates the acknowledgment of time of day as a new prognostic factor in patients suffering acute myocardial infarction, which would open up a new field for chronotherapeutic targets and lead to the inclusion of time of day as a variable in clinical trials that test novel cardioprotective strategies.Keywords: cardioprotection, circadian rhythm, reperfusion injury, ST-segment elevation myocardial infarction
The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronizes these with daily cycles, feeding patterns also regulates circadian clocks. The clock genes and adipocytokines show circadian rhythmicity. Dysfunction of these genes are involved in the alteration of these adipokines during the development of obesity. Food availability promotes the stimuli associated with food intake which is a circadian oscillator outside of the suprachiasmatic nucleus (SCN). Its circadian rhythm is arranged with the predictable daily mealtimes. Food anticipatory activity is mediated by a self-sustained circadian timing and its principal component is food entrained oscillator. However, the hypothalamus has a crucial role in the regulation of energy balance rather than food intake. Fatty acids or their metabolites can modulate neuronal activity by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. The timing of three-meal schedules indicates close association with the plasma levels of insulin and preceding food availability. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition can lead to uncoupling of peripheral clocks from the central pacemaker and to the development of metabolic disorders. Metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, eventual disruption of circadian clock functioning can lead to obesity. While CLOCK expression levels are increased with high fat diet-induced obesity, peroxisome proliferator-activated receptor (PPAR) alpha increases the transcriptional level of brain and muscle ARNT-like 1 (BMAL1) in obese subjects. Consequently, disruption of clock genes results in dyslipidemia, insulin resistance and obesity. Modifying the time of feeding alone can greatly affect body weight. Changes in the circadian clock are associated with temporal alterations in
Hong, Christian I; Zámborszky, Judit; Baek, Mokryun; Labiscsak, Laszlo; Ju, Kyungsu; Lee, Hyeyeong; Larrondo, Luis F; Goity, Alejandra; Chong, Hin Siong; Belden, William J; Csikász-Nagy, Attila
The cell cycle and the circadian clock communicate with each other, resulting in circadian-gated cell division cycles. Alterations in this network may lead to diseases such as cancer. Therefore, it is critical to identify molecular components that connect these two oscillators. However, molecular mechanisms between the clock and the cell cycle remain largely unknown. A model filamentous fungus, Neurospora crassa, is a multinucleate system used to elucidate molecular mechanisms of circadian rhythms, but not used to investigate the molecular coupling between these two oscillators. In this report, we show that a conserved coupling between the circadian clock and the cell cycle exists via serine/threonine protein kinase-29 (STK-29), the Neurospora homolog of mammalian WEE1 kinase. Based on this finding, we established a mathematical model that predicts circadian oscillations of cell cycle components and circadian clock-dependent synchronized nuclear divisions. We experimentally demonstrate that G1 and G2 cyclins, CLN-1 and CLB-1, respectively, oscillate in a circadian manner with bioluminescence reporters. The oscillations of clb-1 and stk-29 gene expression are abolished in a circadian arrhythmic frq(ko) mutant. Additionally, we show the light-induced phase shifts of a core circadian component, frq, as well as the gene expression of the cell cycle components clb-1 and stk-29, which may alter the timing of divisions. We then used a histone hH1-GFP reporter to observe nuclear divisions over time, and show that a large number of nuclear divisions occur in the evening. Our findings demonstrate the circadian clock-dependent molecular dynamics of cell cycle components that result in synchronized nuclear divisions in Neurospora.
Baker, T.L.; Morisseau, D.; Murphy, N.M. [ShiftWork Systems, Cambridge, MA (United States)] [and others
The Nuclear Regulatory Commission`s (NRC) Headquarters Operations Officers (HOOs) receive and respond to events reported in the nuclear industry on a 24-hour basis. The HOOs have reported reduced alertness on the night shift, leading to a potential deterioration in their on-shift cognitive performance during the early morning hours. For some HOOs, maladaptation to the night shift was also reported to be the principal cause of: (a) reduced alertness during the commute to and from work, (b) poor sleep quality, and (c) personal lifestyle problems. ShiftWork Systems, Inc. (SWS) designed and installed a Circadian Lighting System (CLS) at both the Bethesda and Rockville HOO stations with the goal of facilitating the HOOs physiological adjustment to their night shift schedules. The data indicate the following findings: less subjective fatigue on night shifts; improved night shift alertness and mental performance; higher HOO confidence in their ability to assess event reports; longer, deeper and more restorative day sleep after night duty shifts; swifter adaptation to night work; and a safer commute, particularly for those with extensive drives.
Sarkar, Dipak K
The body's internal system to control the daily rhythm of the body's functions (i.e., the circadian system), the body's stress response, and the body's neurobiology are highly interconnected. Thus, the rhythm of the circadian system impacts alcohol use patterns; at the same time, alcohol drinking also can alter circadian functions. The sensitivity of the circadian system to alcohol may result from alcohol's effects on the expression of several of the clock genes that regulate circadian function. The stress response system involves the hypothalamus and pituitary gland in the brain and the adrenal glands, as well as the hormones they secrete, including corticotrophin-releasing hormone, adrenocorticotrophic hormone, and glucocorticoids. It is controlled by brain-signaling molecules, including endogenous opioids such as β-endorphin. Alcohol consumption influences the activity of this system and vice versa. Finally, interactions exist between the circadian system, the hypothalamic-pituitary-adrenal axis, and alcohol consumption. Thus, it seems that certain clock genes may control functions of the stress response system and that these interactions are affected by alcohol.
Yeim, S; Boudebesse, C; Etain, B; Belliviera, F
Bipolar disorder is a severe and complex multifactorial disease, characterized by alternance of acute episodes of depression and mania/hypomania, interspaced by euthymic periods. The etiological determinants of bipolar disorder yet, are still poorly understood. For the last 30 years, chronobiology is an important field of investigation to better understand the pathophysiology of bipolar disorder. We conducted a review using Medline, ISI Database, EMBase, PsyInfo up to January 2015, using the following keywords combinations: "mood disorder", "bipolar disorder", "depression", "unipolar disorder", "major depressive disorder", "affective disorder", for psychiatric conditions; and "circadian rhythms", "circadian markers", "circadian gene", "clock gene", "melatonin" for circadian rhythms. The search critera was presence of word in any field of the article. Quantitative and qualitative circadian abnormalities are associated with bipolar disorders both during acute episodes and euthymic periods, suggesting that these altered circadian rhythms may represent biological trait markers of the disorder. These circadian dysfunctions were assessed by various validated tools including polysomnography, actigraphy, sleep diaries, chronotype assessments and blood melatonin/cortisol measures. Other altered endogenous circadian activities have also been reported in bipolar patients, such as hormones secretion, core body temperature or fibroblasts activity. Moreover, these markers were also altered in healthy relatives of bipolar patients, suggesting a degree of heritability. Several genetic association studies have also showed associations between multiple circadian genes and bipolar disorder, such as CLOCK, ARTNL1, GSK3β, PER3, NPAS2, NR1D1, TIMELESS, RORA, RORB, and CSNK1ε. Thus, these circadian gene variants may contribute to the genetic susceptibility of the disease. Furthermore, the study of the clock system may help to better understand some phenotypic aspects like the
C. Feillet (Céline); G.T.J. van der Horst (Gijsbertus); F.A. Lévi (Francis); D.A. Rand (David); F. Delaunay (Franck)
textabstractUncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift wor
Full Text Available This paper discusses the application of feature extraction of facial expressions with combination of neural network for the recognition of different facial emotions (happy, sad, angry, fear, surprised, neutral etc... Humans are capable of producing thousands of facial actions during communication that vary in complexity, intensity, and meaning. This paper analyses the limitations with existing system Emotion recognition using brain activity. In this paper by using an existing simulator I have achieved 97 percent accurate results and it is easy and simplest way than Emotion recognition using brain activity system. Purposed system depends upon human face as we know face also reflects the human brain activities or emotions. In this paper neural network has been used for better results. In the end of paper comparisons of existing Human Emotion Recognition System has been made with new one.
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...
Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A
Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1(-/-) and Clock(Δ19) mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle.
Circadian rhythms refer to the endogenous rhythms that are generated to synchronize physiology and behavior with 24-h environmental cues. These rhythms are regulated by both external cues and molecular clock mechanisms in almost all cells. Disruption of circadian rhythms, which is called circadian disruption, affects many biological processes within the body and results in different long-term diseases, including cancer. Circadian regulatory pathways result in rhythmic epigenetic modifications and the formation of circadian epigenomes. Aberrant epigenetic modifications, such as hypermethylation, due to circadian disruption may be involved in the transformation of normal cells into cancer cells. Several studies have indicated an epigenetic basis for the carcinogenic effects of circadian disruption. In this review, I first discuss some of the circadian genes and regulatory proteins. Then, I summarize the current evidence related to the epigenetic modifications that result in circadian disruption. In addition, I explain the carcinogenic effects of circadian disruption and highlight its potential role in different human cancers using an epigenetic viewpoint. Finally, the importance of chronotherapy in cancer treatment is highlighted.
Brodin, Petter; Davis, Mark M
The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual's immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases.
Full Text Available BACKGROUND: The cyanobacterium Microcystis aeruginosa is one of the principal bloom-forming cyanobacteria present in a wide range of freshwater ecosystems. M. aeruginosa produces cyanotoxins, which can harm human and animal health. Many metabolic pathways in M. aeruginosa, including photosynthesis and microcystin synthesis, are controlled by its circadian rhythms. However, whether xenobiotics affect the cyanobacterial circadian system and change its growth, physiology and biochemistry is unknown. We used real-time PCR to study the effect of hydrogen peroxide (H(2O(2 on the expression of clock genes and some circadian genes in M. aeruginosa during the light/dark (LD cycle. RESULTS: The results revealed that H(2O(2 changes the expression patterns of clock genes (kaiA, kaiB, kaiC and sasA and significantly decreases the transcript levels of kaiB, kaiC and sasA. H(2O(2 treatment also decreased the transcription of circadian genes, such as photosynthesis-related genes (psaB, psbD1 and rbcL and microcystin-related genes (mcyA, mcyD and mcyH, and changed their circadian expression patterns. Moreover, the physiological functions of M. aeruginosa, including its growth and microcystin synthesis, were greatly influenced by H(2O(2 treatment during LD. These results indicate that changes in the cyanobacterial circadian system can affect its physiological and metabolic pathways. CONCLUSION: Our findings show that a xenobiotic can change the circadian expression patterns of its clock genes to influence clock-controlled gene regulation, and these influences are evident at the level of cellular physiology.
Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.
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.
the necessary functional qualities but also the needed human qualities. The author's main argument is, that the design process should be a dialectical synthesis of the two points of view: Man as a System Component, and System as Man's Environment. Based on a man's presentation of the state of the art a set...... of design criteria is suggested and their relevance discussed. The point is to focus on the operator rather than on the computer. The crucial question is not to program the computer to work on its own conditions, but to “program” the operator to function on human conditions.......This paper deals with the problem of designing more humanised computer systems. This problem can be formally described as the need for defining human design criteria, which — if used in the design process - will secure that the systems designed get the relevant qualities. That is not only...
Barandas, Rita; Landgraf, Dominic; McCarthy, Michael J; Welsh, David K
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.
L. C. Roden
Full Text Available Humans have evolved in a rhythmic environment and display daily (circadian rhythms in physiology, metabolism and behaviour that are in synchrony with the solar day. Modern lifestyles have compromised the exposure to bright light during the day and dark nights, resulting in the desynchronisation of endogenously generated circadian rhythms from the external environment and loss of coordination between rhythms within the body. This has detrimental effects on physical and mental health, due to the misregulation and uncoupling of important cellular and physiological processes. Long-term shift workers who are exposed to bright light at night experience the greatest disruption of their circadian rhythms. Studies have shown an association between exposure to light at night, circadian rhythm disruption and an increased risk of cancer. Previous reviews have explored the relevance of light and melatonin in cancer, but here we explore the correlation of circadian rhythm disruption and cancer in terms of molecular mechanisms affecting circadian gene expression and melatonin secretion.
Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabol...
Bastiaan C. Du Pré
Full Text Available Stem cell antigen 1-positive (SCA1+ cells (SPCs have been investigated in cell-based cardiac repair and pharmacological research, although improved cardiac function after injection has been variable and the mode of action remains unclear. Circadian (24-hr rhythms are biorhythms regulated by molecular clocks that play an important role in (pathophysiology. Here, we describe (1 the presence of a molecular circadian clock in SPCs and (2 circadian rhythmicity in SPC function. We isolated SPCs from human fetal heart and found that these cells possess a molecular clock based on typical oscillations in core clock components BMAL1 and CRY1. Functional analyses revealed that circadian rhythmicity also governs SPC proliferation, stress tolerance, and growth factor release, with large differences between peaks and troughs. We conclude that SPCs contain a circadian molecular clock that controls crucial cellular functions. Taking circadian rhythms into account may improve reproducibility and outcome of research and therapies using SPCs.
Elizabeth M Harrison
Full Text Available Circadian disruption in shift-work is common and has deleterious effects on health and performance. Current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker, which unfortunately in humans, shifts slowly and often incompletely. Temporal reorganization of rhythmic waveform (i.e. the shape of its 24 h oscillation, rather than phase, however, may better match performance demands of shift-workers and can be quickly and feasibly implemented in animals. In fact, a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep/wake rhythm promoting alertness in both night and daylight hours. Although bifurcation has yet to be formally assessed in humans, evidence of conserved properties of circadian organization and plasticity predict its occurrence: humans respond to conventional manipulations of waveform (e.g., photoperiodism; behaviorally, the sleep/wake rhythm is adaptable; and finally, the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker. In short, investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified.
Harrison, Elizabeth M; Gorman, Michael R
Circadian disruption in shift-work is common and has deleterious effects on health and performance. Current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker, which unfortunately in humans, shifts slowly and often incompletely. Temporal reorganization of rhythmic waveform (i.e., the shape of its 24 h oscillation), rather than phase, however, may better match performance demands of shift-workers and can be quickly and feasibly implemented in animals. In fact, a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep/wake rhythm promoting alertness in both night and daylight hours. Although bifurcation has yet to be formally assessed in humans, evidence of conserved properties of circadian organization and plasticity predict its occurrence: humans respond to conventional manipulations of waveform (e.g., photoperiodism); behaviorally, the sleep/wake rhythm is adaptable; and finally, the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker. In short, investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified.
BULT, R; SCHULING, FH; MASTEBROEK, HAK
Long-term extracellular recordings from a spiking, movement-sensitive giant neuron (H1) in the third optic ganglion of the blowfly Calliphora vicina (L.) revealed periodic endogenous sensitivity fluctuations. The sensitivity changes showed properties typical of an endogenous circadian rhythm. This
Meijer, J.H.; Daan, S.; Overkamp, G.J.F.; Hermann, P.M.
The wheel-running activity rhythm of tree shrews (tupaias; Tupaia belangeri) housed in constant darkness (DD) phase-advanced following a 3-hr light pulse at circadian time (CT) 21. Dark pulses of 3 hr presented to tupaias in bright constant light (LL) did not induce significant phase shifts of the
Meijer, J.H.; Daan, S.; Overkamp, G.J.F.; Hermann, P.M.
The wheel-running activity rhythm of tree shrews (tupaias; Tupaia belangeri) housed in constant darkness (DD) phase-advanced following a 3-hr light pulse at circadian time (CT) 21. Dark pulses of 3 hr presented to tupaias in bright constant light (LL) did not induce significant phase shifts of the f
In our attempts to understand the circadian system, we unavoidably rely on abstractions. Instead of describing the behavior of the circadian system in all its complexity, we try to derive basic features from which we form a global concept on how the system works. Such a basic concept is a model of
A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
Full Text Available The circadian rhythm sleep disorders define the clinical conditions where sleep and ndash;wake rhythm is disrupted despite optimum environmental and social conditions. They occur as a result of the changes in endogenous circadian hours or non-compatibility of environmental factors or social life with endogenous circadian rhythm. The sleep and ndash;wake rhythm is disrupted continuously or in repeating phases depending on lack of balance between internal and external cycles. This condition leads to functional impairments which cause insomnia, excessive sleepiness or both in people. Application of detailed sleep anamnesis and sleep diary with actigraphy record, if possible, will be sufficient for diagnosis. The treatment aims to align endogenous circadian rhythm with environmental conditions. The purpose of this article is to review pathology, clinical characteristics, diagnosis and treatment of circadian rhythm disorder. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2016; 8(2: 178-189
Full Text Available Circadian organization means the way in which the entire circadian system above the cellular level is put together physically and the principles and rules that determine the interactions among its component parts which produce overt rhythms of physiology and behavior. Understanding this organization and its evolution is of practical importance as well as of basic interest. The first major problem that we face is the difficulty of making sense of the apparently great diversity that we observe in circadian organization of diverse vertebrates. Some of this diversity falls neatly into place along phylogenetic lines leading to firm generalizations: i in all vertebrates there is a "circadian axis" consisting of the retinas, the pineal gland and the suprachiasmatic nucleus (SCN, ii in many non-mammalian vertebrates of all classes (but not in any mammals the pineal gland is both a photoreceptor and a circadian oscillator, and iii in all non-mammalian vertebrates (but not in any mammals there are extraretinal (and extrapineal circadian photoreceptors. An interesting explanation of some of these facts, especially the differences between mammals and other vertebrates, can be constructed on the assumption that early in their evolution mammals passed through a "nocturnal bottleneck". On the other hand, a good deal of the diversity among the circadian systems of vertebrates does not fall neatly into place along phylogenetic lines. In the present review we will consider how we might better understand such "phylogenetically incoherent" diversity and what sorts of new information may help to further our understanding of the evolution of circadian organization in vertebrates
Facer-Childs, Elise; Brandstaetter, Roland
Circadian rhythms, among other factors, have been shown to regulate key physiological processes involved in athletic performance. Personal best performance of athletes in the evening was confirmed across different sports. Contrary to this view, we identified peak performance times in athletes to be different between human "larks" and "owls" (also called "morningness/eveningness types" or "chronotypes" and referred to as circadian phenotypes in this paper), i.e., individuals with well-documented genetic and physiological differences that result in disparities between their biological clocks and how they entrain to exogenous cues, such as the environmental light/dark cycle and social factors. We found time since entrained awakening to be the major predictor of peak performance times, rather than time of day, as well as significant individual performance variations as large as 26% in the course of a day. Our novel approach combining the use of an athlete-specific chronometric test, longitudinal circadian analysis, and physical performance tests to characterize relevant sleep/wake and performance parameters in athletes allows a comprehensive analysis of the link between the circadian system and diurnal performance variation. We establish that the evaluation of an athlete's personal best performance requires consideration of circadian phenotype, performance evaluation at different times of day, and analysis of performance as a function of time since entrained awakening.
Full Text Available The best known daily rhythms in humans include: the sleep-wake rhythm, the circadian core body temperature variability, daily fluctuations in arterial blood pressure and heartbeat frequency, and daily changes in hormone secretion: e.g. melatonin, cortisol, growth hormone, prolactin. The core body temperature in humans has a characteristic sinusoidal course, with the maximum value occurring between 3:00-5:00 pm and the minimum between 3:00-5:00 am. Analysis of literature indicates that the obtained results concerning core body temperature are to a large extent influenced by the type of method applied in the measurement. Depending on test protocols, we may apply various methodologies to measuring core body temperature. One of the newest methods of measuring internal and external body temperature consists in the utilisation of remote temperature sensors transmitting the obtained value via a radio signal. The advantages of this method includes the ability to perform: continuous core temperature measurement, observe dynamic changes in core body temperature occurring in circadian rhythm and the repeatability and credibility of the obtained results, which is presented in numerous scientific reports.
Videnovic, A.; Lazar, A.S.; Barker, R.A.; Overeem, S.
Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodeg
Videnovic, A.; Lazar, A.S.; Barker, R.A.; Overeem, S.
Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of
Videnovic, A.; Lazar, A.S.; Barker, R.A.; Overeem, S.
Circadian rhythms are physiological and behavioural cycles generated by an endogenous biological clock, the suprachiasmatic nucleus. The circadian system influences the majority of physiological processes, including sleep-wake homeostasis. Impaired sleep and alertness are common symptoms of neurodeg
Glotzbach, S. F.
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.
Full Text Available Since 1960, magnetic fields have been discussed as Zeitgebers for circadian clocks, but the mechanism by which clocks perceive and process magnetic information has remained unknown. Recently, the radical-pair model involving light-activated photoreceptors as magnetic field sensors has gained considerable support, and the blue-light photoreceptor cryptochrome (CRY has been proposed as a suitable molecule to mediate such magnetosensitivity. Since CRY is expressed in the circadian clock neurons and acts as a critical photoreceptor of Drosophila's clock, we aimed to test the role of CRY in magnetosensitivity of the circadian clock. In response to light, CRY causes slowing of the clock, ultimately leading to arrhythmic behavior. We expected that in the presence of applied magnetic fields, the impact of CRY on clock rhythmicity should be altered. Furthermore, according to the radical-pair hypothesis this response should be dependent on wavelength and on the field strength applied. We tested the effect of applied static magnetic fields on the circadian clock and found that flies exposed to these fields indeed showed enhanced slowing of clock rhythms. This effect was maximal at 300 muT, and reduced at both higher and lower field strengths. Clock response to magnetic fields was present in blue light, but absent under red-light illumination, which does not activate CRY. Furthermore, cry(b and cry(OUT mutants did not show any response, and flies overexpressing CRY in the clock neurons exhibited an enhanced response to the field. We conclude that Drosophila's circadian clock is sensitive to magnetic fields and that this sensitivity depends on light activation of CRY and on the applied field strength, consistent with the radical pair mechanism. CRY is widespread throughout biological systems and has been suggested as receptor for magnetic compass orientation in migratory birds. The present data establish the circadian clock of Drosophila as a model system
Skelton, Rachel L; Kornhauser, Jon M; Tate, Barbara A
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.
Blakeman, Victoria; Jack L. Williams; Meng, Qing-Jun; Streuli, Charles H
Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, an...
Erik Steven Musiek
Full Text Available Disturbance of the circadian system, manifested as disrupted daily rhythms of physiologic parameters such as sleep, activity, and hormone secretion, has long been observed as a symptom of several neurodegenerative diseases, including Alzheimer Disease. Circadian abnormalities have generally been considered consequences of the neurodegeneration. Recent evidence suggests, however, that circadian disruption might actually contribute to the neurodegenerative process, and thus might be a modifiable cause of neural injury. Herein we will review the evidence implicating circadian rhythms disturbances and clock gene dysfunction in neurodegeneration, with an emphasis on future research directions and potential therapeutic implications for neurodegenerative diseases.
Rabinovich Gabriel A
Full Text Available Abstract Background Recent evidence suggests a two-way interaction between the immune and circadian systems. Circadian control of immune factors, as well as the effect of immunological variables on circadian rhythms, might be key elements in both physiological and pathological responses to the environment. Among these relevant factors, galectin-1 is a member of a family of evolutionarily-conserved glycan-binding proteins with both extracellular and intracellular effects, playing important roles in immune cell processes and inflammatory responses. Many of these actions have been studied through the use of mice with a null mutation in the galectin-1 (Lgals1 gene. To further analyze the role of endogenous galectin-1 in vivo, we aimed to characterize the circadian behavior of galectin-1 null (Lgals1-/- mice. Methods We analyzed wheel-running activity in light-dark conditions, constant darkness, phase responses to light pulses (LP at circadian time 15, and reentrainment to 6 hour shifts in light-dark schedule in wild-type (WT and Lgals1-/- mice. Results We found significant differences in free-running period, which was longer in mutant than in WT mice (24.02 vs 23.57 h, p alpha (14.88 vs. 12.35 circadian h, p Conclusions Given the effect of a null mutation on circadian period and entrainment, we indicate that galectin-1 could be involved in the regulation of murine circadian rhythmicity. This is the first study implicating galectin-1 in the mammalian circadian system.
Full Text Available Most organisms use 24-hr circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila melanogaster CLOCK (CLK and CYCLE (CYC initiates the circadian system by promoting rhythmic transcription of hundreds of genes. However, it is still not clear whether high amplitude transcriptional oscillations are essential for circadian timekeeping. In order to address this issue, we generated flies in which the amplitude of CLK-driven transcription can be reduced partially (approx. 60% or strongly (90% without affecting the average levels of CLK-target genes. The impaired transcriptional oscillations lead to low amplitude protein oscillations that were not sufficient to drive outputs of peripheral oscillators. However, circadian rhythms in locomotor activity were resistant to partial reduction in transcriptional and protein oscillations. We found that the resilience of the brain oscillator is depending on the neuronal communication among circadian neurons in the brain. Indeed, the capacity of the brain oscillator to overcome low amplitude transcriptional oscillations depends on the action of the neuropeptide PDF and on the pdf-expressing cells having equal or higher amplitude of molecular rhythms than the rest of the circadian neuronal groups in the fly brain. Therefore, our work reveals the importance of high amplitude transcriptional oscillations for cell-autonomous circadian timekeeping. Moreover, we demonstrate that the circadian neuronal network is an essential buffering system that protects against changes in circadian transcription in the brain.
Flyvholm, Anton; Sen, Sumit; Xylakis, Emmanouil
-door daylight. CaLED lighting seems that may positively influence age-related needs, mood, cognition, alertness, sleep and improve well-being in general . To build this intelligent system 3 different types of data are considered and cross-checked: a) medical (biofactors), b) sensor-based (activity...... of immobility. J Gerontol Nurs. Sep;17(9):5–11.  Gate 21, Abertslund Kommune, Amager-Hvidovre Hospital, Zumtobel, AAU Copenhagen. (2015) LighTel project. Available from http://www.gate21.dk/project/lightel/  Turner PL, Van Someren EJW, Mainster MA. (2010). The role of environmental light in sleep...... and health: effects of ocular aging and cataract surgery. Sleep Med Rev. Aug;14(4):269–80.  Kuijsters, A., Redi, J., de Ruyter, B., & Heynderickx, I. (2015). Lighting to make you feel better: Improving the mood of elderly people with affective ambiences. PloS one, 10(7), e0132732....
Bloch, Guy; Hazan, Esther; Rafaeli, Ada
Many behavioral and physiological processes in adult insects are influenced by both the endocrine and circadian systems, suggesting that these two key physiological systems interact. We reviewed the literature and found that experiments explicitly testing these interactions in adult insects have only been conducted for a few species. There is a shortage of measurements of hormone titers throughout the day under constant conditions even for the juvenile hormones (JHs) and ecdysteroids, the best studied insect hormones. Nevertheless, the available measurements of hormone titers coupled with indirect evidence for circadian modulation of hormone biosynthesis rate, and the expression of genes encoding proteins involved in hormone biosynthesis, binding or degradation are consistent with the hypothesis that the circulating levels of many insect hormones are influenced by the circadian system. Whole genome microarray studies suggest that the modulation of farnesol oxidase levels is important for the circadian regulation of JH biosynthesis in honey bees, mosquitoes, and fruit flies. Several studies have begun to address the functional significance of circadian oscillations in endocrine signaling. The best understood system is the circadian regulation of Pheromone Biosynthesis Activating Neuropeptide (PBAN) titers which is important for the temporal organization of sexual behavior in female moths. The evidence that the circadian and endocrine systems interact has important implications for studies of insect physiology and behavior. Additional studies on diverse species and physiological processes are needed for identifying basic principles underlying the interactions between the circadian and endocrine systems in insects.
Freeman, D A; Goldman, B D
role for locomotor activity feedback in modulating the circadian system and, subsequently, photoperiodic responsiveness in PNRj hamsters.
Uryu, Outa; Kamae, Yuichi; Tomioka, Kenji; Yoshii, Taishi
RNA interference (RNAi) strategy, which enables gene-specific knock-down of transcripts, has been spread across a wide area of insect studies for investigating gene function without regard to model and non-model insects. This technique is of particular benefit to promote molecular studies on non-model insects. However, the optimal conditions for RNAi are still not well understood because of its variable efficiency depending on the species, target genes, and experimental conditions. To apply RNAi technique to long-running experiments such as chronobiological studies, the effects of RNAi have to persist throughout the experiment. In this study, we attempted to determine the optimal concentration of double-stranded RNA (dsRNA) for systemic RNAi and its effective period in two different insect species, the cricket Gryllus bimaculatus and the firebrat Thermobia domestica. In both species, higher concentrations of dsRNA principally yielded a more efficient knock-down of mRNA levels of tested clock genes, although the effect depended on the gene and the species. Surprisingly, the effect of the RNAi reached its maximum effect 1-2 weeks and 1 month after the injection of dsRNA in the crickets and the firebrats, respectively, suggesting a slow but long-term effect of RNAi. Our study provides fundamental information for utilizing RNAi technique in any long-running experiment.
McCarthy, Michael J; Welsh, David K
Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks
Hastings, M H; Maywood, E S; Reddy, A B
Circadian rhythms coordinate our physiology at a fundamental level. Over the last 20 years, we have witnessed a paradigm shift in our perception of what the clocks driving such rhythms actually are, moving from 'black boxes' to talking about autoregulatory transcriptional/post-translational feedback loops with identified molecular components. We also now know that the pacemaker of the suprachiasmatic nuclei (SCN) is not our only clock but quite the opposite because circadian clocks abound in our bodies, driving local rhythms of cellular metabolism, and synchronised to each other and to solar time, by cues from the SCN. This discovery of dispersed local clocks has far-reaching implications for understanding our physiology and the pathological consequences of clock dysfunction, revealing that clocks are critical in a variety of metabolic and neurological conditions, all of which have long-term morbidity attributable to them. Without the currently available molecular framework, these insights would have not have been possible. In the circadian future, a growing appreciation of the systems-level functioning of these clocks and their various cerebral and visceral outputs, will likely stimulate the development of novel therapies for major illnesses.
Remi, Jan; Merrow, Martha; Roenneberg, Till
The two major prerequisites for a functional circadian system are the generation of an internal day (circadian cycle) and adjusting its length- and phase-to that of the external day (zeitgeber cycle). The generation of circadian cycles can be observed in constant conditions where organisms show a se
Megumi Hatori; Satchidananda Panda
@@ Circadian oscillators based on a transcriptional feedback loop exist in almost all cells of animals. The cellular oscillators synchronize each other via paracrine or systemic communications,resulting in rhythmic changes of tissue- and whole body-level physiologies and behaviors. Circadian regulation of metabolism is well documented and disruption of such temporal regulation is known to predispose organisms to metabolic diseases.
Full Text Available Abstract Background Circadian rhythms with varying components exist in organisms ranging from humans to cyanobacteria. A simple evolutionarily plausible mechanism for the origin of such a variety of circadian oscillators, proposed in earlier work, involves the non-disruptive coupling of pre-existing ultradian transcriptional-translational oscillators (TTOs, producing "beats," in individual cells. However, like other TTO models of circadian rhythms, it is important to establish that the inherent stochasticity of the protein binding and unbinding does not invalidate the finding of clear oscillations with circadian period. Results The TTOs of our model are described in two versions: 1 a version in which the activation or inhibition of genes is regulated stochastically, where the 'unoccupied" (or "free" time of the site under consideration depends on the concentration of a protein complex produced by another site, and 2 a deterministic, "time-averaged" version in which the switching between the "free" and "occupied" states of the sites occurs so rapidly that the stochastic effects average out. The second case is proved to emerge from the first in a mathematically rigorous way. Numerical results for both scenarios are presented and compared. Conclusion Our model proves to be robust to the stochasticity of protein binding/unbinding at experimentally determined rates and even at rates several orders of magnitude slower. We have not only confirmed this by numerical simulation, but have shown in a mathematically rigorous way that the time-averaged deterministic system is indeed the fast-binding-rate limit of the full stochastic model.
Harrison, Elizabeth M; Walbeek, Thijs J; Sun, Jonathan; Johnson, Jeremy; Poonawala, Qays; Gorman, Michael R
The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.
Hu, Kun; Hilton, Michael F.
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.
Andrew J Zele
Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGC signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central or intrinsic (retinal network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC and outer retina (cone photoreceptors was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux. Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin retinal ganglion cells mediate this circadian variation.
Kessel, Line; Lundeman, Jesper Holm; Herbst, Kristina;
To characterize age-related changes in the transmission of light through noncataractous human lenses.......To characterize age-related changes in the transmission of light through noncataractous human lenses....
Kumar Jha, Pawan; Challet, Etienne; Kalsbeek, Andries
Most aspects of energy metabolism display clear variations during day and night. This daily rhythmicity of metabolic functions, including hormone release, is governed by a circadian system that consists of the master clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and many secondary clocks in the brain and peripheral organs. The SCN control peripheral timing via the autonomic and neuroendocrine system, as well as via behavioral outputs. The sleep-wake cycle, the feeding/fasting rhythm and most hormonal rhythms, including that of leptin, ghrelin and glucocorticoids, usually show an opposite phase (relative to the light-dark cycle) in diurnal and nocturnal species. By contrast, the SCN clock is most active at the same astronomical times in these two categories of mammals. Moreover, in both species, pineal melatonin is secreted only at night. In this review we describe the current knowledge on the regulation of glucose and lipid metabolism by central and peripheral clock mechanisms. Most experimental knowledge comes from studies in nocturnal laboratory rodents. Nevertheless, we will also mention some relevant findings in diurnal mammals, including humans. It will become clear that as a consequence of the tight connections between the circadian clock system and energy metabolism, circadian clock impairments (e.g., mutations or knock-out of clock genes) and circadian clock misalignments (such as during shift work and chronic jet-lag) have an adverse effect on energy metabolism, that may trigger or enhancing obese and diabetic symptoms.
Prendergast, Brian J; Onishi, Kenneth G; Patel, Priyesh N; Stevenson, Tyler J
Emotional behaviors are influenced by the circadian timing system. Circadian disruptions are associated with depressive-like symptoms in clinical and preclinical populations. Circadian rhythm robustness declines markedly with aging and may contribute to susceptibility to emotional dysregulation in aged individuals. The present experiments used a model of chronic circadian arrhythmia generated noninvasively, via a series of circadian-disruptive light treatments, to investigate interactions between circadian desynchrony and aging on depressive- and anxiety-like behaviors, and on limbic neuroinflammatory gene expression that has been linked with emotionality. We also examined whether a social manipulation (group housing) would attenuate effects of arrhythmia on emotionality. In aged (14-18 months of age) male Siberian hamsters, circadian arrhythmia increased behavioral despair and decreased social motivation, but decreased exploratory anxiety. These effects were not evident in younger (5-9 months of age) hamsters. Social housing (3-5 hamsters/cage) abolished the effects of circadian arrhythmia on emotionality. Circadian arrhythmia alone was without effect on hippocampal or cortical interleukin-1β (IL-1β) and indoleamine 2,3-dioxygenase (Ido) mRNA expression in aged hamsters, but social housing decreased hippocampal IL-1β and Ido mRNAs. The data demonstrate that circadian disruption can negatively impact affective state, and that this effect is pronounced in older individuals. Although clear associations between circadian arrhythmia and constitutive limbic proinflammatory activity were not evident, the present data suggest that social housing markedly inhibits constitutive hippocampal IL-1β and Ido activity, which may contribute to the ameliorating effects of social housing on a number of emotional behaviors.
Full Text Available June Nguyen, Kenneth P Wright JrDepartment of Integrative Physiology, Sleep and Chronobiology Laboratory, University of Colorado, Boulder, CO, USAAbstract: The neurobiology of circadian, wakefulness–sleep, and feeding systems interact to influence energy homeostasis. Sleep and circadian disruptions are reported to be associated with increased risk of diabetes and obesity, yet the roles of energy balance hormones in these associations are largely unknown. Therefore, in the current study we aimed to assess the influence of several weeks of circadian misalignment (sleep and wakefulness occurring at an inappropriate biological time on the anorexigenic adipocyte hormone leptin. We utilized data from a previous study designed to assess physiological and cognitive consequences of changes in day length and light exposure as may occur during space flight, including exploration class space missions and exposure to the Martian Sol (day length. We hypothesized that circadian misalignment during an exploration class spaceflight simulation would reduce leptin levels. Following a three-week ~8 hours per night home sleep schedule, 14 healthy participants lived in the laboratory for more than one month. After baseline data collection, participants were scheduled to either 24.0 or 24.6 hours of wakefulness–sleep schedules for 25 days. Changes in the phase of the circadian melatonin rhythm, sleep, and leptin levels were assessed. Half of participants analyzed exhibited circadian misalignment with an average change in phase angle from baseline of ~4 hours and these participants showed reduced leptin levels, sleep latency, stage 2 and total sleep time (7.3 to 6.6 hours and increased wakefulness after sleep onset (all P < 0.05. The control group remained synchronized and showed significant increases in sleep latency and leptin levels. Our findings indicate that weeks of circadian misalignment, such as that which occurs in circadian sleep disorders, alters leptin
Haydon, Michael J; Hearn, Timothy J; Bell, Laura J; Hannah, Matthew A; Webb, Alex A R
Circadian clocks are 24-h timekeeping mechanisms, which have evolved in plants, animals, fungi and bacteria to anticipate changes in light and temperature associated with the rotation of the Earth. The current paradigm to explain how biological clocks provide timing information is based on multiple interlocking transcription-translation negative feedback loops (TTFL), which drive rhythmic gene expression and circadian behaviour of growth and physiology. Metabolism is an important circadian output, which in plants includes photosynthesis, starch metabolism, nutrient assimilation and redox homeostasis. There is increasing evidence in a range of organisms that these metabolic outputs can also contribute to circadian timing and might also comprise independent circadian oscillators. In this review, we summarise the mechanisms of circadian regulation of metabolism by TTFL and consider increasing evidence that rhythmic metabolism contributes to the circadian network. We highlight how this might be relevant to plant circadian clock function.
Zámborszky, Judit; Hong, Christian I; Csikász Nagy, Attila
Cell cycle and circadian rhythms are conserved from cyanobacteria to humans with robust cyclic features. Recently, molecular links between these two cyclic processes have been discovered. Core clock transcription factors, Bmal1 and Clock (Clk), directly regulate Wee1 kinase, which inhibits entry into the mitosis. We investigate the effect of this connection on the timing of mammalian cell cycle processes with computational modeling tools. We connect a minimal model of circadian rhythms, which consists of transcription-translation feedback loops, with a modified mammalian cell cycle model from Novak and Tyson (2004). As we vary the mass doubling time (MDT) of the cell cycle, stochastic simulations reveal quantized cell cycles when the activity of Wee1 is influenced by clock components. The quantized cell cycles disappear in the absence of coupling or when the strength of this link is reduced. More intriguingly, our simulations indicate that the circadian clock triggers critical size control in the mammalian cell cycle. A periodic brake on the cell cycle progress via Wee1 enforces size control when the MDT is quite different from the circadian period. No size control is observed in the absence of coupling. The issue of size control in the mammalian system is debatable, whereas it is well established in yeast. It is possible that the size control is more readily observed in cell lines that contain circadian rhythms, since not all cell types have a circadian clock. This would be analogous to an ultradian clock intertwined with quantized cell cycles (and possibly cell size control) in yeast. We present the first coupled model between the mammalian cell cycle and circadian rhythms that reveals quantized cell cycles and cell size control influenced by the clock.
Winget, C. M.; Singh, M. S.; Syrkin, N. C.; Holley, D. C.
The synchronization of physiological and behavioral rhythms are controlled by an endogenous biological clock. It is generally accepted that environmental lighting is the strongest entrainer of this clock. The pineal gland is an important physiological transducer of environmental lighting via systemic melatonin secretion. We have used a novel light source using light emitting diode (LED) technology to entrain circadian rhythms in rats, and propose a novel percutaneous exogenous melatonin delivery system to entrain rat rhythms. We used 5 groups of Sprague-Dawley rats (175-350 g; N = 8/group) and showed normal entrainment of gross locomotor activity, feeding, and drinking circadian rhythms at light intensities varying from 80 lux to 0.1 lux (22.4 to 0.03 sq cm). To improve the delivery of melatonin across the skin stratum corneum it was formulated in a suitable vehicle in a transdermal drug delivery system. Various saturated and unsaturated fatty acids were used E, akin penetration enhancers. Our best vehicle formulation was achieved with a combination-of ethano1:water (60:40) along with 5% oleic acid as the enhancer. This formulation mixture was studied using Franz diffusion cell (0.636 sq cm diffusional area) and 1 cu cm dorsal skin isolated from Sprague Dawley rats. Our results showed that oleic acid in combination with the water ethanol mixture improved the flux of melatonin by more than 18 fold. The lag time for melatonin permeation was 2-3 hrs and the peak concentrations were achieved in 8-10 hrs. Our approaches in the future will involve the use of our transdermal melatonin delivery system and under the influence of LED light and microgravity.
Full Text Available Bhanu P Kolla,1,2 R Robert Auger,1,2 Timothy I Morgenthaler11Mayo Center for Sleep Medicine, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Misalignment between endogenous circadian rhythms and the light/dark cycle can result in pathological disturbances in the form of erratic sleep timing (irregular sleep–wake rhythm, complete dissociation from the light/dark cycle (circadian rhythm sleep disorder, free-running type, delayed sleep timing (delayed sleep phase disorder, or advanced sleep timing (advanced sleep phase disorder. Whereas these four conditions are thought to involve predominantly intrinsic mechanisms, circadian dysrhythmias can also be induced by exogenous challenges, such as those imposed by extreme work schedules or rapid transmeridian travel, which overwhelm the ability of the master clock to entrain with commensurate rapidity, and in turn impair approximation to a desired sleep schedule, as evidenced by the shift work and jet lag sleep disorders. This review will focus on etiological underpinnings, clinical assessments, and evidence-based treatment options for circadian rhythm sleep disorders. Topics are subcategorized when applicable, and if sufficient data exist. The length of text associated with each disorder reflects the abundance of associated literature, complexity of management, overlap of methods for assessment and treatment, and the expected prevalence of each condition within general medical practice.Keywords: circadian rhythm sleep disorders, assessment, treatment
Full Text Available Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumour growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.
Feillet, Celine; van der Horst, Gijsbertus T J; Levi, Francis; Rand, David A; Delaunay, Franck
Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.
Merrow, M.; Roenneberg, T.
The circadian clock evolved under entraining conditions, yet most circadian experiments and much circadian theory are built around free-running rhythms. The interpretation of entrainment experiments is certainly more complex than that of free-running rhythms due to the relationship between exogenous
Shostak, Anton; Ruppert, Bianca; Ha, Nati; Bruns, Philipp; Toprak, Umut H; Eils, Roland; Schlesner, Matthias; Diernfellner, Axel; Brunner, Michael
The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.
Full Text Available Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis-elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i drought stress affects gene expression of circadian clock components and (ii several stress responsive genes display diurnal oscillation in soybeans.
Lance J Kriegsfeld
Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.
Tsuchiya, Yoshiki; Minami, Yoichi; Umemura, Yasuhiro; Watanabe, Hitomi; Ono, Daisuke; Nakamura, Wataru; Takahashi, Tomoyuki; Honma, Sato; Kondoh, Gen; Matsuishi, Toyojiro; Yagita, Kazuhiro
Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice. We successfully generated both male and female Mecp2-deficient mice on the wild-type C57BL/6 background and PER2(Luciferase) (PER2(Luc)) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. Generated Mecp2-deficient mice recapitulated reduced activity in mouse models of RTT, and their activity rhythms were diminished in constant dark conditions. Furthermore, real-time bioluminescence imaging showed that the amplitude of PER2(Luc)-driven circadian oscillation was significantly attenuated in Mecp2-deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes of PER2(Luc) bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.
U.S. Environmental Protection Agency — The Human Exposure Database System (HEDS) provides public access to data sets, documents, and metadata from EPA on human exposure. It is primarily intended for...
Matsumura, Ritsuko; Tsuchiya, Yoshiki; Tokuda, Isao; Matsuo, Takahiro; Sato, Miho; Node, Koichi; Nishida, Eisuke; Akashi, Makoto
The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system.
Full Text Available Circadian clocks generate 24-hr rhythms in physiology and behavior. Despite numerous studies, it is still uncertain how circadian rhythms emerge from their molecular and neural constituents. Here, we demonstrate a tight connection between the molecular and neuronal circadian networks. Using fluorescent transcriptional reporters in a Drosophila ex vivo brain culture system, we identified a reciprocal negative regulation between the master circadian regulator CLK and expression of pdf, the main circadian neuropeptide. We show that PDF feedback is required for maintaining normal oscillation pattern in CLK-driven transcription. Interestingly, we found that CLK and neuronal firing suppresses pdf transcription, likely through a common pathway involving the transcription factors DHR38 and SR, establishing a direct link between electric activity and the circadian system. In sum, our work provides evidence for the existence of an uncharacterized CLK-PDF feedback loop that tightly wraps together the molecular oscillator with the circadian neuronal network in Drosophila.
Yeom, Mijung; Pendergast, Julie S; Ohmiya, Yoshihiro; Yamazaki, Shin
Two prominent timekeeping systems, the cell cycle, which controls cell division, and the circadian system, which controls 24-h rhythms of physiology and behavior, are found in nearly all living organisms. A distinct feature of circadian rhythms is that they are temperature-compensated such that the period of the rhythm remains constant (approximately 24 h) at different ambient temperatures. Even though the speed of cell division, or growth rate, is highly temperature-dependent, the cell-mitosis rhythm is temperature-compensated. Twenty-four-hour fluctuations in cell division have also been observed in numerous species, suggesting that the circadian system is regulating the timing of cell division. We tested whether the cell-cycle rhythm was coupled to the circadian system in immortalized rat-1 fibroblasts by monitoring cell-cycle gene promoter-driven luciferase activity. We found that there was no consistent phase relationship between the circadian and cell cycles, and that the cell-cycle rhythm was not temperature-compensated in rat-1 fibroblasts. These data suggest that the circadian system does not regulate the cell-mitosis rhythm in rat-1 fibroblasts. These findings are inconsistent with numerous studies that suggest that cell mitosis is regulated by the circadian system in mammalian tissues in vivo. To account for this discrepancy, we propose two possibilities: (i) There is no direct coupling between the circadian rhythm and cell cycle but the timing of cell mitosis is synchronized with the rhythmic host environment, or (ii) coupling between the circadian rhythm and cell cycle exists in normal cells but it is disconnected in immortalized cells.
Nora L Salaberry
Full Text Available Drug addiction is a brain disease involving alterations in anatomy and functional neural communication. Drug intake and toxicity show daily rhythms in both humans and rodents. Evidence concerning the role of clock genes in drug intake has been previously reported. However, the implication of a timekeeping brain locus is much less known. The epithalamic lateral habenula (LHb is now emerging as a key nucleus in drug intake and addiction. This brain structure modulates the activity of dopaminergic neurons from the ventral tegmental area, a central part of the reward system. Moreover, the LHb has circadian properties: LHb cellular activity (i.e., firing rate and clock genes expression oscillates in a 24h range, and the nucleus is affected by photic stimulation and has anatomical connections with the main circadian pacemaker, the suprachiasmatic nucleus. Here, we describe the current insights on the role of the LHb as a circadian oscillator and its possible implications on the rhythmic regulation of the dopaminergic activity and drug intake. This data could inspire new strategies to treat drug addiction, considering circadian timing as a principal factor.
Johanna L Barclay
Full Text Available Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.
Zheng, Li; Seon, Yoon Ji; Mourão, Marcio A; Schnell, Santiago; Kim, Doohak; Harada, Hidemitsu; Papagerakis, Silvana; Papagerakis, Petros
Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization.
Soták, Matúš; Sumová, Alena; Pácha, Jiří
The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.
Curtis, Anne M; Bellet, Marina M; Sassone-Corsi, Paolo; O'Neill, Luke A J
Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
Antonio Carlos Alves Meireles-Filho
Full Text Available Organisms from bacteria to humans have evolved under predictable daily environmental cycles owing to the Earth’s rotation. This strong selection pressure has generated endogenous circadian clocks that regulate many aspects of behaviour, physiology and metabolism, anticipating and synchronising internal time-keeping to changes in the cyclical environment. In haematophagous insect vectors the circadian clock coordinates feeding activity, which is important for the dynamics of pathogen transmission. We have recently witnessed a substantial advance in molecular studies of circadian clocks in insect vector species that has consolidated behavioural data collected over many years, which provided insights into the regulation of the clock in the wild. Next generation sequencing technologies will facilitate the study of vector genomes/transcriptomes both among and within species and illuminate some of the species-specific patterns of adaptive circadian phenotypes that are observed in the field and in the laboratory. In this review we will explore these recent findings and attempt to identify potential areas for further investigation.
McMahon, Douglas G; Iuvone, P Michael; Tosini, Gianluca
The retinal circadian system represents a unique structure. It contains a complete circadian system and thus the retina represents an ideal model to study fundamental questions of how neural circadian systems are organized and what signaling pathways are used to maintain synchrony of the different structures in the system. In addition, several studies have shown that multiple sites within the retina are capable of generating circadian oscillations. The strength of circadian clock gene expression and the emphasis of rhythmic expression are divergent across vertebrate retinas, with photoreceptors as the primary locus of rhythm generation in amphibians, while in mammals clock activity is most robust in the inner nuclear layer. Melatonin and dopamine serve as signaling molecules to entrain circadian rhythms in the retina and also in other ocular structures. Recent studies have also suggested GABA as an important component of the system that regulates retinal circadian rhythms. These transmitter-driven influences on clock molecules apparently reinforce the autonomous transcription-translation cycling of clock genes. The molecular organization of the retinal clock is similar to what has been reported for the SCN although inter-neural communication among retinal neurons that form the circadian network is apparently weaker than those present in the SCN, and it is more sensitive to genetic disruption than the central brain clock. The melatonin-dopamine system is the signaling pathway that allows the retinal circadian clock to reconfigure retinal circuits to enhance light-adapted cone-mediated visual function during the day and dark-adapted rod-mediated visual signaling at night. Additionally, the retinal circadian clock also controls circadian rhythms in disk shedding and phagocytosis, and possibly intraocular pressure. Emerging experimental data also indicate that circadian clock is also implicated in the pathogenesis of eye disease and compelling experimental data
Merrow, Martha; Roenneberg, Till
Gating of cell division by the circadian clock is well known, yet its mechanism is little understood. Genetically tractable model systems have led to new hypotheses and questions concerning the coupling of these two cellular cycles.
Merrow, Martha; Roenneberg, Till
Gating of cell division by the circadian clock is well known, yet its mechanism is little understood. Genetically tractable model systems have led to new hypotheses and questions concerning the coupling of these two cellular cycles.
Full Text Available Sleep and/or circadian rhythm disruption (SCRD is seen in up to 80% of schizophrenia patients. The co-morbidity of schizophrenia and SCRD may in part stem from dysfunction in common brain mechanisms, which include the glutamate system, and in particular, the group II metabotropic glutamate receptors mGlu2 and mGlu3 (encoded by the genes Grm2 and Grm3. These receptors are relevant to the pathophysiology and potential treatment of schizophrenia, and have also been implicated in sleep and circadian function. In the present study, we characterised the sleep and circadian rhythms of Grm2/3 double knockout (Grm2/3-/- mice, to provide further evidence for the involvement of group II metabotropic glutamate receptors in the regulation of sleep and circadian rhythms. We report several novel findings. Firstly, Grm2/3-/- mice demonstrated a decrease in immobility-determined sleep time and an increase in immobility-determined sleep fragmentation. Secondly, Grm2/3-/- mice showed heightened sensitivity to the circadian effects of light, manifested as increased period lengthening in constant light, and greater phase delays in response to nocturnal light pulses. Greater light-induced phase delays were also exhibited by wildtype C57Bl/6J mice following administration of the mGlu2/3 negative allosteric modulator RO4432717. These results confirm the involvement of group II metabotropic glutamate receptors in photic entrainment and sleep regulation pathways. Finally, the diurnal wheel-running rhythms of Grm2/3-/- mice were perturbed under a standard light/dark cycle, but their diurnal rest-activity rhythms were unaltered in cages lacking running wheels, as determined with passive infrared motion detectors. Hence, when assessing the diurnal rest-activity rhythms of mice, the choice of assay can have a major bearing on the results obtained.
Lee, Kathryn A; Gay, Caryl; Byun, Eeeseung; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E
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
Yeom, Mijung; Pendergast, Julie S.; Ohmiya, Yoshihiro; Yamazaki, Shin
Two prominent timekeeping systems, the cell cycle, which controls cell division, and the circadian system, which controls 24-h rhythms of physiology and behavior, are found in nearly all living organisms. A distinct feature of circadian rhythms is that they are temperature-compensated such that the period of the rhythm remains constant (~24 h) at different ambient temperatures. Even though the speed of cell division, or growth rate, is highly temperature-dependent, the cell-mitosis rhythm is ...
Slats, D.; Claassen, J.A.H.R.; Verbeek, M.M.; Overeem, S.
AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems
Rakshit, Kuntol; Qian, Jingyi; Colwell, Christopher S; Matveyenko, Aleksey V.
Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today’s society and is likely responsible in part for the considerable rise in Type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease preventio...
Akdeniz, K. Gediz
Since the world of human and whose life becomes more and more complex every day because of the digital technology and under the storm of knowledge (media, internet, governmental and non-governmental organizations, etc...) the simulation is rapidly growing in the social systems and in human behaviors. The formation of the body and mutual interactions are left to digital technological, communication mechanisms and coding the techno genetics of the body. Deconstruction begins everywhere. The linear simulation mechanism with modern realities are replaced by the disorder simulation of human behaviors with awareness realities. In this paper I would like to introduce simulation theory of "Disorder Sensitive Human Behaviors". I recently proposed this theory to critique the role of disorder human behaviors in social systems. In this theory the principle of realty is the chaotic awareness of the complexity of human systems inside of principle of modern thinking in Baudrillard's simulation theory. Proper examples will be also considered to investigate the theory.
Ede, M. C. M.
The mechanisms that underlie the circadian variations in electrolyte content in body fluid compartments were investigated, and the mechanisms that control the oscillations were studied in order to investigate what effects internal desynchronization in such a system would have during manned space flight. The studies were performed using volunteer human subjects and squirrel monkeys. The intercompartmental distribution of potassium was examined when dietary intake, activity, and posture are held constant throughout each 24-hour day. A net flux of potassium was observed out of the body cell mass during the day and a reverse flux from the extracellular fluid into the body cell mass during the night, counterbalanced by changes in urinary potassium excretion. Experiments with monkeys provided evidence for the synchronization of renal potassium excretion by the rhythm of cortisol secretion with the light-dark cycle. Three models of the circadian timing system were formalized.
Full Text Available Since Bünning’s observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Based on molecular and neuronal studies in Drosophila melanogaster, photoperiodic changes have been reported for expression patterns of the circadian clock genes, subcellular distribution of clock proteins, fiber distribution, or the number of plausible clock neurons in different species. Photoperiod sets peaks of per or tim mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.
Shostak, Anton; Meyer-Kovac, Judit; Oster, Henrik
In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity-associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, ClockΔ19, and Bmal1(-/-) circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis.
Danica F Patton
Full Text Available Circadian rhythms of behavior and physiology are generated by central and peripheral circadian oscillators entrained by periodic environmental or physiological stimuli. A master circadian pacemaker in the hypothalamic suprachiasmatic nucleus is directly entrained by daily light-dark cycles, and coordinates the timing of other oscillators by direct and indirect neural, hormonal and behavioral outputs. The daily rhythm of food intake provides stimuli that entrain most peripheral and central oscillators, some of which can drive a daily rhythm of food anticipatory activity if food is restricted to one daily mealtime. The location of food-entrainable oscillators (FEOs that drive food anticipatory rhythms, and the food-related stimuli that entrain these oscillators, remain to be clarified. Here, we critically examine the role of peripheral metabolic hormones as potential internal entrainment stimuli or outputs for FEOs controlling food anticipatory rhythms in rats and mice. Hormones for which data are available include corticosterone, ghrelin, leptin, insulin, glucagon, and glucagon-like peptide 1. All of these hormones exhibit daily rhythms of synthesis and secretion that are synchronized by meal timing. There is some evidence that ghrelin and leptin modulate the expression of food anticipatory rhythms, but none of the hormones examined so far are necessary for entrainment. Ghrelin and leptin likely modulate food-entrained rhythms by actions in hypothalamic circuits utilizing melanocortin and orexin signaling, although again food-entrained behavioral rhythms can persist in lesion and gene knockout models in which these systems are disabled. Actions of these hormones on circadian oscillators in central reward circuits remain to be evaluated. Food-entrained activity rhythms are likely mediated by a distributed system of circadian oscillators sensitive to multiple feeding related inputs. Metabolic hormones appear to play a modulatory role within this
Full Text Available Neutrophil alloantigens are involved in a variety of clinical conditions including immune neutropenias, transfusion-related acute lung injury (TRALI, refractoriness to granulocyte transfusions and febrile transfusion reactions. In the last decade, considerable progress has been made in the characterization of the implicated antigens. Currently, seven antigens are assigned to five human neutrophil antigen (HNA systems. The HNA-1a, HNA-1b and HNA-1c antigens have been identified as polymorphic forms of the neutrophil Fcγ receptor IIIb (CD16b, encoded by three alleles. Recently, the primary structure of the HNA-2a antigen was elucidated and the HNA-2a-bearing glycoprotein was identified as a member of the Ly-6/uPAR superfamily, which has been clustered as CD177. The HNA-3a antigen is located on a 70-95 kDa glycoprotein; however, its molecular basis is still unknown. Finally, the HNA-4a and HNA-5a antigens were found to be caused by single nucleotide mutations in the αM (CD11b and αL (CD11a subunits of the leucocyte adhesion molecules (β2 integrins. Molecular and biochemical characterization of neutrophil antigenshave expanded our diagnostic tools by the introduction of genotyping techniques and immunoassays for antibody identification. Further studies in the field of neutrophil immunology will facilitate the prevention and management of transfusion reactions and immune diseases caused by neutrophil antibodies.Os aloantígenos de neutrófilos estão associados a várias condições clínicas como neutropenias imunes, insuficiência pulmonar relacionada à transfusão (TRALI, refratariedade à transfusão de granulócitos, e reações transfusionais febris. Na última década, foi observado considerável progresso na caracterização dos aloantígenos envolvidos nestas condições clínicas. Atualmente sete antígenos estão incluídos em cinco sistemas de antígenos de neutrófilo humano (HNA. Os antígenos HNA-1a, HNA-1b e HNA-1c foram
Full Text Available Pablo Valdez, Candelaria Ramírez, Aída GarcíaLaboratory of Psychophysiology, School of Psychology, University of Nuevo León, Monterrey, Nuevo León, MéxicoAbstract: Circadian variations have been found in human performance, including the efficiency to execute many tasks, such as sensory, motor, reaction time, time estimation, memory, verbal, arithmetic calculations, and simulated driving tasks. Performance increases during the day and decreases during the night. Circadian rhythms have been found in three basic neuropsychological processes (attention, working memory, and executive functions, which may explain oscillations in the performance of many tasks. The time course of circadian rhythms in cognitive performance may be modified significantly in patients with brain disorders, due to chronotype, age, alterations of the circadian rhythm, sleep deprivation, type of disorder, and medication. This review analyzes the recent results on circadian rhythms in cognitive performance, as well as the implications of these rhythms for the neuropsychological assessment of patients with brain disorders such as traumatic head injury, stroke, dementia, developmental disorders, and psychiatric disorders.Keywords: human circadian rhythms, cognitive performance, neuropsychological assessment, attention, working memory, executive functions
Full Text Available Behavioral and physiological circadian rhythms are controlled by endogenous oscillators in animals. Voluntary wheel-running in rodents is thought to be an appropriate model of aerobic exercise in humans. We evaluated the effects of chronic voluntary exercise on the circadian system by analyzing temporal profiles of feeding, core body temperature, plasma hormone concentrations and peripheral expression of clock and clock-controlled genes in mice housed under sedentary (SED conditions or given free access to a running-wheel (RW for four weeks. Voluntary wheel-running activity advanced the circadian phases of increases in body temperature, food intake and corticosterone secretion in the mice. The circadian expression of clock and clock-controlled genes was tissue- and gene-specifically affected in the RW mice. The temporal expression of E-box-dependent circadian clock genes such as Per1, Per2, Nr1d1 and Dbp were slightly, but significantly phase-advanced in the liver and white adipose tissue, but not in brown adipose tissue and skeletal muscle. Peak levels of Per1, Per2 and Nr1d1 expression were significantly increased in the skeletal muscle of RW mice. The circadian phase and levels of hepatic mRNA expression of the clock-controlled genes that are involved in cholesterol and fatty acid metabolism significantly differed between SED and RW mice. These findings indicated that endogenous clock-governed voluntary wheel-running activity provides feedback to the central circadian clock that systemically governs behavioral and physiological rhythms.
Bodenstein, C.; Heiland, I.; Schuster, S.
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.
Gerhart-Hines, Zachary; Lazar, Mitchell A.
A review. Circadian rhythm, or daily oscillation, of behaviors and biol. processes is a fundamental feature of mammalian physiol. that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine...... energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health. [on SciFinder(R)]...
of hydrogen sulfide (H2S, methyl mercaptan (CH3SH and dimethyl sulfide [(CH32S] gases. They are the main gases that cause halitosis. Circadian rhythm influenced the function of several organs of the human body including salivary secretion, hormone production, the body’s systems function, and activity of microorganisms. The purpose of this research is to examine the influence of circadian rhythm to oral VSC production measured by using a portable Oral Chroma. The research was carried-out by measuring the individual VSC gases in the morning, afternoon and evening at the integrated research laboratory, Faculty of Dentistry, UGM. Gases of H2S, CH3SH and (CH32S were tested by two-way ANOVA followed by Post-hoc LSD and Pearson correlation test with 95% significance level. The results showed the positive significant differences among the production of H2S, CH3SH and (CH32S with circadian time (p=0.000. Highly significant difference was also detected in amount of H2S and (CH32S gases in the morning, afternoon and evening (p=0.01 and p=0.00, as well as the amount of CH3SH gas in the afternoon and night (p=0.006, but not in amount of CH3SH gas in the morning (p=0.061. The highest production of H2S gas was known in the morning (mean 1.198 ng/10 ml, CH3SH gas was detected in the night (mean 0.099 ng/10 ml, and (CH32S gas was observed in the afternoon (mean 1.216 ng/10 ml. The strength of relationship among amount of three gases with circadian effects was r = 0.738. It is concluded that circadian rhythm markedly influences the production of oral VSCs. H2S and (CH32S gases production were significantly different among in the morning, afternoon and evening. However, amount of CH3SH gas production was significantly different only in the afternoon and the night. The highest gas production of H2S, CH3SH, and (CH32S was observed in the morning, in the night, and in the afternoon, respectively.
Full Text Available Abstract Background Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies. Methods Four groups of subjects were recruited from several sources: 1 bipolar proband-parent trios or sib-pair-parent nuclear families, 2 unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3 sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4 a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples. Results In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005. Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample. Conclusion Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may
Marcos G. Frank
Full Text Available 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.
Dijk, Derk Jan; Beersma, Domien G.M.; Daan, Serge; Lewy, Alfred J.
Eight male subjects were exposed to either bright light or dim light between 0600 and 0900 h for 3 consecutive days each. Relative to the dim light condition, the bright light treatment advanced the evening rise in plasma melatonin and the time of sleep termination (sleep onset was held constant) fo
Full Text Available Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary-adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.
areas produce life long disability Problem: The combination of jet fuel and high noise environment can exacerbate hearing loss Objective: Expose...Personalized Assessment, Education , and Training Systems Interfaces and Cognitive Processes Protection, Sustainment, and Warfighter...Infrastructure, & Information Distribution Statement A: Approved for Public Release 4 Personalized Assessment, Education , and Training System
Fuller, C. A.; Sulzman, F. M.; Moore-Ede, M. C.
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.
The Dutch Ministry of Defence research programme Human-System Task Integration aims at acquiring knowledge for the optimal cooperation between human and computer, under the following constraints: freedom of choice in decisions to automate and multiple, dynamic task distributions. This paper describe
The main circadian clock in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN), however, central timing mechanisms are also present in other brain structures beyond the SCN. The lateral habenula (LHb), known for its important role in the regulation of the monoaminergic system, contains such a circadian clock whose molecular and cellular mechanisms as well as functional role are not well known. However, since monoaminergic systems show circadian activity, it is possible that the LHb-clock's role is to modulate the rhythmic activity of the dopamine, serotonin and norephinephrine systems, and associated behaviors. Moreover, the LHb is involved in different pathological states such as depression, addiction and schizophrenia, states in which sleep and circadian alterations have been reported. Thus, perturbations of circadian activity in the LHb might, in part, be a cause of these rhythmic alterations in psychiatric ailments. In this review the current state of the LHb clock and its possible implications in the control of monoaminergic systems rhythms, motivated behaviors (e.g., feeding, drug intake) and depression (with circadian disruptions and altered motivation) will be discussed. Copyright © 2017 Elsevier Inc. All rights reserved.
Czeisler, Charles A.
Long-duration manned space flight requires crew members to maintain a high level of cognitive performance and vigilance while operating and monitoring sophisticated instrumentation. However, the reduction in the strength of environmental synchronizers in the space environment leads to misalignment of circadian phase among crew members, coupled with restricted time available to sleep, results in sleep deprivation and consequent deterioration of neurobehavioral function. Crew members are provided, and presently use, long-acting benzodiazepine hypnotics on board the current, relatively brief space shuttle missions to counteract such sleep disruption, a situation that is only likely to worsen during extended duration missions. Given the known carry-over effects of such compounds on daytime performance, together with the reduction in emergency readiness associated with their use at night, NASA has recognized the need to develop effective but safe countermeasures to allow crew members to obtain an adequate amount of sleep. Over the past eight years, we have successfully implemented a new technology for shuttle crew members involving bright light exposure during the pre-launch period to facilitate adaptation of the circadian timing system to the inversions of the sleep-wake schedule often required during dual shift missions. However for long duration space station missions it will be necessary to develop effective and attainable countermeasures that can be used chronically to optimize circadian entrainment. Our current research effort is to study the effects of light-dark cycles with reduced zeitgeber strength, such as are anticipated during long-duration space flight, on the entrainment of the endogenous circadian timing system and to study the effects of a countermeasure that consists of scheduled brief exposures to bright light on the human circadian timing system. The proposed studies are designed to address the following Specific Aims: (1) test the hypothesis that
Whitehurst, Lauren N; Fogler, Kethera; Hall, Kate; Hartmann, Matthew; Dyche, Jeff
Animal literature suggests a connection between marijuana use and altered circadian rhythms. However, the effect has not yet been demonstrated in humans. The present study examined the effect of chronic marijuana use on human circadian function. Participants consisted of current users who reported smoking marijuana daily for at least a year and non-marijuana user controls. Participants took a neurocognitive assessment, wore actigraphs and maintained sleep diaries for three weeks. While no significant cognitive changes were found between groups, data revealed that chronic marijuana use may act as an additional zeitgeber and lead to increased entrainment in human users.
P. Gómez Abellán
Full Text Available Introduction: Circadian variability of circulating leptin levels has been well established over the last decade. However, the circadian behavior of leptin in human adipose tissue remains unknown. This also applies to the soluble leptin receptor. Objective: We investigated the ex vivo circadian behavior of leptin and its receptor expression in human adipose tissue (AT. Subjects and methods: Visceral and subcutaneous abdominal AT biopsies (n = 6 were obtained from morbid obese women (BMI ≥ 40 kg/m². Anthropometric variables and fasting plasma glucose, leptin, lipids and lipoprotein concentrations were determined. In order to investigate rhythmic expression pattern of leptin and its receptor, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h, using quantitative real-time PCR. Results: Leptin expression showed an oscillatory pattern that was consistent with circadian rhythm in cultured AT. Similar patterns were noted for the leptin receptor. Leptin showed its achrophase (maximum expression during the night, which might be associated to a lower degree of fat accumulation and higher mobilization. When comparing both fat depots, visceral AT anticipated its expression towards afternoon and evening hours. Interestingly, leptin plasma values were associated with decreased amplitude of LEP rhythm. This association was lost when adjusting for waist circumference. Conclusion: Circadian rhythmicity has been demonstrated in leptin and its receptor in human AT cultures in a site-specific manner. This new knowledge paves the way for a better understanding of the autocrine/paracrine role of leptin in human AT.Introducción: La variabilidad circadiana de los niveles de leptina circulante se ha establecido en la última década, pero actualmente se desconoce el comportamiento circadiano de leptina y su receptor en tejido adiposo (TA humano. Objetivo: Investigar si existe un comportamiento
Nielsen, René Nesgaard
Human resources in innovation systems: With focus on introduction of highly educated labour in small Danish firms This thesis has two purposes: (1) a ‘general' purpose to enhance our knowledge on the relationship between innovation, technological and organisational change, and human resources......, including knowledge and skills embodied in human resources, and (2) a more ‘specific' purpose to enhance our knowledge on introduction of highly educated labour, innovation, and upgrading changes in small Danish firms. Chapter 1 establishes the relevance of this research interest, and it also states...... stemming from human resources - such as insight, understanding, creativity, and action - are inherently important to all innovation processes. The chapter also suggests a tentative conceptual and analytical framework for studying human resources and their development within a system of innovation approach...
Full Text Available The mammalian circadian system controls various physiology processes and behavior responses by regulating thousands of circadian genes with rhythmic expressions. In this study, we redefined circadian-regulated genes based on published results in the mouse liver and compared them with other gene groups defined relative to circadian regulations, especially the non-circadian-regulated genes expressed in liver at multiple molecular levels from gene position to protein expression based on integrative analyses of different datasets from the literature. Based on the intra-tissue analysis, the liver circadian genes or LCGs show unique features when compared to other gene groups. First, LCGs in general have less neighboring genes and larger in both genomic and 3'-UTR lengths but shorter in CDS (coding sequence lengths. Second, LCGs have higher mRNA and protein abundance, higher temporal expression variations, and shorter mRNA half-life. Third, more than 60% of LCGs form major co-expression clusters centered in four temporal windows: dawn, day, dusk, and night. In addition, larger and smaller LCGs are found mainly expressed in the day and night temporal windows, respectively, and we believe that LCGs are well-partitioned into the gene expression regulatory network that takes advantage of gene size, expression constraint, and chromosomal architecture. Based on inter-tissue analysis, more than half of LCGs are ubiquitously expressed in multiple tissues but only show rhythmical expression in one or limited number of tissues. LCGs show at least three-fold lower expression variations across the temporal windows than those among different tissues, and this observation suggests that temporal expression variations regulated by the circadian system is relatively subtle as compared with the tissue expression variations formed during development. Taken together, we suggest that the circadian system selects gene parameters in a cost effective way to improve tissue
Nielsen, René Nesgaard
the research questions which are studied in the thesis. Chapter 2 reviews relevant literature on systems of innovation, human capital, and skill-biased technological and organisational change. It is stated in the chapter that this thesis primarily refers to a system of innovation approach as its......Human resources in innovation systems: With focus on introduction of highly educated labour in small Danish firms This thesis has two purposes: (1) a ‘general' purpose to enhance our knowledge on the relationship between innovation, technological and organisational change, and human resources......, including knowledge and skills embodied in human resources, and (2) a more ‘specific' purpose to enhance our knowledge on introduction of highly educated labour, innovation, and upgrading changes in small Danish firms. Chapter 1 establishes the relevance of this research interest, and it also states...
Johnson, Carl Hirschie; Egli, Martin
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
Masri, Selma; Cervantes, Marlene; Sassone-Corsi, Paolo
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.
Ross E.F. Harper
Full Text Available Periodic changes in light and temperature synchronize the Drosophila circadian clock, but the question of how the fly brain integrates these two input pathways to set circadian time remains unanswered. We explore multisensory cue combination by testing the resilience of the circadian network to conflicting environmental inputs. We show that misaligned light and temperature cycles can lead to dramatic changes in the daily locomotor activities of wild-type flies during and after exposure to sensory conflict. This altered behavior is associated with a drastic reduction in the amplitude of PERIOD (PER oscillations in brain clock neurons and desynchronization between light- and temperature-sensitive neuronal subgroups. The behavioral disruption depends heavily on the phase relationship between light and temperature signals. Our results represent a systematic quantification of multisensory integration in the Drosophila circadian system and lend further support to the view of the clock as a network of coupled oscillatory subunits.
Winter, de L.
Abstract Thesis: Circadian rhythms in microalgae production Lenneke de Winter The sun imposes a daily cycle of light and dark on nearly all organisms. The circadian clock evolved to help organisms program their activities at an appropriate time during this daily cycle. For example,
Gerkema, Menno P.; Binder, Marc D.; Hirokawa, Nobutaka; Windhorst, Uwe
One of the defining characteristics of circadian pacemakers and indicates the independence of the speed of circadian clock processes of environmental temperature. Mechanisms involved, so far not elucidated in full detail, entail at least two processes that are similarly affected by temperature chang
Winter, de L.
Abstract Thesis: Circadian rhythms in microalgae production Lenneke de Winter The sun imposes a daily cycle of light and dark on nearly all organisms. The circadian clock evolved to help organisms program their activities at an appropriate time during this daily cycle. For example,
Full Text Available Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of
Kang, Bin; Li, Yuan-Yuan; Chang, Xiao; Liu, Lei; Li, Yi-Xue
Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.
Strijkstra, AM; Meerlo, P; Beersma, DGM
The daily rhythm in body temperature is thought to be the result of the direct effects of activity and the effects of an endogenous circadian clock. Forced desynchrony (FD) is a tool used in human circadian rhythm research to disentangle endogenous and activity-related effects on daily rhythms. In t
Hussain, M Mahmood; Pan, Xiaoyue
Various intestinal functions exhibit circadian rhythmicity. Disruptions in these rhythms as in shift workers and transcontinental travelers are associated with intestinal discomfort. Circadian rhythms are controlled at the molecular level by core clock and clock-controlled genes. These clock genes are expressed in intestinal cells, suggesting that they might participate in the circadian regulation of intestinal functions. A major function of the intestine is nutrient absorption. Here, we will review absorption of proteins, carbohydrates, and lipids and circadian regulation of various transporters involved in their absorption. A better understanding of circadian regulation of intestinal absorption might help control several metabolic disorders and attenuate intestinal discomfort associated with disruptions in sleep-wake cycles.
Devi Verma; Onn Haji Hashim; Jaime Jacqueline Jayapalan; Perumal Subramanian
Aim: Alteration of circadian systems can cause cancer and affects its development and response to therapeutics. The present study investigates whether cancer can disrupt circadian locomotor rhythms and evaluated the influence of melatonin (MLT) and oxaliplatin on the levels of antioxidants and circadian locomotor activity rhythms in N-nitrosodiethylamine (NDEA)-induced liver tumor in Indian field mouse (Mus booduga). Materials and Methods: Effects of NDEA, NDEA, and MLT, as well as NDEA an...
Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A
The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation.
Like all circadian (near-24-h) rhythms, those of cognition have endogenous and exogenous components. The origins of these components, together with effects of time awake upon cognitive performance, are described in subjects living conventionally (sleeping at night and active during the daytime). Based on these considerations, predictions can be made about changes that might be expected in the days after a time-zone transition and during night work. The relevant literature on these circumstances is then reviewed. The last section of the chapter deals with sleep-wake schedules where both regular and irregular sleeps are taken (anchor sleep). Copyright © 2010 Elsevier B.V. All rights reserved.
Hill, S.G.; Harbour, J.L.; Sullivan, C.; Hallbert, B.P. (Idaho National Engineering Lab., Idaho Falls, ID (USA))
HSYS is a model-based methodology developed to examine the many factors which influence Human-SYStem interactions. HSYS is built around a linear model of human performance, called the Input-Action model, which describes five sequential steps: Input Detection, Input Understanding, Action Selection, Action Planning, and Action Execution. HSYS is structured in an hierarchical tree which presents a logical structure for examining potential areas where human performance, hardware or other system components are less than adequate. The HSYS tree consists of five major branches which correspond to the five major components of the Input-Action model. Initial validation was begun by studying accident reports via HSYS and identifying sources of error. The validation process has continued with accident investigations in operational settings. 9 refs., 3 figs.
Cheng, Bo; Anea, Ciprian B; Yao, Lin; Chen, Feng; Patel, Vijay; Merloiu, Ana; Pati, Paramita; Caldwell, R William; Fulton, David J; Rudic, R Daniel
The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.
Veissier, Isabelle; Mialon, Marie-Madeleine; Sloth, Karen Helle
Biological rhythms are an essential regulator of life. There is evidence that circadian rhythm of activity is disrupted under chronic stress in animals and humans, and it may also be less marked during diseases. Here we investigated whether a detectable circadian rhythm of activity exists in dairy cows in commercial settings using a real-time positioning system. We used CowView (GEA Farm Technologies) to regularly record the individual positions of 350 cows in a Danish dairy farm over 5 mo and to infer the cows' activity (resting, feeding, in alley). We ran a factorial correspondence analysis on the cows' activities and used the first component of this analysis to express the variations in activity. On this axis, the activities obtained the following weights: resting = -0.15; in alleys = +0.12; feeding = +0.34. By applying these weights to the proportions of time each cow spent on each of the 3 activities, we were able to chart a circadian rhythm of activity. We found that average level of activity of a cow on a given day and its variations during that day varied with specific states (i.e., estrus, lameness, mastitis). More specifically, circadian variations in activity appeared to be particularly sensitive and to vary 1 to 2 d before the farmer detected a disorder. These findings offer promising avenues for further research to design models to predict physiological or pathological states of cows from real-time positioning data.
Kessler, K; Pivovarova, O; Pfeiffer, A F H
On behavioural as well as physiological levels our daily life is regulated by the circadian clock - endogenous oscillators present in the hypothalamus and in peripheral tissues - which is believed to have evolved as an adaptation to Earth rotation around the Sun and its consequent 24 h dark-light cycle. Accumulative evidence suggests that the circadian clock plays a pivotal role for energy metabolism and energy homeostasis: many hormones, enzymes and transport systems involved in the regulation of energy metabolism have been shown to display circadian rhythms in their expression, secretion and/or activity patterns. The energy metabolism, in turn, can impact on the circadian clock - a process that is called entrainment. Thus, the circadian clock and energy metabolism are intimately intertwined. So far this interplay and its implications for health have not been understood very well. For health maintenance, however, it seems to be crucial to avoid any desynchronisation between the circadian clock and energy metabolism. Form a clinical point of view this might be important for the treatment of obesity and associated disorders and may lead to new life-style approaches. © Georg Thieme Verlag KG Stuttgart · New York.
Zhang, Ray; Lahens, Nicholas F; Ballance, Heather I; Hughes, Michael E; Hogenesch, John B
To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.
Full Text Available Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g. obesity involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude enhancing small molecules (CEMs identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep and metabolism will also have far-reaching implications for various chronic human diseases and aging.
Nohara, Kazunari; Yoo, Seung-Hee; Chen, Zheng Jake
Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock, and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g., obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude-enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep, and metabolism will also have far-reaching implications for various chronic human diseases and aging.
Roenneberg, Till; Merrow, Martha
This review uses three examples to summarise our knowledge about the complexity and the evolution of circadian systems. The first example describes the ecology of unicellular algae, which use their circadian system to optimise the daily exploitation of resources that are spatially separated. The sec
Kas, M J; Edgar, D M
The circadian timing system in mammals is thought to promote wakefulness and oppose sleep drive that accumulates across the activity phase in diurnal and nocturnal species. Whether the circadian system actively opposes compensatory sleep responses in mammals with episodes of alertness consolidated a
Wardlaw, Sarah M.; Phan, Trongha X.; Saraf, Amit; Chen, Xuanmao; Storm, Daniel R.
Perturbing the circadian system by electrolytically lesioning the suprachiasmatic nucleus (SCN) or varying the environmental light:dark schedule impairs memory, suggesting that memory depends on the circadian system. We used a genetic approach to evaluate the role of the molecular clock in memory. Bmal1[superscript -/-] mice, which are arrhythmic…
Roenneberg, Till; Merrow, Martha
This review uses three examples to summarise our knowledge about the complexity and the evolution of circadian systems. The first example describes the ecology of unicellular algae, which use their circadian system to optimise the daily exploitation of resources that are spatially separated. The sec
Prendergast, Brian J; Cisse, Yasmine M; Cable, Erin J; Zucker, Irving
Three experiments addressed whether pronounced alterations in the circadian system yielded concomitant changes in ultradian timing. Female Siberian hamsters were housed in a 16L:8D photoperiod after being subjected to a disruptive phase-shifting protocol that produced 3 distinct permanent circadian phenotypes: some hamsters entrained their circadian rhythms (CRs) with predominantly nocturnal locomotor activity (ENTR), others displayed free-running CRs (FR), and a third cohort was circadian arrhythmic (ARR). The period of the ultradian locomotor rhythm (UR) did not differ among the 3 circadian phenotypes; neuroendocrine generation of URs remains viable in the absence of coherent circadian organization and appears to be mediated by substrates functionally and anatomically distinct from those that generate CRs. Pronounced light-dark differences in several UR characteristics in ENTR hamsters were completely absent in circadian arrhythmic hamsters. The disruptive phase-shifting protocol may compromise direct visual input to ultradian oscillators but more likely indirectly affects URs by interrupting visual afference to the circadian system. Additional experiments documented that deuterium oxide and constant light, each of which substantially lengthened the period of free-running CRs, failed to change the period of concurrently monitored URs. The resistance of URs to deuteration contrasts with the slowing of virtually all other biological timing processes, including CRs. Considered together, the present results point to the existence of separable control mechanisms for generation of circadian and ultradian rhythms.
Mazzoccoli, Gianluigi; Vinciguerra, Manlio; Papa, Gennaro; Piepoli, Ada
Colorectal cancer is the most prevalent among digestive system cancers. Carcinogenesis relies on disrupted control of cellular processes, such as metabolism, proliferation, DNA damage recognition and repair, and apoptosis. Cell, tissue, organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery. Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis, and altered expression of clock genes has been found in cancer patients. Epidemiological studies have shown that circadian disruption, that is, alteration of bodily temporal organization, is a cancer risk factor, and an increased incidence of colorectal neoplastic disease is reported in shift workers. In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer.
Full Text Available The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture. To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny.
Fuller, C. A.
The influence of chronic centrifugation upon the homestatic regulation of the circadian timekeeping system was examined. The interactions of body temperature regulation and the behavioral state of arousal were studied by evaluating the influence of cephalic fluid shifts induced by lower body positive air pressure (LBPP), upon these systems. The small diurnal squirrel monkey (Saimiri sciureus) was used as the non-human primate model. Results show that the circadian timekeeping system of these primates is functional in the hyperdynamic environment, however, some of its components appear to be regulated at different homeostatic levels. The LBPP resulted in an approximate 0.7 C decrease in DBT (p 0.01). However, although on video some animals appeared drowsy during LBPP, sleep recording revealed no significant changes in state of arousal. Thus, the physiological mechanisms underlying this lowering of body temperature can be independent of the arousal state.
Fuller, C. A.
The influence of chronic centrifugation upon the homestatic regulation of the circadian timekeeping system was examined. The interactions of body temperature regulation and the behavioral state of arousal were studied by evaluating the influence of cephalic fluid shifts induced by lower body positive air pressure (LBPP), upon these systems. The small diurnal squirrel monkey (Saimiri sciureus) was used as the non-human primate model. Results show that the circadian timekeeping system of these primates is functional in the hyperdynamic environment, however, some of its components appear to be regulated at different homeostatic levels. The LBPP resulted in an approximate 0.7 C decrease in DBT (p 0.01). However, although on video some animals appeared drowsy during LBPP, sleep recording revealed no significant changes in state of arousal. Thus, the physiological mechanisms underlying this lowering of body temperature can be independent of the arousal state.
Fang, Mingzhu; Guo, Wei-Ren; Park, Youngil; Kang, Hwan-Goo; Zarbl, Helmut
We previously reported that dietary methylselenocysteine (MSC) inhibits N-methyl-N-nitrosourea (NMU)-induced mammary tumorigenesis by resetting circadian gene expression disrupted by the carcinogen at the early stage of tumorigenesis. To investigate the underlying mechanism, we developed a circadian reporter system comprised of human mammary epithelial cells with a luciferase reporter driven by the promoter of human PERIOD 2 (PER2), a core circadian gene. In this in vitro model, NMU disrupted cellular circadian rhythm in a pattern similar to that observed with SIRT1-specific inhibitors; in contrast, MSC restored the circadian rhythms disrupted by NMU and protected against SIRT1 inhibitors. Moreover, NMU inhibited intracellular NAD+/NADH ratio and reduced NAD+-dependent SIRT1 activity in a dose-dependent manner, while MSC restored NAD+/NADH and SIRT1 activity in the NMU-treated cells, indicating that the NAD+-SIRT1 pathway was targeted by NMU and MSC. In rat mammary tissue, a carcinogenic dose of NMU also disrupted NAD+/NADH oscillations and decreased SIRT1 activity; dietary MSC restored NAD+/NADH oscillations and increased SIRT1 activity in the mammary glands of NMU-treated rats. MSC-induced SIRT1 activity was correlated with decreased acetylation of BMAL1 and increased acetylation of histone 3 lysine 9 at the Per2 promoter E-Box in mammary tissue. Changes in SIRT1 activity were temporally correlated with loss or restoration of rhythmic Per2 mRNA expression in NMU-treated or MSC-rescued rat mammary glands, respectively. Together with our previous findings, these results suggest that enhancement of NAD+-dependent SIRT1 activity contributes to the chemopreventive efficacy of MSC by restoring epigenetic regulation of circadian gene expression at early stages of mammary tumorigenesis.
Jin Wook Kim
Full Text Available 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.
Mitchell, C. M. (Editor); Vanbalen, P. M. (Editor); Moe, K. L. (Editor)
Human factors considerations in systems design was examined. Human factors in automated command and control, in the efficiency of the human computer interface and system effectiveness are outlined. The following topics are discussed: human factors aspects of control room design; design of interactive systems; human computer dialogue, interaction tasks and techniques; guidelines on ergonomic aspects of control rooms and highly automated environments; system engineering for control by humans; conceptual models of information processing; information display and interaction in real time environments.
Full Text Available Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
Umetani, Miki; Hosokawa, Norimune; Kitayama, Yohko; Iwasaki, Hideo
Cyanobacteria are unique organisms with remarkably stable circadian oscillations. These are controlled by a network architecture that comprises two regulatory factors: posttranslational oscillation (PTO) and a transcription/translation feedback loop (TTFL). The clock proteins KaiA, KaiB, and KaiC are essential for the circadian rhythm of the unicellular species Synechococcus elongatus PCC 7942. Temperature-compensated autonomous cycling of KaiC phosphorylation has been proposed as the primary oscillator mechanism that maintains the circadian clock, even in the dark, and it controls genome-wide gene expression rhythms under continuous-light conditions (LL). However, the kaiC(EE) mutation (where "EE" represents the amino acid changes Ser431Glu and Thr432Glu), where phosphorylation cycling does not occur in vivo, has a damped but clear kaiBC expression rhythm with a long period. This suggests that there must be coupling between the robust PTO and the "slave" unstable TTFL. Here, we found that the kaiC(EE) mutant strain in LL was hypersensitive to the dark acclimation required for phase shifting. Twenty-three percent of the genes in the kaiC(EE) mutant strain exhibited genome-wide transcriptional rhythms with a period of 48 h in LL. The circadian phase distribution was also conserved significantly in most of the wild-type and kaiC(EE) mutant strain cycling genes, which suggests that the output mechanism was not damaged severely even in the absence of KaiC phosphorylation cycles. These results strongly suggest that the KaiC phosphorylation cycle is not essential for generating the genome-wide rhythm under light conditions, whereas it is important for appropriate circadian timing in the light and dark.
Full Text Available The neuroendocrine substance melatonin is a hormone synthesized rhythmically by the pineal gland under the influence of the circadian system and alternating light/dark cycles. Melatonin has been shown to have broad applications, and consequently becoming a molecule of great controversy. Undoubtedly, however, melatonin plays an important role as a time cue for the endogenous circadian system. This review focuses on melatonin as a regulator in the circadian modulation of memory processing. Memory processes (acquisition, consolidation and retrieval are modulated by the circadian system. However, the mechanism by which the biological clock is rhythmically influencing cognitive processes remains unknown. We also discuss, how the circadian system by generating cycling melatonin levels can implant information about daytime into memory processing, depicted as day and nighttime differences in acquisition, memory consolidation and/or retrieval.
AIM: To analyze pituitary hormone and melatonin cir- cadian rhythms, and to correlate hormonal alterations with clinical performance, hepatic disease severity and diagnostic tests used for the detection of hepatic en- cephalopathy in cirrhosis. METHODS: Twenty-six patients with cirrhosis were enrolled in the study. Thirteen patients hospitalized for systemic diseases not affecting the liver were included as controls. Liver disease severity was assessed by the Child-Pugh score. All patients underwent detailed neurological assessment, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), assays of pi- tuitary hormone, cortisol and melatonin, and complete blood chemistry evaluation. RESULTS: Pituitary hormone and melatonin circadian patterns were altered in cirrhosis patients without clinical encephalopathy. Circadian hormone alterations were different in cirrhosis patients compared with con- trois. Although cortisol secretion was not altered in any patient with cirrhosis, the basal cortisol levels were low and correlated with EEG and brain MRI abnormalities. Melatonin was the only hormone associated with the severity of liver insufficiency. CONCLUSION: Abnormal pituitary hormone and mel- atonin circadian patterns are present in cirrhosis before the development of hepatic encephalopathy. These abnormalities may be early indicators of impending hepatic encephalopathy. Factors affecting the human biologic clock at the early stages of liver insufficiency require further study.
Camargo-Sanchez, Andrés; Niño, Carmen L; Sánchez, Leonardo; Echeverri, Sonia; Gutiérrez, Diana P; Duque, Andrés F; Pianeta, Oscar; Jaramillo-Gómez, Jenny A; Pilonieta, Martin A; Cataño, Nhora; Arboleda, Humberto; Agostino, Patricia V; Alvarez-Baron, Claudia P; Vargas, Rafael
The circadian system controls the daily rhythms of a variety of physiological processes. Most organisms show physiological, metabolic and behavioral rhythms that are coupled to environmental signals. In humans, the main synchronizer is the light/dark cycle, although non-photic cues such as food availability, noise, and work schedules are also involved. In a continuously operating hospital, the lack of rhythmicity in these elements can alter the patient’s biological rhythms and resilience. This paper presents a Theory of Inpatient Circadian Care (TICC) grounded in circadian principles. We conducted a literature search on biological rhythms, chronobiology, nursing care, and middle-range theories in the databases PubMed, SciELO Public Health, and Google Scholar. The search was performed considering a period of 6 decades from 1950 to 2013. Information was analyzed to look for links between chronobiology concepts and characteristics of inpatient care. TICC aims to integrate multidisciplinary knowledge of biomedical sciences and apply it to clinical practice in a formal way. The conceptual points of this theory are supported by abundant literature related to disease and altered biological rhythms. Our theory will be able to enrich current and future professional practice. PMID:25767632
Brianne Alyssia Kent
Full Text Available Alzheimer’s disease (AD is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behaviour and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.
Giglio, Larriany Maria Falsin; Magalhães, Pedro V S; Andersen, Mônica Levy; Walz, Julio Cesar; Jakobson, Lourenço; Kapczinski, Flávio
A role for circadian rhythm abnormalities in the pathogenesis of bipolar disorder (BD) has been suggested. The present study assessed circadian preference, a subjective preference for activities in the morning or evening related to chronotype. The sample was comprised of 81 outpatients with BD in remission and 79 control subjects. Circadian preference was derived from an interview evaluating biological rhythms and sleep pattern from the Pittsburgh Sleep Quality Index. Patients were significantly more likely to have an evening preference than control subjects. Circadian preference was also associated with sleep latency. The association of evening preference and longer sleep latency may be related to the frequent clinical observation of a sleep/wake cycle reversal in bipolar disorder.
Jitka A. I. Virag
Full Text Available Components of circadian rhythm maintenance, or clock genes, are found in all peripheral tissues, including the heart, and influence such diverse phenomena as cytokine expression immune cells, metabolic activity of cardiac myocytes, and vasodilator regulation by vascular endothelial cells. 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 cardiovascular disease 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 cardiovascular disease may provide insights into possible preventative and therapeutic strategies for susceptible populations.
Full Text Available BACKGROUND: The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity 'room' light (∼90-150 lux or moderate light supplemented with bright light (∼10,000 lux for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h. Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17-94% and after bright light by 52% (range 12-84%, as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness. CONCLUSIONS/SIGNIFICANCE: Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift
John Griniatsos; George Marinos; John Bramis; Panayiotis O Michail; Othon P Michail; Stamatios Theocharis; Antonios Arvelakis; Ioannis Papaconstantinou; Evangelos Felekouras; Emmanouel Pikoulis; Ioannis Karavokyros; Chris Bakoyiannis
AIM: To evaluate whether the cellular proliferation rate in the large bowel epithelial cells is characterized by circadian rhythm.METHODS: Between January 2003 and December 2004,twenty patients who were diagnosed as suffering from primary, resectable, non-metastatic adenocarcinoma of the lower rectum, infiltrating the sphincter mechanism,underwent abdominoperineal resection, total mesorectal excision and permanent left iliac colostomy. In formalinfixed and paraffin-embedded biopsy specimens obtained from the colostomy mucosa every six hours (00:00,06:00, 12:00, 18:00 and 24:00), we studied the expression of G1 phase cydins (D1 and E) as well as the expression of the G1 phase cyclin-dependent kinase (CDK)inhibitors p16 and p21 as indicators of cell cycle progression in colonic epithelial cells using immunohistochemical methods.RESULTS: The expression of both cyclins showed a similar circadian fashion obtaining their lowest and highest values at 00:00 and 18:00, respectively (P＜ 0.001).A circadian rhythm in the expression of CDK inhibitor proteins p16 and p21 was also observed, with the lowest levels obtained at 12:00 and 18:00 (P＜0.001), respectively. When the complexes cyclins D1-p21 and E-p21were examined, the expression of the cyclins was adversely correlated to the p21 expression throughout the day. When the complexes the cyclins D1-p16 and E-p16were examined, high levels of p16 expression were correlated to low levels of cyclin expression at 00:00, 06:00and 24:00. Meanwhile, the highest expression levels of both cyclins were correlated to high levels of p16 expression at 18:00.CONCLUSION: Colonic epithelial cells seem to enter the G1 phase of the cell cycle during afternoon (between 12:00 and 18:00) with the highest rates obtained at 18:00. From a clinical point of view, the present results suggest that G1-phase specific anticancer therapies in afternoon might maximize their anti-tumor effect while minimizing toxicity.
Yamanaka Iori; Yagita Kazuhiro; Emoto Noriaki; Kawakami Koichi; Shimada Shoichi
Abstract Background The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between circadian oscillator and physiological functions in periph...
Yagita, Kazuhiro; Yamanaka, Iori; Emoto, Noriaki; Kawakami, Koichi; Shimada, Shoichi
Background The circadian rhythm in mammals is orchestrated by a central pacemaker in the brain, but most peripheral tissues contain their own intrinsic circadian oscillators. The circadian rhythm is a fundamental biological system in mammals involved in the regulation of various physiological functions such as behavior, cardiovascular functions and energy metabolism. Thus, it is important to understand the correlation between circadian oscillator and physiological functions in peripheral tiss...
Full Text Available Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies.
Full Text Available 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.
OHara, J.M.; Higgins,J. (BNL); Fleger, S.; Barnes V. (NRC)
Automation is ubiquitous in modern complex systems, and commercial nuclear- power plants are no exception. Automation is applied to a wide range of functions including monitoring and detection, situation assessment, response planning, and response implementation. Automation has become a 'team player' supporting personnel in nearly all aspects of system operation. In light of its increasing use and importance in new- and future-plants, guidance is needed to conduct safety reviews of the operator's interface with automation. The objective of this research was to develop such guidance. We first characterized the important HFE aspects of automation, including six dimensions: levels, functions, processes, modes, flexibility, and reliability. Next, we reviewed literature on the effects of all of these aspects of automation on human performance, and on the design of human-system interfaces (HSIs). Then, we used this technical basis established from the literature to identify general principles for human-automation interaction and to develop review guidelines. The guidelines consist of the following seven topics: automation displays, interaction and control, automation modes, automation levels, adaptive automation, error tolerance and failure management, and HSI integration. In addition, our study identified several topics for additional research.
The intracellular circadian clock consists of a series of transcriptional modulators that together allow the cell to perceive the time of day. Circadian clocks have been identified within various components of the cardiovascular system (e.g., cardiomyocytes, vascular smooth muscle cells) and possess...
Numano, Rika; Yamazaki, Shin; Umeda, Nanae; Samura, Tomonori; Sujino, Mitsugu; Takahashi, Ri-ichi; Ueda, Masatsugu; Mori, Akiko; Yamada, Kazunori; Sakaki, Yoshiyuki; Inouye, Shin-ichi T; Menaker, Michael; Tei, Hajime
Three mammalian Period (Per) genes, termed Per1, Per2, and Per3, have been identified as structural homologues of the Drosophila circadian clock gene, period (per). The three Per genes are rhythmically expressed in the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. The phases of peak mRNA levels for the three Per genes in the SCN are slightly different. Light sequentially induces the transcripts of Per1 and Per2 but not of Per3 in mice. These data and others suggest that each Per gene has a different but partially redundant function in mammals. To elucidate the function of Per1 in the circadian system in vivo, we generated two transgenic rat lines in which the mouse Per1 (mPer1) transcript was constitutively expressed under the control of either the human elongation factor-1alpha (EF-1alpha) or the rat neuron-specific enolase (NSE) promoter. The transgenic rats exhibited an approximately 0.6-1.0-h longer circadian period than their wild-type siblings in both activity and body temperature rhythms. Entrainment in response to light cycles was dramatically impaired in the transgenic rats. Molecular analysis revealed that the amplitudes of oscillation in the rat Per1 (rPer1) and rat Per2 (rPer2) mRNAs were significantly attenuated in the SCN and eyes of the transgenic rats. These results indicate that either the level of Per1, which is raised by overexpression, or its rhythmic expression, which is damped or abolished in over expressing animals, is critical for normal entrainment of behavior and molecular oscillation of other clock genes.
Touitou, Yvan; Reinberg, Alain; Touitou, David
Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50-100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption. Shift and/or night work generally decreases the time spent sleeping, and it disrupts the circadian time structure. In the long run, this desynchronization is detrimental to health, as underscored by a large number of epidemiological studies that have uncovered elevated rates of several diseases, including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. It amounts to a public health issue in the light of the very substantial number of individuals involved. The IARC has classified shift work in group 2A of "probable carcinogens to humans" since "they involve a circadian disorganization". Countermeasures to the effects of ALAN, such as melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work. We review the evidence for the ALAN impacts on health. Furthermore, we highlight the importance of an in-depth mechanistic understanding to combat the detrimental properties of exposure to ALAN and develop strategies of prevention. Copyright © 2017 Elsevier Inc. All rights reserved.
Winget, C. M.; Vernikos-Danellis, J.; Cronin, S. E.; Leach, C. S.; Rambaut, P. C.; Mack, P. B.
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.
Müller, Niels A; Wijnen, Cris L; Srinivasan, Arunkumar; Ryngajllo, Malgorzata; Ofner, Itai; Lin, Tao; Ranjan, Aashish; West, Donnelly; Maloof, Julin N; Sinha, Neelima R; Huang, Sanwen; Zamir, Dani; Jiménez-Gómez, José M
The circadian clock is a critical regulator of plant physiology and development, controlling key agricultural traits in crop plants. In addition, natural variation in circadian rhythms is important for local adaptation. However, quantitative modulation of circadian rhythms due to artificial selection has not yet been reported. Here we show that the circadian clock of cultivated tomato (Solanum lycopersicum) has slowed during domestication. Allelic variation of the tomato homolog of the Arabidopsis gene EID1 is responsible for a phase delay. Notably, the genomic region harboring EID1 shows signatures of a selective sweep. We find that the EID1 allele in cultivated tomatoes enhances plant performance specifically under long day photoperiods, suggesting that humans selected slower circadian rhythms to adapt the cultivated species to the long summer days it encountered as it was moved away from the equator.
Fanjul-Moles, María Luisa; López-Riquelme, Germán Octavio
This work reviews concepts regarding oxidative stress and the mechanisms by which endogenous and exogenous factors produce reactive oxygen species (ROS). It also surveys the relationships between oxidative stress, circadian rhythms, and retinal damage in humans, particularly those related to light and photodamage. In the first section, the production of ROS by different cell organelles and biomolecules and the antioxidant mechanisms that antagonize this damage are reviewed. The second section includes a brief review of circadian clocks and their relationship with the cellular redox state. In the third part of this work, the relationship between retinal damage and ROS is described. The last part of this work focuses on retinal degenerative pathology, age-related macular degeneration, and the relationships between this pathology, ROS, and light. Finally, the possible interactions between the retinal pigment epithelium (RPE), circadian rhythms, and this pathology are discussed. PMID:26885250
This paper describes a modular, extensible, open-systems design for a multiprocessor network which emulates the major functions of the human nervous system. Interchangeable hardware/software components, a socketed software bus with plug-and-play capability and self diagnostics are included. The computer hardware is based on IEEE P996.1 bus cards. Its operating system utilizes IEEE 1275 standard software. Object oriented design techniques and programming are featured. A machine-independent high level script-based command language was created for this project. Neural anatomical structures which were emulated include the cortex, brainstem, cerebellum, spinal cord, autonomic and peripheral nervous systems. Motor, sensory, autoregulatory, and higher cognitive artificial intelligence, behavioral and emotional functions are provided. The author discusses how he has interfaced this emulator to machine vision, speech recognition/speech synthesis, an artificial neural network and a dexterous hand to form an android robotic platform.
Roenneberg, Till; Merrow, Martha
Circadian clocks control the daily life of most light-sensitive organisms- from cyanobacteria to humans. Molecular processes generate cellular rhythmicity, and cellular clocks in animals coordinate rhythms through interaction ( known as coupling). This hierarchy of clocks generates a complex, simila
Beersma, Domien G. M.; Gordijn, Marijke C. M.
It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling
Miller, Jae-Eun Kang; Granados-Fuentes, Daniel; Wang, Thomas; Marpegan, Luciano; Holy, Timothy E; Herzog, Erik D
Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system.
Prosenc Zmrzljak U
Full Text Available Ursula Prosenc ZmrzljakFaculty of Medicine, Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, University of Ljubljana, Ljubljana, SloveniaAbstract: The patterns of activity/sleep, eating/fasting, etc show that our lives are under the control of an internal clock. Cancer is a systemic disease that affects sleep, feeding, and metabolism. All these processes are regulated by the circadian clock on the one hand, but on the other hand, they can serve as signals to tighten up the patient's circadian clock by robust daily routine. Usually, anticancer treatments take place in hospitals, where the patient's daily rest/activity pattern is changed. However, it has been shown that oncology patients with a disturbed circadian clock have poorer survival outcomes. The administration of different anticancer therapies can disturb the circadian cycle, but many cases show that circadian rhythms in tumors are deregulated per se. This fact can be used to plan anticancer therapies in such a manner that they will be most effective in antitumor action, but least toxic for the surrounding healthy tissue. Metabolic processes are highly regulated to prevent waste of energy and to ensure sufficient detoxification; as a consequence, xenobiotic metabolism is under tight circadian control. This gives the rationale for planning the administration of anticancer therapies in a chronomodulated manner. We review some of the potentially useful clinical praxes of anticancer therapies and discuss different possible approaches to be used in drug development and design in the future.Keywords: circadian rhythms, cancer, chronotherapy, detoxification metabolism
Milev, Nikolay B.; Rey, Guillaume; Valekunja, Utham K.; Edgar, Rachel S.; O’Neill, John S.; Reddy, Akhilesh B.
The evolution of tight coupling between the circadian system and redox homeostasis of the cell has been proposed to coincide roughly with the appearance of the first aerobic organisms, around 3 billion years ago. The rhythmic production of oxygen and its effect on core metabolism are thought to have exerted selective pressure for the temporal segregation of numerous metabolic pathways. Until recently, the only evidence for such coupling came from studies showing circadian cycles in the abundance of various redox metabolites, with many arguing that these oscillations are simply an output from the transcription/translation-feedback loop (TTFL). The recent discovery that the peroxiredoxin (PRX) proteins exhibit circadian cycles in their oxidation status, even in the absence of transcription, demonstrated the existence of autonomous oscillations in the redox status of the cell. The PRXs are a family of cellular thiol peroxidases whose abundance and high reaction rate make them the major cellular sink for cellular peroxides. Interestingly, as part of the normal catalytic cycle, PRXs become inactivated by their own substrate via over-oxidation of the catalytic residue, with the inactivated form of the enzyme displaying circadian accumulation. Here, we describe the biochemical properties of the PRX system, with particular emphasis on the features important for the experimental analysis of these enzymes. We will also present a detailed protocol for measuring PRX over-oxidation across circadian time in adherent cell cultures, red blood cells and fruit flies (Drosophila melanogaster), providing practical suggestions for ensuring consistency and reproducibility of the results. PMID:25707278
Ray, Sandipan; Reddy, Akhilesh B
Integration of knowledge concerning circadian rhythms, metabolic networks, and sleep-wake cycles is imperative for unraveling the mysteries of biological cycles and their underlying mechanisms. During the last decade, enormous progress in circadian biology research has provided a plethora of new insights into the molecular architecture of circadian clocks. However, the recent identification of autonomous redox oscillations in cells has expanded our view of the clockwork beyond conventional transcription/translation feedback loop models, which have been dominant since the first circadian period mutants were identified in fruit fly. Consequently, non-transcriptional timekeeping mechanisms have been proposed, and the antioxidant peroxiredoxin proteins have been identified as conserved markers for 24-hour rhythms. Here, we review recent advances in our understanding of interdependencies amongst circadian rhythms, sleep homeostasis, redox cycles, and other cellular metabolic networks. We speculate that systems-level investigations implementing integrated multi-omics approaches could provide novel mechanistic insights into the connectivity between daily cycles and metabolic systems.
Full Text Available This paper describes a system for human body analysis (segmentation, tracking, face/hands localisation, posture recognition from a single view that is fast and completely automatic. The system first extracts low-level data and uses part of the data for high-level interpretation. It can detect and track several persons even if they merge or are completely occluded by another person from the camera's point of view. For the high-level interpretation step, static posture recognition is performed using a belief theory-based classifier. The belief theory is considered here as a new approach for performing posture recognition and classification using imprecise and/or conflicting data. Four different static postures are considered: standing, sitting, squatting, and lying. The aim of this paper is to give a global view and an evaluation of the performances of the entire system and to describe in detail each of its processing steps, whereas our previous publications focused on a single part of the system. The efficiency and the limits of the system have been highlighted on a database of more than fifty video sequences where a dozen different individuals appear. This system allows real-time processing and aims at monitoring elderly people in video surveillance applications or at the mixing of real and virtual worlds in ambient intelligence systems.
Full Text Available Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.
Salgado-Delgado, Roberto; Tapia Osorio, Araceli; Saderi, Nadia; Escobar, Carolina
Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication) indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.
Eelderink-Chen, Zheng; Mazzotta, Gabriella; Sturre, Marcel; Bosman, Jasper; Roenneberg, Till; Merrow, Martha
Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily
Hong, Christian I.; Zámborszky, Judit; Baek, Mokryun; Labiscsak, Laszlo; Ju, Kyungsu; Lee, Hyeyeong; Luis F. Larrondo; Goity, Alejandra; Chong, Hin Siong; Belden, William J.; Csikász-Nagy, Attila
Circadian rhythms provide temporal information to other cellular processes, such as metabolism. We investigate the coupling between the cell cycle and the circadian clock using mathematical modeling and experimentally validate model-driven predictions with a model filamentous fungus, Neurospora crassa. We demonstrate a conserved coupling mechanism between the cell cycle and the circadian clock in Neurospora as in mammals, which results in circadian clock-gated mitotic cycles. Furthermore, we ...
Lee, Boyoung; Li, Aiqing; Hansen, Katelin F; Cao, Ruifeng; Yoon, Jae Hwa; Obrietan, Karl
The transcriptional feedback circuit, which is at the core of the suprachiasmatic nucleus (SCN) circadian (i.e., 24 h) clock, is tightly coupled to both external entrainment cues, such as light, as well as rhythmic cues that arise on a system-wide level within the SCN. One potential signaling pathway by which these cues are conveyed to the molecular clock is the CREB/CRE transcriptional cascade. In this study, we employed a tetracycline-inducible CREB repressor mouse strain, in which approximately 60% of the SCN neurons express the transgene, to test CREB functionality in the clock and its effects on overt rhythmicity. We show that attenuated CREB signaling in the SCN led to a significant reduction in light-evoked clock entrainment. An examination of circadian timing revealed that CREB repressor mice exhibited normal free-running rhythms in the absence of external lighting cues. However, under conditions of constant light, which typically leads to a lengthening of the circadian period, CREB repressor mice exhibited a dramatic arrhythmic phenotype, which could be reversed with doxycycline. At a cellular level, the repression of CREB led to a significant reduction in both the expression of the circadian clock proteins PERIOD1 and PERIOD2 and the clock output hormones AVP and VIP. Together, these data support the idea that the CRE transcriptional pathway orchestrates transcriptional events that are essential for both the maintenance of SCN timing and light entrainment of the circadian clock.
Bodenstein, C.; Heiland, I.; Schuster, S.
Many biological species possess a circadian clock, which helps them anticipate daily variations in the environment. In the absence of external stimuli, the rhythm persists autonomously with a period of approximately 24 h. However, single pulses of light, nutrients, chemicals or temperature can shift the clock phase. In the case of light- and temperature-cycles, this allows entrainment of the clock to cycles of exactly 24 h. Circadian clocks have the remarkable property of temperature compensation, that is, the period of the circadian rhythm remains relatively constant within a physiological range of temperatures. For several organisms, temperature-regulated processes within the circadian clock have been identified in recent years. However, how these processes contribute to temperature compensation is not fully understood. Here, we theoretically investigate temperature compensation in general oscillatory systems. It is known that every oscillator can be locally temperature compensated around a reference temperature, if reactions are appropriately balanced. A balancing is always possible if the control coefficient with respect to the oscillation period of at least one reaction in the oscillator network is positive. However, for global temperature compensation, the whole physiological temperature range is relevant. Here, we use an approach which leads to an optimization problem subject to the local balancing principle. We use this approach to analyse different circadian clock models proposed in the literature and calculate activation energies that lead to temperature compensation.
Wang, Qingqing; Ao, Yiran; Yang, Kai; Tang, Hong; Chen, Dan
Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (Pcycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.
Graf, Alexander; Coman, Diana; Walsh, Sean; Flis, Anna; Stitt, Mark; Gruissem, Wilhelm
The circadian clock regulates physiological processes central to growth and survival. To date, most plant circadian clock studies have relied on diurnal transcriptome changes to elucidate molecular connections between the circadian clock and observable phenotypes in wild-type plants. Here, we have integrated RNA-sequencing and protein mass spectrometry data to comparatively analyse the lhycca1, prr7prr9, gi and toc1 circadian clock mutant rosette at the end of day and end of night. Each mutant affects specific sets of genes and proteins, suggesting that the circadian clock regulation is modular. Furthermore, each circadian clock mutant maintains its own dynamically fluctuating transcriptome and proteome profile specific to subcellular compartments. Most of the measured protein levels do not correlate with changes in their corresponding transcripts. Transcripts and proteins that have coordinated changes in abundance are enriched for carbohydrate- and cold-responsive genes. Transcriptome changes in all four circadian clock mutants also affect genes encoding starch degradation enzymes, transcription factors and protein kinases. The comprehensive transcriptome and proteome datasets demonstrate that future system-driven research of the circadian clock requires multi-level experimental approaches. Our work also shows that further work is needed to elucidate the roles of post-translational modifications and protein degradation in the regulation of clock-related processes. PMID:28250106
Graf, Alexander; Coman, Diana; Uhrig, R Glen; Walsh, Sean; Flis, Anna; Stitt, Mark; Gruissem, Wilhelm
The circadian clock regulates physiological processes central to growth and survival. To date, most plant circadian clock studies have relied on diurnal transcriptome changes to elucidate molecular connections between the circadian clock and observable phenotypes in wild-type plants. Here, we have integrated RNA-sequencing and protein mass spectrometry data to comparatively analyse the lhycca1, prr7prr9, gi and toc1 circadian clock mutant rosette at the end of day and end of night. Each mutant affects specific sets of genes and proteins, suggesting that the circadian clock regulation is modular. Furthermore, each circadian clock mutant maintains its own dynamically fluctuating transcriptome and proteome profile specific to subcellular compartments. Most of the measured protein levels do not correlate with changes in their corresponding transcripts. Transcripts and proteins that have coordinated changes in abundance are enriched for carbohydrate- and cold-responsive genes. Transcriptome changes in all four circadian clock mutants also affect genes encoding starch degradation enzymes, transcription factors and protein kinases. The comprehensive transcriptome and proteome datasets demonstrate that future system-driven research of the circadian clock requires multi-level experimental approaches. Our work also shows that further work is needed to elucidate the roles of post-translational modifications and protein degradation in the regulation of clock-related processes. © 2017 The Authors.
Paulose, Jiffin K; Cassone, Vincent M
Circadian clocks are fundamental properties of all eukaryotic organisms and at least some prokaryotic organisms. Recent studies in our laboratory have shown that the gastrointestinal system contains a circadian clock that controls many, if not all, aspects of gastrointestinal function. We now report that at least one species of intestinal bacteria, Enterobacter aerogenes, responds to the pineal and gastrointestinal hormone melatonin by an increase in swarming activity. This swarming behavior is expressed rhythmically, with a period of approximately 24 hrs. Transformation of E. aerogenes to express luciferase with a MotA promoter reveals circadian patterns of bioluminescence that are synchronized by melatonin and whose periods are temperature compensated from 26°C to 40°C. Bioinformatics suggest similarities between the E. aerogenes and cyanobacterial clocks, suggesting the circadian clock may have evolved very early in the evolution of life. They also point to a coordination of host circadian clocks with those residing in the microbiota themselves.
Shibuya, Katsuhiko; Funaki, Yoshihito; Hiraoka, Kotaro; Yoshikawa, Takeo; Naganuma, Fumito; Miyake, Masayasu; Watanuki, Shoichi; Sato, Hirotoshi; Tashiro, Manabu; Yanai, Kazuhiko
Molecular imaging in neuroscience is a new research field that enables visualization of the impact of molecular events on brain structure and function in humans. While magnetic resonance-based imaging techniques can provide complex information at the level of system, positron emission tomography (PET) enables determination of the distribution and density of receptor and enzyme in the human brain. Previous studies using [11C]raclopride and [11C]FLB457 revealed that the release of neuronal dopamine was increased in human brain by psychostimulants or reward stimuli. Following on from these previous [11C]raclopride studies, we examined whether the levels of neuronal release of histamine might change [11C]doxepin binding to the H1 receptors under the influence of physiological stimuli. The purpose of the present study was to evaluate the test–retest reliability of quantitative measurement of [11C]doxepin binding between morning and afternoon and between resting and attentive waking conditions in healthy human subjects. There was a trend for a decrease in [11C]doxepin binding during attentive calculation tasks compared with that in resting conditions, but the difference (less than 10%) was not significant. Similarly, the binding potential of [11C]doxepin in the cerebral cortex was slightly higher in the morning than that in the afternoon, but it was also insignificant. These data suggest that higher histamine release during wakefulness could not decrease the [11C]doxepin binding in the brain. This study confirmed the reproducibility and reliability of [11C]doxepin in the previous imaging studies to measure the H1 receptor. PMID:22701403
Patricia V. Agostino
Full Text Available Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range and the circadian clock. The molecular basis of these two mechanisms is the subject of intense research, as well as their possible relationship. This article summarizes data from studies investigating a possible interaction between interval and circadian timing and reviews the molecular basis of both mechanisms, including the discussion of the contribution from studies of genetically modified animal models. While a common neurochemical substrate for timing mechanisms in the brain has been related to dopamine-reward systems, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes.
Mészáros, Krisztina; Pruess, Linda; Szabó, Attila J.
The circadian molecular clock is an internal time-keeping system composed of centrally synchronized tissue-level pacemakers. Here, we explored the ontogeny of the clock machinery in the developing kidney. Pregnant rats were housed at 12-12 h light-dark cycles. Offsprings were killed at 4-h...... was modified postpartum. Clock, Rev-erbα, Per2, αENaC, SGK1, NHE3, and AVPR2 showed circadian expression at the end of intrauterine development. By 1 week, all genes oscillated with a distinct acrophase shift toward the time of peak feeding activity. Daily 4-hour withdrawal of mothers induced a 12-hour phase...... shift of Clock and Bmal1 expression, while disrupting oscillations of the other genes. After weaning, oscillation phases shifted back toward the adult pattern, which was fully expressed at 12 weeks. Thus, functional circadian molecular clockwork evolves in the late fetal and early postnatal kidney...
Enciso, R; Ramos, M A; Badui, E; Hurtado, R
In order to determine if the beginning of the Myocardial Infarction (MI) is at random along the day or if it follows a circadian rhythm, we analyzed the clinical charts of 819 patients admitted to the Coronary Care Unite. Among them, 645 were male and 174 female. It was established that the beginning of the MI follows a circadian rhythm with maximal frequency between 8 and 9 a.m. and minimal at 0 hours (p greater than 0.01). This rhythm is sex independent. In patients younger than 45 years as well as those who received beta-block agents in less than 24 hours previous the MI no circadian rhythm was observed.
Cohen, Susan E.; Erb, Marcella L.; Pogliano, Joe; Golden, Susan S.
Summary This chapter deals with methods of monitoring the subcellular localization of proteins in single cells in the circadian model system Synechococcus elongatus PCC 7942. While genetic, biochemical and structural insights into the cyanobacterial circadian oscillator have flourished, difficulties in achieving informative subcellular imaging in cyanobacterial cells have delayed progress of the cell biology aspects of the clock. Here, we describe best practices for using fluorescent protein tags to monitor localization. Specifically we address how to vet fusion proteins and overcome challenges in microscopic imaging of very small autofluorescent cells. PMID:25662459
Rath, Martin Fredensborg; Rohde, Kristian; Fahrenkrug, Jan
The circadian master clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the clock of the SCN is driven by a transcriptional/posttranslational autoregulatory network with clock gene products as core elements. Recent investigations...... have shown the presence of peripheral clocks in extra-hypothalamic areas of the central nervous system. However, knowledge on the clock gene network in the cerebral cortex is limited. We here show that the mammalian clock genes Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Nr1d1 and Dbp are expressed...
Full Text Available BACKGROUND: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh, an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long circadian rhythm of approximately 27 hours. METHODOLOGY: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. PRINCIPAL FINDINGS: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009. CONCLUSIONS: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.
Laura M Beaver
Full Text Available Circadian clocks generate daily rhythms in neuronal, physiological, and metabolic functions. Previous studies in mammals reported daily fluctuations in levels of the major endogenous antioxidant, glutathione (GSH, but the molecular mechanisms that govern such fluctuations remained unknown. To address this question, we used the model species Drosophila, which has a rich arsenal of genetic tools. Previously, we showed that loss of the circadian clock increased oxidative damage and caused neurodegenerative changes in the brain, while enhanced GSH production in neuronal tissue conferred beneficial effects on fly survivorship under normal and stress conditions. In the current study we report that the GSH concentrations in fly heads fluctuate in a circadian clock-dependent manner. We further demonstrate a rhythm in activity of glutamate cysteine ligase (GCL, the rate-limiting enzyme in glutathione biosynthesis. Significant rhythms were also observed for mRNA levels of genes encoding the catalytic (Gclc and modulatory (Gclm subunits comprising the GCL holoenzyme. Furthermore, we found that the expression of a glutathione S-transferase, GstD1, which utilizes GSH in cellular detoxification, significantly fluctuated during the circadian day. To directly address the role of the clock in regulating GSH-related rhythms, the expression levels of the GCL subunits and GstD1, as well as GCL activity and GSH production were evaluated in flies with a null mutation in the clock genes cycle and period. The rhythms observed in control flies were not evident in the clock mutants, thus linking glutathione production and utilization to the circadian system. Together, these data suggest that the circadian system modulates pathways involved in production and utilization of glutathione.
It is increasingly recognized that obesity is an important health problem. The mechanisms that underlie obesity have not been fully elucidated, and effective therapeutic approaches are currently of general interest. Recent studies have provided evidence that circadian clock is a crucial factor in the development of obesity and related metabolic disease. Genetic disruption of clock genes in mice displayed metabolic dysfunctions of specific tissues at distinct phases of the sleep/wake cycle. In addition, circadian desynchrony, a characteristic of shift work and short sleep, are associated with obesity in human. Here, I describe the advances in understanding the interrelationship among circadian disruption, sleep deprivation and obesity.
Lynn James R
Full Text Available Abstract Background The circadian system drives pervasive biological rhythms in plants. Circadian clocks integrate endogenous timing information with environmental signals, in order to match rhythmic outputs to the local day/night cycle. Multiple signaling pathways affect the circadian system, in ways that are likely to be adaptively significant. Our previous studies of natural genetic variation in Arabidopsis thaliana accessions implicated FLOWERING LOCUS C (FLC as a circadian-clock regulator. The MADS-box transcription factor FLC is best known as a regulator of flowering time. Its activity is regulated by many regulatory genes in the "autonomous" and vernalization-dependent flowering pathways. We tested whether these same pathways affect the circadian system. Results Genes in the autonomous flowering pathway, including FLC, were found to regulate circadian period in Arabidopsis. The mechanisms involved are similar, but not identical, to the control of flowering time. By mutant analyses, we demonstrate a graded effect of FLC expression upon circadian period. Related MADS-box genes had less effect on clock function. We also reveal an unexpected vernalization-dependent alteration of periodicity. Conclusion This study has aided in the understanding of FLC's role in the clock, as it reveals that the network affecting circadian timing is partially overlapping with the floral-regulatory network. We also show a link between vernalization and circadian period. This finding may be of ecological relevance for developmental programing in other plant species.
Hoban-Higgins, Tana M.
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
Duffy, J. F.; Dijk, D. J.; Klerman, E. B.; Czeisler, C. A.
The contribution of the circadian timing system to the age-related advance of sleep-wake timing was investigated in two experiments. In a constant routine protocol, we found that the average wake time and endogenous circadian phase of 44 older subjects were earlier than that of 101 young men. However, the earlier circadian phase of the older subjects actually occurred later relative to their habitual wake time than it did in young men. These results indicate that an age-related advance of circadian phase cannot fully account for the high prevalence of early morning awakening in healthy older people. In a second study, 13 older subjects and 10 young men were scheduled to a 28-h day, such that they were scheduled to sleep at many circadian phases. Self-reported awakening from scheduled sleep episodes and cognitive throughput during the second half of the wake episode varied markedly as a function of circadian phase in both groups. The rising phase of both rhythms was advanced in the older subjects, suggesting an age-related change in the circadian regulation of sleep-wake propensity. We hypothesize that under entrained conditions, these age-related changes in the relationship between circadian phase and wake time are likely associated with self-selected light exposure at an earlier circadian phase. This earlier exposure to light could account for the earlier clock hour to which the endogenous circadian pacemaker is entrained in older people and thereby further increase their propensity to awaken at an even earlier time.
Merrow, Martha; Roenneberg, Till
Models of biological systems are increasingly used to generate and test predictions in silico. This article explores the basic workings of a multifeedback network model of a circadian clock. In a series of in silico experiments, we investigated the influence of the number of feedbacks by adding and
Hofman, M.A.; Swaab, D.F.
The suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be a critical component of a neural oscillator system implicated in the timing of a wide variety of biological processes. The circadian cycles established by this biological clock occur throughout nature and have a period of appr
Kilduff, Thomas S.; Lein, Ed S; de la Iglesia, Horacio; Sakurai, Takeshi; Fu, Ying-Hui; Shaw, Paul
Understanding the mechanisms that underlie the control of sleep and wakefulness is a major research area in neuroscience. This mini-symposium review highlights some recent developments at the gene, molecular, cellular, and systems level that have advanced this field. The studies discussed below utilize organisms ranging from flies to humans and focus on the interaction between the sleep homeostatic and circadian systems, the consequences of mutations in genes involved in the circadian clock o...
Butler, Matthew P; Paul, Matthew J; Turner, Kevin W; Park, Jin Ho; Driscoll, Joseph R; Kriegsfeld, Lance J; Zucker, Irving
Short day lengths increase the duration of nocturnal melatonin (Mel) secretion, which induces the winter phenotype in Siberian hamsters. After several months of continued exposure to short days, hamsters spontaneously revert to the spring-summer phenotype. This transition has been attributed to the development of refractoriness of Mel-binding tissues, including the suprachiasmatic nucleus (SCN), to long-duration Mel signals. The SCN of Siberian hamsters is required for the seasonal response to winter-like Mel signals, and becomes refractory to previously effective long-duration Mel signals restricted to this area. Acute Mel treatment phase shifts circadian locomotor rhythms of photosensitive Siberian hamsters, presumably by affecting circadian oscillators in the SCN. We tested whether seasonal refractoriness of the SCN to long-duration Mel signals also renders the circadian system of Siberian hamsters unresponsive to Mel. Males manifesting free-running circadian rhythms in constant dim red light were injected with Mel or vehicle for 5 days on a 23.5-h T-cycle beginning at circadian time 10. Mel injections caused significantly larger phase advances in activity onset than did the saline vehicle, but the magnitude of phase shifts to Mel did not differ between photorefractory and photosensitive hamsters. Similarly, when entrained to a 16-h light/8-h dark photocycle, photorefractory and photosensitive hamsters did not differ in their response to Mel injected 4 h before the onset of the dark phase. Activity onset in Mel-injected hamsters was masked by light but was revealed to be significantly earlier than in vehicle-injected hamsters upon transfer to constant dim red light. The acute effects of melatonin on circadian behavioral rhythms are preserved in photorefractory hamsters.
Causton, Helen C; Feeney, Kevin A; Ziegler, Christine A; O'Neill, John S
Cell-autonomous circadian rhythms allow organisms to temporally orchestrate their internal state to anticipate and/or resonate with the external environment. Although ∼24-hr periodicity is observed across aerobic eukaryotes, the central mechanism has been hard to dissect because few simple models exist, and known clock proteins are not conserved across phylogenetic kingdoms. In contrast, contributions to circadian rhythmicity made by a handful of post-translational mechanisms, such as phosphorylation of clock proteins by casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), appear conserved among phyla. These kinases have many other essential cellular functions and are better conserved in their contribution to timekeeping than any of the clock proteins they phosphorylate. Rhythmic oscillations in cellular redox state are another universal feature of circadian timekeeping, e.g., over-oxidation cycles of abundant peroxiredoxin proteins. Here, we use comparative chronobiology to distinguish fundamental clock mechanisms from species and/or tissue-specific adaptations and thereby identify features shared between circadian rhythms in mammalian cells and non-circadian temperature-compensated respiratory oscillations in budding yeast. We find that both types of oscillations are coupled with the cell division cycle, exhibit period determination by CK1 and GSK3, and have peroxiredoxin over-oxidation cycles. We also explore how peroxiredoxins contribute to YROs. Our data point to common mechanisms underlying both YROs and circadian rhythms and suggest two interpretations: either certain biochemical systems are simply permissive for cellular oscillations (with frequencies from hours to days) or this commonality arose via divergence from an ancestral cellular clock.
Pechacek, C.S.; Andersen, M. [Massachusetts Inst. of Technology, Cambridge, MA (United States). Dept. of Architecture, Building Technology; Lockley, S.W. [Harvard Medical School, Boston, MA (United States). Div. of Sleep Medicine, Brigham and Women' s Hospital
This paper addressed the issue of hospital design and the role of daylight in patient health care. It presented a new approach for integrating empirical data and findings in photobiology into the performance assessment of a space, thus combining both visual and health-related criteria. Previous studies have reported significant health care outcomes in daylit environments, although the mechanism and photoreceptor systems controlling these effects remain unknown. This study focused on furthering the previous studies beyond windows to describing the characteristics of daylight that may promote human health by providing daylighting for the appropriate synchronization of circadian rhythms, and then make specific daylighting recommendations, grounded in biological findings. In particular, this study investigated the use of daylight autonomy (DA) to simulate the probabilistic and temporal potential of daylight for human health needs. Results of photobiology research were used to define threshold values for lighting, which were then used as goals for simulations. These goals included spectrum, intensity and timing of light at the human eye. The study investigated the variability of key architectural decisions in hospital room design to determine their influence on achieving the goals. The simulations showed how choices in building orientation, window size, user-window position and interior finishes affect the circadian efficacy of a space. Design decisions can improve or degrade the health potential for the space considered. While the findings in this research were specific to hospitals, the results can be applied to other building types such as office buildings and residences. 33 refs., 7 figs.
Alexiou, Athanasios; Rekkas, John
In this chapter we present Excess Entropy Production for human aging system as the sum of their respective subsystems and electrophysiological status. Additionally, we support the hypothesis of human brain and central neural system quantumness and we strongly suggest the theoretical and philosophical status of human brain as one of the unknown natural Dirac magnetic monopoles placed in the center of a Riemann sphere.
Wynchank, Dora S.; Bijlenga, Denise; Lamers, Femke; Bron, Tannetje I.; Winthorst, Wim H.; Vogel, Suzan W.; Penninx, Brenda W.; Beekman, Aartjan T.; Kooij, J. Sandra
Objective: We evaluated whether the association between Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Seasonal Affective Disorder (SAD) was mediated by the circadian rhythm. Method: Data of 2239 persons from the Netherlands Study of Depression and Anxiety (NESDA) were used. Two groups we
Wynchank, Dora S.; Bijlenga, Denise; Lamers, Femke; Bron, Tannetje I.; Winthorst, Wim H.; Vogel, Suzan W.; Penninx, Brenda W.; Beekman, Aartjan T.; Kooij, J. Sandra
Objective: We evaluated whether the association between Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Seasonal Affective Disorder (SAD) was mediated by the circadian rhythm. Method: Data of 2239 persons from the Netherlands Study of Depression and Anxiety (NESDA) were used. Two groups we
Wynchank, Dora S.; Bijlenga, Denise; Lamers, Femke; Bron, Tannetje I.; Winthorst, Wim H.; Vogel, Suzan W.; Penninx, Brenda W.; Beekman, Aartjan T.; Kooij, J. Sandra
Objective: We evaluated whether the association between Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Seasonal Affective Disorder (SAD) was mediated by the circadian rhythm. Method: Data of 2239 persons from the Netherlands Study of Depression and Anxiety (NESDA) were used. Two groups
Skene, DJ; Deacon, S; Arendt, J.
Following abrupt phase shifts (real or simulated time zone changes, night shift work) there is desynchronisation between the internal circadian rhythms (including melatonin) and the external environment with consequent disturbances in sleep, mood and performance. In humans the pineal hormone melatonin has phase-shifting and resynchronising properties with regard to a number of circadian rhythms. Suitably timed melatonin adrninstration hastened adaptation to phase shift and significantly impro...
Colleen A. McClung
Full Text Available Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.
Full Text Available Graham R McGinnis, Martin E Young Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Abstract: 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. Keywords: circadian rhythm, circadian clocks, metabolic homeostasis, neurohumoral factors, dyssynchrony, time-of-day-dependent rhythms
Wilson, John R
Ergonomics/human factors is, above anything else, a systems discipline and profession, applying a systems philosophy and systems approaches. Many things are labelled as system in today's world, and this paper specifies just what attributes and notions define ergonomics/human factors in systems terms. These are obviously a systems focus, but also concern for context, acknowledgement of interactions and complexity, a holistic approach, recognition of emergence and embedding of the professional effort involved within organization system. These six notions are illustrated with examples from a large body of work on rail human factors.
Mezan, Shaul; Feuz, Jean Daniel; Deplancke, Bart; Kadener, Sebastian
Circadian clocks generate 24-hr rhythms in physiology and behavior. Despite numerous studies, it is still uncertain how circadian rhythms emerge from their molecular and neural constituents. Here, we demonstrate a tight connection between the molecular and neuronal circadian networks. Using fluorescent transcriptional reporters in a Drosophila ex vivo brain culture system, we identified a reciprocal negative regulation between the master circadian regulator CLK and expression of pdf, the main circadian neuropeptide. We show that PDF feedback is required for maintaining normal oscillation pattern in CLK-driven transcription. Interestingly, we found that CLK and neuronal firing suppresses pdf transcription, likely through a common pathway involving the transcription factors DHR38 and SR, establishing a direct link between electric activity and the circadian system. In sum, our work provides evidence for the existence of an uncharacterized CLK-PDF feedback loop that tightly wraps together the molecular oscillator with the circadian neuronal network in Drosophila. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
Wong, Douglas T.
This paper summarizes the past and present successes of the Habitability and Human Factors Branch (HHFB) at NASA Johnson Space Center s Space Life Sciences Directorate (SLSD) in including the Human-As-A-System (HAAS) model in many NASA programs and what steps to be taken to integrate the Human-Centered Design Philosophy (HCDP) into NASA s Systems Engineering (SE) process. The HAAS model stresses systems are ultimately designed for the humans; the humans should therefore be considered as a system within the systems. Therefore, the model places strong emphasis on human factors engineering. Since 1987, the HHFB has been engaging with many major NASA programs with much success. The HHFB helped create the NASA Standard 3000 (a human factors engineering practice guide) and the Human Systems Integration Requirements document. These efforts resulted in the HAAS model being included in many NASA programs. As an example, the HAAS model has been successfully introduced into the programmatic and systems engineering structures of the International Space Station Program (ISSP). Success in the ISSP caused other NASA programs to recognize the importance of the HAAS concept. Also due to this success, the HHFB helped update NASA s Systems Engineering Handbook in December 2007 to include HAAS as a recommended practice. Nonetheless, the HAAS model has yet to become an integral part of the NASA SE process. Besides continuing in integrating HAAS into current and future NASA programs, the HHFB will investigate incorporating the Human-Centered Design Philosophy (HCDP) into the NASA SE Handbook. The HCDP goes further than the HAAS model by emphasizing a holistic and iterative human-centered systems design concept.
Samar Hayat Khan Tareen
Full Text Available Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.
Tareen, Samar Hayat Khan; Ahmad, Jamil
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.
@@ In the recent editorial comment, Duboule1 emphasized that "animal development is, in fact, nothing but time".That a circadian timing system is apparently universal in biology is the evidence for the important physiological role that rhythmicity plays.
John C Means
Full Text Available While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in
Flávia Cal Sabino
Full Text Available The PER3 gene is one of the clock genes, which function in the core mammalian molecular circadian system. A variable number of tandem repeats (VNTR locus in the 18th exon of this gene has been strongly associated to circadian rhythm phenotypes and sleep organization in humans, but it has not been identified in other mammals except primates. To better understand the evolution and the placement of the PER3 VNTR in a phylogenetical context, the present study enlarges the investigation about the presence and the structure of this variable region in a large sample of primate species and other mammals. The analysis of the results has revealed that the PER3 VNTR occurs exclusively in simiiforme primates and that the number of copies of the primitive unit ranges from 2 to 11 across different primate species. Two transposable elements surrounding the 18th exon of PER3 were found in primates with published genome sequences, including the tarsiiforme Tarsius syrichta, which lacks the VNTR. These results suggest that this VNTR may have evolved in a common ancestor of the simiiforme branch and that the evolutionary copy number differentiation of this VNTR may be associated with primate simiiformes sleep and circadian phenotype patterns.
Bravo Santos, R; Delgado, J; Cubero, J; Franco, L; Ruiz-Moyano, S; Mesa, M; Rodríguez, A B; Uguz, C; Barriga, C
The objective of the present study was to compare differences between elderly rats and young obesity-induced rats in their activity/inactivity circadian rhythm. The investigation was motivated by the differences reported previously for the circadian rhythms of both obese and elderly humans (and other animals), and those of healthy, young or mature individuals. Three groups of rats were formed: a young control group which was fed a standard chow for rodents; a young obesity-induced group which was fed a high-fat diet for four months; and an elderly control group with rats aged 2.5 years that was fed a standard chow for rodents. Activity/inactivity data were registered through actimetry using infrared actimeter systems in each cage to detect activity. Data were logged on a computer and chronobiological analysis were performed. The results showed diurnal activity (sleep time), nocturnal activity (awake time), amplitude, acrophase, and interdaily stability to be similar between the young obesity-induced group and the elderly control group, but different in the young control group. We have concluded that obesity leads to a chronodisruption status in the body similar to the circadian rhythm degradation observed in the elderly.
Hut, Roelof A; Oklejewicz, Malgorzata; Rieux, Camille; Cooper, Howard M
Mammalian retinal photoreceptors form an irradiance detection system that drives many nonvisual responses to light such as pupil reflex and resetting of the circadian clock. To understand the role of pupil size in circadian light responses, pupil diameter was pharmacologically manipulated and the effect on behavioral phase shifts at different irradiance levels was studied in the Syrian hamster. Dose-response curves for steady-state pupil size and for behavioral phase shifts were constructed for 3 pupil conditions (dilated, constricted, and control). Retinal irradiance was calculated from corneal irradiance, pupil size, retinal surface area, and absorption of ocular media. The sensitivity of photic responses to retinal irradiance is approximately 1.5 log units higher than to corneal irradiance. When plotted against corneal irradiance, pharmacological pupil constriction reduces the light sensitivity of the circadian system, but pupil dilation has no effect. As expected, when plotted against retinal irradiance all dose-response curves superimposed, confirming that the circadian system responds to photon flux on the retina. Pupil dilation does not increase the circadian response to increasing irradiance, since the response of the circadian system attains saturation at irradiance levels lower than those required to induce pupil constriction. The main finding shows that due to the different response sensitivities, the effect of pupil constriction on the light sensitivity of the circadian system in the hamster under natural conditions is virtually negligible. We further suggest the existence of distinct modulating mechanisms for the differential retinal irradiance sensitivity of the pupil system and the circadian system, which enables the different responses to be tuned to their specific tasks while using similar photoreceptive input.
Full Text Available Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction--TSR. We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects
Hussain, M. Mahmood; Pan, Xiaoyue
Among all the metabolites present in the plasma, lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in lipid absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circa...
Full Text Available Several topics in projects for mechatronics studies, which are 'Human Adaptive Mechatronics (HAM' and 'Human-System Modelling (HSM', are presented in this paper. The main research theme of the HAM project is a design strategy for a new intelligent mechatronics system, which enhances operators' skills during machine operation. Skill analyses and control system design have been addressed. In the HSM project, human modelling based on hierarchical classification of skills was studied, including the following five types of skills: social, planning, cognitive, motion and sensory-motor skills. This paper includes digests of these research topics and the outcomes concerning each type of skill. Relationships with other research activities, knowledge and information that will be helpful for readers who are trying to study assistive human-mechatronics systems are also mentioned.
Grone, Brian P; Chang, Doris; Bourgin, Patrice; Cao, Vinh; Fernald, Russell D; Heller, H Craig; Ruby, Norman F
Light can induce arrhythmia in circadian systems by several weeks of constant light or by a brief light stimulus given at the transition point of the phase response curve. In the present study, a novel light treatment consisting of phase advance and phase delay photic stimuli given on 2 successive nights was used to induce circadian arrhythmia in the Siberian hamster ( Phodopus sungorus). We therefore investigated whether loss of rhythms in behavior was due to arrhythmia within the suprachiasmatic nucleus (SCN). SCN tissue samples were obtained at 6 time points across 24 h in constant darkness from entrained and arrhythmic hamsters, and per1, per2 , bmal1, and cry1 mRNA were measured by quantitative RT-PCR. The light treatment eliminated circadian expression of clock genes within the SCN, and the overall expression of these genes was reduced by 18% to 40% of entrained values. Arrhythmia in per1, per2, and bmal1 was due to reductions in the amplitudes of their oscillations. We suggest that these data are compatible with an amplitude suppression model in which light induces singularity in the molecular circadian pacemaker.
Naylor, E; Bergmann, B M; Krauski, K; Zee, P C; Takahashi, J S; Vitaterna, M H; Turek, F W
The onset and duration of sleep are thought to be primarily under the control of a homeostatic mechanism affected by previous periods of wake and sleep and a circadian timing mechanism that partitions wake and sleep into different portions of the day and night. The mouse Clock mutation induces pronounced changes in overall circadian organization. We sought to determine whether this genetic disruption of circadian timing would affect sleep homeostasis. The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12. In particular, in LD 12:12, heterozygous and homozygous Clock mutants slept, respectively, approximately 1 and approximately 2 hr less than wild-type mice, and they had 25 and 51% smaller increases in rapid eye movement (REM) sleep during 24 hr recovery, respectively, than wild-type mice. The effects of the mutation on sleep are not readily attributable to differential entrainment to LD 12:12 because the baseline sleep differences between genotypes were also present when animals were free-running in DD. These results indicate that genetic alterations of the circadian clock system and/or its regulatory genes are likely to have widespread effects on a variety of sleep and wake parameters, including the homeostatic regulation of sleep.
María Paz Fernández
Full Text Available Clock output pathways are central to convey timing information from the circadian clock to a diversity of physiological systems, ranging from cell-autonomous processes to behavior. While the molecular mechanisms that generate and sustain rhythmicity at the cellular level are well understood, it is unclear how this information is further structured to control specific behavioral outputs. Rhythmic release of pigment dispersing factor (PDF has been proposed to propagate the time of day information from core pacemaker cells to downstream targets underlying rhythmic locomotor activity. Indeed, such circadian changes in PDF intensity represent the only known mechanism through which the PDF circuit could communicate with its output. Here we describe a novel circadian phenomenon involving extensive remodeling in the axonal terminals of the PDF circuit, which display higher complexity during the day and significantly lower complexity at nighttime, both under daily cycles and constant conditions. In support to its circadian nature, cycling is lost in bona fide clockless mutants. We propose this clock-controlled structural plasticity as a candidate mechanism contributing to the transmission of the information downstream of pacemaker cells.
Glaser, F T; Stanewsky, R
The natural light/dark and temperature cycles are considered to be the most prominent factors that synchronize circadian clocks with the environment. Understanding the principles of temperature entrainment significantly lags behind our current knowledge of light entrainment in any organism subject to circadian research. Nevertheless, several effects of temperature on circadian clocks are well understood, and similarities as well as differences to the light-entrainment pathways start to emerge. This chapter provides an overview of the temperature effects on the Drosophila circadian clock with special emphasis on synchronization by temperature cycles. As in other organisms, such temperature cycles can serve as powerful time cues to synchronize the clock. Mutants that specifically interfere with aspects of temperature entrainment have been isolated and will likely help to reveal the underlying mechanisms. These mechanisms involve transcriptional and posttranscriptional regulation of clock genes. For synchronization of fly behavior by temperature cycles, the generation of a whole organism or systemic signal seems to be required, even though individual fly tissues can be synchronized under isolated culture conditions. If true, the requirement for such a signal would reveal a fundamental difference to the light-entrainment mechanism.
Circadian rhythms are acquired through evolution to increase the chances for survival by synchronizing to the daylight cycle. Reliable synchronization is realized through two trade-off properties: regularity to keep time precisely, and entrainability to synchronize the internal time with daylight. Since both properties have been tuned through natural selection, their adaptation can be formalized in the framework of mathematical optimization. By using a succinct model, we found that simultaneous optimization of regularity and entrainability entails inherent features of the circadian mechanism irrespective of model details. At the behavioral level we discovered the existence of a dead zone, a time during which light pulses neither advance nor delay the clock. At the molecular level we demonstrate the role-sharing of two light inputs, phase advance and delay, as is well observed in mammals. We also reproduce the results of phase-controlling experiments and predict molecular elements responsible for the clockwork...
Zhu, Yong; Fu, Alan; Hoffman, Aaron E; Figueiro, Mariana G; Carskadon, Mary A; Sharkey, Katherine M; Rea, Mark S
Human circadian rhythms are regulated by the interplay between circadian genes and environmental stimuli. The influence of altered sleep-wake schedules or light on human circadian gene expression patterns is not well characterized. Twenty-one young adults were asked to keep to their usual sleep schedules and two blood samples were drawn at the end of the first week from each subject based on estimated time of dim light melatonin onset (DLMO); the first sample was obtained one and a half hours before the estimated DLMO and the second three hours later, at one and a half hours after the estimated DLMO. During the second week, participants were randomized into two groups, one that received a one hour blue-light (λmax=470 nm) exposure in the morning and one that received a comparable morning dim-light exposure. Two blood samples were obtained at the same clock times as the previous week at the end of the second week. We measured the expression of 10 circadian genes in response to sleep-wake schedule advancement and morning blue-light stimulation in the peripheral blood of 21 participants during a two-week field study. We found that nine of the 10 circadian genes showed significant expression changes from the first to the second week for participants in both the blue-light and dim-light groups, likely reflecting significant advances in circadian phase. This wholesale change in circadian gene expression may reflect considerable advances in circadian phase (i.e., advance in DLMO) from the first to the second week resulting from the advanced, daily personal light exposures. Copyright © 2013 Elsevier B.V. All rights reserved.
Fong, Terrence; Kunz, Clayton; Hiatt, Laura M.; Bugajska, Magda
In order for humans and robots to work effectively together, they need to be able to converse about abilities, goals and achievements. Thus, we are developing an interaction infrastructure called the "Human-Robot Interaction Operating System" (HRI/OS). The HRI/OS provides a structured software framework for building human-robot teams, supports a variety of user interfaces, enables humans and robots to engage in task-oriented dialogue, and facilitates integration of robots through an extensible API.
Full Text Available Blue light, a key abiotic signal, regulates a wide variety of physiological processes in many organisms. One of these phenomena is the circadian rhythm presents in organisms sensitive to the phase-setting effects of blue light and under control of the daily alternation of light and dark. Circadian clocks consist of autoregulatory alternating negative and positive feedback loops intimately connected with the cellular metabolism and biochemical processes. Neurospora crassa provides an excellent model for studying the molecular mechanisms involved in these phenomena. The White Collar Complex (WCC, a blue-light receptor and transcription factor of the circadian oscillator, and Frequency (FRQ, the circadian clock pacemaker, are at the core of the Neurospora circadian system. The eukaryotic circadian clock relies on transcriptional/translational feedback loops: some proteins rhythmically repress their own synthesis by inhibiting the activity of their transcriptional factors, generating self-sustained oscillations over a period of about 24 h. One of the basic mechanisms that perpetuate self-sustained oscillations is post translation modification (PTM. The acronym PTM generically indicates the addition of acetyl, methyl, sumoyl, or phosphoric groups to various types of proteins. The protein can be regulatory or enzymatic or a component of the chromatin. PTMs influence protein stability, interaction, localization, activity, and chromatin packaging. Chromatin modification and PTMs have been implicated in regulating circadian clock function in Neurospora. Research into the epigenetic control of transcription factors such as WCC has yielded new insights into the temporal modulation of light-dependent gene transcription. Here we report on epigenetic and protein PTMs in the regulation of the Neurospora crassa circadian clock. We also present a model that illustrates the molecular mechanisms at the basis of the blue light control of the circadian clock.
Gérard, Claude; Goldbeter, Albert
The cell division cycle and the circadian clock represent two major cellular rhythms. These two periodic processes are coupled in multiple ways, given that several molecular components of the cell cycle network are controlled in a circadian manner. For example, in the network of cyclin-dependent kinases (Cdks) that governs progression along the successive phases of the cell cycle, the synthesis of the kinase Wee1, which inhibits the G2/M transition, is enhanced by the complex CLOCK-BMAL1 that plays a central role in the circadian clock network. Another component of the latter network, REV-ERBα, inhibits the synthesis of the Cdk inhibitor p21. Moreover, the synthesis of the oncogene c-Myc, which promotes G1 cyclin synthesis, is repressed by CLOCK-BMAL1. Using detailed computational models for the two networks we investigate the conditions in which the mammalian cell cycle can be entrained by the circadian clock. We show that the cell cycle can be brought to oscillate at a period of 24 h or 48 h when its autonomous period prior to coupling is in an appropriate range. The model indicates that the combination of multiple modes of coupling does not necessarily facilitate entrainment of the cell cycle by the circadian clock. Entrainment can also occur as a result of circadian variations in the level of a growth factor controlling entry into G1. Outside the range of entrainment, the coupling to the circadian clock may lead to disconnected oscillations in the cell cycle and the circadian system, or to complex oscillatory dynamics of the cell cycle in the form of endoreplication, complex periodic oscillations or chaos. The model predicts that the transition from entrainment to 24 h or 48 h might occur when the strength of coupling to the circadian clock or the level of growth factor decrease below critical values.
Yang, Sheng-Li; Yu, Chao; Jiang, Jian-Xin; Liu, Li-Ping; Fang, Xiefan; Wu, Chao
The human circadian rhythm is controlled by at least eight circadian clock genes and disruption of the circadian rhythm is associated with cancer development. The present study aims to elucidate the association between the expression of circadian clock genes and the development of hepatocellular carcinoma (HCC), and also to reveal whether the hepatitis B virus X protein (HBx) is the major regulator that contributes to the disturbance of circadian clock gene expression. The mRNA levels of circadian clock genes in 30 HCC and the paired peritumoral tissues were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A stable HBx-expressing cell line, Bel-7404-HBx, was established through transfection of HBx plasmids. The mRNA level of circadian clock genes was also detected by RT-qPCR in these cells. Compared with the paired peritumoral tissues, the mRNA levels of the Per1, Per2, Per3 and Cry2 genes in HCC tissue were significantly lower (P0.05). Compared with Bel-7404 cells, the mRNA levels of the CLOCK, Per1 and Per2 genes in Bel-7404-HBx cells were significantly increased, while the mRNA levels of the BMAL1, Per3, Cry1, Cry2 and CKIɛ genes were decreased (Pgenes is common in HCC. HBx disrupts the expression of circadian clock genes and may, therefore, induce the development of HCC.
Nagorny, Cecilia; Lyssenko, Valeriya
Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease.
Agrawal, Parul; Hardin, Paul E
Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC) complexes activate transcription of period (per) and timeless (tim) genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi) knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls) or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans.
Full Text Available Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC complexes activate transcription of period (per and timeless (tim genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans.
Komin, Niko; Hernandez-Garcia, Emilio; Toral, Raul
Circadian rhythms in mammals are controlled by the neurons located in the suprachiasmatic nucleus of the hypothalamus. In physiological conditions, the system of neurons is very efficiently entrained by the 24-hour light-dark cycle. Most of the studies carried out so far emphasize the crucial role of the periodicity imposed by the light dark cycle in neuronal synchronization. Nevertheless, heterogeneity as a natural and permanent ingredient of these cellular interactions is seemingly to play a major role in these biochemical processes. In this paper we use a model that considers the neurons of the suprachiasmatic nucleus as chemically-coupled modified Goodwin oscillators, and introduce non-negligible heterogeneity in the periods of all neurons in the form of quenched noise. The system response to the light-dark cycle periodicity is studied as a function of the interneuronal coupling strength, external forcing amplitude and neuronal heterogeneity. Our results indicate that the right amount of heterogeneity hel...
Loh, D H; Kuljis, D A; Azuma, L; Wu, Y; Truong, D; Wang, H B; Colwell, C S
The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN neurons. On a molecular level, the VIP-deficient SCN tissue exhibits lower amplitude oscillations with altered phase relationships between the SCN and peripheral oscillators as measured by PER2-driven bioluminescence. The simplest explanation of our data is that the loss of VIP results in a weakened SCN oscillator, which reduces the synchronization of the female circadian system. These results clarify one of the mechanisms by which disruption of the circadian system reduces female reproductive success.
Danilo E. F. L. Flôres; Crystal N. Bettilyon; Shin Yamazaki
The mammalian circadian system is a hierarchical network of oscillators organized to optimally coordinate behavior and physiology with daily environmental cycles. The suprachiasmatic nucleus (SCN) of the hypothalamus is at the top of this hierarchy, synchronizing to the environmental light-dark cycle, and coordinates the phases of peripheral clocks. The Period genes are critical components of the molecular timekeeping mechanism of these clocks. Circadian clocks are disabled in Period1/2/3 tri...
Stothard, Ellen R; McHill, Andrew W; Depner, Christopher M; Birks, Brian R; Moehlman, Thomas M; Ritchie, Hannah K; Guzzetti, Jacob R; Chinoy, Evan D; LeBourgeois, Monique K; Axelsson, John; Wright, Kenneth P
Reduced exposure to daytime sunlight and increased exposure to electrical lighting at night leads to late circadian and sleep timing [1-3]. We have previously shown that exposure to a natural summer 14 hr 40 min:9 hr 20 min light-dark cycle entrains the human circadian clock to solar time, such that the internal biological night begins near sunset and ends near sunrise . Here we show that the beginning of the biological night and sleep occur earlier after a week's exposure to a natural winter 9 hr 20 min:14 hr 40 min light-dark cycle as compared to the modern electrical lighting environment. Further, we find that the human circadian clock is sensitive to seasonal changes in the natural light-dark cycle, showing an expansion of the biological night in winter compared to summer, akin to that seen in non-humans [4-8]. We also show that circadian and sleep timing occur earlier after spending a weekend camping in a summer 14 hr 39 min:9 hr 21 min natural light-dark cycle compared to a typical weekend in the modern environment. Weekend exposure to natural light was sufficient to achieve ∼69% of the shift in circadian timing we previously reported after a week's exposure to natural light . These findings provide evidence that the human circadian clock adapts to seasonal changes in the natural light-dark cycle and is timed later in the modern environment in both winter and summer. Further, we demonstrate that earlier circadian timing can be rapidly achieved through natural light exposure during a weekend spent camping.
Baker, Ryan S.
The initial vision for intelligent tutoring systems involved powerful, multi-faceted systems that would leverage rich models of students and pedagogies to create complex learning interactions. But the intelligent tutoring systems used at scale today are much simpler. In this article, I present hypotheses on the factors underlying this development,…
Lisa Carlson Lyons
Full Text Available Unraveling the complexities of learning and the formation of memory requires identification of the cellular and molecular processes through which neural plasticity arises as well as recognition of the conditions or factors through which those processes are modulated. With its relatively simple nervous system, the marine mollusk Aplysia californica has proven an outstanding model system for studies of memory formation and identification of the molecular mechanisms underlying learned behaviors, including classical and operant associative learning paradigms and non-associative behaviors. In vivo behavioral studies in Aplysia have significantly furthered our understanding of how the endogenous circadian clock modulates memory formation. Sensitization of the tail-siphon withdrawal reflex represents a defensive non-associative learned behavior for which the circadian clock strongly modulates intermediate and long-term memory formation. Likewise, Aplysia exhibit circadian rhythms in long-term memory, but not short-term memory, for an operant associative learning paradigm. This review focuses on circadian modulation of intermediate and long-term memory and the putative mechanisms through which this modulation occurs. Additionally, potential functions and the adaptive advantages of time of day pressure on memory formation are considered. The influence of the circadian clock on learning and memory crosses distant phylogeny highlighting the evolutionary importance of the circadian clock on metabolic, physiological and behavioral processes. Thus, studies in a simple invertebrate model system have and will continue to provide critical mechanistic insights to complementary processes in higher organisms.
Lambert, Guillaume; Rust, Michael
Cyanobacteria are light-harvesting microorganisms that contribute to 30% of the photosynthetic activity on Earth and contain one of the simplest circadian systems in the animal kingdom. In Synechococcus elongatus , a species of freshwater cyanobacterium, circadian oscillations are regulated by the KaiABC system, a trio of interacting proteins that act as a biomolecular pacemaker of the circadian system. While the core oscillator precisely anticipates Earth's 24h light/dark cycle, it is unclear how much individual cells benefit from the expression and maintenance of a circadian clock. By studying the growth dynamics of individual S . elongatus cells under sudden light variations, we show that several aspects of cellular growth, such as a cell's division probability and its elongation rate, are tightly coupled to the circadian clock. We propose that the evolution and maintenance of a circadian clock increases the fitness of cells by allowing them to take advantage of cyclical light/dark environments by alternating between two phenotypes: expansionary, where cells grow and divide at a fast pace during the first part of the day, and conservative, where cells enter a more quiescent state to better prepare to the stresses associated with the night's prolonged darkness.
National Aeronautics and Space Administration — The objective of this proposal is to develop a hybrid battery-ultra capacitor storage system that powers human-robotic systems in space missions. Space missions...
Nicol, David B.; Ferguson, Ian T.
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.
Chang, Anne-Marie; Santhi, Nayantara; St Hilaire, Melissa; Gronfier, Claude; Bradstreet, Dayna S; Duffy, Jeanne F; Lockley, Steven W; Kronauer, Richard E; Czeisler, Charles A
Light exposure in the early night induces phase delays of the circadian rhythm in melatonin in humans. Previous studies have investigated the effect of timing, intensity, wavelength, history and pattern of light stimuli on the human circadian timing system. We present results from a study of the duration–response relationship to phase-delaying bright light. Thirty-nine young healthy participants (16 female; 22.18±3.62 years) completed a 9-day inpatient study. Following three baseline days, participants underwent an initial circadian phase assessment procedure in dim light (bright light pulse (∼10,000 lux) of 0.2 h, 1.0 h, 2.5 h or 4.0 h duration during a 4.5 h controlled-posture episode centred in a 16 h wake episode. After another 8 h sleep episode, participants completed a second circadian phase assessment. Phase shifts were calculated from the difference in the clock time of the dim light melatonin onset (DLMO) between the initial and final phase assessments. Exposure to varying durations of bright light reset the circadian pacemaker in a dose-dependent, non-linear manner. Per minute of exposure, the 0.2 h duration was over 5 times more effective at phase delaying the circadian pacemaker (1.07±0.36 h) as compared with the 4.0 h duration (2.65±0.24 h). Acute melatonin suppression and subjective sleepiness also had a dose-dependent response to light exposure duration. These results provide strong evidence for a non-linear resetting response of the human circadian pacemaker to light duration.
Shi, Shu-qun; Bichell, Terry Jo; Ihrie, Rebecca A; Johnson, Carl Hirschie
The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS. We found a unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS-model mice, indicating an important role for Ube3a in modulating BMAL1 turnover. Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients. Copyright © 2015 Elsevier Ltd. All rights reserved.
Francisco, D.; Romero, E.
NASA utilizes an evidence based system to perform risk assessments for the human system for spaceflight missions. The center of this process is the multi-disciplinary Human System Risk Board (HSRB). The HSRB is chartered from the Chief Health and Medical Officer (OCHMO) at NASA Headquarters. The HSRB reviews all human system risks via an established comprehensive risk and configuration management plan based on a project management approach. The HSRB facilitates the integration of human research (terrestrial and spaceflight), medical operations, occupational surveillance, systems engineering and many other disciplines in a comprehensive review of human system risks. The HSRB considers all factors that influence human risk. These factors include pre-mission considerations such as screening criteria, training, age, sex, and physiological condition. In mission factors such as available countermeasures, mission duration and location and post mission factors such as time to return to baseline (reconditioning), post mission health screening, and available treatments. All of the factors influence the total risk assessment for each human risk. The HSRB performed a comprehensive review of all potential inflight medical conditions and events and over the course of several reviews consolidated the number of human system risks to 30, where the greatest emphasis is placed for investing program dollars for risk mitigation. The HSRB considers all available evidence from human research and, medical operations and occupational surveillance in assessing the risks for appropriate mitigation and future work. All applicable DRMs (low earth orbit for 6 and 12 months, deep space for 30 days and 1 year, a lunar mission for 1 year, and a planetary mission for 3 years) are considered as human system risks are modified by the hazards associated with space flight such as microgravity, exposure to radiation, distance from the earth, isolation and a closed environment. Each risk has a summary
Homeostatic systems have adapted to respond to the diurnal light/dark cycle. Numerous physiological pathways, including metabolism, are coordinated by this 24-h cycle. Animals with mutations in clock genes show abnormal glucose and lipid metabolism, indicating a critical relationship between the circadian clock and metabolism. Energy homeostasis is achieved through circadian regulation of the expression and activity of several key metabolic enzymes. Temporal organization of tissue metabolism is coordinated by reciprocal cross-talk between the core clock mechanism and key metabolic enzymes and transcriptional activators. The aim of this review is to define the role of the circadian clock in the regulation of insulin sensitivity by describing the interconnection between the circadian clock and metabolic pathways.
Tae Won Kim
Full Text Available 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.
Weerth, C. de; Zijl, R.H.
BACKGROUND AND AIMS: Cortisol is the final product of the hypothalamus-pituitary-adrenal (HPA) axis. It is secreted in a pulsatile fashion that displays a circadian rhythm. Infants are born without a circadian rhythm in cortisol and they acquire it during their first year of life. Studies do not agr
Jespersen, C M; Frederiksen, M; Hansen, J F;
Circadian variation in the metabolism of verapamil was investigated in 10 patients with stable angina pectoris during treatment with sustained-release verapamil 360 mg at 08.00 h or 22.0 h. No major difference in exercise parameters was found. During the evening dosage schedule a significantly gr...... or to circadian variation in hepatic microsomal metabolism....
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...
Eelderink-Chen, Zheng; Mazzotta, Gabriella; Sturre, Marcel; Bosman, Jasper; Roenneberg, Till; Merrow, Martha
Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily cha
Eelderink-Chen, Zheng; Olmedo, Maria; Bosman, Jasper; Merrow, Martha
Three properties are most often attributed to the circadian clock: a ca. 24-h free-running rhythm, temperature compensation of the circadian rhythm, and its entrainment to zeitgeber cycles. Relatively few experiments, however, are performed under entrainment conditions. Rather, most chronobiology pr
陈意; 陶人川; 林雪芳; 刘贞敏; 雍翔智; 李润英
Objective To detect the human neutrophil peptide 1-3(HNP1-3) expression in circadian rhythm. Methods Saliva, peripheral venous blood and gingival crevicular fluid(GCF) samples from mesio-buccal gingival crevice of four first molars of six healthy individuals were collected at two consecutive days from 6∶00 to 22∶00, and the expression of HNP1-3 was detected by enzyme-linked immunosorbent assay(ELISA) method. Results The median in GCF was 5.86μg·L-1, the overall trend was a sinusoidal waveform, with peak at 14∶00 and valley at 20∶00. The median in saliva was 2.15μg·L-1, the overall trend was the “V” word waveform, higher in the morning and evening, the valley at 14∶00. The median in peripheral venous blood was 4.79μg·L-1, the overall trend was single peak waveform, reach-ing a peak from 6∶00 to 10∶00, and then declining slowly. Conclusion The expression HNP1-3 in saliva, GCF, pe-ripheral venous blood samples existed differences. The trend from high to low was GCF, blood, saliva and showed a certain circadian rhythm.% 目的探索人中性粒细胞防御素1~3（HNP1~3）表达水平的日节律性，为其作为生物学指标提供科学依据。方法对6名健康志愿者，连续2 d从6时至22时定点采集唾液、外周血及4颗第一恒磨牙近颊沟处的龈沟液，运用酶联免疫吸附测定（ELISA）方法检测HNP1～3的表达量。结果6名受试者HNP1~3的表达量和变化趋势为：龈沟液的中位数为5.86μg·L-1，总体变化趋势为正弦波形，14时最高，18时最低；唾液的中位数为2.15μg·L-1，总体变化趋势为“V”字波形，早晚较高，14时达峰谷；血液的中位数为4.79μg·L-1，总体变化趋势为单峰波形，6时至10时呈上升趋势并达峰值，继而缓慢下降。结论在3种体液中， HNP1~3表达量存在差异性，其昼夜的表达呈现一定节律性。
A solution of virtual human skeleton system is proposed. Some issues on integration of anatomical geometry, biodynamics and computer animation are studied. The detailed skeleton system model that incorporates the biodynamic and geometric characteristics of a human skeleton system allows some performance studies in greater detail than that performed before. It may provide an effective and convenient way to analyze and evaluate the movement performance of a human body when the personalized anatomical data are used in the models. An example shows that the proposed solution is effective for the stated problems.
Full Text Available Irrespective of the immune status, the vast majority of all lymphocytes reside in peripheral tissues whereas those present in blood only amount to a small fraction of the total. It has been estimated that T cells in healthy human skin outnumber those present in blood by at least a factor of two. How lymphocytes within these two compartments relate to each other is not well understood. However, mounting evidence suggest that the study of T cell subsets present in peripheral blood does not reflect the function of their counterparts at peripheral sites. This is especially true under steady-state conditions whereby long-lived memory T cells in healthy tissues, notably those in epithelial tissues at body surfaces, are thought to fulfil a critical immune surveillance function by contributing to the first line of defence against a series of local threats, including microbes, tumours and toxins, and by participating in wound healing. The relative scarcity of information regarding peripheral T cells and the factors regulating their localization is primarily due to inherent difficulties in obtaining healthy tissue for the extraction and study of immune cells on a routine basis. This is most certainly true for humans. Here, we review our current understanding of T cell homing to human skin and discuss candidate chemokines that may account for the tissue selectivity in this process.
Full Text Available Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ. Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte
High level indicators of where human system interactions may occur • Textual descriptions of the overall human component of the system • Use cases...for specific team tasks Type of interaction – i.e., collaborate, coordinate, supervise, etc. Team cohesiveness indicators – i.e., trust
Lu, Sheen X; Knowles, Stephen M; Webb, Candace J; Celaya, R Brandon; Cha, Chuah; Siu, Jonathan P; Tobin, Elaine M
Histone methylation plays an essential role in regulating chromatin structure and gene expression. Jumonji C (JmjC) domain-containing proteins are generally known as histone demethylases. Circadian clocks regulate a large number of biological processes, and recent studies suggest that chromatin remodeling has evolved as an important mechanism for regulating both plant and mammalian circadian systems. Here, we analyzed a subgroup of JmjC domain-containing proteins and identified Arabidopsis (Arabidopsis thaliana) JMJ30 as a novel clock component involved in controlling the circadian period. Analysis of loss- and gain-of-function mutants of JMJ30 indicates that this evening-expressed gene is a genetic regulator of period length in the Arabidopsis circadian clock. Furthermore, two key components of the central oscillator of plants, transcription factors CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL, bind directly to the JMJ30 promoter to repress its expression, suggesting that JMJ30 regulates the pace of the circadian clock in close association with the central oscillator. JMJ30 represents, to our knowledge, the first JmjC domain-containing protein involved in circadian function, and we envision that this provides a possible molecular connection between chromatin remodeling and the circadian clock.
Full Text Available Background/Aims: Circadian locomotor output cycles protein kaput (CLOCK plays a key role in maintaining circadian rhythms and activation of downstream elements. However, its function on human female reproductive system remains unknown. Methods: To investigate the potential role of CLOCK, CLOCK-shRNAs were transfected into mouse 129 ES cells or injected into the ovaries of adult female mice. Western blotting was utilized to analyze the protein interactions and flow cytometry was used to assess apoptosis. Results: The expression of CLOCK peaked at the 6th week in the healthy fetuses. However, an abnormal expression of CLOCK was detected in fetuses from spontaneous miscarriage. To determine the effect of CLOCK on female fertility, a small hairpin RNA (shRNA strategy was used to specifically knockdown the CLOCK gene expression in vitro and in vivo. Knockdown of CLOCK induced apoptosis in mouse embryonic stem (mES cells and inhibited the proliferation in mES cells in vitro. CLOCK knockdown also led to decreased release of oocytes and smaller litter size compared with control in vivo. Conclusions: Collectively, theses findings indicate that CLOCK plays an important role in fertility and that the CLOCK knockdown leads to reduction in reproduction and increased miscarriage risk.
Dakup, Panshak; Gaddameedhi, Shobhan
The skin is in constant exposure to various external environmental stressors, including solar ultraviolet (UV) radiation. Various wavelengths of UV light are absorbed by the DNA and other molecules in the skin to cause DNA damage and induce oxidative stress. The exposure to excessive ultraviolet (UV) radiation and/or accumulation of damage over time can lead to photocarcinogenesis and photoaging. The nucleotide excision repair (NER) system is the sole mechanism for removing UV photoproduct damage from DNA, and genetic disruption of this repair pathway leads to the photosensitive disorder xeroderma pigmentosum (XP). Interestingly, recent work has shown that NER is controlled by the circadian clock, the body's natural time-keeping mechanism, through regulation of the rate-limiting repair factor xeroderma pigmentosum group A (XPA). Studies have shown reduced UV-induced skin cancer after UV exposure in the evening compared to the morning, which corresponds with times of high and low repair capacities, respectively. However, most studies of the circadian clock-NER connection have utilized murine models, and it is therefore important to translate these findings to humans to improve skin cancer prevention and chronotherapy.
Rath, Martin F; Rovsing, Louise; Møller, Morten
and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes......The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators...... residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice...
Full Text Available Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.
St John, Peter C; Taylor, Stephanie R; Abel, John H; Doyle, Francis J
Bioluminescence rhythms from cellular reporters have become the most common method used to quantify oscillations in circadian gene expression. These experimental systems can reveal phase and amplitude change resulting from circadian disturbances, and can be used in conjunction with mathematical models to lend further insight into the mechanistic basis of clock amplitude regulation. However, bioluminescence experiments track the mean output from thousands of noisy, uncoupled oscillators, obscuring the direct effect of a given stimulus on the genetic regulatory network. In many cases, it is unclear whether changes in amplitude are due to individual changes in gene expression level or to a change in coherence of the population. Although such systems can be modeled using explicit stochastic simulations, these models are computationally cumbersome and limit analytical insight into the mechanisms of amplitude change. We therefore develop theoretical and computational tools to approximate the mean expression level in large populations of noninteracting oscillators, and further define computationally efficient amplitude response calculations to describe phase-dependent amplitude change. At the single-cell level, a mechanistic nonlinear ordinary differential equation model is used to calculate the transient response of each cell to a perturbation, whereas population-level dynamics are captured by coupling this detailed model to a phase density function. Our analysis reveals that amplitude changes mediated at either the individual-cell or the population level can be distinguished in tissue-level bioluminescence data without the need for single-cell measurements. We demonstrate the effectiveness of the method by modeling experimental bioluminescence profiles of light-sensitive fibroblasts, reconciling the conclusions of two seemingly contradictory studies. This modeling framework allows a direct comparison between in vitro bioluminescence experiments and in silico ordinary
team processes and team outcomes. Computers in Human Behavior , 15, 463-494. 0 Herl, H. E. (1995). Construct validation of an approach to modeling...system to measure content understanding. Computers in Human Behavior , 15, 315-334. Johnson, R.F. (2001). Statistical measures of marksmanship (ARI...problem-solving. Computers in Human Behavior , 15, 403-418. West, C. D., Pomeroy, J. R., Park, J. K., Gerstenberger, E. A., & Sandoval, J. (2000
A modeling approach is presented to describe complex manned robotic systems. The robotic system is modeled as a (highly) nonlinear, possibly time-varying dynamic system including any time delays in terms of optimal estimation, control and decision theory. The role of the human operator(s) is modeled
Full Text Available Although the circadian clock is a universal biological system in plants and it orchestrates important role of plant production such as photosynthesis, floral induction and growth, there are few such studies on cultivated species. Lettuce is one major cultivated species for both open culture and plant factories and there is little information concerning its circadian clock system. In addition, most of the relevant genes have not been identified. In this study, we detected circadian oscillation in the lettuce transcriptome using time-course RNA sequencing (RNA-Seq data. Constant light (LL and light–dark (LD conditions were used to detect circadian oscillation because the circadian clock has some basic properties: one is self-sustaining oscillation under constant light and another is entrainment to environmental cycles such as light and temperature. In the results, 215 contigs were detected as common oscillating contigs under both LL and LD conditions. The 215 common oscillating contigs included clock gene-like contigs CCA1 (CIRCADIAN CLOCK ASSOCIATED 1-like, TOC1 (TIMING OF CAB EXPRESSION 1-like and LHY (LATE ELONGATED HYPOCOTYL-like, and their expression patterns were similar to those of Arabidopsis. Functional enrichment analysis by GO (Gene Ontology Slim and GO Fat showed that the GO terms of response to light stimulus, response to stress, photosynthesis and circadian rhythms were enriched in the 215 common oscillating contigs and these terms were actually regulated by circadian clocks in plants. The 215 common oscillating contigs can be used to evaluate whether the gene expression pattern related to photosynthesis and optical response performs normally in lettuce.
Morris, Christopher J; Purvis, Taylor E; Mistretta, Joseph; Hu, Kun; Scheer, Frank A J L
Shift work is a risk factor for inflammation, hypertension, and cardiovascular disease. This increased risk cannot be fully explained by classical risk factors. Shift workers' behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in shift workers, independent of differences in work stress, food quality, and other factors that are likely to differ between night and day shifts. Thus, our objectives were to determine the independent effect of circadian misalignment on 24-h high-sensitivity C-reactive protein (hs-CRP; a marker of systemic inflammation) and blood pressure levels-cardiovascular disease risk factors-in chronic shift workers. Chronic shift workers undertook two 3-day laboratory protocols that simulated night work, comprising 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment), using a randomized, crossover design. Circadian misalignment increased 24-h hs-CRP by 11% ( p Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 1.4 mmHg and 0.8 mmHg, respectively (both p ≤ 0.038). The misalignment-mediated increase in 24-h SBP was primarily explained by an increase in SBP during the wake period (+1.7 mmHg; p = 0.017), whereas the misalignment-mediated increase in 24-h DBP was primarily explained by an increase in DBP during the sleep opportunity (+1.8 mmHg; p = 0.005). Circadian misalignment per se increases hs-CRP and blood pressure in shift workers. This may help explain the increased inflammation, hypertension, and cardiovascular disease risk in shift workers.
Pregueiro, Antonio M; Price-Lloyd, Nathan; Bell-Pedersen, Deborah; Heintzen, Christian; Loros, Jennifer J; Dunlap, Jay C
Circadian systems include slave oscillators and central pacemakers, and the cores of eukaryotic circadian clocks described to date are composed of transcription and translation feedback loops (TTFLs). In the model system Neurospora, normal circadian rhythmicity requires a TTFL in which a White Collar complex (WCC) activates expression of the frequency (frq) gene, and the FRQ protein feeds back to attenuate that activation. To further test the centrality of this TTFL to the circadian mechanism in Neurospora, we used low-amplitude temperature cycles to compare WT and frq-null strains under conditions in which a banding rhythm was elicited. WT cultures were entrained to these temperature cycles. Unlike those normal strains, however, frq-null mutants did not truly entrain to the same cycles. Their peaks and troughs always occurred in the cold and warm periods, respectively, strongly suggesting that t